Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1B(O)O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27]([C:35]4[CH:36]=[C:31]([O:30][CH3:29])[CH:32]=[CH:33][C:34]=4[O:37][CH3:38])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Temperature: 70 °C

Procedure:
0.78 ml of 2 M aqueous sodium carbonate solution and 21.2 mg (0.03 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.52 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 94.4 mg (0.52 mmol) of 2,5-dimethoxyphenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 70° C. for 17 h and then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of a 3:1 mixture of methanol and 1N hydrochloric acid, concentration and drying under high vacuum result in 75 mg (31.7% of theory) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:18])[CH:10]=[CH:11][C:12]1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2]1([CH:1]=[CH:12][CH:11]=[CH:10][CH2:9][OH:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCC=CC=Cc1ccccc1

Procedure:
Analysis by GC and MS showed the major component to have m/e 160. Minor impurities included benzaldehyde and cinnamaldehyde. IR (CHCl3): cm-1 3620 (s), 3430 (br, OH), 3020 (s), 1650 (m), 1620 (m), 1600 (m).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(C(F)(F)F)c2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C(F)(F)F)c2)C1=O
Yield: 77 %

Procedure:
A solution of Example 140B (0.261 g, 0.623 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.172 g 77%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.O>CS(C)=O>[Br:1][C:2]1[C:7]([NH:23][CH2:22][CH:19]2[CH2:21][CH2:20]2)=[N:6][C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:3]=1[NH2:18]
Reactant: Nc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Reactant: NCC1CC1
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(-n2ncc3ccccc32)nc(NCC2CC2)c1Br
Temperature: 65 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
A mixture of 0.1 g (0.31 mmol) of 5-bromo-6-chloro-2-(1H-indazol-1-yl)pyrimidine-4-amine (intermediate 5) and 160 μl (1.85 mmol) of cyclopropylmethylamine in 0.5 ml of DMSO in a closed glass tube was stirred for 5 h at 65° C. The reaction mixture was poured onto 20 ml of cold water. The formed white precipitate was filtered, washed several times with water and dried. 0.088 g (79.7%) of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CC(Cc1ccc(Cl)nc1)C(=O)O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a stirred solution of 3-(6-chloropyridin-3-yl)-2-methylpropanoic acid (6.5 g, 32.6 mmol) in THF (75 mL) cooled in an ice-water bath was added a solution of 1 M borane in THF (48 mL, 48 mmol) in a rapid dropwise fashion. The mixture was stirred at room temperature for 4 h. Water (25 mL) was added carefully followed by 2 N NaOH solution. The two phases were separated and the aqueous phase washed with ether (100 mL). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated to give 4.2 g of the product as a nearly colorless oil in 69% crude yield. [M+H]+=186, 188; IR: 3414 (OH)
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH3:21])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][C@H:11]1[CH3:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 78.8 %

Procedure:
A solution of (2R,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine (3.9 g) and tetrabutylammonium fluoride (1 Mol-tetrahydrofuran solution, 12.4 ml) in tetrahydrofuran (40 ml) was stirred at 0° C. for one hour. The reaction mixture was extracted with ethyl acetate, the organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (1.96 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
tert-Butyl 6-aminonicotinate (0.467 g, 2.406 mmol), triethylamine (0.244 g, 2.406 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.407 g, 2.406 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.300 g, 0.802 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.240 g, 0.436 mmol, 54%).
Reaction SMILES: OCCCCCCCCCCCCC[C:15]([O:17][CH2:18][CH:19]=[C:20](C)[CH2:21][CH2:22][CH2:23][CH:24](C)[CH2:25][CH2:26][CH2:27][CH:28](C)[CH2:29][CH2:30]CC(C)C)=[O:16].CC(CCCC(C)CCCC(C)CCCC(C)C)=CCO.[O-2].[Mg+2]>>[CH2:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(=CCOC(=O)CCCCCCCCCCCCCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Mg+2]
Agent: [O-2]
Product: O=C1CCCCCCCCCCCCCO1
Yield: 89 %

Procedure:
A 31.4 g (60.0 mmol) portion of 3,7,11,15-tetramethyl-2-hexadecenyl 14-hydroxytetradecanoate, 5.9 g (20 mmol) of 3,7,11,15-tetramethyl-2-hexadecenol and 0.5 g of magnesium oxide were put into the same apparatus of Inventive Example 1 and the reaction was carried out under conditions of 190 to 220° C. and 1.3 kPa to 130 Pa to obtain 33.5 g of a colorless and transparent distillate 6.5 hours thereafter. This distillate contained 12.1 g of cyclotetradecanolide (yield 89%) and 18.9 g of 3,7,11,15-tetramethyl-2-hexadecenol (recovery ratio 80%).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][O:34][C:35]=1[CH3:36]>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: Cc1noc(C)c1CCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1c(C)noc1C
Yield: 71.6 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of potassium iodide (16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give 4-(3-acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline (342 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:18][C:19]4[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:27][CH3:28])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CN(C)C=O>[CH2:27]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][CH3:26])[C:19]=1[NH:18][C:16]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([NH:1][CH:39]4[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH2:38]4)=[N:3][C:4]=3[C:5]=2[N:14]([CH3:15])[N:13]=1)=[O:17])[CH3:28]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc1-2
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 8-amino-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (1.0 g, 2.66 mmol) in dry dimethylformamide (20 mL), were added 1-Boc-4-piperidone (1.06 g mL, 5.32 mmol), CF3COOH (1.7 mL, 22.7 mmol) and NaBH(OAc)3 (1.12 g, 5.32 mmol). After 20 hours, NaOH 2N (12 mL, 24 mmol) was added dropwise to the mixture. The precipitate was filtered, washed with water and dried. The crude material was purified by flash chromatography on silica gel eluted with dichloromethane/methanol 97:3 to give the 1.2 g of to the pure title compound (80% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][Li].[Cl-].[NH4+].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH3:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(F)cn1
Yield: 33 %

Procedure:
To a −78° C. solution of 5-fluoro-2-formylpyridine (0.66 g, 5.3 mmol) in THF (20 mL) was methyl lithium (1.6 M in diethyl ether, 4.0 mL) added dropwise. After stirring for 1.5 h at −78° C. a saturated solution of ammonium chloride (25 mL) followed by water (25 mL) was added. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: chloroform:methanol 98:2) affording the title compound (0.25 g, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:31])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:31])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[CH3:32])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(/C=C/[C@@H]1CCCN1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of N-(3-Chloro-4-fluorophenyl)-7-{(2E)-3-[(25)-pyrrolidin-2-yl]prop-2-enoyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 13 (60 mg, 0.13 mmol) in DMF (1 mL) was added potassium carbonate (27 mg, 0.20 mmol) and iodomethane (20 mg, 0.14 mmol), and the mixture was stirred overnight at rt. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM/MeOH 10:1) to yield 8 mg (13%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Br[CH2:22][CH2:23][O:24][CH3:25].[H-].[Na+]>CN(C)C=O>[F:17][C:11]1[CH:10]=[C:9]([C:7]2[N:6]([CH2:22][CH2:23][O:24][CH3:25])[C:5]3[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1cc2nc(-c3ccc(C#N)c(F)c3)[nH]c2cc1C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C#N)c(F)c2)nc2cc(C)c(C)cc21
Temperature: 100 °C

Procedure:
4-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-fluorobenzonitrile 3 (110 mg, 0.4 mmol) was combined with 1-bromo-2-methoxyethane (76 mg, 0.55 mmol), NaH (13 mg, 0.55 mmol), and N,N-dimethyl formamide (5 ml). The reaction was heated at 100° C. for 1.5 hours. The product solution (confirmed by LCMS: 324.22) was carried on to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a slurry of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine from step A (1.17 g, 5 mmol) in DMF (10 ml) at 0° C., was added NaH (60% in mineral oil, 0.28 g, 7 mmol). After stirring 15 min., benzensulfonyl chloride (0.64 ml, 5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours, resulting in precipitation of a white solid. More DMF (5 ml) was added, and the reaction was quenched with 10 ml of water. The solid was collected by filtration and dried in vacuum to afford 5-bromo-4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (1.62 g, 4.35 mmol, 87%) as a white solid, which was carried on without further purification. MS (ES+) [M+H]+=373.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]([CH2:15][C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:28]([N:19]1[CH2:20][CH2:21][C:16]([CH2:15][N:5]([C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (108 mg, 0.281 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added benzaldehyde (35.8 mg, 0.337 mmol) and sodium triacetoxyborohydride (95 mg, 0.450 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 78 mg or product as colorless oil. MS: (M+H)+=475.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.42 (q, 1H), 1.53-1.76 (m, 3H), 2.08-2.34 (m, 4H), 2.42 (ddd, J=10.11, 6.44, 3.66 Hz, 1H), 2.78-2.99 (m, 2H), 3.13-3.24 (m, 1H), 3.53-3.65 (m, 5H), 3.70-3.86 (m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.18-7.25 (m, 1H), 7.27-7.40 (m, 7H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].O>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1Cl
Reactant: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(OCc3ccccc3Cl)ccc2CCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
To a suspension of 32 mg of sodium hydride (about 60%) in 10 ml of dimethylformamide was added 100 mg of 3,4-dihydro-7-hydroxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, and the resultant mixture was stirred for 15 minutes. Then, 95 mg of 2-chloromethylchlorobenzene was added to the mixture, which was stirred at room temperature for 20 hours. After finishing the reaction, the mixture was mixed with water and shaken with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 144 mg of the titled compound.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:19])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=[O:8].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH3:19][N:4]([CH3:3])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([N:15]([CH2:20][CH3:21])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reaction time: 6 h

Procedure:
36.2 gm Powdered potassium hydroxide was added portion wise to a clear solution of a mixture of 100 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl] acetamide and 70 ml ethyl iodide in 1000 ml of dimethyl formamide at 39°-42° C. over 60 min. the reaction mixture was stirred for 6 hrs. after completion, the reaction mixture was quenched in water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated to get oil, which upon trituration in hexane gave a solid product which was filtered and dried at 40° C. under vacuum to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=C(Cl)C(Cl)=CC=1[O:34][C:35](=O)[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:13](=[O:16])[CH2:14][NH:15][C:35](=[O:34])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 6.1 parts glycyl-L-phenylalanine benzyl ester hydrochloride, 7.0 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvents are then removed by evaporation under reduced pressure to yield the crude tripeptide. Purification by low pressure column chromatography affords pure N-t-butoxycarbonylglycylglycyl-L-phenylalanine benzyl ester.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([OH:16])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH2:22]Cl>CN(C=O)C>[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([O:16][CH2:22][C:21]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:20]=2[F:19])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: Fc1ccc(F)c(CCl)c1
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC1(OCc2cc(F)ccc2F)CCN(C(C)=O)CC1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A solution of 7.04 g of potassium t-butoxide (62.9 mmole) in 20 ml of dry DMF was added dropwise to a chilled solution of 10 g of 1-acetyl-4-ethynyl-4-hydroxypiperidine (59.9 mmole) in 75 ml of dry DMF, at such a rate as to maintain the temperature at 10° C. The mixture was allowed to equilibrate at 10° C. for 15 min. after which time it was cooled to -20° C. To this solution was added 9.73 g of 2,5-difluorobenzylchloride (59.9 mmole) at such a rate as to maintain the temperature around -20° C. After complete addition, the reaction mixture was warmed to 0° C. and allowed to react for 1 hr. The reaction appeared to be complete by GLC and was quenched with ice and water. The products were extracted into ether and dried over K2CO3. After filtration, the solvent was removed under vacuum. The crystalline product was recrystallized from cyclohexane and dried, affording 10.5 g of 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine (35.8 mmole, 59.83%). This material appeared pure by GLC (99% on OV225, temperature program: 200° C. (2 min), rate=25° C./min, 250° C. (15 min), flow=30 ml/min tR =4.00 min) and by TLC on silica gel in hexane:ethylacetate (1:1), Rf =0.2. MS (ci MH+ =294), NMR-CDCl3 and IR-CHCl3 were consistent with the structure; m.p.=90°-93° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:21]1([CH2:26][CH2:27]Br)[CH2:25][CH2:24][CH:23]=[CH:22]1>>[CH:21]1([CH2:26][CH2:27][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: BrCCC1C=CCC1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 25.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (98 mg).