Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.N(CCO)CCO>C1COCC1.CCOCC>[OH:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([CH3:16])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@H](O)C(C)(C)C1
Temperature: 5 °C
Reaction time: 96 h

Procedure:
To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (10.0 g, 44.0 mmol) in THF (45 mL) at 0° C. was added dropwise (−)-DIP-Chloride (50-65 wt. % in heptane, 48.9 mL, 79.0 mmol), and the reaction mixture was stirred at 5° C. for 4 days. The reaction mixture was then diluted with Et2O (250 mL) and diethanol amine (8.0 g) was added to give a massive amount of white precipitate. The resulting mixture was vigorously stirred at room temperature for 3 h. The heterogeneous mixture was then filtered through a Buchner funnel packed with Celite®, and the resulting filtrate was concentrated to give a yellow residue. The residue was purified by silica gel chromatography (25-70% EtOAc/heptane) to provide (S)-tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate. (90% ee). Enantiomeric excess determined by Mosher ester analysis. 1H NMR (400 MHz, CDCl3) δ ppm 3.79-3.94 (m, 1 H), 3.53 (d, J=13.4 Hz, 1 H), 3.42 (dd, J=9.2, 4.2 Hz, 1 H), 3.05 (ddd, J=13.2, 9.8, 3.5 Hz, 1 H), 2.74 (d, J=13.1 Hz, 1 H), 1.69-1.80 (m, 2 H), 1.58 (m, 1 H), 1.46 (s, 9 H), 0.97 (s, 3 H), 0.90 (s, 3 H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:31])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[K].[NH2:33][O:34]C1CCCCO1.C(Cl)C[Cl:43].C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.O>[ClH:43].[OH:34][NH:33][C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]1[CH:22]=[CH:21][C:20](/[CH:19]=[CH:18]/[C:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: ClCCCl
Reactant: NOC1CCCCO1
Reactant: CC(C)CN1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Agent: On1nnc2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CN1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (E)-3-(4-{(E)-3-[4-(4-isobutyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as potassium salt (450 mg, 1 mmol), NH2OTHP (117 mg, 1 mmol), EDC (230 mg, 1.2 mmol), HOBT (160 mg, 1.2 mmol) and TEA (0.420 ml, 3 mmol) in THF (5 ml) and DMF (5 ml) was stirred for 24 hours at room temperature. The mixture was then diluted with water and extracted with AcOEt. The organic phase was washed with water, then with a saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash chromatography (DCM:MeOH:NH3 98:2:0.2). The product was then dissolved in DCM and a few drops of HCl in ether were added. The mixture was stirred for 12 hours at room temperature. The precipitate was then filtered and ground in acetonitrile to obtain 300 mg of (E)-N-hydroxy-3-(4-{(E)-3-[4-(4-isobutyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylamide hydrochloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(OCC)C>ClCCl>[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:27][C:26]=1[CH3:34]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)Cl)ccc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (9.38 g, 0.0509 mol) and N,N-diisopropylethylamine (13.31 mL, 0.0764 mol) in dry dichloromethane (250 mL) at 0° C. under nitrogen was added dropwise a solution of 4-iodo-3-methyl-benzoyl chloride (10.71 g, 0.0382 mol) in dry dichloromethane (30 mL) over ca. 10 minutes. The reaction mixture was allowed to warm slowly to room temperature with stirring over 3 hours then quenched by the addition of water (100 mL). The organic phase was separated, washed with 1 M hydrochloric acid (2×200 mL) and 5% wt/v aqueous sodium carbonate solution (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a cream solid. Diethyl ether (150 mL) was added and the resulting suspension stirred vigorously for 3 hours then filtered to afford the title compound (14.73 g, 90%) as a white solid, m.p. 152-153° C.
Reaction SMILES: [C:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=O)(=[S:3])[CH3:2].[NH2:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13]>>[C:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13])=[O:7])(=[S:3])[CH3:2]
Reactant: CC(=S)C(C(=O)O)C(C)C
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: CC(=S)C(C(=O)N[C@@H](C)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O)C(C)C

Procedure:
Following General Procedure D above using 2-thioacetyl-3-methyl butanoic acid (Coric et al., J. Med. Chem. 39, 1210 (1996)) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7].CO>C(O)C.[Pd]>[NH2:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)C(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(OC)c1)C(=O)OCC
Reaction time: 1 h

Procedure:
A solution of diethyl N-(3-methoxy-4-nitrobenzoyl)-(L)-glutamate (11.0 g, 28.8 mmoles) in 95% ethanol (200 mL) was mixed with 10% palladium on carbon (0.8 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 1 hour. The reaction mixture was filtered, spin evaporated, and dried to give a clear viscous oil which on long-standing hardened to a white wax; yield, 9.95 g (99%); 1H-NMR (DMSO-d6) δ 1.15 and 1.17 (2t overlapped, 6H), 1.8-2.2 (m, 2H), 2.40 (t, 2H), 3.79 (s, 3H), 4.0-4.2 (2 q overlapped, 4H), 4.36 (m, 1H), 5.29 (br s, 2H), 6.60 (d, Jo =8 Hz, 1H), 7.3-7.4 (m, 2H), 8.25 (d, 1H); uv (MeOH) 301 nm max (17800), 280 sh (15700), 266 min (12600), 263 max (13200), 256 sh (12500), 245 min (8630), 204 max (40900); mass spec (CI) m/e 353 (56%), 150 (100).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:14][CH2:15][CH2:16][O:17]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[NH:26][C:25]([C:27]#[N:28])=[CH:24][N:23]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)OCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amide (as prepared in the previous step, 45 mg, 0.088 mmol) in 3 mL of THF was added tetrabutyl ammonium fluoride (TBAF) (69 mg, 0.264 mmol). The reaction was stirred for 14 h at room temperature, at which time the temperature was raised to 60° C. for 15 min and then diluted with EtOAc (25 mL) and washed with water (3×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue using preparative TLC (10% MeOH—CHCl3) afforded 31 mg (93%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.28 (s, 1H), 7.97 (d, 1H, J=8.3 Hz), 7.33 (dd, 1H, J=8.3, 2.0 Hz), 7.21 (s, 1H, J=2.0 Hz), 5.77 (s, 1H), 3.98 (m, 2H), 3.72 (m, 2H), 2.20-2.15 (m, 4H), 1.75-1.66 (m, 4H), 1.56 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O3, 379.1 (M+H), found 379.1.
Reaction SMILES: Br[CH2:2][CH3:3].[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1>>[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[N:14]([CH2:2][CH3:3])[C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1
Reactant: CCc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCBr
Product: CCc1nc(Cl)c2c(n1)N(CC)C(=O)CO2

Procedure:
Using the procedure of Example 80, except that 1-bromoethane was used instead of methyl iodide, 4-chloro-6,7-dihydro 2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was alkylated providing 4-chloro-2,8-diethyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-7-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate (0.59 g, 1.9 mmol), THF (13.5 mL) and methanol (8.5 mL) was added aqueous lithium hydroxide (9.3 mL, 2.0 M). The solution was maintained at 50° C. for 15 h. The solution was cooled to room temperature, adjusted to below pH 4 with aqueous HCl (22 mL, 1.0 N) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with brine (15 mL), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid as white solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.99 (s, 1H), 7.93 (d, J=8.55 Hz, 1H), 7.80 (d, J=2.44 Hz, 1H), 7.59 (dd, J=8.55, 5.49 Hz, 2H), 7.32 (t, J=8.70 Hz, 2H), 7.11 (dd, J=8.85, 2.44 Hz, 1H), 3.82-3.87 (m, 3H). LCMS: retention time: 1.532 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 303 (MH+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([N+]([O-])=O)[CH:21]=1>CCO>[C:9]12([NH:8][C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[N+:26]([O-:28])=[O:27])[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][CH:13]([CH2:12]3)[CH2:18]1)[CH2:16]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC12CC3CC(CC(C3)C1)C2
Yield: 23.1 %

Procedure:
15.5 ml of triethylamine and then a suspension of 15 g of 1-aminoadamantane in 50 ml of 96° EtOH are added to a solution of 20 g of 4-chloro-1,2-dinitrobenzene in 80 ml of 96° EtOH. The mixture is refluxed for 7 hours and, after cooling, the precipitate formed is filtered off to give 7 g of the expected product. M.p.=146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C#N)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:23]([OH:26])(=[O:25])[CH3:24].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:24]([C:23]([OH:26])=[O:25])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: N#Cc1cc(F)c2[nH]nc(-c3ccc4ccccc4c3)c2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)c2[nH]nc(-c3ccc4ccccc4c3)c2c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To 1.0 g of 7-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile were sequentially added 5.0 ml of glacial acetic acid, 5.0 ml of water and 10.0 ml of concentrated sulfuric acid, and the mixture was stirred at 120° C. for one day. After standing to cool, 20 ml of water was added to the reaction mixture and the resulting crystals were collected by filtration. The crystals were sequentially washed with water and diethyl ether, to give 1.0 g of the title compound as colorless crystals.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.C(N(CC)CC)C>C(#N)C>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Cl)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6 ml phosphorus oxychloride are added dropwise to 12.1 g of 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and left to stand overnight. The solution of the product is reacted further without purification (see Example III).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:26](OCC)=[O:27]>CN(C=O)C>[CH:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: CCOC=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=CNc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
200 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 5 ml of ethyl formate are stirred in 2.5 ml of DMF for 60 hours at 90° C. After removal of the solvent in vacuo ethyl acetate is added and the mixture is again concentrated by evaporation. The residue is stirred with ether, suction filtered and dried.
Reaction SMILES: CO.[C:3]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:20])[C:18]#N)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-:21].[Na+].[OH2:23]>>[C:3]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:20])[C:18]([OH:23])=[O:21])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(C#N)c1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 84 %

Procedure:
Methanol (1 ml) and 1 ml of water were added to 200 mg of alpha-(m-benzoylphenyl)propionitrile, and 50 mg of sodium hydroxide was added. The mixture was heated under reflux for 24 hours. The reaction mixture was cooled, and after adding 10 ml of water, extracted with 5 ml of ether three times. The extract was washed with 5 ml of water three times. The aqueous layers were combined, and after adding conc. hydrochloric acid to adjust the pH to below 1, were extracted with 5 ml of ether three times. The extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; methylene chloride and ethyl acetate) to afford 181 mg (yield 84%) of alpha-(m-benzoylphenyl)propionic acid as colorless crystals. The IR spectrum and NMR spectrum of the product coincided completely with those of an authentic sample.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][OH:4].[CH3:5][C:6]([CH3:37])([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([O:9]CC)=[O:8]>C1COCC1>[CH3:5][C:6]([CH3:37])([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([OH:9])=[O:8].[C:3]([OH:4])([C:32]([F:35])([F:34])[F:33])=[O:1]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(C)(C)C(=O)O)nc2)c1
Product: O=C(O)C(F)(F)F
Temperature: 50 °C

Procedure:
1 M NaOH (0.230 mL, 0.230 mmol) and MeOH (0.400 mL) were added to a solution of ethyl 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate (20.7 mg, 0.045 mmol) in THF (0.50 mL) and the reaction mixture was heated to 50° C. for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was directly purified by reverse phase HPLC to afford 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanic acid as a TFA salt. C22H22F3N4O2 [M+H]+ 431. found 431. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.79 (s, 1H), 8.17-8.04 (m, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.44 (d, 1H), 7.27 (d, J=4.9 Hz, 1H), 7.22 (s, 1H), 3.05 (s, 2H), 2.36 (s, 3H), 1.14 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([CH2:13]O)=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[ClH:17].[Cl:17][CH2:13][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][C:6]=2[CH:12]=1
Reactant: CCCc1nc2cc(CO)ccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCc1nc2cc(CCl)ccc2[nH]1
Product: Cl
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 6.2 parts of 2-propyl-1H-benzimidazole-5-methanol and 38 parts of trichloromethane are added dropwise 40 parts of thionyl chloride. Upon completion, stirring is continued for 15 minutes at reflux temperature. The solvent is evaporated and the residue is dissolved in 80 parts of 2-propanone. The product is allowed to crystallize. It is filtered off and dried, yielding 4.3 parts of 5-(chloromethyl)-2-propyl-1H-benzimidazole monohydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][C:22]3[CH:23]=[C:24]([Cl:28])[CH:25]=[N:26][CH:27]=3)=[C:16]([CH:20]=2)[C:17](O)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH3:33]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][C:22]3[CH:23]=[C:24]([Cl:28])[CH:25]=[N:26][CH:27]=3)=[C:16]([CH:20]=2)[C:17]([NH2:33])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: NC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a stirred solution of the acid from Example 10 (20 mg, 0.046 mmol) in CH2Cl2 (0.5 mL) and pyridine (0.5 mL) was added thionyl chloride (17 mL, 0.228 mmol). After one hour, the solution was evaporated and placed under vacuum overnight. The residue was then dissolved in MeOH (1 mL) and CH2Cl2 (1 mL) and NH3 (0.12 mL, 0.227 mmol, 0.757 M solution in ethanol) was added dropwise. The mixture was stirred for 8 hours and the solvent was evaporated. The residue was purified by chromatography (1:1 hexane/diethyl ether) to yield 7.3 mg of the title compound (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Li]C(CC)C.CN([CH:19]=[O:20])C>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:19]=[O:20]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dichloro-5-methoxybenzene (1.0 g, 5.65 mmol) in THF (15 mL), cooled to −78° C., under N2 protection, was added dropwise sec-BuLi (4.18 ml of a 1.4 M solution in hexane, 5.82 mmol). After 30 minutes, anhydrous DMF (0.65 ml, 8.48 mmol) was added slowly to the solution and the mixture was stirred for at −78° C. 1.5 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (10:1) as eluent to give 2,4-dichloro-6-methoxybenzaldehyde as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCCCNCc1ccccc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCCCO)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 4-benzylamino-butan-1-ol
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3=[CH:12][NH:13][C:14](=[O:23])[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[C:9]3[NH:8][C:7]=2[CH:24]=1.[OH-:27].[Na+].[CH2:29]=O>CN(C)C=O>[F:26][C:2]([F:25])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3=[CH:12][N:13]([CH2:29][OH:27])[C:14](=[O:23])[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[C:9]3[NH:8][C:7]=2[CH:24]=1
Reactant: C=O
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1cc(C(F)(F)F)ccc1S2
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(C(F)(F)F)cc1N2
Yield: 94 %

Procedure:
To 1.0 g. of 7-trifluoromethyl-4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.5 mmol.) in 10 ml. dimethylformamide was added 6.0 ml. of a 5% sodium hydroxide solution (7.5 mmol.), and the resulting suspension was heated on a steam bath until a solution formed. To the solution was then added 10 ml. of a 36% formaldehyde solution (12.0 mmol.), and the resulting reaction mixture was heated until a yellow precipitate formed. The hot reaction mixture was filtered, and the precipitate was washed with water and dried under high vacuum at room temperature to yield 7-trifluoromethyl-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow powder (1.0 g.; 94% yield) having the structural formula, ##STR24## a melting point of 204° C. (with decomposition) and the following elemental analysis: