Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])[CH:35]=2)[C:30]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)=[CH:29]1>C1COCC1.CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[N:6]=[C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:37]([C:34]2[CH:35]=[C:36]3[C:31]([C:30]([C:52]4[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=4[C:62]4[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=4)=[CH:29][N:28]3[CH3:27])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[S:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Br)ns2)cc1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)cc1
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
A 25-mL round-bottom flask was charged with 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE K) (157 mg, 0.522 mmol) and THF (2.6 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (653 μl, 0.653 mmol) was added dropwise. The resulting clear solution was stirred for 20 min, then a solution perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (157 mg, 0.261 mmol) in THF (1 mL with a 0.5 mL vial/syringe wash) was added dropwise over 1 min. The resulting solution was stirred for 10 min, then the flask was lowered into an ice bath for 2.5 h. The reaction mixture was quenched with saturated aq ammonium chloride solution, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (0 to 60% EtOAc/Heptane) N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (136.87 mg, 0.191 mmol, 73.1% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.09 (d, J=1.8 Hz, 1 H), 7.96-7.83 (m, 2 H), 7.79 (d, J=1.4 Hz, 1 H), 7.66-7.49 (m, 2 H), 7.39 (d, J=1.9 Hz, 1 H), 7.31 (s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.86-6.79 (m, 2 H), 6.33 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 3.24 (s, 3H). m/z (ESI) 717.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27](=[O:29])[NH2:28])[CH:20]=1)[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1SCCCS1)(=[O:3])[CH3:2].C(#N)C.[OH2:33]>>[C:1]([O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27](=[O:29])[NH2:28])[CH:20]=1)[C:6](=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)OC(c1cccc(OCC(N)=O)c1)C(c1ccccc1)C1SCCCS1
Solvent: CC#N
Product: CC(=O)OC(C(=O)c1ccccc1)c1cccc(OCC(N)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-acetoxy-1-(3-carbamylmethoxyphenyl)-2-phenyl-2-(1,3-dithian-2-yl)-ethane (110 mg, 0.26 mmol) in 5 mL 9:1 (v/v) acetonitrile/water was added mercuric perchiorate (148 mg, 0.33 mmol). The solution was stirred for 15 min, filtered through a 0.45 mm PTFE syringe filter (Gelman) into a 5% sodium bicarbonate solution (10 mL), and extracted with 50 mL dichloromethane. The organic phase was dried and evaporated under reduced pressure to yield a colorless oil. Samples for analysis were evaporated from methanol, dissolved in warm water and lyophilized. Yield: 65 mg (76%). IR: 3445, 1743, 1694, 1462, 1236, 1075, 720 cm-1. 1H NMR (CDCl3, TMS) d 7.936 (d, J=7.82 Hz, 2 H), 7.529 (t, J=7.56 Hz, 1 H), 7.412 (t, J=7.57 Hz, 2 H), 7.319 (t, J=7.86 Hz, 1 H), 7.139 (d, J=7.51 Hz, 1 H), 7.051 (s, 1 H), 6.884 (dd, J=8.21, 2.75 Hz, 1 H) 6.835 (s, 1 H), 6.558 (s, 1 H), 6.148 (s, 1 H), 4.462 (s, 2 H), 2.207 (s, 3 H). 13C NMR (CDCl3, TMS) d 193.577, 170.825, 170.348, 157.593, 135.473, 134.494, 133.637, 130.516, 128.768, 128.711, 122.371, 115.205, 115.140, 77.144, 67.115, 20.715. Anal. Calcd. for C18H17NO5.H2O: C, 62.59; H, 5.54; N, 4.05. Found: C, 62.53; H, 5.12; N, 3.90.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]3[CH2:43][CH2:42]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]3[CH2:43][CH2:42]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(C3CC3)c2c1=O
Yield: 93 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 2.72 g (containing an amount corresponding to 3.88 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-cyclopropyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 14-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, whereby 3.95 g of the title compound was obtained as a white solid. (Yield: 93%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNC(=O)C(C)C)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 592.2 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.016 g) (Example 285) in tetrahydrofuran (2 mL) was added isobutyryl chloride (0.038 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl{2-isobutyl-6-[(isobutyrylamino)methyl]-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.11 g, 75%) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: O=C(CCCCl)Nc1ccccc1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: ClCCCc1nc2ccccc2n1-c1ccccc1
Yield: 31.6 %

Procedure:
A solution of 4-chloro-N-(2-anilinophenyl)butyramide (0.5 g) and p-toluenesulfonic acid monohydrate (33 mg) in toluene (15 ml) was refluxed for 1.5 hours. Toluene was removed under reduced pressure to afford a residue, which was dissolved in dichloromethane (20 ml), washed with a saturated aqueous solution of sodium bicarbonate and water in turn and dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded an oily residue, which was subjected to column chromatography on silica gel (5 g) eluting with a mixture of dichloromethane and ethyl acetate (10:1) to give crystals of 2-(3-chloropropyl)-1-phenyl-1H-benzimidazole (148 mg).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 5-iodovanillin (7 g, 25.18 mmole), potassium carbonate (8.78 g, 63.53 mmole) and iodomethane (6.43 g, 45.30 mmole) was suspended in 60 mL of DMF and stirred at room temperature for 14 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to obtain a solid which was recrystallized from hexane/ethyl acetate (2:1) (6.28 g, 85.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[O:17]=[C:16]1[CH2:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(C(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Sodium 4-aminobenzoate (42.5 g, 0.267 mol) was suspended in 250 ml benzene. To this solution, upon vigorous stirring, 4-chlorobutyryl chloride (29 ml, 0.248 mol) was added slowly. The temperature of the reaction mixture was heated to 60° C. It is at 60° C. that the reaction was continued for another 20 hours. Na2CO3 solution (20%, 600 ml) was then added and the benzene layer was separated. The aqueous layer was acidified and the white precipitate was filtrated and recrystallized from methanol to form colorless crystal of 4- (2-oxo-pyrrolidin-1-yl)-benzoic acid. Mass Spectra: m/e (relative intensity) 205(M+, 44.23).
Reaction SMILES: [OH:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]>O1CCCC1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH2:20][O:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: OC(/C=C/c1ccccc1)Cn1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(COC(/C=C/c2ccccc2)Cn2ccnc2)c(Cl)c1
Temperature: 25 °C

Procedure:
trans-1-[2-Hydroxy-4-phenylbut-3-enyl]imidazole (430 mg.) in 5 ml. dry tetrahydrofuran was treated under nitrogen with stirring with 96 mg. of sodium hydride (56% dispersion in mineral oil) and the mixture heated under reflux for 30 minutes. After cooling in an ice bath the mixture was treated with stirring with 430 mg. of α,2,4-trichlorotoluene in 5 ml. tetrahydrofuran for 30 minutes at 0° C., one hour at 25° C. and overnight under reflux. The resulting mixture was evaporated to dryness, ether (150 ml.) added and the ether extract washed with water, dried over magnesium sulfate and evaporated to afford trans-1-[2-(2,4-dichlorobenzyloxy)-4-phenylbut-3-enyl]imidazole. The nitrate salt precipitated from ether and was crystallized from ethyl acetate, m.p. 133.5°-134.5° C. (foaming).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH2:7]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Yield: 185.1 %

Procedure:
A mixture of (R)-2-methyl-piperazine (300 mg, 2.99 mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol), tris(dibenzylidineacetone)dipalladium (0) (24.72 mg, 0.027 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (51.06 mg, 0.082 mmol) and sodium tert-butoxide (326.77 mg, 3.4 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated at (R)-2-methyl-piperazine (1.0 g, 9.98 mmol). Reaction mixtures were combined, diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine as yellow oil (1.23 g, 39.6% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.07 (d, J=6.32 Hz, 3H) 2.41-2.51 (m, 1H) 2.74-2.84 (m, 1H) 2.90-2.98 (m, 2H) 3.00-3.13 (m, 3H) 7.18-7.25 (m, 1H) 7.35 (d, J=8.08 Hz, 1H) 7.47-7.55 (m, 1H) 7.62 (d, J=7.83 Hz, 1H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2
Reactant: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In accordance with the general method, 60 mg (0.17 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4-bromophenyl)acetamide hydrochloride, 23.3 mg (0.17 mmol) of 4-fluorophenylboronic acid, 0.17 ml of 2M sodium carbonate solution and 6.1 mg (0.01 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of dimethylformamide. 32 mg (51% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[OH:13][C:12]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:7]=[CH:6]2
Reactant: C=CCc1c(O)ccc2c1ccn2CC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c1ccn2CC(C)(C)C

Procedure:
4-Allyl-5-hydroxy-N-neopentylindole (Step C; 1.0 g, 3.54 mmol) was taken up in 25 mL ethyl acetate and hydrogenated (1 atm) at ambient temperature using 5% palladium on charcoal (40 mg) for 2 hours. The reaction was filtered through celite and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:6]1=2.O.NN>CCO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:13]=1
Reactant: COCCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COCCN1C(=O)CCCc2cc(N)ccc21
Yield: 54 %

Procedure:
To a solution of the above 1-(2-methoxy-ethyl)-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in EtOH (10 mL) was sequentially added 10% Pd/C (120 mg) and hydrazine-monohydrate (1 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine. The residue was recrystallized from EtOAc/heptane to afford transparent prisms of 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (345 mg, 54%) that had the following properties: mp: 134-135° C.; LC/MS (ESI+): 235 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 7.08 (d, J=8.4, 1H), 6.60 (d, J=8.4, 1H), 6.51 (s, 1H), 4.20 (br s, 1H), 3.65 (m, 2H), 3.53 (m, 2H), 3.28 (s, 3H), 2.60 (br s, 1H), 2.27 (m, 2H), 1.58 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:32])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl)(=[O:25])=[O:24]>C(N(C(C)C)C(C)C)C>[CH3:21][N:22]([CH3:32])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:24])=[O:25]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CN(C)S(=O)(=O)CCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-dimethyl-5-chloropentanesulfonamide (470.2 mg, 2.20 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-dimethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (857.7 mg) as a yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.4%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:19][CH2:20][CH3:21])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH3:18][C:13]1[C:12]2[C:17](=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[N:10]([CH2:19][CH2:20][CH3:21])[N:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc2c(C)cccc2c1-c1ccc(O)cc1
Yield: 52.6 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-7-methyl-2-propyl-2H-indazole (0.014 g, 0.05 mmol), boron tribromide (0.050 mL, 1.0 mmol) and 0.2 mL of cyclohexene to give the product (0.007 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][SH:14]>>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][S:14][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: Nc1nc(CCl)cs1
Product: COC(=O)CCSCc1csc(N)n1
Yield: 59.7 %

Procedure:
3-(2-Amino-thiazol-4-ylmethylsulfanyl)-propionic acid methyl ester (0.75 g, 60%) was prepared from 4-chloromethyl-thiazol-2-ylamine (1.00 g, 5.41 mmol) and 3-mercaptopropionic acid methyl ester (0.97 g, 8.11 mmol) according to procedure Z.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
METHOD 2 N-tert-butoxycarbonyl L-proline (3.04 g, 14.1 mmol) and L-proline methyl ester hydrochloride (2.34 g, 14.1 mmol) were dissolved in CH2Cl2 (25 mL). N,N-diisopropylethylamine (1.82 g, 14.1 mmol) was added and the solution cooled to 0° C. (icebath). HOBt hydrate (2.16 g, 14.1 mmol) and then EDC hydrochloride (2.97 g, 15.5 mmol) were added together with 15 mL CH2Cl2. The icebath was removed and the reaction mixture stirred for 16 h 15 min at room temperature. The reaction mixture was diluted with CH2Cl2 (60 mL) and the solution washed with 1M HCl(3×25 mL), 7.5% (w/w) K2CO3 solution (3×25 mL) and saturated brine (25 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a very pale yellow, almost clear oil, which was dried under high vacuum overnight. The compound (3.67 g, 79%) showed spectral characteristics in accordance with published data1; δH (200 MHz; d6-DMSO) 4.56-4.31 (2H, m, CαH(Pro1)/CαH(Pro2)), 3.78-3.28 (4H, m, CδH2(Pro1)/CδH2(Pro2)), 3.67 (3H, s, OCH3, rotomer 1), 3.65 (3H, s, OCH3, rotomer 2), 2.26-1.65 (8H, m, CH2), 1.40/1.34/1.22 (9H, s, (CH3)3, all rotomers); δC (75 MHz; CDCl3) 172.8, 172.5, 171.5, 171.0, 154.4, 153.6, 79.3, 58.5, 57.6, 57.5, 53.3, 52.0, 51.9, 46.7, 46.5, 46.3, 29.8, 28.9, 28.7, 28.6, 28.3, 28.2, 24.9, 24.8, 23.9, 23.4
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH2:13])=[O:11])=[CH:5][C:4]=1[O:16][CH3:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH:13][C:26](=[S:27])[NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:11])=[CH:5][C:4]=1[O:16][CH3:17]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1cc(C(C)(C)C(=O)NN)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanehydrazide hydrochloride (6.88 g, 0.02 mol) and 4-fluorophenylisothiocyanate (3.96 g, 0.03 mol, 1.05 eq.) in DCM (500 mL) at 0° C. was added Et3N (7 mL, 1.29 mol, 2.0 eq.) and the resulting solution was stirred for 1.5 h at room temperature. The reaction mixture was washed with 1M HCl, satd NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with DCM/Et2O, collected by filtration and dried to give 2-(2-(4-Chloro-3-methoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)hydrazine carbothioamide (8.13 g, 83% as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32-7.30 (d, 1H), 7.25-7.22 (m, 2H), 7.01-7.05 (t, 2H), 6.95-6.94 (d, 1H), 6.93-6.90 (dd, 1H), 3.88 (s, 3H), 1.64 (s, 6H).