Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=4)=[N:12][C:11]=3[N:10]([CH3:33])[C:9]2=[O:34])=[CH:5][CH:4]=1.Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:14]2[C:15]3[C:16](=[O:17])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=4)[C:9](=[O:34])[N:10]([CH3:33])[C:11]=3[N:12]=[C:13]2[CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(CCCOc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(CCCOc4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (130 mg, 0.261 mmol, intermediate 60) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (70 mg, 0.345 mmol), followed by potassium carbonate (107 mg, 0.775 mmol) and TBAI (5 mg, 0.014 mmol). The mixture was stirred at 60° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give the crude product 7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 92.5% yield) as a yellow oil. LCMS retention time 2.075 min; LCMS MH+ 629.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:21][CH:20]=1)[CH3:18]
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 2.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-ethylaniline (0.08 mL, 0.65 mmol) to provide 244 (4 mg, 15% yield) as a dark brown solid. LC-MS (M+H (parent)=316, obsd.=316).
Reaction SMILES: CO[C:3]([NH2:5])=[NH:4].OS(O)(=O)=O.[ClH:11].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:13]1.[OH-].[Na+]>O>[ClH:11].[C:3]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:13]1)(=[NH:4])[NH2:5]
Reactant: O=C(O)CCCC1CCNCC1
Reactant: COC(=N)N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N=C(N)N1CCC(CCCC(=O)O)CC1
Yield: 86.4 %

Procedure:
A mixture of 13.0 g of o-methylisourea sulfate and 15.7 g of 4-piperidinebutyric acid hydrochloride was dissolved with stirring and ice-cooling in 60 ml of a 4 N sodium hydroxide solution. To the solution was added 20 ml of water, and the resulting mixture was stirred at room temperature for 64 hours. The crystals obtained were washed with 300 ml of ice-water and dehydrated with acetone and further washed with ether. The crystals were dissolved in 90 ml of a 1 N hydrochloric acid solution, and the solution was dried under reduced pressure. The residue was washed with acetone and then with ether and air-dried to obtain 16.3 g (yield: 86.7%) of 1-amidino-4-piperidinebutyrate hydrochloride as colorless crystals having a melting point of 178° to 180° C.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:8][CH2:7][CH2:6][S:5][CH:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[CH2:17][CH2:18][O:19][CH3:20].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:20][O:19][CH2:18][CH2:17][C:4]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[S:5][CH2:6][CH2:7][CH2:8][S:3]1
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (705 mg, 16.2 mmol) was suspended in anhydrous toluene (21 mL), and the suspension was cooled to 0° C. in an ice bath. In a different flask, tert-butyl 1,3-dithiane-2-carboxylate (3.235 g, 14.7 mmol) and 1-bromo-2-methoxyethane (1.52 mL, 16.15 mmol) were dissolved in N,N-dimethylformamide (7.0 mL), and the solution was added dropwise to the first flask over 15 minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 5 minutes, and successively at room temperature for further 2 hours. The progress of the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with a mixture (1:1 v/v) of n-hexane and ethyl acetate. The separated organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound at a yield of 90% (GC m/z 278 (M+); Rt 5.3 min.).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[C:19]=1[CH:20]=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:2][C:3]2[CH2:8][CH2:7][O:6][CH2:5][C:4]=2[C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=2)[C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(C)n1nccc1C1=C(CBr)CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nccc1C1=C(COc2cccc(O)c2C=O)CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (110 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg, 0.76 mmol) in DMF (6 mL) was added K2CO3 (110 mg, 0.76 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 2-hydroxy-6-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (90 mg). 1H NMR (400 MHz, CDCl3) 8 (ppm) 11.89 (s, 1H), 10.33 (s, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.33 (t, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.40 (dd, J=12.8, 6.4 Hz, 1H), 4.35 (s, 2H), 4.18 (s, 2H), 3.97 (t, J=5.2 Hz, 2H), 2.44 (s, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESD m/z 343.3 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH3:8])[CH2:3][CH3:4].[CH2:11]([N:13]([CH2:25][CH3:26])[C:14](=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1)[CH3:12]>>[CH3:4][CH:3]([O:21][C:20]1[CH:22]=[CH:23][C:15]([C:14]([N:13]([CH2:25][CH3:26])[CH2:11][CH3:12])=[O:24])=[CH:16][C:17]=1[O:18][CH3:19])[CH2:2][CH2:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH3:8]
Reactant: CCC(Br)CC(C)=C(C)C
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC(C)CCC(C)=C(C)C)c(OC)c1

Procedure:
2-bromo-1,4,5-trimethyl-hex-4-ene was reacted with vanillic acid N,N-diethyl amide to obtain p-[(1,4,5-trimethyl-hex-4-enyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 160°-162° C/0.02 mmHg, nD28 = 1.5185);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:35])[CH2:19][O:20][CH2:21][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:25]([NH:24][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18](=[O:35])[NH:17][C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:14]=2)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cccnc2)c1

Procedure:
0.48 g (3.88 mmol) of 3-pyridineboronic acid, 1.3 g (2.85 mmol) of 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester, 95.9 mg (0.08 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 0.41 g (3.88 mmol) of 2N sodium carbonate were heated under reflux for 8 hours in 9.2 mL of toluene and 2.6 mL of methanol. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. Thereafter, the organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-3-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C:19](=[O:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@@H:19]([OH:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Am. Chem. Soc., 1954, 76, 4013, (3β,5α,25R)-spirostan-3-ol-12-one was reduced with lithium aluminum hydride in ether to give a mixture of C-12 alcohols from which the title compound was isolated.
Reaction SMILES: [C:1]1([C:7]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[S:10](=[O:22])(=[O:21])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29]>O1CCOCC1>[ClH:29].[C:23]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[S:10](=[O:21])(=[O:22])[CH2:9][CH2:8]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=COC(=O)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21

Procedure:
0.58 g of (4aRS,7aRS)-4,4-diphenyl-6-vinyloxycarbonyl perhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is treated with 25 cm3 of a 5.7N solution of hydrochloric acid in dry dioxane for 30 minutes while making lukewarm. The reaction solution is concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The residue is taken up in 15 cm3 of ethanol, the solution obtained is refluxed for 30 minutes and then concentrated to dryness. The solid obtained is washed with ethyl ether, drained and dried. 0.46 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:19](=[C:16]1[CH:17]=[CH:18][NH:13][CH:14]=[CH:15]1)[C:5]2=[O:12]
Reactant: Cc1ccncc1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Product: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under N2 atmosphere, a mixture of 30 g (132 mmol) 5-bromoisobenzofuran-1,3-dione (|4-bromophthalic acid anhydride; Apin, GB) and 12.87 ml (132 mmol) 4-picoline is heated for 15 h to 180° C. The resulting black mass is cooled to 100° C., mixed with 160 ml ethanol,boiled for 2 hours, and filtered off. The dried residue is triturated in a mortar, boiled further for 1 h in 180 ml ethanol, filtered, and washed with ethanol. The residue is dissolved at 140° C. in 90 ml DMEU, cooled, mixed with 250 ml ethyl acetate and filtered (→residue is washed out with ethyl acetate and discarded). The ethyl acetate from the filtrate is evaporated off and the residue then diluted with 260 ml acetonitrile, the title compound crystallizing out in the process: HPLC: tRet(Grad20-100)=10.4; MS (M)+=301/303.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Li+].[OH-]>O.O1CCOCC1>[CH3:1][N:2]([CH3:31])[CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate (115 mg, 0.265 mmol) and LiOH (31.7 mg, 1.33 mmol) in water (1.5 mL) and dioxane was heated to 50° C. and stirred for 2 h. The solvent was evaporated, water was added and neutralized to pH 7 and evaporated. The residue was dissolved in 35% methanol in DCM, loaded onto a PTLC plate and eluted with 30% methanol in DCM. To afford 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid. MS ESI: m/z 421.17 [M+1+].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH3:29])[CH:23]([CH3:30])[NH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH3:29])[CH:23]([CH3:30])[NH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCN1C(=O)N(c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)NC1C
Agent: Br
Solvent: O
Product: CCCN1C(=O)N(c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)NC1C
Yield: 85 %

Procedure:
A mixture of 16 parts of 4,5-dihydro-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-4-propyl-3H-1,2,4-triazol-3-one and 375 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 4 hours. After cooling, the precipitated product was filtered off and dissolved in a mixture of methanol and water. The whole was neutralised with a sodium hydrogen carbonate solution. The precipitated product was filtered off and crystallized from 1,4-dioxane, yielding 13 parts (85%) of 4,5-dihydro-2-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-5-methyl-4-propyl-3H-1,2,4-triazol-3-one; mp. 252.9° C. (compound 8.10).
Reaction SMILES: C(=O)(O)[O-].[Na+].ClCC([O:10][C@@H:11]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:27]2[C@@H:26]([O:32][C:33](=[O:36])[CH2:34][Cl:35])[CH2:25][C@@:24]2([CH3:37])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12]1)=O>CO>[Cl:35][CH2:34][C:33]([O:32][C@H:26]1[CH2:25][C@@:24]2([CH3:37])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:27]1[C@:28]1([CH3:31])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:10])[CH2:30][CH2:29]1)=[O:36]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)CCl)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Yield: 78.6 %

Procedure:
Saturated sodium bicarbonate solution (200 ml) was added slowly to a stirred refluxing solution of 3α,11β-bischloroacetoxy-5α-pregnan-20-one (89 g) in methanol (1800 ml). After about 3.5 hours the mixture was evaporated to half its volume, water was added and the steroid was extracted with ethyl acetate. The washed and dried extract was evaporated in vacuo, the residue was filtered through a short column of silica in ethyl acetate-petroleum ether (1:1) and crystallised from ethyl acetate-petroleum ether to afford title compound (59 g), m.p. 83°-86°, [α]D +101° (c 1.0).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Cl[C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=2)[C:26]2[CH:31]=[CH:30][N:29]([CH3:32])[C:27]=2[N:28]=1.CCOC(C)=O.C[C:53]([N:55](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[CH2:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([C:25]2[C:26]3[CH:31]=[CH:30][N:29]([CH3:32])[C:27]=3[N:28]=[C:23]([C:53]#[N:55])[N:24]=2)=[CH:34][C:35]=1[C:42]([F:45])([F:44])[F:43])[CH3:41]
Reactant: CC(=O)N(C)C
Reactant: CCOc1ccc(-c2nc(Cl)nc3c2ccn3C)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(C#N)nc3c2ccn3C)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Zinc (11 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), zinc cyanide (25 mg), and palladium (II) trifluoroacetate (12 mg) were added to a solution of 2-chloro-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (125 mg) in DMAc (2.5 mL) at room temperature in an argon atmosphere, and the mixture was stirred at 110° C. for 5 hours. After the reaction mixture was cooled to room temperature, EtOAc was added thereto, followed by stirring, and the insoluble material was separated by filtration using Celite. Extraction was performed on the filtrate using EtOAc, and the extract was washed with a saturated aqueous NaHCO3 solution, water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 1:1), whereby 4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (52.9 mg) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1(/[C:7](/[C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:8]2/[CH2:9][NH:10][CH2:11][CH2:12]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(/C(=C2/CCNC2)c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(c2ccccc2)C2CCNC2)c1
Yield: 74.1 %

Procedure:
To a solution of (Z)-3-(phenyl(m-tolyl)methylene)pyrrolidine (4.0 g, 16.1 mmol) in methanol (40 mL) at room temperature was added 10% Pd/C (9.5 g) and the contents were hydrogenated at 50 psi hydrogen atmosphere and at room temperature for 12 h. The reaction mixture was filtered through celite bed and the bed was washed with methanol. The filtrate was concentrated under reduced pressure to afford 3.0 g of 3-(phenyl(m-tolyl)methyl)pyrrolidine.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:21][CH3:22])=[C:11]([CH:15](SC)[C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C(=O)C2C=CC=CC=2)=CC=CC=1C(SC)C(N)=O>>[C:1]([C:9]1[C:10]([NH:21][CH3:22])=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1c(C(=O)c2ccccc2)cccc1C(SC)C(N)=O
Agent: CSC(C(N)=O)c1cccc(C(=O)c2ccccc2)c1N
Product: CNc1c(CC(N)=O)cccc1C(=O)c1ccccc1

Procedure:
When in the procedure of Example 2, 3-benzoyl-2-(N-methylamino)-α-(methylthio)phenylacetamide is substituted for 2-amino-3-benzoyl-α-(methylthio)phenylacetamide, the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:22]#[C:21][CH2:20][OH:23])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Fc1ccc(C2CC(c3cccc(I)c3)=NO2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of the product of Step 1, above (13, 5.5 g, 15 mmol) in triethylamine (40 ml), was added bis(triphenylphosphine)palladium (II) chloride (0.63 g, 0.9 mmol) and propargyl alcohol (1.4 g, 25 mmol) under a nitrogen atmosphere. After stirring at room temperature for 1 hour, Cul (0.25 g, 1.3 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours, insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) and the aqueous layer were separated and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with aqueous 1N HCl (150 ml), aqueous NaHCO3 (150 ml) and brine (150 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:4) to give 4.3 g (95% yield) of the title compound (14) as pale yellow solids.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH3:22])[C:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CC(C)N=C=NC(C)C.C1(N)CC1>CN(C=O)C>[CH:27]1([NH:29][C:11](=[O:13])[C:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:20][CH2:21][CH3:22])[CH2:28][CH2:26]1
Reactant: On1nnc2ccccc21
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
(S)-3-(tert-butoxycarbonylamino)-2,2-diethoxyhexanoic acid (8.03 g, 25.1 mmol) was dissolved under nitrogen in 400 mL DMF and HOBt (4.10 g, 30.3 mmol), DIC (7.7 mL, 49.7 mmol) and cyclopropylamine (3.5 mL, 50.0 mmol) were added to the reaction mixture. After stirring for 24 hours at room temperature, the mixture was quenched with 400 mL 5% NaCl and 800 mL EtOAc and the phases were separated. The aqueous phase was extracted with 100 mL EtOAc, the combined organic phases were dried over Na2SO4 and the solvent was removed in vacuo. Purification by column chromatography on silica gel (CHX:EE 10:1→3:1) yielded 3.2 g (S)-tert-butyl 1-(cyclopropylamino)-2,2-diethoxy-1-oxohexan-3-ylcarbamate.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:26]O>>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:26])=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCN1C(=O)NC(Cc2ccc(C(=O)O)cc2)C1=O
Solvent: O=S(Cl)Cl
Product: CCCCN1C(=O)NC(Cc2ccc(C(=O)OC)cc2)C1=O

Procedure:
3-n-Butyl-5-(4-carboxybenzyl) hydantoin (7.2 g., 0.025 mole) was added to a stirred solution of thionyl chloride (1.8 ml., 0.025 mole) in methanol (100 ml) prepared at -5° to -10° C. The mixture was allowed to come to room temperature and finally heated under reflux for 1 hour. After cooling, the clear solution was evaporated in vacuo to dryness and the resultant white crystalline solid was recrystallised from ethyl acetate to give the title compound. Yield 7.1 g (94%) m.p. 144° C.