Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25].[K+].[Br-].CC#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:10][NH:11][C:24]2=[S:25])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1ccc(C(F)(F)F)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S

Procedure:
N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in THF (450 ml) under N2 and 1,1′-thiocarbonyldiimidazole (1.95 g, 11.0 mmol) added. The solution was stirred at reflux for 18 h and solvent removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 1.91 g (68%) mp 275-280° C.; IR(KBr, υ=cm−1) 3080, 3058, 3020, 2916, 1506, 1488, 1322, 1288, 1174, 1130, 1110; 1H NMR (300 MHz, DMSO-d6) δ 3.51 (3H, s), 7.17 (1H, d, J=9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J=2.6 Hz), 7.77 (2H, d, J=8.4 Hz.s), 14.29 (1H, s); MS(DCl)m/z: 386(MH+). Anal. calcd. for C16H11ClF3N3OS.0.06 CH3CN: C, 49.87; H, 2.90; N, 11.04. Found: C, 50.03; H, 2.94; N, 11.07.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: NC(=O)C1C2C=CC(C2)C1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
In an analogous procedure to Example 651, part c, 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide as a white solid. 1H-NMR (CDCl3) δ 9.12 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.70 (m, 1H), 7.52 (m, 1H), 7.46 (d, J=21.2 Hz, 1H), 7.26 (s, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.35 (s, 1H), 6.27 (s, 1H), 4.13 (m, 1H), 3.31 (s, 3H), 2.87 (s, 1H), 2.77 (s, 1H), 2.56 (m, 6H), 2.45 (m, 4H), 2.10 (d, J=8.6 Hz, 1H), 1.95 (m, 2H), 1.40 (d, J=8.8 Hz, 1H), 1.31 (m, 2H). LC/MS (ESI+)=509 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:51]=[CH:50][N:49]=[CH:48][C:47]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cnccc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccncc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-chloropyridine hydrobromide and isolated as yellow gum. MS(m/e): 408.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.B1([C:33]2[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:9]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]=4[S:14][C:13]=3[C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[CH:20][CH:21]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5cccnc5)ccc4c23)cc1
Temperature: 110 °C

Procedure:
To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) in DMF (0.1 M) were added the pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.5 equiv), 2 M Na2CO3 (3 equiv) and PdCl2dppf (0.05 equiv). The mixture was heated in the microwave reactor at 110° C. for 10 min. The reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organic phase was separated, dried over MgSO4, filtered, evaporated and purified by flash chromatography (70:30 hexanes/EtOAc to 100% EtOAc) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[H][H].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 50 °C

Procedure:
5,5-Dimethyl hydantoin (5.15 g, 0.039 mole) was added to a suspension of sodium hydride (1.87 g, 50% oil dispersion) in dry dimethylformamide (50 ml) and the mixture stirred and heated at 50° C. until evolution of hydrogen ceased. The solution was cooled and benzyl chloride (4.94 ml, 1.1 equivalents) was added and the mixture heated at 50° C. for 11/2 hours. The dimethylformamide was removed under reduced pressure and the residue partitioned between ether and brine. The ethereal extracts were combined, washed with water, dried (MgSO4) and the solvent evaporated to yield the title compound as a white crystalline solid m.p. 100°-102° C. Yield=8.0 g=91%.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[OH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1
Temperature: 0 °C

Procedure:
A mixture of 25.0 g of 3,4,5,6-tetrahydrophthalic anhydride (THPA), 17.9 g of 3-aminophenol and 350 mL of glacial acetic acid was refluxed for 1 hour, then cooled and poured slowly into 1400 mL of ice-water. The resulting mixture was filtered. The collected solids were washed with cold water and dried (oven, reduced pressure) to give N-(3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (1A), as yellow crystals, m.p.: 196°-197.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:16])[F:14])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[CH:7]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2[nH]c(=O)ccc12)C(F)(F)F
Yield: 60.6 %

Procedure:
Analogously to Example 20, 226 mg (0.73 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 140 mg (0.87 mmol) of 5-amino-2-quinolone are reacted to form 200 mg of the product.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=[N:2]1.[OH-].[NH4+:17]>O1CCCC1>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccno1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1-c1ccno1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 37 g of 2-(isoxazol-5-yl)benzenesulfonyl chloride, prepared in Example 4, in 200 ml of tetrahydrofuran, was cooled in an ice-water bath while about 40 ml of concentrated aqueous ammonium hydroxide was added slowly at 10° to 30° C. The resulting suspension was stirred at room temperature for 4 hours, then the solvent was evaporated under reduced pressure. The residue was stirred in 150 ml of water for 0.5 hour, the filtered. The crude, wet solid was dissolved in tetrahydrofuran and dried over sodium sulfate. The solid was recrystallized from 2-propanol to give 20 g of the title compound; m.p. 132°-135° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.OC1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.[C:22](=O)([O-])[O-].[K+].[K+].C1(C)C(C)=CC=CC=1>[Cu].O>[CH3:22][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1ccc(Sc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.3 %

Procedure:
The mixture of 4-bromothioanisole (10.0 g, 49.2 mM), ethyl 4-hydroxybenzoate (8.17 g, 49.2 mM), potassium carbonate (6.80 g, 49.2 mM), copper (0.5 g) and xylene (300 ml) was stirred for 24 h under reflux. The mixture was cooled to the room temperature and poured into water. The mixture was filtered through celite, and the toluene solution was washed with water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give ethyl 4-(4-methylthiophenoxy)benzoate (4.86 g, 36%) as colorless crystals, m.p. 46.4° C.
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC.C(OC([N:34]1[CH2:39][CH2:38][CH:37]([N:40](C(OC(C)(C)C)=O)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]3[CH2:53][O:52]C(C)(C)[O:50]3)=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.Cl>O1CCOCC1.C(O)C>[NH:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:41]2[N:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([OH:50])[CH2:53][OH:52])=[CH:45][CH:46]=2)[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC3COC(C)(C)O3)cn2)CC1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: OCC(O)COc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2) from rac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylic acid tert-butyl ester by cleavage of both the BOC and the isopropylidene group with 4 M HCl in dioxane and ethanol at rt followed by ion exchange chromatography on Q-Sepharose Fast Flow. MS (ISP): 268.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)[CH3:22]
Reactant: CCNCC
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: CCN(CC)CC1CCN(c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 16 and diethylamine.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[K+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)=[CH:18]/[C@@H:19]2[NH:23][C:22](=[O:24])[CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15]C.O>C(#N)C>[Cl:8][C:9]1[C:14](=[O:15])[NH:13][C:12](/[C:17](/[C:25]2[CH:26]=[CH:27][C:28]([CH2:31][OH:32])=[CH:29][CH:30]=2)=[CH:18]/[C@H:19]2[CH2:20][CH2:21][C:22](=[O:24])[NH:23]2)=[CH:11][CH:10]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(CO)cc2)ccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@H](/C=C(\c2ccc(CO)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
Chlorotrimethylsilane (0.123 mL) and potassium iodide (263 mg) were sequentially added to a solution of (5R)-5-{(E)-2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(hydroxymethyl)phenyl]ethenyl}pyrrolidin-2-one (142 mg) in acetonitrile (1.5 mL) at room temperature, after which the mixture was stirred at 60° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=1:10) to give the title compound as a colorless solid (19 mg, 14%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[C:35]2([CH3:43])[CH3:42].[I-].[K+]>CO.ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[NH:37][C:36](=[O:41])[C:35]4([CH3:42])[CH3:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC1(C)C(=O)Nc2ccc(CCCCl)cc21
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCc3ccc4c(c3)C(C)(C)C(=O)N4)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combined extracts with brine (50 mL), dry over MgSO4, filter and concentrate in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum oven to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (481 mg) that was used without further purification. MS (ES+) m/z: 537 (M+Na)+.
Reaction SMILES: [CH:1]([S:14][CH:15]1[CH2:20][CH2:19][N:18](C)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([N:18]1[CH2:19][CH2:20][CH:15]([S:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:17]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(SC(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(SC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
The solution of 4-benzhydrylsulfanyl-1-methyl-piperidine (350 mg, 1.18 mmol) and ethyl chloroformate (0.33 mL, 3.54 mmol, 3 eq.) in toluene (15 ml) was refluxed for 5 hrs. The solution was cooled to room temperature and then washed with diluted HCl (2.0 N, 2×5 mL). The solution was dried over anhydrous Na2SO4. The solvent was moved and the crude product 4-benzhydrylsulfanyl-piperidine-1-carboxylic acid ethyl ester was yielded (322 mg, 76.8% yield).
Reaction SMILES: [CH3:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[NH:21]([C:23]([O:25][CH3:26])=[O:24])[NH2:22].[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1.CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[CH3:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:27]([NH:22][NH:21][C:23]([O:25][CH3:26])=[O:24])=[O:28])=[CH:7][CH:8]=1
Reactant: COC(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: C1CCOC1
Product: COC(=O)NNC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a mixture of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.396 g (1.5 mmol) in THF 10 mL and DMF 3 mL was added methyl hydrazine carboxylate 0.135 g (1.5 mmol), followed by addition of carbonyldiimidazole (CDI) 0.243 g (1.5 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 4 h, heated under reflux for 0.5 h, and then stirred at 23° C. for another 16 h. After removal of THF, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the titled compound in 75% yield, which was used without further purification. 1H NMR (CD3OD, 400 MHz): δ 7.98 (s, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.59-7.54 (m, 1H), 7.52 (d, 2H, J=8.3 Hz), 7.13 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=7.2 Hz), 7.03-6.98 (m, 1H), 3.74 (s, 3H), 3.70 (s, 1H), 2.99 (s, 3H), 2.86 (s, 3H). m/e: 381.19 (M+1), 379.03 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C1(S([N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)(=O)=O)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:27][C:25]2[CH:26]=[N:22][NH:23][CH:24]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1cnn(S(=O)(=O)c2ccccc2)c1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CSc1nc(C)c(C#N)c(Nc2cn[nH]c2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (6.45 g, 32.2 mmol) and 1-(phenylsulfonyl)-1H-pyrazol-4-amine (7.2 g, 32.2 mmol) in 1,4-dioxane (150 mL) was added 4-methylbenzenesulfonic acid (3.06 g, 16.1 mmol). The reaction mixture was stirred overnight at 90° C. After cooling to room temperature, the precipitate was filtered, washed with saturated NaHCO3 solution and then water, dried and washed with petroleum and the mixture solvent (petroleum ether:ethyl acetate=4:1) successively to give 4-methyl-2-(methylthio)-6-(1H-pyrazol-4-ylamino)-5-pyrimidinecarbonitrile (intermediate 30, 3.6 g) as a pale solid. MS: M(C10H10N6S)=246.30, (M+1)+=247.1; 1HNMR (300 mHz, DMSO-d6) δ ppm 12.69 (1H, s), 9.87 (1H, s), 7.97 (1H, s), 3.33 (3H, m), 2.42 (3H, s). The organic eluents were concentrated under reduced pressure and the residue was treated with the same method above to afford 4-methyl-2-(methylthio)-6-{[1-(phenylsulfonyl)-1H-pyrazol-4-yl]amino}-5-pyrimidinecarbonitrile (intermediate 29, 4.26 g, 34.4% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C@@H:3]1[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])#[C-:2].C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30]>O1CCCC1.C(O)(=O)C>[N+:1]([C@@:3]1([C:25]([CH3:27])([O:26][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[CH3:24])[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])#[C-:2]
Reactant: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Reactant: CC(C)=O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+][C@]1(C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (127.6 mg) in tetrahydrofuran (2.55 ml) was added dropwise a solution of n-butyl lithium (0.409 ml of 1.51 M solution in hexane) at -78° C. over a period of 3 minutes. After stirring for 15 minutes at -78° C., the reaction mixture was added dropwise with a solution of acetone (0.0459 ml) in tetrahydrofuran (0.459 ml) at -78° C. over a period of 3 minutes. After stirring for 25 minutes at -78° C., the reaction mixture was added dropwise with a solution of 4-nitrobenzyl chloroformate (124.1 mg) in tetrahydrofuran (1.24 ml) at -78° C. over a period of 3 minutes. The resulting solution was allowed to warm to 0° C. over a period of 40 minutes and added with acetic acid (0.0412 ml) at 0° C. The solvent was distilled off in vacuo at 0° C. and the residue was dissolved in ethyl acetate (30 ml) and washed with brine, aqueous sodium bicarbonate, brine and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (285.4 mg) was chromatographed on silica gel (5.7 g) eluting with a mixture of ethyl acetate and hexane (1:5→1:3) to give methyl 2-{(3R, 4R)-3-isocyano-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl}-3-methylbut-2-enoate (211.2 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Product: CCOP(=O)(Cc1nc2ccccc2c(OCc2ccccc2)c1C)OCC
Temperature: 150 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (1.00 g) and triethyl phosphite (3.84 g) was stirred at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to obtain diethyl {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}phosphonate (1.12 g).