Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:46]=[CH:45][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[C:30]=2[CH3:44])=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([C:31]3[C:30]([CH3:44])=[C:29]([NH:28][C:26](=[O:27])[C:25]4[CH:24]=[CH:23][C:22]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:46][CH:45]=4)[CH:34]=[CH:33][CH:32]=3)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)cc(Nc2cccc(N)n2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2cccc(N)n2)c(=O)n(C)c1
Temperature: 95 °C
Yield: 40.4 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 3-(6-amino-pyridin-2-ylamino)-5-bromo-1-methyl-1H-pyridin-2-one (2) (0.054 g, 0.18 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.086 g, 0.22 mmol), and Pd(PPh3)4 (0.010 g, 0.010 mmol) in DME (10 mL) and 1N Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10%, MeOH in dichloromethane/ether (1/1), to afford 0.035 g (40%) of N-{3-[5-(6-amino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (3) as a solid; LCMS m/z 482.2018 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1.CCCCCCC=CCCC>C(#N)C>[C:33]([O:32][C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:25]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[CH:3][C:2]=2[F:1])[CH2:26]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: CCCC=CCCCCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.24 g (3.6 mmol) of 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.0 g (5.4 mmol) of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate, 0.56 g (3.6 mmol) of 1,8-dizabicyclo[5.4.0]undec7-ene, and 25 ml of acetonitrile is heated at reflux for four hours and is allowed to stir at room temperature overnight. The precipitated solids are filtered washed with ether to give 7-[3-t-butoxycarbonylamino-1-pyrrolidinyl]-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:43]=[CH:42][C:37]3[O:38][C:39]([CH3:41])=[CH:40][C:36]=3[CH:35]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19]/[CH:18]=[C:17](/[C:34]2[CH:43]=[CH:42][C:37]3[O:38][C:39]([CH3:41])=[CH:40][C:36]=3[CH:35]=2)\[C:14]2[CH:15]=[CH:16][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:12][CH:13]=2)[CH:32]=[CH:31][C:24]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 96 h

Procedure:
N-Propargylmorpholine (270 mg, 2.16 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL). The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]phenoxy]acetate.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].CCN(C(C)C)C(C)C.ClC(OC(Cl)C)=O>ClCCl>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15]
Reactant: C[C@@H](c1ccccn1)c1c(CCN(C)C)sc2ccccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNCCc1sc2ccccc2c1[C@@H](C)c1ccccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-{2-[3-((R)-1-pyridin-2-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 12-2) (0.305 mg, 0.98 mmol) in dichloromethane (3 mL), DIEA (1 mL, 5.8 mmol) and 1-chloroethyl chloroformate (0.32 mL, 2.95 mmol) were added. The mixture was stirred for 1 hour at 40° C. The solvent was removed in vacuo and 1N HCl was added to the residue. The mixture was stirred at 40° C. for an additional hour and cooled to ambient temperature. After neutralization with NH4OH the product was extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 300 mg of crude product, which was purified by mass triggered HPLC to give methyl-{2-[3-((R)-1-pyridin-2-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 21-1). (MH+=297, tR=1.675, Method 4)
Reaction SMILES: [C:1]1([C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH:12]=[N:11][C:10]([S:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:31]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:8]2[CH:12]=[N:11][C:10]([S:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=3)=[N:9]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 41 %

Procedure:
A solution of 2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridine-4-carbonitrile obtained in Reference Example 19 (5.00 g, 10.2 mmol) in THF (40 mL) was added to a suspension of lithium aluminum hydride (0.775 g, 20.4 mmol) in THF (60 mL) at 0° C., and the mixture was stirred at room temperature for 7 hr. The mixture was cooled to 0° C., water and 1N aqueous sodium hydroxide solution were added, and the insoluble material was filtered off. The filtrate was dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (0-20% methanol/ethyl acetate) to give the title compound as a yellow oil (2.06 g, 41%).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH2:23][CH3:24])[N:11]=1)=[O:9])C.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:31][C:29]1[N:30]=[C:26]([NH:25][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH2:23][CH3:24])[N:11]=2)=[O:9])[S:27][CH:28]=1
Reactant: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Product: CCc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C)cs2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Ethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methyl-thiazole in accordance with the general method of Example 78, step 2 yielded the title compound as a yellow cristalline solid, MS (ISP): m/e=340.9 (M+H+).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][C:24]=2[O:23]1.C(N(CC)CC)C>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]2[O:32][CH2:22][O:23][C:24]=2[CH:25]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1ccc2c(c1)OCO2
Agent: Br
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccc4c(c3)OCO4)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 2.4 g of 3,4-methylenedioxybenzyl amine and 3.5 g of triethyl amine and worked up. Colorless crystals from isopropanol, melting point: 131°-132° C. (decomposition).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:12][C:11]([F:14])([F:13])[CH:10]([OH:15])[CH2:9][CH2:8][NH:7][CH3:6]
Reactant: CC(C)(C)OC(=O)NCCC(O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(O)C(F)(F)F
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A solution of (4,4,4-trifluoro-3-hydroxybutyl)carbamic acid tert-butyl ester (0.55 g, 2.26 mmol) in THF (21 mL) was treated with lithium aluminium hydride (0.321 g, 8.46 mmol) at ambient temperature, followed by refluxing for 3 h. The mixture was cooled to ambient temperature and carefully quenched with excess sodium sulphalte decahydrate. Additional THF and diethyl ether were added to aid stirring. The mixture was filtered through a bed of Celite™ and the filtrate was evaporated to a white solid. The solid was purified by silica gel chromatography, eluting with 10% 2M ammonia in methanol/90% dichloromethane and 20% 2M ammonia in methanol/80% dichloromethane (v/v), to give the product as a white solid (0.218 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc(C)nc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc(C)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of the enone 16-1 (2.65 g, 6.36 mmol) in MeOH (150 mL) at 0° was treated with NaBH4 (0.264 g, 6.99 mmol). The ice bath was removed and the solution was stirred at room temperature for 1 hr. The reaction was quenched with water (25 mL) and extracted with EtOAc (3×125 mL). The organics were combined, dried (Na2SO4), concentrated in vacuo, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to afford 2.35 g of 16-4.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>Cl[Pd]Cl.[Cu]I.C(NCC)C>[OH:35][CH2:31][CH2:32][C:33]#[C:34][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccccc1C#CCCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
50 ml (0.36 M) of methyl 2-bromobenzoate, 930 mg (3.56 mM) of triphenylphosphine and 316 mg (1.78 mM) of PdCl2 are added to 1200 ml of diethylamine in a 2000 ml reactor. After stirring at room temperature for 5 minutes, 27 ml (0.36 M) of 3-butyn-1-ol and 680 mg (3.56 mM) of CuI (1) are added. The reaction medium is then stirred at 20° C. for 120 hours, the solvent is then evaporated off and the residue obtained is then purified by chromatography on silica, using dichloromethane as eluent. After evaporation, 46.7 g of a brown oil are thus obtained (64% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.ClCC1N=C2C=CN(C3C=CC(F)=CC=3)C(=O)N2C=1>>[Cl:17][CH2:18][C:19]1[N:1]=[C:2]2[C:7]([I:8])=[CH:6][N:5]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[C:4](=[O:16])[N:3]2[CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1nc(=O)n(-c2ccc(F)cc2)cc1I
Agent: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Product: O=c1n(-c2ccc(F)cc2)cc(I)c2nc(CCl)cn12

Procedure:
2-Chloromethyl-6-(4-fluoro-phenyl)-8-iodo-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods as described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]=1[S:17](C)=O)=[O:5])[CH3:2].S.[Na]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]=1[SH:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(S(C)=O)sc2ccccc2c1=O
Agent: S
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(S)sc2ccccc2c1=O
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of 100 mg (0.337 mmol) of the compound of Example 18 in 1.8 ml of tetrahydrofuran was added 1N sodium hydrogensulfide (0.697 mmol), and the mixture was stirred for 3 hours. Solvent was distilled off and 87 mg of sodium bicarbonate and 6.5 ml of water were added to the residue, which was washed with dichloromethane. After added 2.2 ml of 1N hydrochloric acid, this was extracted with dichloromethane. The organic layer was washed with saturated saline solution and concentrated. The residue was purified by means of silica gel column chromatography (CHCl3) to obtain title compound (yield 23%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](O)=[O:12])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
Indole-3-acetic acid (5 g, 28.54 mmol) was dissolved in diethyl ether (100 mL) and the solution was cooled to 0° C. Lithium aluminum hydride (1.19 g, 31.39 mmol) was added thereto, followed by stirring for 4 hours. The reaction was terminated with the addition of water and a 10% sodium hydroxide solution. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (1.24 g, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15]O)[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[N:48]1C(=O)CC[C:49]1=O.C([Na])#N>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15][C:49]#[N:48])[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(Br)ccc1[C@H]1SC[C@H](CO)Nc2c1c(-c1ccccn1)nn2C
Reactant: O=C1CCC(=O)N1Br
Agent: N#C[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H]1SC[C@H](CC#N)Nc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of rac-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)methanol (0.070 g, 0.16 mmol, Example #K.10) and triphenylphosphine (0.041 g, 0.16 mmol) in DCM (5 ml)/DMF (0.5 ml) at 0° C. was added 1-bromopyrrolidine-2,5-dione (0.028 g, 0.16 mmol). The reaction was stirred at 0° C. for about 2 h. The reaction was partitioned between DCM (25 mL) and saturated solution of NaHCO3 (40 mL). The organic layer was dried with Na2SO4, filtered and was concentrated in vacuo. The resulting residue was dissolved in DMF (1.5 ml) and cyanosodium (0.077 g, 1.57 mmol) was added. The reaction was heated at about 100° C. for about 1 h. The reaction was partitioned between EtOAc (25 mL) and brine (25 mL). The organic layer was washed with brine (25 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to give rac-2-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)acetonitrile (0.005 g, 0.005 mmol, 3%) as a white solid: LC-MS (Table 1, Method g): LC-MS (Table 1, Method g) Rt=2.57 min, m/z 454/456 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.48-8.45 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.70 (m, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.74 (s, 1H), 6.19 (d, J=5.7 Hz, 1H), 4.03-3.92 (m, 1H), 3.77 (s, 3H), 2.95-2.85 (m, 2H), 2.79-2.74 (m, 1H), 2.71-2.63 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:2]=1[CH3:1])=[O:29])#[N:24]
Reactant: Cc1c(N)cccc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cccc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 mg (0.346 mmol) of the compound of Example 69A and 111 mg (0.346 mmol, 85% pure) of the compound from Example 23A were dissolved in 1.9 ml of anhydrous DMF and 158 mg (0.415 mmol) of HATU and 72 μl (0.415 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT overnight (about 15 h) and then stirred into about 10 ml of water. The resulting precipitate was filtered off with suction, dissolved in dichloromethane and washed successively with semisaturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, filtration and removal of the solvent on a rotary evaporator, the residue obtained in this manner was purified by preparative HPLC (Method 33). After evaporation of the product fractions, the solid was re-dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution to convert the product into the form of the free base. After drying of the organic phase over anhydrous magnesium sulphate, filtration and evaporation, the product was finally triturated with 3 ml of pentane to which a few drops of diisopropyl ether had been added. Filtration with suction and drying of the solid under high vacuum gave 66 mg (35% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[Li+].[CH3:16]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([F:14])[CH2:3][CH2:4][CH:5]([CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC1CCC(F)(F)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate (0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85 mmol, 2M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.606 mL, 9.70 mmol) was then added at −78° C. and the reaction mixture was slowly warmed to RT and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 232A as a pale yellow liquid (0.27 g, 50%). 1H NMR (300 MHz, chloroform-d) δ ppm 4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-1.11 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[CH:4][CH:3]=1.OS(O)(=O)=O.CS(O)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Product: Fc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
4-Fluoro-N-(2-hydroxyphenyl) benzamide (IVa), acid (H2SO4, methanesulfonic acid (MeSO3H) or p-toluene sulfonic acid (p-TsOH)) and solvent were heated under the conditions outlined in table 2 with a Dean-Stark tube.
Reaction SMILES: [C:1]1([C:7]2([OH:15])[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[C:23]2[O:24][C@H:25]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[C:23]2[O:24][C@@H:25]([CH2:28][N:14]3[CH:9]4[CH2:10][CH2:11][CH:12]3[CH2:13][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([OH:15])[CH2:8]4)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1ccccc1)C3)CO2
Yield: 76 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-phenyl-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 76%, white solid.