Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Br:16]N1C(=O)CCC1=O>ClCCl>[Br:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: c1cncc(-c2ccnc3ccnn23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Brc1cnn2c(-c3cccnc3)ccnc12
Temperature: 0 °C

Procedure:
A mixture of 1.96 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine and 1.97 g. of N-bromosuccinimide in 100 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into ice cold 2.5 N sodium hydroxide. The organic layer is separated and dried then is passed through a column of hydrous magnesium silicate. The column is washed with dichloromethane and the eluent is concentrated and diluted with hexane to give 1.8 g. of the product of the example, m.p. 243°-244° C.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.FC(F)(F)S(O[CH2:57][CH2:58][C:59]([F:62])([F:61])[F:60])(=O)=O>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:57][CH2:58][C:59]([F:62])([F:61])[F:60])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Yield: 85 %

Procedure:
A solution of 4-bromo-benzenesulfonyl chloride (100 mmol) and 2-aminothiazole (100 mmol) in dichloromethane and pyridine (300 mL, 8:2) was stirred for one day. After concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL) and the solution was washed with 1N HCl solution, sat NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized in ethyl acetate to give 4-bromo-N-thiazol-2-yl-benzenesulfonamide (85 mmol) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](O)=[O:11].C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO>[OH:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: C[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Product: OCC1Cc2ccccc2N1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
Racemic 2,3-dihydro-1H-indole-2-carboxylic acid (5.0 g, 30.6 mmol) was suspended in methanol (50 ml). Sodium methoxide (1.66 g, 30.6 mmol) was added, and the resulting slurry was stirred several minutes before the solvent was removed in vacuo. The entire sample was suspended in anhydrous tetrahydrofuran (60 ml). Lithium aluminum hydride (1.0M solution in tetrahydrofuran; 30.6 ml, 30.6 mmol) was added dropwise over 15 minutes. The reaction mixture was refluxed for 3 hours. The ice-bath-chilled mixture was then cautiously quenched by dropwise addition of 15 percent aqueous sodium hydroxide (4 ml). The reaction was filtered, and the filtrate was concentrated in vacuo to afford (+)-2-hydroxymethyl-indoline (3.69 g) as a viscous brown oil, used in the next step without further purification. TLC Rf (silica gel plates; u.v. detection, elution with ethyl acetate/hexane=1:4 in volume): 0.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9](=[N:11]O)[CH3:10])=[CH:4][CH:3]=1>CO.[Ni]>[NH2:11][CH:9]([C:8]([N:15]1[C:23]2[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:13][CH3:14])[CH3:10]
Reactant: CCC(C(C)=NO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Ni]
Solvent: CO
Product: CCC(c1ccc(Cl)cc1)(C(C)N)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step A (68 mg, 0.162 mmol) and Raney-Ni (1 mg) in MeOH (10 mL) was purged air three times and then backfilled with H2. The mixture was stirred at ambient temperature overnight. The suspension was filtered off and the filtrate was concentrated to afford the title compound as a colorless solid. LC/MS m/z=406.0 [M+H]+. Compound 176 was obtained by the below chiral separation conditions:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:18][C:19]([CH3:21])=O>>[CH2:4]([C@:2]12[CH2:7][C:6](=[CH2:21])[C@@H:5]3[C@@H:19]4[C:21]([CH2:19][CH2:18][C@H:4]3[C@@H:3]1[CH2:7][CH2:6][CH2:12]2)=[CH:3][CH2:2][CH2:12][CH2:18]4)[CH3:5]
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C1C[C@]2(CC)CCC[C@H]2[C@@H]2CCC3=CCCC[C@@H]3[C@@H]12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.3 g (3.79 mmoles) of 13-ethyl-11-methylen-17,17-(1,3-propilendioxy)-gon-4-ene (compound XVIIa) were dissolved in acetone (21 ml) under stirring at room temperature. 250 mg of p-toluensulfonic acid monohydrate were added to the solution so obtained and the stirring at room temperature was continued for 17 hours. After this period a saturated solution of sodium bicarbonate (21 ml) was added to the reaction mixture and the organic solvent was evaporated under vacuum. The so obtained aqueous suspension was extracted with dichloromethane (3×30 ml) and the organic extracts dried on sodium sulfate, filtered and evaporated under vacuum to give 0.88 g (3.11 mmoles; yields 82%) of the intermediate 13-ethyl-11-methylen-gon-4-ene (compound XVIII).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:22][OH:23])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:24][C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:22][OH:23])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3[nH]1)cn2C

Procedure:
The product is prepared by following the procedure described in example 34, stage (k), starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34, stage (k) and 1 cm3 of 5N potassium hydroxide. After purification by preparative LC/MS (acetonitrile/water/trifluoroacetic acid as eluents), 0.040 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime is obtained with the following characteristics:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([CH:18]=[N:19][C:20]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15]C)([CH3:7])[CH3:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[CH3:29][C:28]1[C:20]([NH:19][CH:18]2[C:13]3[CH:12]=[CH:11][C:10]([F:14])=[C:9]([OH:15])[C:8]=3[C:5]([CH3:6])([CH3:7])[CH2:4][C:3]2([C:2]([F:31])([F:30])[F:1])[OH:17])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1c(C)ccc2[nH]ncc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]ncc2c1NC1c2ccc(F)c(O)c2C(C)(C)CC1(O)C(F)(F)F
Reaction time: 4 h

Procedure:
1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)-methyl]-pentan-2-ol (150 mg, 0.34 mmol) is mixed with boron tribromide (3.40 ml of a 1 M solution in dichloromethane, 3.4 mmol) at room temperature. After 4 hours at room temperature, the reaction mixture is allowed to stand overnight at −30° C., then saturated sodium bicarbonate solution and ethyl acetate are added. It is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum as well as purification by means of preparative thin-layer chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 56 mg (39% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[CH3:21][C:22]1[NH:23][CH:24]=[C:25](Br)[N:26]=1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:25]1[NH:26][C:22]([CH3:21])=[N:23][CH:24]=1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc(Br)c[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2cnc(C)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 600 mg, 2.17 mmol) in dioxane (20 mL) was added 2-methyl-4-bromo imidazole (419 mg, 2.6 mmol), Pd(dppf)Cl2.CH2Cl2 (180 mg, 0.22 mmol). The mixture was degassed argon and stirred for 10 minutes then aqueous potassium carbonate (1M, 10 mL, 10 mmol) was added and the mixture was stirred at 90° C. for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and filtered through Celite®. The organic phase was washed by brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in EtOAc) to yield the title compound as a foam (324 mg, 65%). m/z (ES+) 231 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.30 (br s, 1H), 7.86 (dd, J=7.9, 1.9 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (s, 1H), 3.92 (s, 3H), 2.53 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1ncccc1C(=O)Cl
Product: CC(=O)c1ncccc1CN1CCOCC1

Procedure:
Following the procedures of Example 14, 2-acetylnicotinic acid chloride (1.0 g, 5.5 mmol) and morpholine (0.6 g, 6.7 mmol) are reacted together to give 4-(2-acetylnicotinyl)morpholine, which compound (1.0 g, 4.2 mmol) is then reacted with 4-(3-fluorophenyl)semicarbazide (0.7 g, 4.2 mmol) to give 4-(2-acetylnicotinyl)morpholine 4-(3-fluorophenyl)semicarbazone, m.p. 193°-195° (compound 150).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:13]2/[C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@H:4]3[C:3]([N:2]([CH3:16])[CH3:1])=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of N,N-dimethyl-1-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-prolinamide (724 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (389 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\Br)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Zn]CC)[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[CH2:24][CH3:25])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccccc2)COC1(C)C
Reactant: CC[Zn]CC
Product: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1

Procedure:
In analogy to example 162c (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with diethylzinc to give (S)-2,2-dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester. Colourless oil. MS (ISP): 332.3 ([M+H]+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]([O:19][CH3:30])([C:15]([F:18])([F:17])[F:16])/[CH:13]=[CH:12]/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CI
Reactant: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0° C. The reaction was allowed to stir at 0° C. for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aq NH4Cl solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C(OC([C@@H]1C[C@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1)=O)C.[Cl:46][C:47]1[N:51]=[C:50](Cl)[S:49][N:48]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:50]1[S:49][N:48]=[C:47]([Cl:46])[N:51]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: Clc1nsc(Cl)n1
Agent: CCOC(=O)[C@@H]1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nc(Cl)ns1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described for the corresponding (2S,4S)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester in example 192e) was reacted with 3,5-dichloro-[1,2,4]thiadiazole (CAS Reg. No. 2254-88-8) in a shaking reactor at 55° C. for 12 h to give the title compound as orange solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:44]3[CH2:43][CH2:42][N:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:47])([F:48])[F:33])[CH:36]=4)[CH2:46][CH2:45]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.3 g, 0.014 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through the mixture for 21/2 hrs. A solution of N-(α, α, α-trifluoro-m-tolyl)-piperazine (3.2 g, 0.014 mole) in dry tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature for 41/2 hrs. The tetrahydrofuran was evaporated and the residue dissolved was extracted with 5% potassium hydroxide solution (2×30 ml), water (30 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (6.6 g) was twice recrystallized from isopropyl alcohol-isopropyl ether to give 3.3 g (47%) of white needles, mp 185°-186.5° C.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[C:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:7][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([C:21](=[O:40])/[N:22]=[C:23]4\[S:24][C:25]5[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=5[N:27]\4[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:9][CH:10]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:7][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([C:21](=[O:40])/[N:22]=[C:23]4\[S:24][C:25]5[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=5[N:27]\4[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCCO
Yield: 82.3 %

Procedure:
Compound 94E (0.91 g, 1.351 mmol) in THF (30 mL) and methanol (5 mL) was treated with NaBH4 (0.102 g, 2.7 mmol). The reaction mixture was heated under reflux for 1 hour. The solvents were removed under vacuum. The residue was re-dissolved in EtOAc and treated with water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give 0.75 g of the title compound 94F (82%): APCI (+)LC/MS: 675 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[NH:10][C:9]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].I[CH3:26]>COCCOC>[CH3:26][N:10]1[C:11]2[C:3]([S:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:9]1=2
Reactant: CI
Reactant: CSc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CSc1cccc2c3c(n(C)c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Tert-butyl 6-methylsulfanyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7.2 g, 22.6 mmol), potassium hydroxide (6.3 g, 113 mmol), and iodomethane (32 g, 226 mmol) were combined with dry DME (110 mL) and stirred at rt for 10 h. The reaction was then filtered and the residue washed with chloroform. The filtrate was concentrated under reduced pressure to give tert-butyl 5-methyl-6-methylsulfanyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as an oily brown residue (7.7 g, 105%). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1H, J=7.7 Hz), 7.12 (d, 1H, J=6.6 Hz), 7.03 (t, 1H, J=7.0 Hz), 4.61 (s, 2H), 4.08 (s, 3H), 3.85 (br s, 2H), 2.80 (br s, 2H), 2.49 (s, 3H), 1.49 (s, 9H) ppm
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[CH:28]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([NH:20][CH3:28])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C[O-]
Reactant: Cc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)C1
Temperature: 0 °C
Yield: 25.3 %

Procedure:
To 1-cyclopropyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.38 g) are added formic acid (3 ml), 37% formalin (3 ml) and sodium formate (0.4 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and adjusted to below pH 8 with aqueous sodium hydrogen carbonate, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from ethanol-diethyl ether to give 1-cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g), as white powder, m.p. 185.5°-187.5° C. (decomp.)
Reaction SMILES: I[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([I:13])[C:9]=2[OH:12])[O:4][C:3]1([CH3:20])[CH3:19].[C-:21]#[N:22].[K+]>C(O)C>[C:21]([CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([I:13])[C:9]=2[OH:12])[O:4][C:3]1([CH3:20])[CH3:19])#[N:22]
Reactant: CCCCCc1cc2c(c(O)c1I)CC(I)C(C)(C)O2
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: CCCCCc1cc2c(c(O)c1I)CC(C#N)C(C)(C)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 21.8 %

Procedure:
3,6-Diiodo-2,2-dimethyl-5-hydroxy-7-pent-1-yl chromane (0.293 g) and potassium cyanide (50 mg) were dissolved in 15 ml absolute ethanol and heated to reflux. After 4.5 hours, the reaction was allowed to cool to room temperature. The solvent was removed in vacuo. Water was added and extracted with methylene chloride. The methylene chloride was removed in vacuo. The residue was chromatographed on a silica gel column eluted with chloroform (TLC Rf=0.2, chloroform). The appropriate fractions were combined to yield 51 mg of product.