Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH:17]1[CH:29]=[C:21]2[CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=32)[C:18]1([C:32]1[N:37]=[C:36](S(C)=O)[N:35]=[C:34]([NH2:41])[N:33]=1)[C:30]#[N:31].O>CN(C)C=O.C(OCC)(=O)C>[Cl:16][CH:17]1[CH:29]=[C:21]2[CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=32)[C:18]1([C:32]1[N:37]=[C:36]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:35]=[C:34]([NH2:41])[N:33]=1)[C:30]#[N:31]
Reactant: COc1ccccc1S
Reactant: CS(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1Sc1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Temperature: 85 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
2-Methoxythiophenol (39 mg, 0.278 mmol) was added to a suspension of potassium carbonate (95.7 mg, 0.692 mmol) and 4-(5-chloro-6-cyano-1H,3H benzo[de]isochromen-6-yl)-6-methylsulfinyl-[1,3,5]triazin-2-ylamine (50 mg, 0.139 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature under argon atmosphere. The reaction solution was stirred at 85° C. for 12 hours, and then allowed to return to room temperature. The reaction solution was diluted with ethyl acetate, and then water was added. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using methylene chloride-ethyl acetate (mixing ratio=7:1 to 4:1) and dried under reduced pressure to give the title compound (34 mg, 56%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:55]([Cl:57])[Cl:56]>C(O)(=O)C>[NH3:1].[CH2:55]([Cl:57])[Cl:56].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]3[CH2:24][CH2:23][CH:22]([N:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(N(CCN2CCCC2)C2CCNCC2)nc1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N
Product: c1ccc(N(CCN2CCCC2)C2CCN(Cc3ccc(OCCCN4CCCCC4)cc3)CC2)nc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (30 mg), piperidin-4-yl-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine (29.8 mg), and acetic acid (0.015 mL) in DCM (1 mL) was treated with sodium triacetoxyborohydride (38 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-10% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (26 mg). 1H NMR (400 MHz, CDCl3): 8.12 (m, 1H), 7.39 (m, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.53-6.47 (m, 2H), 4.44 (m, 1H), 3.99 (t, J=6.3 Hz, 2H), 3.51-3.47 (m, 2H), 3.46 (s, 2H), 2.95 (m, 2H), 2.62 (m, 6H), 2.49 (m, 2H), 2.42 (m, 4H), 2.12 (m, 2H), 1.98 (m, 2H), 1.84-1.78 (m, 5H), 1.75 (m, 1H), 1.68 (m, 2H), 1.63-1.57 (m, 4H), 1.44 (m, 2H).
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1>CS(C)=O>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:28]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cncs2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 50 mg, 0.131 mmol), (R)-pyrrolidin-3-ol (22.8 mg, 0.262 mmol) and TEA (72.9 μL, 0.523 mmol) in DMSO (98 μL) was stirred at 100° C. overnight. The RM was filtered and the filtrate was purified by preparative SFC (Column Diol, isocratic 30% in 6 min) to yield the title compound as a pale brown solid. UPLC-MS (Condition 1) tR=1.05 min, m/z=450.3 [M+H]+, m/z=448.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.82 (m, 1H) 1.82-1.99 (m, 1H) 2.79 (d, J=10.29 Hz, 1H) 3.06-3.14 (m, 1H) 3.14-3.21 (m, 1H) 3.24-3.33 (m, 1H) 4.24 (br. s, 1H) 4.80-5.00 (m, 1H) 6.98 (d, J=8.78 Hz, 1H) 7.35 (d, J=8.41 Hz, 2H) 7.76-8.02 (m, 5H) 9.17 (s, 1H) 10.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].BrC1C=CC(CN2CCN(C(OCC3C=CC=CC=3)=O)[C@@H](C)C2)=CC=1.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH2:8][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(C=O)c(Cl)c1
Agent: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(Cl)c1

Procedure:
The title compound was prepared from methyl (3-chloro-4-formylphenyl)acetate (Epple, R. et al., PCT Int. Appl. WO2005116000) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride using a method similar to that described for D6 with the addition of triethylamine (1.1 eq) to the reaction mixture and a reaction time of ˜3 days.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[S:11][C:12]([CH2:14][CH3:15])=[CH:13][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:7][CH2:6][CH2:5]1)=[O:3].[CH2:23]([N:25](CC)[CH2:26]C)C.CNC.O>O1CCCC1>[ClH:1].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:10]=2[N:4]([C:2](=[O:3])[N:25]([CH3:26])[CH3:23])[CH2:5][CH2:6][N:7]=1
Reactant: CCN(CC)CC
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccc1Cl
Product: Cl

Procedure:
To a solution of 8.7 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine and 2.8 g of triethylamine in 50 ml of tetrahydrofuran is added dropwise 50 ml of 25%(W/V) tetrahydrofuran solution of dimethylamine with stirring. The whole mixture is refluxed with stirring for 2 hours, and then cooled and transferred to water. The resultant solution is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-dimethylcarbamoyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 240°-241° C with decomposition.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H].[CH3:45]O>[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([O:38][CH3:45])=[O:37])[CH2:19][C:20]3[CH:21]=[C:22]([CH3:35])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: CO
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1cc(C)c(O)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A suspension of 1.00 g (1.75 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 7g) and 150 mg 10% Pd/C in 30 mL MeOH was hydrogenated at RT and 3000 hPa hydrogen pressure until the reaction stopped. The catalyst was suction filtered and the residue was purified by chromatography (silica gel, EtOAc).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNC(=O)c1cccnc1)OCC
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a mixture of diethyl 2-aminoethylphosphonate (8.1 g), triethylamine (9.1 g) and dichloromethane (100 ml) at 5° C. was added nicotinic acid chloride hydrochloride (10.4 g) in small portions over a period of 15 minutes. After being stirred for additional 1.5 hours, the reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol in chloroform) to give 11.2 g of N-(2-diethoxyphosphorylethyl)-3-pyridinecarboxamide as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[C:16]([O:20][C:21]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](O)=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CSc1ccc2c(c1)CCC(N)C(=O)N2
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CSc1ccc2c(c1)CCC(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N2

Procedure:
Prepared from the intermediate obtained in Step D and 3-t-butoxycarbonylamino-3-methyl-butanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.33 (s,6H), 1.40 (s,9H), 1.91 (m,1H), 2.4-3.0 (m,5H), 2.48 (s,3H), 4.50 (m,1H), 5.22 (br s,1H), 6.68 (d,7 Hz,1H), 6.90 (d,8 Hz,1H), 7.11 (m,2H), 7.66 (br s,1H).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CO.O>[CH2:9]([CH2:2][C:1]([OH:4])=[S:3])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC/C=C\CCCCCBr
Reactant: CC(O)=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C\CCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
Thioacetic acid (35 mg, 0.38 mmol) in methanol (20 ml) was treated successively with sodium methoxide (50 mg, 0.9144 mmol) and bromide 8 (105 mg, 0.381 mmol) and stirred at r.t. for 2 d. The reaction mixture was diluted in water and acidified with cold conc. aq. HCl. The aqueous layer was extracted with hexanes, dried (MgSO4) and concentrated invacuo to afford a crude residue was purified by flash column chromatography (eluent gradient elution 65-75% EtOAc in Hexanes) to afford the pure 4 as a viscous oil (105 mg, 0.367 mmol, 96%); δH(270 MHz, CDCl3); 0.86 (3H, t, J 6.8), 1.35 (14H, m), 1.60 (2H, m), 2.00 (4H, m), 2.65 (21, t, J 7.4), 3.24 (2H, s), 5.34 (2H, m) and 10.0 (1H, br s); δC(67.5 MHz, CDCl3) 14.20, 22.76, 27.09, 27.31, 28.45, 28.89, 29.32, 29.35, 29.35, 29.83, 31.95, 32.82, 33.54, 129.44, 130.36 and 176.77; MS (CI) 304 (M+NH4)+; HRMS: Found [M+NH4]+ 304.230876. Calc. for C16H34NO2S: [M+NH4]+0304.231026.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([OH:36])=O)=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19].[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:24][N:23]2[C:31]([C:34]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]3)=[O:36])=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19]
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2
Reactant: OCCN1CCNCC1
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2)N1CCN(CCO)CC1

Procedure:
The title compound was prepared from 10-{[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C and 1-(2-hydroxyethyl)-piperazine in the manner of Example 1, Step G.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][CH:31]=[C:30]([OH:38])[CH:29]=1>>[OH:37][CH:34]([C:33]1[CH:32]=[CH:31][C:30]([OH:38])=[CH:29][CH:28]=1)[CH2:35][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)c1ccc(O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-octopamine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 2.00-2.15 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.60-3.70 (m, 2H), 4.80-4.90 (m, 1H), 6.00 (brs, 1H), 6.76 (d, J=9.7 Hz, 2H), 6.80 (d, J=9.7 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 9.47 (s, 1H), 10.43 (s, 1H); MS (ES) m/z: 525.3 (MH+); HRMS Calcd. for C27H33N4O5S(MH+): 525.2172. Found: 525.2178.
Reaction SMILES: C[C:2]1[CH:7]=C[C:5]([S:8](OC2CCSC2)(=O)=O)=[CH:4][CH:3]=1.[C:17]([O-:20])(=[S:19])[CH3:18].[K+].CC1C=CC(S(OC2CCSCC2)(=O)=O)=CC=1>CN(C)C=O>[CH3:18][C:17]([S:19][CH:3]1[CH2:4][CH2:5][S:8][CH2:7][CH2:2]1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)OC2CCSC2)cc1
Reactant: CC([O-])=S
Agent: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCSCC1
Yield: 69 %

Procedure:
Similar procedures employed in Preparation J in reacting 3-(p-methylphenylsulfonyloxy)thiolane with potassium thioacetate by reacting 4-(p-methylphenylsulfonyloxy)thiane and 1.5 equivalents of potassium thioacetate at 80° C. in dimethylformamide to obtain 4-methylcarbonylthiothiane in 69% yield after chromatography on silica gel eluted with 10% ethyl acetate/hexane. The NMR spectrum of a deuterochloroform solution of 4-methylcarbonylthiothiane had peaks at 1.62-2.2 (4H, m); 2.32 (3H, s); 2.5-2.8 (4H, m); and 3.52 (1H, tt, J=9, 3 Hz) ppm.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.CI>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:22][CH3:6])=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: CI
Product: CSC(Nc1ccc(Cl)cc1)=C(C#N)C#N
Reaction time: 0.08 h

Procedure:
Dissolved malononitrile (5.0 g) in DMF (50 mL), added triethylamine (1 eq), and stirred for 5 minutes before adding 4-chlorophenylisothiocyanate (1 eq) dropwise, then stirred until complete by TLC (absence of 4-chlorophenylisothiocyanate, 3 hrs). Added methyl iodide (1 eq) dropwise, then stirred until intermediate was fully consumed (absent on TLC, 18 hrs); poured into 100 mL ice water, then filtered resulting solution to obtain 2-(((4-chlorophenyl)amino)(methylthio)methylene)malononitrile as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:10][N:11]1[C:15](=[O:16])[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:21])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 4-bromo-n-butyric acid ethyl ester (1.2 g, 6.13 mmol) in dimethylformamide (9 ml) were added N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig base (N,N-diisopropylethylamine, 2.13 mL) at room temperature, and the mixture was stirred at 80° C. over night. The reaction mixture was poured into saturated aqueous ammonium chloride, and the resultant mixture was extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate (2:1)) to give 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester (1.47 g, 100%).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccn2cncc2c1
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-Formamidomethylpyridine (39 g., 0.29 mole) was dissolved in 150 ml. of benzene. Phosphorus oxychloride (100 ml.) was added dropwise at such a rate that the reaction began to reflux. By external heating, reflux was maintained for 3.5 hours. After standing approximately 16 hours at room temperature, the reaction was concentrated to an oil. The oil was poured onto approximately 300 g. of ice, the mixture made basic (approximately pH 10) with 10N sodium hydroxide, and extracted with three 300 ml. portions of methylene chloride. The aqueous was made more basic and extracted with a further three 300 ml. portions of methylene chloride. All of the extracts were combined, back-washed with 75 ml. of water and concentrated to yield crystalline imidazo[3,4-a]pyridine (29 g., Rf 0.25 on thin layer chromatography on silica gel with ethyl acetate/5% acetic acid as eluant).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].C1COCC1.[CH3:18][C:19]([CH3:29])([CH2:25][CH2:26][CH2:27][CH3:28])[C:20](OCC)=[O:21]>C(O)(=O)C>[O:21]=[C:20]([C:19]([CH3:29])([CH3:18])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithium (400 ml.) is slowly added to a solution of dimethyl methylphosphonate (73.7 g.) in 1.3 l. of THF at about -66° C. To the mixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in 150 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 46 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with portions of dichloromethane (about 1.2 l.) and water (about 150 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 41.6 g., b.p. 117°-120° C./1 mm.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:6]=2[N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:4][CH2:3]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1([CH3:26])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CCC(C)(C)S2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)O)ccc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylate (450 mg, 1.149 mmol) in THF (10 mL), MeOH (10.00 mL) and water (10.00 mL) was added lithium hydroxide (55.1 mg, 2.299 mmol). The reaction was allowed to stir at room temperature for 8 h. The solvent was removed under reduced pressure. The aqueous solution was acidified with 1 N HCl (10 mL), which resulted in the formation of a white solid. The mixture was washed with EtOAc (3×30 mL) and the combined organics were dried over Na2SO4 and concentrated in vacuo. 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylic acid (434 mg, 1.149 mmol, 100% yield) was isolated as an off white solid and used without further purification. LCMS (+ESI) m/z=377.9 [M+H]+.
Reaction SMILES: CO[C:3]([CH:5]1[O:10][C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:7]=2[O:6]1)=[O:4].O.[NH2:29][NH2:30]>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][CH:5]([C:3]([NH:29][NH2:30])=[O:4])[O:10][C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:8]=2[CH:23]=1
Reactant: COC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of 2.47 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid methyl ester in 9 ml ethanol was added to a solution of 0.61 ml hydrazine monohydrate in 9 ml ethanol. The reaction mixture was refluxed for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with water/TFA gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:9]1=[O:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:13]2)[C:9]1=[O:18]
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCNC2
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccccc2Cl)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Temperature: 180 °C

Procedure:
A mixture of 2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (16.0 mg, 0.0000604 mol, which was prepared by using a procedure that was analogous to that used for the synthesis of example 92, steps 1-4), 2-chloro-5-(trifluoromethyl)pyridine (13 mg, 0.000072 mol) and N,N-diisopropylethylamine (0.032 mL, 0.00018 mol) in N-methylpyrrolidinone (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the reaction mixture to 180° C. for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.2/412.2 (M+H)+.