Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:18])[C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].O>CC(=O)OCC.C(O)(C)C>[CH2:27]([O:5][C:4](=[O:6])[C@H:3]([C@@H:2]([CH3:1])[OH:18])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(CBr)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Reaction time: 48 h

Procedure:
25.3 g (0.1 mol) of Z-L-threonine were suspended in 200 ml of EA, and 14 ml (0.1 mol) of triethylamine were added. While stirring, 19.0 g (0.1 mol) of solid ω-bromoacetophenone were added in one portion to result initially in a clear solution, which soon became cloudy. The mixture was left to stand for 2 d, diluted with 500 ml of EA and worked up as usual. The crystalline residue was dissolved in 420 ml of hot isopropanol, 300 ml of hot water were added, and the mixture was left to stand in the dark for 2 d. The long white needles which separated out were filtered off, washed and dried in air in the dark. Yield: 27.8 g (0.075 mol, 75%), melting point 129°-130° C., α!D25 =32.2° (c=2.04, EA)
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:6][C:5]=12
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Reactant: c1nnc2n1CCNC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.16 g) in DMF (8 mL) was added Ag2CO3 (0.98 g) and a solution of 6-(3-chloropropoxy)-N-(4-fluorophenyl)-7-methoxyquinazolin-4-amine (0.32 g) in DMF (2 mL) at room temperature under stirring. The mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a white solid (87.70 mg, 20.41%), HPLC: 90.53%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 450.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.02-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.29 (t, J=6.00 Hz, 1H), 7.38 (s, 1H), 7.54-7.58 (m, 2H), 7.81-7.84 (m, 1H), 8.07 (s, 1H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[N:10]([CH2:13][CH3:14])=[C:11]=[S:12]>C(Cl)Cl>[CH2:13]([NH:10][C:11]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[S:12])[CH3:14]
Reactant: OCCC1CCNCC1
Reactant: CCN=C=S
Solvent: ClCCl
Product: CCNC(=S)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of 2-(piperidin-4-yl)ethanol (509 mg, 3.94 mmol) in CH2Cl2 (13 mL) was added isothiocyanatoethane (343 μL, 3.94 mmol). After stirring for 10 h at rt, the mixture was concentrated in vacuo to provide the titled compound (716 mg, 84%): 1H NMR (CDCl3) δ 5.38 (brs, 1H), 4.59 (d, J=13.6 Hz, 1H), 3.74-3.67 (m, 3H), 3.15 (d, J=12.8 Hz, 1H), 3.00 (t, J=13.2 Hz, 2H), 2.65 (t, J=12.4 Hz, 1H), 1.81-1.72 (m, 3H), 1.55-1.52 (m, 3H), 1.28-1.22 (m, 4H)
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3](O)=[O:4].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([C:3]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4])[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:11][C:10]1=2)=[O:7]
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Reactant: Nc1ccccc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and aniline (6 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=414.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: C(C1C(I)=CC2C(C)(C)C3NC4C(C=3C(=O)C=2C=1)=CC=C(C#N)C=4)C.[CH2:26]([C:28]1[C:49]([N:50]2[CH2:55][CH2:54][C:53](=[O:56])[CH2:52][CH2:51]2)=[CH:48][C:31]2[C:32]([CH3:47])([CH3:46])[C:33]3[NH:34][C:35]4[C:40]([C:41]=3[C:42](=[O:43])[C:30]=2[CH:29]=1)=[CH:39][CH:38]=[C:37]([C:44]#[N:45])[CH:36]=4)[CH3:27]>>[CH2:26]([C:28]1[C:49]([N:50]2[CH2:51][CH2:52][CH:53]([OH:56])[CH2:54][CH2:55]2)=[CH:48][C:31]2[C:32]([CH3:47])([CH3:46])[C:33]3[NH:34][C:35]4[C:40]([C:41]=3[C:42](=[O:43])[C:30]=2[CH:29]=1)=[CH:39][CH:38]=[C:37]([C:44]#[N:45])[CH:36]=4)[CH3:27]
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CCc1cc2c(cc1I)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Product: CCc1cc2c(cc1N1CCC(O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
The compounds described in the following Tables 8-10 were synthesized by introducing a corresponding amine to 9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile according to the method used for the synthesis of Compound PR9-1. Although the relevant literatures are not entirely known, some amines in which a tertiary alkyl group is attached to the nitrogen atom were prepared according to the method described in Journal of Medicinal Chemistry, 45 (14), 3143-3160, 2002. Alternatively, the preparation was carried out by introducing a corresponding amine to 9-ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile based on the method that is used for the synthesis of Compound PR11-1 (i.e., reductive amination).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5](F)[C:4]=1[F:12].[CH3:13][O-:14].[Na+].O>CO>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([O:14][CH3:13])[C:4]=1[F:12]
Reactant: C[O-]
Reactant: OCc1c(F)c(F)nc(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(F)c(F)c(CO)c1F
Yield: 80 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.30 g (0.0055 mole) of sodium methoxide in 25 ml of methanol was refluxed for approximately twenty hours. After being cooled, the reaction mixture was poured into water. The aqueous solution was extracted with diethyl ether. The diethyl ether extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.85 g of 4-hydroxymethyl-2-methoxy-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].[NH2:19][CH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=1>C(#N)C>[CH3:28][O:27][C:25]1[N:24]=[C:23]([O:29][CH3:30])[N:22]=[C:21]([CH2:20][NH:19][C:16]([NH:15][S:12]([C:7]2[C:6]([S:3]([N:2]([CH3:18])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:13])=[O:14])=[O:17])[N:26]=1
Reactant: COc1nc(CN)nc(OC)n1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COc1nc(CNC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)nc(OC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
A solution of 1.3 g of 2-(N,N-dimethylsulfamoyl)-benzenesulfonyl isocyanate in 25 ml of dry acetonitrile was treated at room temperature with 0.58 g of the product from Example 4. The resulting suspension was heated to 50°-55° C. for 11/2 hours and was then stirred at room temperature for an additional 15 hours. The solution was filtered and the collected solid washed well with 1-chlorobutane and then dried to yield 0.96 g of N'-[(4,6-dimethoxy-1,3,5-triazin-2-yl)methylaminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide as a light yellow powder, m.p. 183°-189° C., contaminated with some of the unreacted heterocyclic amine. Stirring the crude product with 5% hydrochloric acid at room temperature for 15 minutes followed by filtration gave the pure product as a white powder, m.p. 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]([NH2:20])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[CH3:12][C:13]([NH:20][S:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
6-Chloro-pyridine-3-sulfonyl chloride (148.0 g, 0.7 mol) was suspended in 1000 ml dry dichloromethane and added in portions over 45 minutes to a solution of 1,1,3,3-tetramethylbutylamine (465 ml 2.8 mol) and triethylamine (195 ml, 1.4 mol) in 2800 ml dry dichloromethane, keeping the temperature between −40° C. and −30° C. After addition the mixture was allowed to warm up to room temperature and stirred for an additional hour. The reaction mixture was washed three times with 1 M HCl (2000 ml each time) and twice with water (1000 ml each time). The organic layer was dried over sodium sulphate and evaporated to dryness. The residue was triturated with iso-hexane and filtered off and dried in vacuo at 40° C. to yield 90 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][CH3:24])[CH2:6]C1C(Cl)=NC(Cl)=NC=1)[CH3:2].NC1C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][CH3:24])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)ccc1OC
Solvent: Nc1ccccc1
Product: CCOC(=O)C(C)c1cc(OC)ccc1OC
Temperature: 120 °C

Procedure:
The mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(2,5-dimethoxy-phenyl)-propionic acid ethyl ester (0.36 g, 0.94 mmol) (from Example 6a supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3), and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2,5-dimethoxy-phenyl propionic acid ethyl ester as a yellow solid, which was used in the next step without further purification. (Yield 437.6 mg, 93.9%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]P(=O)(OCC)OCC)=[N:7][CH:8]=1.CC(C)([O-])C.[K+].O=[C:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:27]2/[CH:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:29][CH2:30][CH2:31]/2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC1=O
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cn1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC/C1=C\c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the suspension of diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate (2.0 g, 6.71 mmol) in THF (50 ml) at 0° C. was added potassium tert-butoxide (1.5 g, 13.42 mmol) and then stirred at room temperature for 30 minutes. To this was then added a solution of tert-butyl N-(2-oxocyclopentyl)carbamate (CAS number 477585-30-1; 1.62 g, 8.05 mmol) in THF (20 ml) and the resulting reaction was stirred at room temperature for 1 hour and then heated at reflux overnight. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-15% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15].[CH3:17]I.[H-].[Na+].Cl>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:17])[C:6]([CH:11]([CH3:12])[CH3:13])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)c1cc(C(C)C)c(CO)cc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(CO)c(C(C)C)cc1C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
31.5 g (0.14 mol) of the compound from Example 3 and 9.6 ml (0.15 mol) of methyl iodide are added under a nitrogen atmosphere to 8.9 g (0.3 mol) of sodium hydride (80% strength in paraffin oil) in 500 ml of tetrahydrofuran. After stirring for 2 h at 80° C., the mixture is cautiously hydrolyzed using 30 ml of dilute hydrochloric acid, the solvent is distilled off, and the residue is taken up in methylene chloride, washed with water, dried and chromatographed on silica gel (230-400 mesh, ethyl acetate/petroleum ether 1:2).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1.C(N(CC)CC)C.[N:24]1[O:25][N:26]=[C:27]2[CH:32]=[C:31]([C:33](Cl)=[O:34])[CH:30]=[CH:29][C:28]=12.OS(O)(=O)=O>C(O)C.ClCCl.[Pd].O>[N:24]1[O:25][N:26]=[C:27]2[CH:32]=[C:31]([C:33]([N:8]3[CH:13]4[CH2:14][CH2:15][CH2:16][CH:9]3[CH2:10][O:11][CH2:12]4)=[O:34])[CH:30]=[CH:29][C:28]=12
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: c1ccc(CN2C3CCCC2COC3)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2nonc2c1)N1C2CCCC1COC2
Reaction time: 0.33 h
Yield: 83 %

Procedure:
9-Benzyl-3-oxa-9-azabicyclo-(3.3.1)nonane (3.0 g, 13.8 mmol, see: WO 03004503) was dissolved in ethanol (100 ml), and 10% Pd/C (0.56 g) was added. The mixture was hydrogenated at 100 psi over night. The solids were filtered off, a solution of HCl in dioxane (4 ml, 4N) was added and the solvent evaporated. The residue was dissolved in dichloromethane (100 ml) and triethylamine (8 ml) and a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (3.5 g, 19.2 mmol) in dichloromethane (10 ml) was added. After stirring the mixture for 20 minutes, water (100 ml) and H2SO4 (→pH2) were added and the organic phase washed with sodium bicarbonate solution (100 ml), the aqueous was re-extracted with dichloromethane (100 ml) and the combined organic phase was dried over magnesium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with hexane/THF (70/30). The product crystallized, when the solvent is was evaporated slowly, which yielded the title compound as a white solid (3.13 g): mp=128-130° C., LC-MS, MH+=274.2; 1H NMR (300 MHz, CDCl3) δ 7.94 (dd, 2H, J=9.0 and 1.2 Hz); 7.89 (t, 1H, J=1.2 Hz); 7.47 (dd, 1H, J=9.0 and 1.2 Hz); 4.62 (s, 1H); 4.05 (d, 1H, J=11.7 Hz); 3.95-3.89 (m, 2H); 3.79 (d, 1H, J=11.7 Hz); 3.66 (s, 1H); 2.71-2.54 (m, 1H); 2.14-1.69 ppm (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[C:24]3[N:20]([C:21]([CH3:26])=[C:22]([CH3:25])[CH:23]=3)[CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:27].O.[OH-].[Li+]>C1COCC1.O.CO.C(Cl)Cl>[CH3:25][C:22]1[CH:23]=[C:24]2[N:20]([C:21]=1[CH3:26])[CH:19]=[CH:18][CH:17]=[C:16]2[CH2:15][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:7]1=[O:27]
Reactant: COC(=O)CCn1c(=O)n(Cc2cccn3c(C)c(C)cc23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc2c(Cn3c(=O)n(CCC(=O)O)c4ccccc43)cccn2c1C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-[3-(2,3-dimethyl-indolizin-8-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-propionic acid methyl ester (110 mg, 0.29 mmol) in THF (5 ml) and water (1.5 ml) was added lithium hydroxide monohydrate (25 mg, 0.58 mmol). After 1.5 h the reaction appeared complete (LC-MS) and was subsequently concentrated. The remaining residue was diluted with water (˜12 ml) and acidified to pH˜5 using HOAc (˜5 drops). The resulting solid was dissolved into DCM and the layers were separated. The aqueous phase was extracted with DCM (1×) and the combined organics were concentrated. The remaining green residue was dissolved into a minimal volume of DCM and applied to a preparative TLC plate (1 mm). Eluted with 8% MeOH/DCM. The product-band was isolated and suspended in 5% MeOH/DCM. The silica gel was removed via filtration and washed with DCM. The combined filtrates were concentrated to give the desired product as a light green solid. LCMS (ESMS): m/z 364.24.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[O-:28][C:29]#[N:30].[K+]>CC#N.O>[F:15][C:14]1[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]([NH2:30])=[O:28])[CH2:4][CH2:5]2)=[N:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[N:12][CH:13]=1
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a suspension of 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (26 mg, 0.070 mmol) in CH3CN (1 mL), an aqueous solution of potassium cyanate (34 mg, 0.42 mmol) in H2O (1 mL) was added. The mixture was stirred at 70° C. for 1 h. Solvents were removed in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 414.3 (M+H);); UV 205.8, 276.8 nm
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:45][NH2:46].CCOC(C)=O>C1COCC1>[CH3:45][NH:46][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
The above mentioned tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate was dissolved in 20 mL 2M THF solution of methanamine (20 mL, 40 mmol) in a microwave heating tube. The tube was heated at 120° C. for 10 minutes. The THF solution was mixed with 200 mL EtOAc. The organic phase was washed with water, twice with saturated aqueous ammonium sulfate twice, and dried over sodium sulfate. After removing the solvent, the product was used directly in the next step.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=[O:23])[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.CO>O1CCOCC1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:21](=[O:23])[CH2:22][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH2:17][C:18]([OH:20])=[O:19]
Reactant: Nc1ccccc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
The solution of commercial 1,2-phenylenediamine (1.08 g) and 3-(4-chlorophenyl)glutaric anhydride (2.25 g) in 1,4-dioxane (7 ml) was stirred at rt for 10 min. A voluminous precipitate is formed which is kept at rt for further 50 min. The thick slurry is heated to reflux with methanol, cooled to rt, isolated by suction filtration, and washed with methanol. After drying in vacuo N-(2-aminophenyl)-3-(4-chlorophenyl)glutaramic acid (2.1 g) is obtained as off-white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]2([CH3:15])[CH3:14].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]2([CH3:15])[CH3:14]
Reactant: COc1cccc2c1C(=O)N(C)C2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)c2c(O)cccc2C1(C)C
Temperature: -78 °C

Procedure:
7-methoxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one (0.18 g) is dissolved in CH2Cl2 (4.5 mL) and cooled to −78° C. After the addition of BBr3 (1 molar in CH2Cl2, 2.92 mL) the reaction mixture is allowed to warm up to −10° C. within 3 h. For working up it is diluted with CH2Cl2 and extracted with NaCl solution (H2O, 10%). The organic phase is dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. The residue is used in the next reaction step without any further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7]2[O:8][C:9]([S:11][CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Sc1nc2ccnc(Br)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2ccnc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.21 g (5.24 mmol) 4-bromo-oxazolo[5,4-c]pyridine-2-thiol, 0.8 g (5.76 mmol) K2CO3, 0.9 g (6.28 mmol) MeI in 12 ml DMF is stirred at room temperature for 1 h. The reaction mixture is then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound in quantitative yield.