Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:65][CH3:66])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH2:53][F:54])[CH2:49][N:48](C(OCC3C=CC=CC=3)=O)[CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]>>[Cl:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[C:37]1[N:38]=[C:39]([CH2:65][CH3:66])[C:40]([NH:45][C@H:46]2[C@@H:50]([O:51][CH2:52][CH2:53][F:54])[CH2:49][NH:48][CH2:47]2)=[N:41][C:42]=1[CH2:43][CH3:44]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.15, 1.29, 2.48, 2.70, 2.90, 2.90, 3.15, 3.23, 3.44, 3.85, 4.11, 4.55, 4.66, 5.32, 6.88, 7.02, 7.24.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[C:30]([C:35]#[N:36])[CH:29]=4)[C:21](OC)=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[C:30]([C:35]#[N:36])[CH:29]=4)[CH2:21][OH:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cc2ccc(C#N)cc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(CO)Cc3cc4ccc(C#N)cc4[nH]3)cc2)C1
Yield: 86.4 %

Procedure:
2.7 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionate was dissolved in 30 ml of tetrahydrofuran, followed by the addition of 6606 mg of sodium borohydride. 12 ml of methanol was added dropwise to the thus prepared solution while stirring under ice cooling, and the resulting mixture was stirred at room temperature for 3 hours. The resulting reaction solution was mixed with 10% citric acid aqueous solution, extracted with dichloromethane, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/methanol mixture as an elution solvent. In this way, 2.2 g of the title compound was obtained in an oily form.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Yield: 71.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (700 mg) obtained from Reference Example 1 was suspended in 1,2-dichloroethane (20 ml). Pyridine (237 mg) and pivaloyl chloride (362 mg) were added thereto, and the mixture was refluxed for two hours. After the reaction mixture was allowed to cool, crystals that precipitated were collected by filtration, to thereby obtain 650 mg of the title compound (yield: 71%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[C:22](=[O:23])[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1COCCC(=O)N1Cc1ccccc1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1COCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide in THF (0.101 M, 100 mL, 10.1 mmol, 1.30 equiv) freshly prepared at −78° C. was added via cannula to a solution of 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3, 1.71 g, 7.80 mmol, 1 equiv) in THF (100 mL) at −78° C. and the resulting mixture was stirred for 20 min. HMPA (1.36 mL, 7.80 mmol, 1.00 equiv) was added followed by methyl cyanoformate (1.24 mL, 15.6 mmol, 2.00 equiv). The resulting mixture was warmed to 0° C., stirred for 20 min, and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4) as a mixture of diastereomers (colorless oil). LRMS m/z (M+H) 278.2 found, 278.1 required.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH3+:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12]([OH:17])=[CH:13][C:14]([CH3:16])=[N:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(N[NH3+])cc1C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2ccc(C)c(C)c2)n1
Yield: 71 %

Procedure:
2-(3,4-Dimethylphenyl)hydrazinium chloride (900 g, 5.21 mol), ethyl acetoacetate (678 g, 5.21 mol), sodium acetate (428 g, 5.21 mol) and glacial acetic acid (10 L) were stirred at 118° C. for about 24 hours. The resulting mixture was cooled and concentrated, and the residue was dissolved in dichloromethane (10 L) and carefully washed with saturated sodium bicarbonate (3×3 L). The organic layer was concentrated to afford a solid. The solid was dissolved in ethanol (450 mL) under reflux. Petroleum ether (7.2 L) was slowly added, and the resulting mixture was cooled and filtered to afford the title compound (748 g, 71%). PXRD analysis provided the diffractogram as shown in FIG. 31.
Reaction SMILES: [CH3:1][C:2]([CH3:51])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:50])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:49])=[CH:11]\[CH2:12][CH2:13]/[C:14](/[CH3:48])=[CH:15]\[CH2:16][CH2:17]/[C:18](/[CH3:47])=[CH:19]\[CH2:20][CH2:21]/[C:22](/[CH3:46])=[CH:23]\[CH2:24][CH2:25]/[C:26](/[CH3:45])=[CH:27]\[CH2:28][CH2:29]/[C:30](/[CH3:44])=[CH:31]\[CH2:32][CH2:33]/[C:34](/[CH3:43])=[CH:35]\[CH2:36][CH2:37]/[C:38](/[CH3:42])=[CH:39]\[CH2:40][OH:41].[C:52](Cl)(=[O:55])[CH:53]=[CH2:54]>N1C=CC=CC=1.CCCCCC>[C:52]([O:41][CH2:40][CH:39]=[C:38]([CH3:42])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:43])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:44])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:45])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:46])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:47])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:48])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:49])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:50])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:51])[CH3:1])(=[O:55])[CH:53]=[CH2:54]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CC/C(C)=C\CO
Reactant: C=CC(=O)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.0 Grams of decaprenol were dissolved in 50 ml of pyridine. The solution was added with 15% solution of 2.1 g of acrylic acid chloride in pyridine at room temperature over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the rection. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentate was purified by chromatography with 80 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain a white solid (m.p. 32.0°-32.8° C.). Yield 5.8 g.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:19]1([C:25]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:33]3[C@H:29]([CH2:30][NH:31][CH2:32]3)[C:28](=[O:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:35]1([C:25]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:33]3[C@H:29]([CH2:30][N:31]([C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:32]3)[C:28](=[O:34])[CH2:27][CH2:26]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
A solution of phenylacetyl chloride (4 cc) and triethylamine (8.6 cc) in dichloromethane (10 cc) is added dropwise to a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (10 g) in dry dichloromethane (80 cc) cooled to +5° C. The reaction mixture is stirred for 2 hours at +5° C. and then for 20 hours at 20° C. The reaction mixture is treated with a saturated aqueous solution (30 cc) of sodium bicarbonate; the organic phase is washed with distilled water (2 * 50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (15 cc). The crystals are drained, washed with acetonitrile (10 cc) and with isopropyl ether (10 cc) and dried. (3aR,7aR)-7,7-diphenyl-2-(phenylacetyl)-4-perhydroisoindolone (5.7 g) melting at 173° C. is obtained; [a]D20 =-282° (c=1, methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Cc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
140.7 mg of the target compound (0.41 mmol, 74.7%) was obtained using 1-(2-methylphenyl)piperazine (193.8 mg, 1.1 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]1([CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([F:20])[F:19])[C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N.[H][H]>[Ni].CO>[C:1]1([CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([F:19])[F:20])[CH2:12][NH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N#CC(CCCCC(F)F)c1cccc2ccccc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(CCCCC(F)F)c1cccc2ccccc12
Yield: 76.6 %

Procedure:
A mixture of 2-(naphth-1-yl)-7,7-difluoroheptanenitrile (413 mg, 1.51 mmol), Raney nickel (413 mg) and ammonia (0.9 g) in methanol (20 ml) was hydrogenated under 340 kPa (50 psi) hydrogen overnight at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (40 ml) and the ethyl acetate extract was washed with brine (30 ml), dried (sodium sulfate) and concentrated in vacuo. The residue (400 mg) was purified by column chromatography on silica gel (100 g), eluting with 85:15 ethyl acetate/methanol to yield the title compound as an oil (321 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ1.35 (c, 6H), 1.78 (c, 4H), 3.08 (c, 2H), 3.61 (c, 1H), 5.52, 5.71, 5.9 (3t, total 1H), 7.37 (d, 1H), 7.5 (m, 3H), 7.75 (d, 1H), 7.88 (d, 1H), 8.16 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: c1ccc(C2CCOCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CCOCC2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.4 g of 4-(phenyl)-tetrahydropyran [Ber., Vol. 56 (1923), p. 2013] in 60 ml of acetic acid was added at -10 to -12° C over an hour to a solution of 120 ml of concentrated nitric acid and 50 ml of acetic acid and the mixture was stirred for 30 minutes at -10° C. 100 ml of ice and 100 ml of water were added to the mixture and the mixture was filtered. The recovered precipitate was washed with water and dried to obtain 35 g of 4-(p-nitrophenyl)-tetrahydropyran melting at 124° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C=O)cc21
Reactant: O=C1CSC(=O)N1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 6-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (intermediate 62) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:23])=[O:10]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (500 mg) was dissolved in chloroform (20 mL), and oxalyl chloride (500 mg) and a catalytic amount of DMF were added, followed by stirring at room temperature for 3 hours. Under reduced pressure, the solvent and an excess reagent were distilled off to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride (520 mg) as an oily product.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[F:9][Si:10](F)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[CH2:5]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[F:9])[CH2:6][CH:7]=[CH2:8]
Reactant: F[Si](F)(c1ccccc1)c1ccccc1
Reactant: C=CCCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC[Si](F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
In a two-neck flask equipped with a condenser was placed magnesium (3.46 g, 142 mmol) and a crystal of iodine. The flask was warmed with heat gun until iodine had sublimed. A solution of 4-bromo-1-butene (9.62 g, 71.3 mmol) in ether (100 mL) was added dropwise in 30 min and the resulting mixture refluxed for 2 h. This Grignard solution was cooled to rt and added over 30 min via cannula to a second flask containing 24 (15.7 g, 71.3 mmol) in ether (100 mL) at rt. After stirring overnight at rt under argon, the reaction mixture was quenched with water (20 mL) and the organic layer isolated. The aqueous layer was extracted twice with 50-mL portions of ether. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Distillation (134° C., 1.5 mm Hg) provided pure 31 as a colorless oil (15.2 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=7.8 Hz, 4H), 7.50–7.39 (m, 6H), 5.97–5.83 (m, 1H), 5.02 (dd, J=17.1, 1.7 Hz, 1H), 4.94 (dd, J=10.2, 1.7 Hz, 1H), 2.28–2.20 (m, 2H), 1.38–1.30 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 140.9, 135.9, 134.1, 129.7, 127.8, 113.1, 26.9, 14.0.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Clc1cccnc1-n1cnc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nc(Br)cn1-c1ncccc1Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of 2-(4-bromo-1H-imidazol-1-yl)-3-chloropyridine in 5 ml of dichloromethane was added dropwise a solution of 0.45 ml of trichloroacetyl chloride in 5 ml of dichloromethane at room temperature. The resulting mixture was stirred at room temperature for 1 day. Thereto 0.57 ml of triethylamine was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 1.0 g of 1-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-2,2,2-trichloroethanone of the formula:
Reaction SMILES: [OH2:1].[O:2]1[C@H:4]2[CH2:5][C@H:6]3[C@:19]([CH3:21])([CH2:20][C@@H:3]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:22])[C@@H:12]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:11]2)[CH2:8][CH2:7]3>N1CCOCC1>[N:23]1([C@H:3]2[CH2:20][C@@:19]3([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@H:12]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[C@@H:13]3[OH:22])[CH2:5][C@@H:4]2[OH:2])[CH2:24][CH2:25][O:1][CH2:11][CH2:12]1
Reactant: O
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: C1COCCN1
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
Water (50 ml) was added to a solution of (2α,3α,5α,16β,17β)2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (85.2 g) in morpholine (500 ml) and the reaction mixture was heated at reflux temperature for 3 d. Evaporation of the reaction mixture gave a crude product, which was crystallised from acetone. Recrystallisation from methanol gave pure (2β,3α,5α,16β,17β)-2(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol (71.2 g), m.p. 212°-219° C.; [α]D20 =+87.9° (c 1.02 in CHCl3).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][N:53]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:11])[CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)C1
Reaction time: 3 h
Yield: 39 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of ethyl acetate:heptane=1:5 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (16.3 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[C:28]=2[CH:39]=1>S(Cl)(Cl)=O>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:29]1[C:28]2[CH:39]=[C:24]([NH:23][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH:25]=[CH:26][C:27]=2[O:32][CH2:31][C:30]1=[O:33]
Reactant: CN(C)CCN1C(=O)COc2ccc(N)cc21
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc5c(c4)N(CCN(C)C)C(=O)CO5)cc3)c(C)c2)no1
Yield: 75.4 %

Procedure:
2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0553268A1) (0.188 g, 0.64 mmol) was converted to the acyl chloride by stirring at reflux under Ar in thionyl chloride (10 ml) for 45 min, cooling, and then evaporating to dryness. This was reacted with 6-amino-4(2-dimethylaminoethyl)-1,4-benzoxazin-3(4H)-one (D8) (0.150 g, 0.64 mmol) following the procedure of Example 1. This gave the title compound (0.247 g, 75%) as a white foam, which was converted to the oxalate, a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][CH:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: OC(CCI)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCC(O)C(F)(F)F
Temperature: 50 °C
Yield: 92.4 %

Procedure:
A solution of 1,1,1-trifluoro-4-iodo-2-butanol (0.604 g, 2.38 mmol) in DMSO (4 mL) was treated with sodium azide (0.178 g, 2.74 mmol) at ambient temperature, followed by heating at 50° C. for 21 h. The mixture was diluted with cold water and extracted with ethyl acetate. The combined organic extracts were washed (brine), dried, and evaporated to give the product as a pale yellow oil (0.372 g, 92%).