Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(Br)n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C)nc1Br
Yield: 88.3 %

Procedure:
A stirred mixture of 2-bromo-3-hydroxy-6-methyl-pyridine (7.89 g, 42.0 mmol), potassium carbonate (11.60 g, 83.9 mmol) and iodomethane (8.93 g, 62.9 mmol, 3.92 mL) in acetone (100 mL) was heated under reflux overnight. The mixture was filtered, evaporated and purified on silica gel (hexane:ethyl acetate, 95:5 to 9:1) to give the desired product as a white solid (7.49 g, 88.3%). 1H NMR (500 MHz, CDCl3): δ 2.46 (s, 3 H), 3.87 (s, 3 H), 7.04 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14]
Reactant: CCN(CC)C(=O)CCBr
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCSc1ccc(Cl)cc1N
Yield: 84.4 %

Procedure:
Following General Procedure A, the title compound (1.0 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (660 mg, 4.13 mmol), crude 3-bromo-N,N-diethylpropanamide (860 mg, 6.60 mmol) and K2CO3 (2.9 g, 20.67 mmol) in DMF (20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24](OCC)=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[NH:36]([CH3:38])[CH3:37].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([N:36]([CH3:38])[CH3:37])=[O:25])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:33])[F:35]
Reactant: CNC
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a vial containing ethyl 5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (57 mg, 0.1 mmol) was added Me2NH in THF (1.0 mL of a 2.0M solution). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (3.7 mg, 7% yield). HPLC retention time=2.91 minutes. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=2.0, 1H), 8.17 (d, J=2.4, 1H), 8.10 (d, J=2.4, 1H), 7.93 (dd, J=2.4, 8.4, 1H), 7.57 (d, J=8.4, 1H), 5.65 (sept, J=7.2, 1H), 3.20 (s, 3H), 3.12 (s, 3H), 1.52 (d, J=7.2, 6H). MS (ES) [M+H]+ expected 551.1, found 551.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>ClC(Cl)C.C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Sc2c(-c3ccc(O)cc3)sc3ccccc23)cc1
Yield: 61 %

Procedure:
A solution of 0.82 g (2.2 mmol) of methyl 4-[[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]thio]phenyl ether (Part B) in 50 mL of dichloroethane was treated with 1.2 mL (3.3 g; 13 mmol) of BBr3 at 0° C. for 5 h. The reaction was quenched by the careful addition of 15 mL of MeOH. Evaporation of the solvent in vacuo gave a residue which was subjected to flash chromatography (SiO2; 1% MeOH in CHCl3) to afford 0.47 g of the desired product as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2C=NCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2ccnc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-4-[methoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole from Step 2 (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-4methoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15](Cl)[C:16]([CH3:22])=[N:17]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.CCOC(C)=O>[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([CH3:22])=[N:17]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(Br)c2nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
LHMDS (1.0M in THF; 14.37 ml, 14.37 mmol) was added to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e, 0.74 g, 2.87 mmol) and aniline (1.309 ml, 14.37 mmol, Alfa Aesar, Ward Hill, Mass.) in dioxane (28.7 ml) at RT, and the resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with saturated aq. NH4Cl (2×150 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 20% EtOAc/hexanes) provided 8-bromo-3-methyl-N-phenylquinoxalin-2-amine (183a, 71% yield) as a brown oil. MS (ESI, pos. ion) m/z: 314.2/316.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Br)(Br)([Br:31])=O>CN(C)C=O>[Br:31][C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Reactant: O=P(Br)(Br)Br
Solvent: CCN(CC)c1ccccc1
Solvent: CN(C)C=O
Product: Clc1ccc(-n2nc3c(c2Br)CCCC3)cc1
Temperature: 25 °C

Procedure:
To 5.0 parts of 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one [from Example 1(c)] with 3.0 parts of N,N-diethylaniline and 5.0 parts of dimethylformamide under nitrogen atmosphere was added 6.3 parts of phosphorous oxybromide. The mixture was heated to 130°-170° for 2 hours. After cooling to room temperature, the reaction mixture was extracted with 100 parts of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. Recrystallization from methanol/water gave 2.7 parts of product, m.p. 101°-102°.
Reaction SMILES: [Mg].II.Br[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]#N)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.Cl.CC[O:25]CC>>[CH:5]1([C:20]([C:17]2([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:19][CH2:18]2)=[O:25])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N#CC1(c2ccc(Cl)cc2)CC1
Reactant: CCOCC
Reactant: BrC1CCCC1
Agent: Cl
Agent: II
Agent: [Mg]
Product: O=C(C1CCCC1)C1(c2ccc(Cl)cc2)CC1

Procedure:
2.4 g (0.1 mol) of magnesium chips are suspended in 10 ml ether. After the addition of a spatula-tip of iodine, 14.9 g (0.1 mol) of bromocyclopentane are slowly added dropwise to 40 ml of ether, the reaction being started off initially by gentle heating. After the addition has ended the mixture is refluxed for 30 minutes. Then a solution of 14.0 g (0.08 mol) of 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile in 75 ml ether is added and refluxed for a further 3 hours. The reaction solution is poured onto ice water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1 and 15:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)cc1
Yield: 90 %

Procedure:
A mixture of crude 2-(4-nitro-phenyl)-malonic acid diethyl ester and 10% palladium on carbon in ethyl acetate (20 ml) was treated with hydrogen gas (40 psi) on a Parr shaker for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexane to provide 2-(4-amino-phenyl)-malonic acid diethyl ester (450 mg, 90% yield for 2 steps).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C[C:7](=[O:11])[C:8]([O-:10])=[O:9].[CH:12]1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC(C)=O>[C:1]([NH:5][CH:7]([OH:11])[C:8]([O:10][CH3:12])=[O:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(N)=O
Reactant: CC(=O)C(=O)[O-]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC(C)=O
Product: C=CC(=O)NC(O)C(=O)OC

Procedure:
Acrylamide (141.7 parts), methylglyoxylate (144 parts), acetone (1200 ml) and phenothiazine (0.05 parts) were mixed and heated to reflux for 6 hours. After filtration and crystallization 180 parts MAG were received as confirmed by chemical analysis.
Reaction SMILES: ClCC1C=CN=CN=1.Cl[CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[CH2:10][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cnccn1
Agent: ClCc1ccncn1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cnccn1
Yield: 46 %

Procedure:
Following the procedure as described in step A of Preparation 14, making variations as required to replace 4-(chloromethyl)pyrimidine with 2-(chloromethyl)pyrazine (prepared according to R. W. Carling, et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) to react with potassium phthalimide, 2-(pyrazin-2-ylmethyl)isoindoline-1,3-dione was obtained as a colorless solid in 46% yield: mp 141-143° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.47 (s, 2H), 7.90-7.87 (m, 2H), 7.76-7.73 (m, 2H), 5.05 (s, 2H); MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14](=[O:35])/[CH:15]=[C:4]1/[O:6][C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]/1=2
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C1/OC(=O)C2=C1CCCC2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) and (triphenylphosphoranylidene)acetic acid methyl ester (6.69 g) in chloroform (50.0 mL) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, it was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9→3:7) to give the title compound (1.93 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: C[C@@H](Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In analogous manner to that described in example 5a), the reaction of (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-butyric acid and 1-fluoro-2-nitro-4-trifluoromethyl-benzene yielded quantitatively the title compound as a brown oil, MS m/e (%): 426.4(M+NH4+, 85).
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:61](Cl)(=[O:63])[CH3:62]>ClC(Cl)C>[C:61]([N:11]([CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][S:2](=[O:51])(=[O:1])[CH2:7][CH2:6]1)[C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)(=[O:63])[CH3:62]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(N(CCN3CCS(=O)(=O)CC3)C(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.05 g, 0.071 mmol) in dichloroethane (1 mL) and Hunig's base (0.062 mL, 0.355 mmol) was added acetyl chloride (0.020 mL, 0.284 mmol). The mixture was heated to 50° C. After heating the mixture for 71.25 h, the mixture was cooled to rt and was directly loaded onto a 12 g Thomson silica gel column and was purified by Biotage flash chromatography using a 0-5% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and were concentrated under reduced pressure to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.054 mmol, 75%) as a clear, colorless film. LCMS: m/e 747.5 (M+H)+, 2.26 min (method 2).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C1COCC1.[BH4-].[Na+].Cl>C(O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(CO)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 6.85 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 200 ml of an ethanol:THF=1:1 mixed solvent there was added 1.52 g of sodium borohydride while cooling on ice. After stirring at room temperature for 30 minutes, 1N hydrochloric acid was added to the reaction mixture while cooling on ice. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-fluoro-2-hydroxymethyl-6-methoxyphenol (6.1 g, crude product).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O-:11][C:12]#[N:13].[K+].Cl>O>[C:5]1([C:3]2[NH:13][C:12](=[O:11])[NH:1][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCC(=O)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(-c2ccccc2)[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
2-Aminoacetophenone (5.6 g, 32.65 mmol) was dissolved in 200 ml of water in a three necked flask equipped with a thermometer and was heated up to 70° C. Potassium cyanate (2.9 g, 35.92 mmol) was added in several portions at 70° C. while the pH of the reaction solution was maintained in the range of 1 to 3 by the continuous addition of conc. HCl. After the addition of potassium cyanate was completed, the reaction mixture was stirred at 70° C. for 4 hours and left at room temperature overnight. The brownish precipitate thus formed was collected by filtration and dried to obtain 3.7 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:18][CH2:17]1.[O:32]=[C:33]1[NH:41][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]1[CH:42]1[CH2:47][CH2:46][N:45](C(Cl)=O)[CH2:44][CH2:43]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25]([N:45]2[CH2:44][CH2:43][CH:42]([N:34]3[C:35]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[NH:41][C:33]3=[O:32])[CH2:47][CH2:46]2)=[O:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Triethylamine (0.45 mL, 3.25 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (416 mg, 1.62 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (466 mg, 1.66 mmol) in dichloromethane (70 mL) and the mixture heated to reflux. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (685 mg). MS 501.0 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:13]#[CH:14])([OH:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[H][H].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[C:20]([F:26])[CH:19]=1>CN(C=O)C>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([O:12][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][C:20]=2[F:26])([C:13]#[CH:14])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC1(OCc2ccc(Cl)cc2F)CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
Sodium hydride (50% mineral oil dispersion, 10.7 g, 223 mmole) was suspended in 100 ml DMF. A solution of 1-acetyl-4-ethynyl-4-hydroxypiperidine (37.4 g, 0.223 mole) in 125 ml DMF was added to the sodium hydride suspension at 20° C. After the complete evolution of hydrogen gas, the solution was cooled to 5° C. and a mixture of 50 g 4-chloro-2-fluorobenzylbromide in 50 ml DMF was added dropwise. The temperature was not allowed to exceed 10° C. during the addition. The mixture was allowed to equilibrate to ambient temperature and after 2 hrs. the reaction was determined to be complete. The mixture was quenched with ice water and extracted with ether. The ether extracts were combined and dried over anhydrous magnesium sulfate. This was filtered and the solvent removed in vacuo. The oily residue was purified by preparative HPLC, eluting with hexane:ethylacetate (1:1). The material was contained in fractions 8-12. When combined and the solvent removed, these fractions afforded 52.6 g 1-acetyl-4-(4-chloro-2-fluorobenzyloxy)-4-ethynylpiperidine (170 mmole, 76.23%). This material appeared pure by TLC on silica gel in chloroform:methanol (9:1), Rf =0.6 and in hexane:ethylacetate (1:1) Rf =0.2, MS(MH+ =310), NMR-CDCl3 and IR-CHCl3 are consistent with the structure; mp=70°-74° C.
Reaction SMILES: [C:1]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]([CH2:18]N(C)C)[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:22]([O-:49])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(#N)C>[C:1]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]([CH:10]=1)[CH2:18][P:22](=[O:49])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCOP([O-])OCCCCCCCCCCCC
Reactant: Cc1c(CN(C)C)cc(C(C)(C)CC(C)(C)C)c(O)c1C
Solvent: CC#N
Product: CCCCCCCCCCCCOP(=O)(Cc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1C)OCCCCCCCCCCCC

Procedure:
This compound was made in a similar manner as Example 5 by reacting 6-tert.-octyl-2,3-dimethyl-4-(dimethylaminomethyl)phenol (Example 2) with di-n-dodecyl phosphite. After trituration with acetonitrile, the desired compound is obtained as white crystals melting at 36° to 40°C (Compound 7).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23][C:22](=O)[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12].N1CCCCC1>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23]/[C:22](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(C)[nH]c2c1CCC2=O
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2c1CC/C2=C1/C(=O)Nc2ccccc21
Temperature: 110 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
A mixture of oxindole (44 mg, 0.33 mmol) and 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid ethyl ester (Example A, 62 mg, 0.3 mmol) in DMF (5 mL)-piperidine (0.5 mL) was heated at 110° C. with stirring for 72 hours. Most of the solvent was removed under reduced pressure and the residue was diluted with ethanol. The resulted precipitate was collected by filtration, washed with ethanol and dried to give 56 mg (58%) of the titled compound as a yellow solid.