Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:33]([NH:40][C@H:41]([C:50](O)=[O:51])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][C:50](=[O:51])[CH:41]([NH:40][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 142.3 %

Procedure:
To an ice-cooled solution of D-valine methyl ester hydrochloride (1000 mg, 3.58 mmol) and HOBt (in DMF (14 mL) was added EDCl (755 mg, 3.94 mmol). After the mixture was stirred for 30 min, N-boc-L-homophenylalanine (600 mg, 3.58 mmol) and N-methylmorpholine (1 mL, 8.95 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude title compound (2000 mg) was obtained and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:44][CH3:43])=[O:21])([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and methylamine (2.0 mol/l THF solution, 60.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-methylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.9 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[C:11]2([CH3:19])[CH3:18].O>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][C:11]2([CH3:19])[CH3:18]
Reactant: CC1(C)C(=O)Nc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNc2ccc(F)cc21
Temperature: 70 °C

Procedure:
Under an argon atmosphere a solution of 9.30 mL (9.30 mmol) of a 1M solution of lithium aluminium hydride in THF and 10 mL THF was slowly added dropwise to 1.40 g (7.81 mmol) 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then the reaction mixture was heated to 70° C. for 1 h. After cooling 2 mL water were added. The solution was dried on sodium sulphate and filtered off. The solvent was eliminated i. vac.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[OH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:9][CH2:10]1
Reactant: CC(C)OC(=O)Cl
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Isopropyl chloroformate (1.0M in toluene, 43.4 mL, 43.4 mmol) was added dropwise to a mixture of 4-piperidinemethanol (5 g, 43.4 mmol) and triethylamine (12.1 mL, 86.8 mmol) in CH2Cl2 (150 mL) at 0° C. over 20 min. The mixture was stirred at ambient temperature overnight. The mixture was washed with water, followed by brine. The organic layer was separated and dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 7.76 g (89%) of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.93-4.78 (m, 1H), 4.19-4.09 (m, 2H), 3.47 (d, 2H, J=6.2 Hz), 2.75-2.65 (m, 2H), 1.75-1.56 (m, 3H), 1.21 (d, 6H, J=6.2 Hz), 1.17-1.06 (m, 2H); LRMS (ESI), m/z 202 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH2:23])=O)=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:23])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(CC(=O)N1CCC[C@H]1C(N)=O)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)CN(CC(=O)N1CCC[C@H]1C#N)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 49.5 %

Procedure:
(2S)-1-(2-(N-tert-Butyloxycarbonyl-N-(2-methylpropyl)amino)acetyl)pyrrolidine-2-carboxamide (330 mg, 1.01 mmol) was dissolved in dry THF (20 ml). The solution was cooled to 0° C., triethylamine (210 mg, 2.1 mmol) was added followed by the slow addition of trifluoroacetic anhydride (460 g, 2.2 mmol). The pH was adjusted to pH9 with triethylamine. After 30 min the reaction mixture was diluted with ethyl acetate (100 ml), washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 3% methanol, 97% chloroform) to give an orange oil identified as the title compound (156 mg, 0.50 mmol, 50%).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[C:19]([OH:22])(=[O:21])[CH3:20]>C([O-])(=O)C.[Ag+].CO>[C:19]([O:22][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)CCCCCCC1=CC(OC(C)=O)CC1=O

Procedure:
A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 1274), 27 g. (0.162 moles) of silver acetate, and 200 ml. of glacial acetic acid is stirred at reflux for 4.5 hours. The mixture is cooled, and solids are removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil. The crude product is distilled at reduced pressure to give a liquid, b.p. 152°-163° C. (0.01 mm); λmax.MeOH = 223 mμ (10700); νmax. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm-1 (acetoxy group).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.O1CCOCC1>[C:19]([O:23][C:24]([NH:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a solution of 3.22 g of (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoic acid and 3.08 ml of triethylamine in 30 ml of water was added a solution of 5.41 g of 2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile in 30 ml of dioxane, and the mixture was stirred for 16 hours at room temperature. To the reaction mixture was added 100 ml of water, and the mixture was extracted with ethyl acetate to remove neutral materials. The aqueous layer was acidified by the addition of an aqueous citric acid solution, and the acid solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.10 g of (2RS,3S)-3-tert-butyloxycarbonylamino-2-hydroxy-5-methylhexanoic acid as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=3[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.60) (1.50 g, 4.35 mmol) and commercially available 3-bromo-benzene-boronic acid (0.96 g, 4.78 mmol) according to the general procedure IVb. Obtained as a white solid (1.23 g, 61%). MS (EI) 466.0 [(M)+]; mp 109° C.
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1.[I:24]I>COCCOC>[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[C:16]([I:24])[CH:15]=1
Reactant: II
Reactant: COc1nc(Cl)ccc1C=O
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: COCCOC
Product: COc1nc(Cl)cc(I)c1C=O
Temperature: -23 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution of N,N,N'-trimethylethylenediamine (2.46 mL, 19.23 mmol) in 15 mL of 1,2-dimethoxyethane at -23° C. was added n-BuLi (9.22 mL, 19.23 mmol), and the solution was stirred at -23° C. for 20 min. The mixture was transferred using a double-tipped needle to a solution of 6-chloro-2-methoxy-3-pyridinecarboxaldehyde (3.0 g, 17.5 mmol) in 40 mL of 1,2-dimethoxyethane at -23° C. After stirring for 15 min, n-BuLi (12.6 mL, 26.2 mmol) was added and the dark mixture was stirred an additional 2 h at -23° C. The solution was transferred using a double-tipped needle to a solution of iodine (8.04 g, 31.7 mmol) in 40 mL of 1,2-dimethoxyethane at -78° C. After stirring at -78° C. for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm for 20 min, then quenched with water. The mixture was extracted with ether (2×30 mL) and the combined organic layers were washed successively with 30-mL portions of 10% aqueous Na2S2O3, water and brine, and dried over MgSO4. Concentration afforded 4.62 g (89%) of crude product to which was added 50 mL of hexanes. The mixture was stirred and allowed to stand at 5° C. overnight. Filtration gave 2.67 g of 6-Chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde as a yellow solid: mp 120°-124° C. Concentration of the hexane washings and purification of the residue by radial preparative thin-layer chromatography (silica gel, 5% ethyl acetate/hexanes) gave an additional 1.41 g of product (mp 120°14 124° C.), raising the total yield of the compound to 78%. Recrystallization from hexanes gave an analytical sample as a bright yellow solid: mp 129°-130° C. 1H NMR (300 MHz, CDCl3) δ10.16 (s, 1H), 7.59 (s, 1H), 4.07 (s, 1H): IR (nujol) 1690, 1350, 1260, 1095, 1010, 900, 840 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([N:27]([CH2:30][C:31]([NH2:33])=[S:32])[CH2:28][CH3:29])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:33]=[C:31]([CH2:30][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH3:29])[S:32][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC(N)=S)C(C)=O
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CC)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(N-acetyl-N-ethylamino)thioacetamide in ethanol gave 1-ethyl-7-[2-[(N-acetyl-N-ethylamino)methyl]-4-thiazolyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 160°-161° C. which was then hydrolyzed in refluxing 6N hydrochloric acid to afford the title compound, mp 289°-300° C. (dec).
Reaction SMILES: [C:1]([CH2:5][OH:6])([F:4])([F:3])[F:2].N1C=CC=CC=1.[CH2:13]([S:15](Cl)(=[O:17])=[O:16])[CH3:14].Cl.N1C=CC=CC=1>>[C:1]([CH2:5][O:6][S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])([F:4])([F:3])[F:2]
Reactant: OCC(F)(F)F
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)OCC(F)(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added CF3CH2OH (337.1 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, ethanesulfonyl chloride (364.15 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: O1CC1COC1C=CC=C2C=1CCC2.Cl.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[NH:26]CC(O)COC1C=CC=C2C=1CCC2>C(O)C>[NH2:26][CH:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1
Reactant: OC(CNC1CCc2ccccc2C1)COc1cccc2c1CCC2
Agent: Cl
Agent: c1cc2c(c(OCC3CO3)c1)CCC2
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)indane (19 g) and 2-aminotetralin (14.81 g) in absolute ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indan-4-yloxypropanamine hydrochloride is obtained ((iA): E and G, taken together, represent a group --CH2 --CH2 --CH2 --, R=H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH:46][C:47](=[O:49])[CH3:48])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:47]([NH:46][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:31][CH2:32]4)[CH2:21]3)=[O:19])[CH:12]=2)[NH:8][N:9]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.8 %

Procedure:
To a solution of 37 from Step 2 (20 mg, 0.03 mmol) 37 in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 17 hrs. The crude was quenched with sat. NaHCO3 at rt. The crude was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. The crude was chromatographed to give 6.1 mg of the product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=O)[C:13]=3[CH:20]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:14]1[C:13]2[CH:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]=2[O:18][CH2:17][CH2:16][N:15]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)C(Cl)=NCCO3)cc1

Procedure:
A solution of 7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (3.6 g, 11.7 mmol) and phosphorous pentachloride (2.56 g, 12.3 mmol) in toluene (80 mL) was refluxed for 2 hours. The reaction mixture was concentrated to yield 5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine and used in subsequent steps without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was added aqueous sodium hydroxide (1 M, 36 mL, 36 mmol). The resulting mixture was heated under reflux for 2 h and then cooled to room temperature and concentrated. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by washing with tert-butylmethylether (100 mL). The aqueous phase was acidified with aqueous hydrogen chloride (conc.) to pH=1 and extracted with tert-butylmethylether (100 mL). The organic layers was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL). Drying over sodium sulfate and concentration afforded the title compound (1.68 g, 45%) as an off white solid. MS: m/e=309.3 [M−H]−.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([NH:8][CH2:9][CH2:10]O)[CH3:7]>C1C=CC=CC=1>[CH:2]([CH:1]1[N:8]([CH2:9][CH3:10])[CH2:6][CH2:7][O:5]1)([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: CCNCCO
Solvent: c1ccccc1
Product: CCN1CCOC1C(C)C

Procedure:
Iso-butyraldehyde (11.1 g; 0.15 moles) was added slowly over a period of 1 hour to N-ethyl-2-hydroxyethylamine (13.3 g; 0.15 moles) at a temperature of 25°-30° C. Benzene (100 ml) was then added, and the resulting solution was heated to reflux. Continuous azeotropic distillation removed 2.8 ml of water. The benzene was then removed by vacuum distillation to give the desired 2-isopropyl-3-ethyl-1,3-oxazolidine as a yellow liquid.
Reaction SMILES: C([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=2)=[N:9]1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(O)CCC>[OH:24][C:20]1[CH:19]=[C:18]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=3)[NH:8][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(Cl)c23)c1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: Oc1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
A mixture of 70 mg (0.2 mmol) of 1-benzyl-4-chloro-3-(3-methoxy-phenyl)-pyrazolo[3,4-d]-pyrimidine, 115.6 μl (1.1 mmol) of 3-chloro-aniline and 7 ml of 1-butanol is heated under reflux for 20 hours and then concentrated by evaporation in vacuo. The residue is digested in hexane and filtered. Repeated digestion of the filter residue in diisopropyl ether and in ethanol yields the title compound; m.p. 118-119° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2]1>C(O)(=O)C.Cl.[Zn]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2]1
Reactant: O=C1c2ccccc2OCC1c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(C2COc3ccccc3C2)cc1
Reaction time: 0.75 h

Procedure:
Isoflavanone (0.90 g) was dissolved in a mixture of acetic acid (15 ml) and concentrated hydrochloric acid (1.5 ml). and the solution added to zinc amalgam prepared from zinc powder (2.5 g) and mercuric chloride (0.25 g). The mixture was stirred for 45 min., then allowed to stand at room temperature for 18 hrs. The mixture was filtered and the filtrate diluted with water. The precipitated oil was extracted into toluene and the extract washed with saturated sodium hydrogen bicarbonate solution, dried, and evaporated. The residue was chromatographed on alumina, eluting with petroleum ether, (60°-80°) to give, on evaporation of the eluate, pure isoflavan, 0.23 g., m.pt. 54°-56°.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([N:21]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[O:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(OCc2ccccc2-c2cnc(N=C(c3ccccc3)c3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2ccccc2COc2ccccc2)s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
150 ml of an aqueous hydrochloric acid solution (1 M) are added to 35 g of 5-{2-[(phenoxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in step 1.4, in solution in 250 ml of methanol, and the mixture is stirred for 18 hours at 20° C. The mixture is evaporated to dryness, the residue is taken up in diethyl ether and washed with an aqueous sodium hydroxide solution (0.5 M). The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a silica gel column, eluting with a dichloromethane/methanol 98/2 (v/v) mixture, to give 15 g of a beige solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O.CCCCC>[N:1]([CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)=[N+:2]=[N-:3]
Reactant: C/C(=C\CCl)COC1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: C/C(=C\CN=[N+]=[N-])COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 11.43 g (175.86 mmol) of sodium azide (NaN3) and 2.20 g (6.45 mmol) of tetrabutylammonium hydrogenosulfate in 60 ml of water was added to a solution of 12.0 g (58.62 mmol) of (E)-2-(4-Chloro-2-methylbut-2-en yloxy)tetrahydro-2H-pyran in 300 ml of pentane. The reaction mixture was stirred at room temperature overnight. The organic phase was separated and the aqueous phase was extracted with 3×150 ml of Et2O. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 11.21 g (53.06 mmol, 90% yield) of a mixture of azides isomers. No purification was done as infeasible separation was observed on silica gel. The product was used without further purification for the next step.