Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH:6]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][OH:4])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCCCCC(C(C)C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(CCO)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Part C: To a solution of 4.4 g (13 mmol) of methyl 3-[(4-methoxyphenyl)sulfonyl]-octanoic acid from Part B in 60 mL of anhydrous THF at zero° C. under nitrogen, was added 14.6 mL (0.5 g, 13 mmol) of a 1.0 M solution of lithium aluminum hydride in THF. After 2 hours, the reaction mixture was cooled to zero° C. and 0.5 mL of water was added, followed by 0.5 mL of 2.5 N sodium hydroxide solution and 1.5 mL of water, the reaction was filtered, the filtrate concentrated in vacuo, ethyl acetate and 5% citric acid solution were added, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 3.3 grams of pure 3-[(4-methoxyphenyl)sulfonyl]-octan-1-ol, m/z=307 (M+Li).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccc2ccccc2c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 2-chloromethyl naphthalene, in 81% overall yield. the crude product was crystallized from ether/hexane to afford a white solid, mp 81°-87° C.; IR (KBr) 3459, 2940, 1665, 1500, 1403, 1277, 1242, 1066, 746 cm-1 ; 1H NMR (CDCl3) δ2.23-2.40 (m, 3H), 3.95 (t, J=5.4 Hz, 2H), 4.90 (dd, J=7.6, 5.6 Hz, 1H), 5.32 (ABq, JAB =16.1 Hz, 2H), 6.87-7.03 (m, 4H), 7.38 (d, J=8.5 Hz, 1H), 7.43-7.48 (m, 2H), 7.67 (s, 1H), 7.75-7.84 (m, 3H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.71; N, 4.02.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:43][NH2:44]>>[NH:43]([C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:36])[NH2:44]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NN
Product: COc1cc(C(=O)NN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with hydrazine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-2-methoxy-phenyl)-amide. MS (ES+) m/z calcd. for C31H32Cl2F2N5O3: [(M+H)+]: 630. found: 630.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:10]=2.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([O:21][CH3:32])([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:18])[F:19])[CH:10]=2
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)SCC2
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCS2)(C(F)(F)F)C(F)(F)F

Procedure:
To a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one in dimethyl formamide can be added sodium hydride and dimethyl sulfate. The mixture can be stirred and heated in a nitrogen atmosphere until the reaction is complete, treated with ethanol and purified to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:28]1([S:34]([NH:37][C:25]([C:23]2[CH:22]=[CH:21][C:11]3[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][C:10]=3[CH:24]=2)=[O:26])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
N,N′-carbonyldiimidazole (0.401 g) is added all at once to an N,N-dimethylformamide (20 ml) solution of 2-benzyl-5-carboxy-1-(2-chlorobenzyl) benzimidazole (0.466 g), and the solution is stirred for one hour at room temperature. Subsequently, a N,N-dimethylformamide (5 ml) solution of benzenesulfonamide (0.389 g) and diazabicycloundecene (0.377 g) is added, and the solution is stirred for 48 hours at 100° C. The reaction solution is cooled, and the solvent is removed through evaporation under reduced pressure. This material is dissolved in a mixture solution of methanol and water. The pH is adjusted to pH 5˜6 using 10% hydrochloric acid. Precipitated crystals are separated through filtration, and are dried. Thus, 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole (0.447 g) is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[CH3:18][O:19][C:20](=[O:23])[CH2:21]Cl>CCOC(C)=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: COC(=O)CCl
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-iodopyrazole (1.000 g, 5.155 mmol), Cs2CO3 (2.016 g, 6.186 mmol) and DMF (20 mL, 0.2 mol) was added chloroacetic acid methyl ester (0.5440 mL, 6.186 mol) at 0° C. The reaction was allowed to stir for 1 h at rt. The material was transferred to a separatory funnel, diluted with EtOAc, and washed with water several times to remove DMF. The organic layer was dry-loaded onto silica gel, and column chromatography was used to purify, eluting with 3:1 Hexanes/EtOAc, affording the title compound as a clear liquid. 1H NMR (400 MHz, CDCl3): δ=3.79 (s, 3H), 4.93 (s, 2H), 7.54 (s, 1H), 7.57 (s, 1H). MS (ES+): m/z=266.95 (100) [MH+]. HPLC: tR=2.73 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([S:16][CH2:17][C:18]([O:20]C)=O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CC(C)([O-])C.[K+]>O1CCCC1>[NH:1]1[C:2]2=[C:3]3[C:8](=[N:9][C:10]4[CH2:11][CH2:12][CH2:13][CH:14]([C:15]=42)[S:16][CH2:17][C:18]1=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4]3
Reactant: COC(=O)CSC1CCCc2nc3ccccc3c(N)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CSC2CCCc3nc4ccccc4c(c32)N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.5 %

Procedure:
To a solution of methyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate (10.3 g) in tetrahydrofuran (150 ml) was added potassium t-butoxide (4.6 g). The reaction mixture was stirred at ambient temperature for 45 mins and then concentrated. The residue was stirred in water, the solid was collected, and dried. The solid was purified by flash chromatography (ethyl acetate/dichloromethane→5% methanol/dichloromethane) to give 4.1 g (44%) of product, mp 223°-226° C. (dec.). Recrystallization from methanol gave the analytical sample, mp 223.5°-226° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-])[O:10][N:11]=[C:7]2[CH:6]=1.P(OCC)(OCC)OCC>C(O)C>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1
Reactant: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: FC(F)(F)c1ccc(Oc2ccc3nonc3c2)c(Cl)c1

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide (2.0 g) and triethyl phosphite (10 ml) is heated under reflux in ~150 ml of ethanol for 4 hours. The reaction is cooled and stripped, and the crude product is purified by prep. TLC (15% ethyl acetate/hexane) to give 5-(2-chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole, m.p. 65°-66°.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([OH:14])=O)[CH:3]=1.C(Cl)(C(Cl)=O)=O.BrC1C2SC=CC=2C(Cl)=C(C(Cl)=O)C=1.[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH2:35][CH3:36])=[CH:39][CH:40]=2)=[O:14])[CH:3]=1
Reactant: CCOc1ccccc1
Reactant: O=C(O)c1cc(Br)c2sccc2c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cc(Br)c2sccc2c1Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)c3sccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
After dissolving crude 7-bromo-4-chlorobenzo[b]thiophene-5-carboxylic acid 97 (847 mg, 2.91 mmol) in CH2Cl2, (COCl)2 (0.49 mL, 5.82 mmol) and catalytic amount DMF was added carefully at 0° C. The resulting solution was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure and dried in vacuo. The crude compound was used for the next step without further purification. To a solution of crude 7-bromo-4-chlorobenzo[b]thiophene-5-carbonyl chloride in CH2Cl2 (50 mL) was added ethoxybenzene (462 mg, 3.78 mmol) and AlCl3 (464 mg, 3.49 mmol) at 0° C. After warming the reaction mixture up to room temperature, it was stirred for 4 hours. The resulting compound was quenched with aq. NH4Cl solution and the normal work-up with EtOAc was conducted. Purification by silica gel chromatography gave the title compound (917 mg, 79.8%) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CNC1CCNC1
Product: CNC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 110 °C

Procedure:
N-methylpyrrolidin-3-amine (0.395 g, 3.94 mmol) was added to 2-bromo-5-nitropyridine (0.8 g, 3.94 mmol) slowly (CAUTION: extreme exotherm!!!). The resulting mixture was heated at 110° C. for 2 h. After cooling down to room temperature, the obtained black solid product (Example 16A, 0.87 g, 99%) was used for next step without further purification. LCMS (ES): m/z 233.4 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:12])[C:8]([F:11])([F:10])[F:9].[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18](Cl)[CH:17]=[CH:16][N+:15]=1[O-:23]>O>[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:12][CH2:7][C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][N+:15]=1[O-:23]
Reactant: OCC(F)(F)F
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Temperature: 0 °C

Procedure:
6.7 g of potassium tert-butoxide were added in portions, at -20° C., while stirring and under a nitrogen atmosphere, 5 to 20 ml of trifluoroethanol. After the mixture had been warmed to 0° C., 5.2 g (30 mmol) of 2-methyl-3-methoxy-4-chloropyridine N-oxide were added in portions. The mixture was heated under reflux for 3 hours, and then left to cool down to room temperature; a further 3.45 g of potassium tert-butoxide were then added and the mixture was heated under reflux for 2 hours. After it had cooled down, 40 ml of water were added to the reaction mixture, which was then extracted with dichloromethane; the extract was then dried over MgSO4 and freed from the solvent in vacuo. The resulting oily product was subjected to further reaction.
Reaction SMILES: C([N:4]1[C:8](=[O:9])[CH:7]=[C:6]([O:10][CH3:11])[N:5]1[C:12]1[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=1[F:25])(=O)C.[OH-].[K+].Cl>O1CCCC1>[F:25][C:13]1[CH:14]=[C:15]([CH3:24])[C:16]([S:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:17][C:12]=1[N:5]1[C:6]([O:10][CH3:11])=[CH:7][C:8]([OH:9])=[N:4]1
Reactant: COc1cc(=O)n(C(C)=O)n1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Then, 0.65 g of 2-acetyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxypyrazol-3-one was dissolved in 20 mL of tetrahydrofuran, and 0.2 g of potassium hydroxide was added, followed by stirring at room temperature for 2 hours. Concentrated hydrochloric acid was added to adjust pH to 3, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.57 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxy-5-methoxypyrazole.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.BrBr.C(OCC)(=O)C>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:14]3[C:13](=[O:16])[NH:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: BrBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1nc2ccc3c(c2s1)C(=O)NCC3
Temperature: -10 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium thiocyanate (8.62 g, 0.088 mol) was added to a stirred solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one (I-66a: 1.8 g, 0.01 mol) in acetic acid (60 mL) at −10° C. and this was followed by the addition of bromine (5.33 g, 0.033 mol). The resulting reaction mass was stirred at −10° C. for 3 hours and further at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was diluted with ice water and filtered. The resulting mixture was basified at 0° C. using KOH solution to pH 10 and extracted using ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1.4 g of the product (58.33% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:19])[C:11]2[C:16]([CH2:17]/1)=[CH:15][C:14]([Cl:18])=[CH:13][CH:12]=2>[Pt]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[C:10]1=[O:19]
Reactant: O=C1/C(=C/c2ccncc2Br)Cc2cc(Cl)ccc21
Agent: [Pt]
Product: O=C1c2ccc(Cl)cc2CC1Cc1ccncc1Br

Procedure:
The title compound 109 is prepared according to the procedure reported in Example 37.2 with compound 94 (67 mg, 0.2 mmol) and Pt/C (5 wt % loading, 6.7 mg) as reactants. White solid. (Yield 67 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (6.40 g) in methylene chloride (30 mL) was added boron tribromide (1.0 M methylene chloride solution, 27 mL), and the mixture was stirred at room temperature for 2 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (6.27 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[C:17]1([S:23]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:28]1[CH2:29][CH2:30][CH:26]([S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:25])=[O:24])[CH2:27]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(benzenesulfonyl)pyrrolidine hydrochloride (12.7 mg, 0.051 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (13.5 mg). Calcd for C20H17ClN2O4 S: 416.0598, found 416.0591.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH:13]([CH3:15])[CH3:14])[C:7](=O)[CH2:6][C:5]2([CH3:18])[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH2:1])=[C:11]([CH3:12])[CH:10]=2)[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7]1)([CH3:15])[CH3:14]
Reactant: Cc1cc2c(cc1N)C(C)(C)CC(=O)N2C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1N)C(C)(C)CCN2C(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 117 %

Procedure:
6-Amino-1-isopropyl-4,4,7-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (12) (0.78 g, 3.2 mmol) was dissolved in tetrahydrofuran (50 mL) and the solution was cooled to 0° C. under argon. The solution was treated with 1M lithium aluminum hydride (4.0 mL, 4.0 mmol) and the reaction stirred at 0° C. to room temperature for 24 hours. The reaction mixture was cooled to 0° C., poured onto ice and extracted with ether (2×). The combined organic extracts were washed with brine and dried (MgSO4). The filtered solution was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (5% ethyl acetate in hexanes) to give the title compound (0.87 g, >100%) as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1([CH3:32])[CH:11](O)[C:10]2[C:13]([CH3:31])=[C:14]([N:19]3[CH:24]=[CH:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]=2[O:8]1.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:6][C:7]1([CH3:32])[CH:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[C:13]([CH3:31])=[C:14]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]=2[O:8]1
Reactant: Cc1c(C)c(N2C=CN(c3ccccc3)C=C2)c(C)c2c1OC(C)(C)C2O
Reactant: C1CCNC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(c3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Yield: 80 %

Procedure:
Using pyrrolidine and 2,2,4,6,7-pentamethyl-5-(4-phenyl pyrazine-1-yl)-2,3-dihydro-benzofuran-3-ol obtained in Reference Example 30, the free base was obtained in the same manner as in Example 57. The free base was treated with a 4N hydrogenchloride in ethyl acetate (10 ml) to obtain the title compound. Yield 80%. Amorphous powder.
Reaction SMILES: [Br:1]N1C(=O)C(C)(C)N(Br)C1=O.[C:12]([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][CH2:20][C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17]1)(=[O:14])[CH3:13]>>[C:12]([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][C@@H:20]([Br:1])[C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Yield: 43.5 %

Procedure:
16.3 g of dibromodimethylhydantoin were added to a solution of 42.8 g of cholesterol acetate in 300 ml of petroleum ether (40°-60° C.). The reaction mixture was refluxed for 1 hour while stirring thoroughly. After cooling, the solid (dimethylhydantoin) was filtered off; the solvent was distilled off from the filtrate under reduced pressure. In order to remove the last traces of solvent, 100 ml of acetone were added, after which the solution was again evaporated under reduced pressure. The residue was recrystallized from 50 ml of acetone; the α-epimer crystallized out at 0° C. After three recrystallizations from acetone, 12.6 g of pure 7α-bromocholesterol acetate were obtained having a melting-point of 113.9°-115.6° C.; according to the bromine content and the NMR spectrum, the substance was 100% pure.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:23][C:24]1[N:29]=[CH:28][C:27](I)=[CH:26][N:25]=1>>[CH3:12][C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Nc1ncc(I)cn1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cnc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and commercially available 2-amino-5-iodopyrimidine (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (110 mg, 28%). MS (ISP) 394.1 [(M+H)+]; mp 236° C.