Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]>ClCCl>[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:10]3[O:14][CH:13]=[N:12][CH:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc(C#N)c2)ccc1-c1cnco1
Yield: 89 %

Procedure:
3-Methoxy-4-(5-oxazolyl)aniline, 1D (1.00 g, 5.26 mmol) and 3-cyanophenyl isocyanate (1.17 g, 7.89 mmol) in dichloromethane (40 mL) were stirred at rt for 20 h. The precipitate formed was collected by filtration, followed by washing with dichlorometnane to provide 1E (1.57 g, 89% yield) as a yellow solid. (LC/MS retention time=3.67 min.; M+=335. Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[CH2:3]([O:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:4]#[CH:5]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Product: C#CCOCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
Sodium hydride (420 mg, 8.75 mmol) was added to propargyl alcohol (68 mL, 1.17 mol) at 4° C. and stirred for 30 minutes at 25° C. 10-Bromodecanoic acid (2g, 7.96 mmol) was added to this mixture and the reaction was stirred at 98° C. for 48 hrs. The reaction mixture was extracted with water and ethyl acetate at pH 1. After drying the organic phase over sodium sulfate, the solvent was removed at reduced pressure. Product was purified over silica gel chromatography in 7-10% ethyl acetate/hexane/0.3% formic acid and then over a second silica gel column in 1-2.5% ethyl acetate/benzene/0.3% formic acid to yield 10-(2-propynoxy)decanoic acid (245 mg, 14%). mp <30° C.; 1H NMR (300 MHz, CDC13) δ 1.25-1.42 (br, 10H, methylene envelope), 1.54-1.70 (bm, 4H, OCH2CH2, CH2CH2COOH), 2.35 (t, 2H, J=7.4, CH2COOH), 2.43 (t, 1H, J=2.3, HC=C), 3.52 (t, 2H, J=6.8, OCH2), 4.14 (d, 2H, J=2.5, C=CCH2O), 10.42 (br, 1H, COOH); 13C NMR (75.4 MHz, CDC13) δ 24.68, 26.06, 29.04, 29.17, 29.35*, 29.46, 34.09, 57.95, 70.22, 74.09, 79.90, 180.02; m/z 227 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.025 g, 0.048 mmol) with 3-(dimethylamino)propylamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.3 min) afforded N1-[3-(dimethylamino)propyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white powder (0.015 g, 0.025 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (m, 1H), 7.96 (m, 1H), 7.76 (m, 1H), 7.43 (t, 1H), 7.30 (m, 2H), 4.93 (s, 2H), 3.12 (m, 2H), 2.82 (m, 2H), 2.50 (s, 6H), 1.73 (m, 2H); MS (M−H)− 593.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].CO>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Sc1ccc2ccccc2c1
Solvent: CCO
Solvent: CO
Product: c1ccc2cc(Sc3ccc4ccccc4c3)ccc2c1

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.08 g, 70%). LCMS: 560.30 (M+1)+; HPLC: 99.22% (@ 254 nm) (Rt; 3.944; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.76 (s, 1H), 8.17 (t, 1H), 8.02 (d, 1H, J=7.6 Hz), 7.50 (d, 1H, J=8 Hz), 7.41 (s, 1H), 7.23 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.85 (d, 2H, J=11.2 Hz), 3.61 (s, 3H), 3.59-3.60 (m, 3H), 3.24-3.29 (m, 2H), 3.02-3.05 (m, 1H), 2.64 (s, 3H), 2.42 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:33][CH2:32]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COc1ccccc1C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-(2-methoxyphenyl)piperidine (1.2 equiv) to give 186 (17.9 mg, M+1 487.1)
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][CH:40]([OH:52])[CH2:41][N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1>C(Cl)Cl.O>[CH2:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:50][CH2:51][N:42]1[CH2:41][CH:40]([OH:52])[CH2:39][NH:38][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(C(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A solution of 4-sulfamoylbenzoic acid (88.4 mg, 0.44 mmol), HATU (182.4 mg, 0.48 mmol) and TEA (48.48 mg, 0.48 mmol) in DCM (10 mL) was stirred at 22° C. for 10 min. 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.48 mmol) was then added and the solution was stirred at 22° C. for another 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (49.5 mg, Yield 29%). 1H NMR (CD3OD, 400 MHz): δ 7.92 (s, 4H), 7.16-7.09 (m, 3H), 7.05-7.02 (m, 1H), 4.14-4.12 (m, 1H), 3.77 (s, 2H), 3.58-3.39 (m, 2H), 2.94-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.75-2.66 (m, 2H). LCMS (m/z): 390.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(Cl)cc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Temperature: -16 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-3-iodo-1-methyl-1H-indazole (108 mg, 0.35 mmol) was dissolved in THF (2 ml) and the solution was cooled to −16° C. using a NaCl/ice bath. Isopropylmagnesium chloride (2.0M in THF, 0.20 ml, 0.40 mmol) was added dropwise and the reaction mixture was stirred at −16° C. for 15 min. Tributylchlorostannane (0.11 ml, 0.40 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 6-chloro-1-methyl-3-tributylstannanyl-1H-indazole as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([C:25]#[N:26])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (140 mg, 0.36 mmol) and CuCN (64 mg, 0.72 mmol) in DMF (5 mL) was refluxed for 30 min. After the mixture was cooled to r.t., CH2Cl2 (50 mL) was added. 4M HCl was added with stirring until no solid was present. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined and dried over MgSO4. After evaporating the solvent in vacuo, the crude residue was chromatographed (20-100 EtOAc/hexanes+2% AcOH) to give 75 mg of the title compound. MS: (+) m/z 338.03 (M+1).
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@H:6]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[OH-:29].[Na+].OO>O1CCCC1.O>[C:18]([O:17][C:15]([NH:14][C@@H:6]([CH2:5][C@H:4]([CH2:1][CH2:2][CH2:3][OH:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15.58 g (39 mmol) of di-tert-butyl (2S,4S)-4-allyl-2-tert-butoxycarbonylamino-pentanedioate 5a were dissolved in 200 mL of tetrahydrofuran (THF) and cooled in an ice-bath. Over a period of about 20 minutes, 54.6 mL (54.6 mmol) of 1 M diboran/tetrahydrofuran complex in tetrahydrofuran were added dropwise with ice-cooling and under nitrogen, and the mixture was stirred on ice for 2 h and at room temperature overnight. It was cooled again to 0° C. and 58.5 mL of 1 N aqueous sodium hydroxide solution and 58.5 mL of 30% aqueous hydrogen peroxide solution were then added dropwise. After 60 minutes, the mixture was diluted with water, the tetrahydrofuran was distilled off and the remaining aqueous solution was extracted with ethyl acetate. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:16][C:15]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: CC(=O)c1ccccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1OCCCNC(C)(C)C
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A mixture of 2.58 g of the product of Step A, 8.3 ml of tert.-butylamine and 2.17 g of potassium carbonate in 7 ml of N,N-dimethylformamide was heated with stirring at 120° C. for 19 hours and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over a deshydrant and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.571 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-ethanone.
Reaction SMILES: Cl.C(O[C:7](=O)[N:8]([CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([C:34]([C:36]2[S:40][C:39]3[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=3[C:37]=2[Cl:45])=[O:35])[CH2:17][C:18]2[CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:12][CH2:11]1)C)(C)(C)C.C(O)C>C(OC)(C)(C)C>[ClH:45].[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:20]2[C:21]([O:24][CH3:25])=[CH:22][CH:23]=[C:18]([CH2:17][N:16]([CH:13]3[CH2:12][CH2:11][CH:10]([NH:8][CH3:7])[CH2:15][CH2:14]3)[C:34]([C:36]3[S:40][C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[C:37]=3[Cl:45])=[O:35])[CH:19]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: COc1ccc(CN(C(=O)c2sc3ccccc3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Product: CNC1CCC(N(Cc2ccc(OC)c(-c3ccc(C#N)cc3)c2)C(=O)c2sc3ccccc3c2Cl)CC1
Yield: 201.5 %

Procedure:
Concentrated hydrochloric acid (27.5 mL) was added to a solution of compound 6 (11.0 g, 17.1 mmol) and ethanol (82.5 mL). The mixture was stirred until reaction was complete as monitored by TLC. The mixture was concentrated in vacuo and dichloromethane added and concentrated again, this was repeated until a solid was obtained. The solid was then slurried with t-butylmethyl ether (30 mL), filtered, and the organic layer dried (MgSO4) and concentrated in vacuo to give the title compound 7 (10.0 g, 99%): δH (360 MHz: DMSO, 70° C.) 1.30–1.50 (m, 2H), 1.85 (br s, 4H), 2.12 (br, d, 2H), 2.48 (s, 3H), 2.91 (br t, 1H), 3.81 (s, 3H), 3.87 (br s, 1H), 4.71 (s, 2H), 7.14 (d, 1H), 7.29 (s, 1H), 7.40 (d, 1H), 7.57–7.68 (m, 4H), 7.80–7.90 (m, 3H), 8.09 (d, 1H), 8.82 (br s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:16][CH3:17])[CH2:12][C:13]([OH:15])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:13]([OH:15])=[O:14])[CH2:16][CH3:17]
Reactant: CC(=O)c1cccnc1
Reactant: CCC(C)CC(=O)O
Product: CCC(C)C(C(=O)O)C(C)(O)c1cccnc1

Procedure:
Analysis of the pyrolyzate by preparative thin layer chromatography indicates that the product mixture contains 810 milligrams (54%) of a 1:1 mixture of 3-acetylpyridine and 3-methylvaleric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[CH3:21][CH:22]1[CH:30]([OH:31])[CH2:29][CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]1[CH2:24]2.[H-].[Na+].O>O1CCOCC1>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[N:4]=[CH:3][C:2]=1[O:31][C@@H:30]1[CH2:29][C@@H:25]2[CH2:24][C@@H:23]([C:26]2([CH3:28])[CH3:27])[C@H:22]1[CH3:21]
Reactant: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Reactant: CC1C(O)CC2CC1C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Oc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 2.9 %

Procedure:
To 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.124 mmol) and (1R,2R,3R,5S)-(−)-isopinocampheol (50 mg, 0.324 mmol) in 1,4-dioxane (2 mL), sodium hydride (15 mg, 0.313 mmol) was added at 0° C., and stirred at 100° C. for 5 days. After completion of the reaction, the reaction mixture was mixed with water and extracted with chloroform and ethyl acetate. The combined organic layer was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (1.7 mg, 3% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([S:36]C2CCCCC2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[Na]>CN(C)C=O>[CH:30]1([S:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: C1CCC(SC2CCCCC2)CC1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSC4CCCCC4)cc2)CCO3)cc1
Yield: 108.7 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.2 g) and sodium cyclohexylsulfide (0.08 g) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(cyclohexylthiomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 53) (0.19 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33](O)=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH3:49][C:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([NH:56][S:53]([C:50]5([CH3:49])[CH2:52][CH2:51]5)(=[O:55])=[O:54])=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.9 %

Procedure:
Compound 3j (120 mg, 0.233 mmol) was dissolved in DCM (10 ml). EDAC (54 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Methyl cyclopropanesulfonic amide (35 mg, 0.256 mmol) and DBU (73 μl, 0.489 mmol) were added and the reaction mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (10.2 mg, 21%), MS (M+H)+632.
Reaction SMILES: [CH2:1]([S:7][CH:8]=[CH:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(C(C)C)CC)(C)C.[CH3:21][OH:22]>CCCCCC>[CH3:21][O:22][CH2:10][CH:9]=[CH:8][S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CO
Reactant: CCCCCCSC=CCCl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCSC=CCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hexylthio-2-propenyl chloride is added to a solution of diisopropyl ethyl amine (3.68 g, 28.5 mmol) in 20 ml of methanol. The mixture is stirred overnight at RT. It is then diluted with hexane, washed with water and with brine and is stripped. The crude product is purified by prep. TLC to give 3-methoxy-1-hexylthio-1-propene.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43]N>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:38](=[C:37]([CH3:36])[CH:42]=[CH:41][CH:40]=4)[NH:43][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(C(F)(F)F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 562.2 (M+H)+.