Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) portionwise at 0° C. The mixture was stirred for 3 hours, quenched with brine, and extracted with methylene chloride. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (0-6% ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52% yield).
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[C:19]1([CH:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[Cl:17][C:12]1[C:11](/[C:2](/[NH:27][CH2:26][CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:28]([CH3:30])[CH3:29])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC(C)C(CN)c1ccccc1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\NCC(c1ccccc1)C(C)C)c1cccnc1Cl
Yield: 86.2 %

Procedure:
To a solution of ethyl 3-chloro-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.2 g, 0.738 mmol, 1 eq.) in 3 ml of acetonitril was added 2-phenyl-3-methylbutylamine hydrochloride (0.147 g, 0.738 mmol, 1 eq.) at room temperature followed by triethylamine (TEA) (0.164 g, 1.62 mmol, 2.2 eq.). The reaction was microwaved (130° C., 600 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-2-cyano-3-[(3-methyl-2-phenylbutyl)amino]acrylate (0.253 g, 85% yield) as a mixture of 2 atropoisomers.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][NH2:12]>C(O)CCC>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH:12][N:11]=1
Reactant: NN
Reactant: N#Cc1ccccc1F
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
2-Fluorobenzonitrile (605 mg, 5 mmol) and 85% aqueous hydrazine hydrate (352 mg, 6 mmol) were mixed with 1-butanol (3 mL). The mixture was heated at reflux with stirring for 5 h then cooled to room temperature. The resulting precipitate was collected by filtration and washed with dichloromethane and the filter cake was dried in vacuo to give 3-amino benzpyrazole (293 mg, 44%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:24]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CCNCC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol) in DMSO (2 mL) was added diethylamine (173 mg, 2.37 mmol) and DIEA (170 mg, 1.32 mmol). The resulting solution was stirred overnight at 70° C. and then quenched by the addition of water/ice (40 mL), extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via silica gel column chromatography (0.5%-4% ethyl acetate in petroleum ether) afforded methyl 3-(diethylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (100 mg, 60%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:34])=[C:24]([NH:27][C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:35])[C:18]=1[C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=1)=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[Cl:34][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=3)[C:19](=[O:35])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([NH:30][CH:31]1[CH2:32][CH2:33]1)=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of (S)-2-{2-[7-chloro-6-(3-cyclopropylureido)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (615 mg in 10 mL dry methylene chloride) was added 10 drops of anisole followed by 10 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1 hour the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (chloroform:10% ammonium hydroxide in methanol, 90:10) to give the title compound (451 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O>O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21](=[CH:44][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=5)[CH2:20][CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cc(-n2ncc3cc4c(cc32)CCCC(=O)C4)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-n2ncc3cc4c(cc32)CCCCC4=Cc2ccccn2)ccn1
Temperature: -77 °C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=2-methylpyridin-4-yl) (2.83 g, 9.71 mmol) and THF (43 mL). The solution was cooled to about −77° C. and then lithium bis(trimethylsilyl)amide (1.0 M in THF, 10.0 mL, 10.0 mmol) was added over about 30 min, keeping the internal temperature below about −75° C. After the addition was the mixture was stirred for about 5 min, the cold bath was removed and the mixture was allowed to warm to about 0° C. over about 1 h. The mixture was again cooled to about −75° C. then 2-pyridinecarboxaldehyde (3.2 mL, 34 mmol) was added. The mixture was allowed to warm to about −10° C. over about 1 h, and then water (40 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL) and then the combined organics were washed with brine (50 mL), dried over Na2SO4 and then concentrated under reduced pressure. The crude material was purified on silica gel (120 g, eluted with 0% to 2.5% MeOH in DCM). Collection and concentration of the appropriate fractions gave 1-(2-methylpyridin-4-yl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H-one (83, R1=2-methylpyridin-4-yl, R2′=pyridin-2-yl) (3.45 g, 93%) LC/MS, method 3, Rt=1.95 min, MS m/z 381 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.7 Hz, 1H), 8.61-8.53 (m, 1H), 8.11-8.08 (m, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.80-7.64 (m, 2H), 7.53 (s, 1H), 7.44-7.35 (m, 1H), 7.14-7.06 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 3.14-3.06 (m, 2H), 2.78 (s, 3H), 2.56-2.48 (m, 2H), 2.23-2.08 (m, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: OCCCCBr
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCCCO)CC2)cc2ccccc12
Yield: 8.8 %

Procedure:
By the reaction in the same manner as in Example 21a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 4-bromo-1-butanol (434 mg), 3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (50 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=C(O)[CH:24]=[C:25]([CH3:27])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=1
Reactant: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2ccccc2Cl)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To 177 mg (0.823 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 195 mg (0.785 mmol) of 3-(2-chlorobenzyloxy)-5-methylphenol, as prepared in the preceding step, 262 mg (1.02 mmol) of triphenylphosphine, and 250 μL (2.27 mmol) of N-methylmorpholine in 3 mL of tetrahydrofuran was added 140 μL (0.892 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred overnight, quenched with saturated NaCl (50 mL), and extracted into ethyl acetate (50 mL). The organic extract was dried (MgSO4), and the product was partially purified by flash chromatography (ethyl acetate/hexane (1:4)), to give 230 mg of impure title compound (contaminated with 3-(2-chlorobenzyloxy)-5-methylphenol). This material was used as is in the next reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[N:11]=[C:10]([NH:19][C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[N:9]=2)[CH:5]=[C:4]([CH3:31])[N:3]=1.[CH2:32]1COCC1.CN1CCCC1=O.C[Mg+].[Br-]>C(OCC)C.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].CO>[F:27][C:25]1([F:28])[O:24][C:23]2[CH:29]=[CH:30][C:20]([NH:19][C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([CH3:31])[N:3]=[C:2]([CH3:32])[CH:7]=4)[N:12]([CH2:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[N:11]=3)=[CH:21][C:22]=2[O:26]1
Reactant: C1CCOC1
Reactant: CCNC(=O)Cn1nc(Nc2ccc3c(c2)OC(F)(F)O3)nc1-c1cc(C)nc(Cl)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg+]
Solvent: CCOCC
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNC(=O)Cn1nc(Nc2ccc3c(c2)OC(F)(F)O3)nc1-c1cc(C)nc(C)c1

Procedure:
Intermediate D4 (0.70 g; 0.0016 mol), Iron(III) acetylacetonate (0.067 g; 0.0002 mol), THF (20 ml) and 1-methyl-2-pyrrolidinone (5 ml) were stirred at 0° C. under N2. Excess CH3MgBr in diethyl ether (2 M) was added and the mixture was brought to room temperature. The reaction mixture was then decomposed with CH3OH and evaporated in vacuo. Water and CH2Cl2 were added and the mixture was filtered over dicalite. The filtrate was evaporated and water and DIPE were added. The precipitate was filtered off, dissolved in CH2Cl2, dried over MgSO4, filtered and evaporated in vacuo. The residue was stirred in water, the precipitate was filtered off and dried. Yield: 400 mg of compound E1. melting point: 242.28° C. LCMS Retention time: 5.12; [M+H]+peak: 431; LCMS procedure 1
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]=[P:11](Cl)([Cl:13])[Cl:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][P:11]([Cl:13])([Cl:12])=[O:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(NP(=O)(Cl)Cl)cc1

Procedure:
A mixture of 39 g (0.33 m) of 4-aminobenzonitrile and 250 ml of POCl3 was heated under reflux for 3 hours. The excess POCl3 was removed by vacuum distillation to yield 72.7 g, m.p. softens 128°, melts 131°-133.5°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9][S:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[N:12]=2)[C:3]=1[CH3:22].O.C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:25].C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9][S@@:10]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[N:12]=2)=[O:25])[C:3]=1[CH3:22]
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(Cl)c3C)nc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(Cl)c3C)nc2c1
Reaction time: 2 h
Yield: 27.8 %

Procedure:
1.2 g (3.6 mmol) of 2-{[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]thio}-5-methoxy-1H-benzimidazole was mixed with toluene (40 mL). The mixture was concentrated until half the volume was left. Water (38 mg, 2.1 mmol), (S,S)-diethyl tartrate (1.85 g, 9.0 mmol) and titanium tetraisopropoxide (1.0 g, 3.6 mmol) were added in the given order while stirring. The mixture was then stirred at 50° C. for an hour and then N,N-diisopropylethylamine (0.46 g, 3.6 mmol) was added at room temperature. After 15 minutes cumene hydroperoxide (80% in cumene, 0.69 g, 3.6 mmol) was added dropwise and stirring was then continued for 2 h at room temperature. The optical purity of crude sulfoxide turned out to be 75% ee as determined by chiral HPLC analysis of the solution. The mixture was washed with water and then evaporated. The product was purified by chromatography on silica gel using methanol/dichloromethane as eluent (gradient, 1-7% MeOH) and this afforded 1.0 g of a crude product as a solid. Recrystallisation from hot acetonitrile gave 0.35 g of a white solid with an enantiomeric excess of 51%. Next, the mother liqueur from the filtration was concentrated and this material was then also recrystallised from acetonitrile to give 0.35 g of the title compound as a crystalline product with an enantiomeric excess of 92.5%.
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:19].[OH-].[Na+]>CCOCC>[NH2:1][CH2:4][CH2:5][CH2:6][O:19][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][CH:4]2[N:1]1[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1
Reactant: O
Reactant: [N-]=[N+]=NC1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCOc1cccc2c1CCC2N1CCCCC1
Reaction time: 1.5 h

Procedure:
A solution of the azido indan ((38 g) (of Step 7 above) in ether (250 ml) is added over a period of 30 min to a suspension of LAH in anhydrous ether (1.5 l) stirred under nitrogen. The mixture is refluxed for about 1.5 hours then cooled and 6 ml H2O added. Aqueous NaOH (15% solution, 6 ml) is added followed by H2O (18 ml) and stirring continued for about 1.5 hours. The reaction mixture is filtered, the solid washed with ether and the filtrate dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in methylene chloride, dried, filtered and evaporated yielding the desired product as an oil.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]([NH2:37])=O)[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]#[N:37])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1c(CC(N)=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CSc1c(CC#N)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
32 mg of p-toluene sulfonyl chloride was added to a solution of 20 mg of 9-benzyl-1-methylthiocarbazole-2-acetamide, as obtained in Example 75, in 0.6 ml of pyridine at room temperature. The reaction mixture was then heated to 60° C. and stirred for 2 hours. The reaction mixture was then cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate, and the organic extract was washed with a 0.5N aqueous solution of hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 mg of silica gel using, as eluent, a 4:1 by volume mixture of hexane and ethyl acetate to yield 18 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1F
Yield: 42 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-2-fluorobenzenesulfonamide (0.19 g, 43%) was provided after purification. HRMS: calcd for C10H13BrFNO2S+H+, 309.99071; found (ESI, [M+H]+), 309.9917. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15](=[O:17])[NH2:16])[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C.C(Cl)Cl>[ClH:1].[C:15]([O:14][C@@H:11]1[CH2:12][CH2:13][NH:9][CH2:10]1)(=[O:17])[NH2:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OC(N)=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)O[C@@H]1CCNC1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
15 ml of a 4M hydrogen chloride solution in ethyl acetate was added to a suspension of 3.00 g of (3R)-1-(t-butoxycarbonyl)-3-carbamoyloxypyrrolidine in 30 ml of methylene chloride, and the mixture was stirred for 30 minutes at 30° C. After completion of the reaction, the precipitated crystals were collected by filtration and washed with ether, giving 1.78 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]#[C:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]([CH3:16])[C:12]1=[O:17]>O1CCOCC1>[N:1]1([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cn1ccn(CC#CCBr)c1=O
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: Cn1ccn(CC#CCn2ccnc2)c1=O
Yield: 79.3 %

Procedure:
Imidazole (3.87 g, 0.057 mol) was added to a stirred solution of 1-(4-bromo-2-butynyl)-1,3-dihydro-3-methyl-2H-imidazol-2-one (3.26 g, 0.014 mol) in dioxane (50 mL). After 18 hr the dioxane was evaporated and the residue was chromatographed on silica gel to give 2.4 g of product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:48])=[C:6]([C:8]2[S:9][C:10]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[C:11]([C:13](=[O:39])[NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:38])[C:19]=3[N:20]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH2:22][CH2:21]3)[N:12]=2)[CH:7]=1.[CH:49]1([B-](F)(F)F)[CH2:51][CH2:50]1.[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:49]1([C:2]2[CH:3]=[CH:4][C:5]([F:48])=[C:6]([C:8]3[S:9][C:10]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[C:11]([C:13](=[O:39])[NH:14][C:15]4[CH:16]=[N:17][N:18]([CH3:38])[C:19]=4[N:20]4[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])[CH2:22][CH2:21]4)[N:12]=3)[CH:7]=2)[CH2:51][CH2:50]1
Reactant: F[B-](F)(F)C1CC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: Cn1ncc(NC(=O)c2nc(-c3cc(C4CC4)ccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(NC(=O)OCc2ccccc2)CC1
Temperature: 105 °C
Yield: 62 %

Procedure:
tert-butyl 2-(5-chloro-2-fluorophenyl)-4-(1-methyl-5-(4-(benzyloxycarbonylamino)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (309 mg, 0.44 mmol), potassium cyclopropyltrifluoroborate (98 mg, 0.66 mmol), palladium acetate (20.0 mg, 0.088 mmol), butyl-di-1-adamantylphosphine (50.1 mg, 0.133 mmol) and cesium carbonate (437 mg, 1.33 mmol) were charged in a 40 mL reaction vial and vacuum purged with nitrogen three times. Toluene (10.8 mL) and water (1.2 mL) were added and the mixture was heated at 105° C. for four days, monitoring with LCMS. The reaction was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography, eluted with 0 to 100% ethyl acetate in heptane to give tert-butyl 2-(5-cyclopropyl-2-fluorophenyl)-4-(1-methyl-5-(4-(benzyloxycarbonylamino)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (192 mg, 62%).
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)cn1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (229 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (101 mg, 0.85 mmol) according to general procedure II. Obtained as a bright orange solid (180 mg, 80%). MS (ISP) 448.2 [(M+H)+]; mp 267° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][CH2:36][O:37][CH2:38][CH:39]=[O:40])[O:7][C@@H:6]1[CH2:41][O:42][C:43](=[O:45])[CH3:44])(=[O:3])[CH3:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[O:7][C@@H:6]1[CH2:41][O:42][C:43](=[O:45])[CH3:44])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(CCOCC=O)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(CCOCCO)cc2Cl)cc1
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2-oxoethoxy)ethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (25 mg, 0.039 mmol) and NaBH4 (5.5 mg, 0.145 mmol) in THF (0.8 mL), was added MeOH (0.03 mL) dropwise. After being stirred for 1 h at the same temperature, the reaction was quenched by addition of saturated NH4Cl. The mixture was extracted 3× with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. Concentration gave the pure product in quantitative yield. MS ESI (m/z) 649 (M+1)+, calc. 648.