Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[N:20]=1)=[O:25]
Reactant: O=C(O)c1cc(Cl)cc(Cl)n1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-dichloro-pyridine-2-carboxylic acid (CAS RN 88912-25-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (7%). MS (ESI): m/z=372.07 [M+H]+.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2[N:18]=[CH:19][C:20]3[N:21]([C:22]([C:25]45[CH2:32][CH2:31][C:28]([NH:33][S:34]([CH:37]6[CH2:39][CH2:38]6)(=[O:36])=[O:35])([CH2:29][CH2:30]4)[CH2:27][CH2:26]5)=[N:23][N:24]=3)[C:16]=2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].I[CH3:41]>CN(C=O)C>[CH3:41][N:33]([C:28]12[CH2:27][CH2:26][C:25]([C:22]3[N:21]4[C:16]5[CH:15]=[CH:14][N:13]([S:3]([C:6]6[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=6)(=[O:4])=[O:5])[C:17]=5[N:18]=[CH:19][C:20]4=[N:24][N:23]=3)([CH2:30][CH2:29]1)[CH2:32][CH2:31]2)[S:34]([CH:37]1[CH2:38][CH2:39]1)(=[O:36])=[O:35]
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N(C)S(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
A round bottom flask was charged with sodium hydride (60% dispersion in mineral oil, 0.013 g, 0.33 mmol) and DMF (1 mL) to give a white suspension. The suspension was cooled to about 0° C. followed by the addition of a solution of N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.15 g, 0.27 mmol, Example #7, Step C) in DMF (2 mL). The reaction mixture was stirred for about 15 min and iodomethane (0.06 g, 0.41 mmol) was added. The reaction mixture was stirred at about 0° C. for about 30 min, warmed to room temperature, and stirring was continued for about 2 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) then purified by flash silica gel chromatography using EtOAc as the eluant to give N-methyl-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.068 g, 45%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.35 min; LC/MS m/z 555 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ncsc1CCC1(C(C)C)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3scnc3C)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-1; 0.22 g, 0.78 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.33 g, 0.90 mmol), potassium carbonate (1.0 g, 7.2 mmol), and DMF (4 mL). The product was chromatographed on silica gel, eluting with 10% MeOH in CH2Cl2, to give the title compound, mp 138-141° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1F
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO4 and concentrated under reduced pressure to afford 10.02 g of methyl 3-bromo-2-fluorobenzoate. 1H-NMR (400 MHz, DMSO-d6) δ 7.95 (ddd, J=8.1, 6.4, and 1.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.26 (t, J=7.9 Hz, 1H), and 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[C:19]([F:21])([F:20])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[CH3:29][N:30]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:30]([CH3:29])[C:37]1[CH:42]=[CH:41][C:40]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]3[C:19]([F:20])([F:21])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:15]3)[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=2)=[CH:39][CH:38]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CNc2nc(Cl)cc3nccnc23)C1
Reactant: CCOC(=O)CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Yield: 155.6 %

Procedure:
A solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate (173 mg, 0.42 mmol), ethyl 2-(methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetate (200 mg, 0.63 mmol), Pd(PPh3)4 and Cs2CO3 in 4 mL of dioxane and 0.5 mL of water was stirred at 160° C. for 1 hour. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:8˜5:1) to give 373 mg of title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:20])[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:21]([C:24]1[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH2:22][CH3:23]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:20])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:25]1[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=1[CH2:21][CH2:22][CH3:23])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Reactant: CCCc1ccccc1OCCCCCBr
Product: CCCc1ccccc1OCCCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1CCC
Yield: 79.9 %

Procedure:
Using essentially the method of Example 2, 2.76 g (10 mmole) of ethyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 8.18 g (11 mmole) of 5-(2-n-propylphenoxy)-1-bromopentane, gave 3.84 g (80%) of the title compound, mp 73°-75°. Calc: C, 72.48; H, 7.55; Found: C, 72.24; H, 7.63.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])[CH3:27]
Reactant: CC(C)(N)CO
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CO
Temperature: 100 °C
Yield: 17 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 2-amino-2-methylpropan-1-ol (31.1 μl, 0.324 mmol, Sigma-Aldrich), heating at 100° C. for 1.5 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 6H) 2.56 (s, 3H) 2.88 (t, J=6.94 Hz, 2H) 3.45 (td, J=6.80, 2.45 Hz, 2H) 3.66 (d, J=5.28 Hz, 2H) 5.15 (t, J=5.58 Hz, 1H) 5.87 (s, 1H) 6.96 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.84 (dd, J=7.43, 1.37 Hz, 1H) 12.03 (br. s., 1H). MS (ESI, pos. ion) m/z: 366.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: COc1ccc2c(c1)C(C)NCC2
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C)N(c1nc(Cl)nc(C)c1C)CC2
Yield: 67.8 %

Procedure:
After 1-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.9 g, 5.1 mmol) and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine (0.8 g, 4.64 mmol) in dimethylformamide, 1.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 70.3%)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:19])[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3.[H][H]>O.[C].[Pd]>[NH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:19])[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2C
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2C
Yield: 82.4 %

Procedure:
The hydrochloric acid salt of (2RS,3SR)-2-aminomethyl-3,5-dimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one obtained in Example 12 (575 mg, 2.05 mmol) in water (20 ml) was combined with 10% palladium-carbon (600 mg), then stirred in the presence of hydrogen gas at 80° C. for 4 hours. From the reaction mixture, palladium-carbon was filtered off. Water was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of methanol--ether. As a result, 416 mg of a hydrochloric acid salt of (2 RS, 3 SR)-2-aminomethyl-3,5-dimethyl-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one was obtained as colorless crystals (71.8%). mp. >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>C(#N)C>[CH3:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 69 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0304 g, 0.0659 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0550 mL, 0.395 mmol) and 2-methylbenzenesulfonyl chloride (0.0280 mL, 0.198 mmol) to obtain 4-(2-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, yield 69%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C@H:19]([N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:36]([CH2:38][NH2:39])[OH:37]>ClCCl>[OH:37][CH2:36][CH2:38][NH:39][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C@@H:23]2[O:24][CH2:25][CH2:26][N:21]([C@@H:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:20])[CH2:22]2)=[CH:28][CH:29]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)NCCO)cc2)C1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1,1′-Carbonyldiimidazole (540 mg, 3.30 mmol) was added to a solution of 4-[(2S)-4-((1R)-1-phenyl-ethy)-morpholin-2-yl]-benzoic acid (944 mg, 3.03 mmol) in dichloromethane at 0° C. After stirring for 2 hours, ethanolamine (0.36 ml, 6.0 mmol) was added to the reaction mixture and the mixture was stirred over night. The resulting suspension was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate-hexane) to afford N-(2-hydroxy-ethyl)-4-[(2S)-4-((1R)-1-phenyl-ethy)-morpholin-2-yl]-benzamide (789 mg, 73%.) as a colorless oil.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.O>CN(C)C=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si:10]([CH3:12])([CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
387 mg of imidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40° C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[C:9]1([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 10 °C

Procedure:
N-phenylmaleimide was synthesized in accordance with a method described in "Organic Synthesis", Vol.41, page 93. That is, 196 parts of maleic anhydride and 2,000 parts of benzene were charged into a four-necked flask. 186 parts of aniline dissolved in 200 parts of benzene were added dropwise to the resulting solution at 25° C. over one hour. The resulting product was cooled to 10° C. and crystals thus formed were filtered off and dried in vacuo to give 370 parts of a pale yellow solid substance. 316 parts of the produced pale yellow substance, 65 parts of anhydrous sodium acetate and 670 parts of acetic anhydride were charged into a flask fitted with a stirrer and a reflux cooler and heated gradually over an hour. Stirring was continued for one hour while the temperature was maintained at 100° C. The resulting product was poured into ice water to precipitate crystals. The crystals were filtered, washed with petroleum ether and dried to give 220 parts of yellow crystals. The melting point and the purity by liquid chromatography of the produced crystals were measured and found to be 88° C. and 97.5%, respectively. The produced maleimide compounds are shown in Table 1-1.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 6.6 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to remove solvent and give a product which distilled at 187° C./0.2 mm. This product solidified and was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-ethylsulphonyl-1,2,4-triazole, m.p. 39° - 42° C. Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]2[CH:17]=[CH:16][N:15]([C@H:18]3[C@H:34]([OH:35])[C@@H:21]4[O:22][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[O:24][CH2:25][C@@H:20]4[CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](Cl)=[S:44])=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:43](=[S:44])([O:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[O:35][C@@H:34]1[C@@H:21]2[O:22][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[O:24][CH2:25][C@@H:20]2[CH2:19][C@H:18]1[N:15]1[C:11]2[N:12]=[CH:13][N:14]=[C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH:17]=[CH:16]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)[C@H](O)[C@@H]3O2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(SCc6ccccc6)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 140 %

Procedure:
To a solution of (4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (990. mg, 2.02 mmol) in DCM (57.0 mL) was added 4-(dimethylamino)-pyridine (748 mg, 6.07 mmol) and phenyl chlorothionocarbonate (0.565 mL, 4.04 mol) under an atmosphere of nitrogen and the yellow reaction was stirred at rt. After 12 h, the dark yellow solution was purified via silica gel chromatography eluting with 10% EtOAc in hexanes, and then 10% MeOH in DCM on a column pre-treated with 1% TEA in hexanes to afford the title compound as a yellow oil (1.77 g, 97%). LC/MS: Rt=2.47 min, ES+ 626 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[CH3:28][C:29]([CH3:31])=O.P([O-])(O)(O)=O.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([CH:29]([CH3:31])[CH3:28])[CH2:7][CH2:6]2
Reactant: CC(C)=O
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Agent: O=P([O-])(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
To a mixture of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.36 g, 1 mmol), acetone (3 mL), and sodium dihydrogenphosphate (0.4 g) in methanol (5 mL) was added sodium cyanoborohydride (0.5 g, 8 mmol). After 48 hours, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (0.321 g, 80% yield): ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[C:26]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:27][CH:28]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[C:26]([N:34]3[CH2:35][CH2:36][N:37]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:38][CH2:39]3)=[N:27][CH:28]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[CH:30]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 78.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (427 mg) was obtained.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=CC=C[C:15]=2[CH:16]=O)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:4]([C:3]1[CH:2]=[CH:21][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([C:22]([F:24])([F:23])[F:25])[CH:9]=2)=[CH:15][CH:16]=1)=[CH2:5]
Reactant: O=Cc1ccccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (5.56 g, 15.57 mmol) in anhydrous tetrahydrofuran (THF) (50 mL) was added BuLi (9.5 ml, 15.20 mmol) dropwise at 0° C. The reaction mixture was turned to clear and stirred for 15 min at 0° C., then a solution of -{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (4.07 g, 13.54 mmol) in THF (10 mL) was added. The reaction mixture was warmed to rt and stirred for 1 h, quenched by sat. NH4Cl, and then concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water, and brine, dried over anhydrous sodium sulfate, concentrated. Purification via ISCO afforded the title compound (3.0 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@H:15]2[CH2:17][O:16]2)[CH:9]=[C:10]([F:12])[CH:11]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@H:15]([OH:16])[CH2:17][CH:1]=[CH2:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Vinylmagnesium bromide was added to copper (I) bromide-dimethyl sulfide complex in tetrahydrofuran at low temperature. Tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2R)-oxiran-2-yl]ethylcarbamate (31) in tetrahydrofuran was added. At room temperature, the reaction was quenched with saturated ammonium chloride, extracted, and dried over sodium sulfate. A white solid (32) was obtained upon concentration.