Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:32]([O:34][C:35]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)=[O:36])[CH3:33].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH2:32]([O:34][C:35]([C:37]1[N:38]=[C:39]([NH:42][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:40][CH:41]=1)=[O:36])[CH3:33]
Reactant: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (233 mg, 0.66 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.36 mL, 0.72 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-amino-thiazole-4-carboxylic acid ethyl ester (367 mg, 1.45 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.40 mL, 2.31 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 95/5 ethyl acetate/heptane) afforded 2-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}propionylamino)-thiazole-4-carboxylic acid ethyl ester (40.5 mg, 12.5%) as an off-white: mp 222-223° C.; EI-HRMS m/e calcd for C26H28N4O4S (M+) 492.1831, found 492.1835.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([OH:27])[CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:35][C:33]=2[N:34]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([OH:27])[CH2:23][CH2:22]2)[C:5]2[C:10]([C:37]3[CH:36]=[CH:35][C:33]4[N:34]=[C:30]([CH3:29])[O:31][C:32]=4[CH:38]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: CC1(O)CCC(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCC(C)(O)CC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a degassed mixture of 4-((2-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexanol (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.2 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.18 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.1 equiv). The reaction mixture was stirred at 70° C. for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-2% DCM in MeOH) to afford the title compound (95% yield) as a red oil. MS (ESI) m/z 543.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:4](=[O:17])[C:3]=1[N:18]=O.Cl.[CH3:21]N(C)CCCN=C=NCC.[OH-].[Na+].Cl>CN(C=O)C.[Pd].C(O)=O>[CH2:13]([N:5]1[C:4](=[O:17])[C:3]2[NH:18][CH:21]=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]1=[O:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCn1c(N)c(N=O)c(=O)n(CCCC)c1=O
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 151.6 %

Procedure:
A mixture of 6-amino-1,3-di-n-butyl-5-nitroso-uracil (3.1 g, 11.6 mmol) and 5% Pd-C in dry DMF (30 ml) was hydrogenated at 50 psi until it became a colorless solution (about 2 h). The catalyst was filtered off through Celite pad and the filtrate was mixed with 88% formic acid (15 ml) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.1 g, 5.74 mmol) at 0° C. under nitrogen. The violet solution was stirred at room temperature for 3 h. DMF and formic acid were removed by rotary evaporation and the solid residue was mixed with 2N sodium hydroxide (50 ml, 100 mmol). The reaction mixture was heated at reflux for 1 h. The yellow solution was cooled and neutralized with 6N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water, and dried to yield 1,3-di-n-butyl-xanthine (2.3 g, 75%), m.p. 165.5°-169° C.; 1H NMR (DMSO-d6) δ1.41-1.47 (m, 6H, 2×CH3), 1.61-1.68 (m, 4H, 2×CH2), 1.74-1.79 (m, 2H, CH2), 1.82-1.85 (m, 2H, CH2), 3.84 (t, 2H, N--CH2), 3.98 (t, 2H, N--CH2), 8.10 (s, 1H, H-8), 13.7 (br s, 1H, NH).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:32])[CH:22]([NH:24]C(OC(C)(C)C)=O)[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:38]>C(O)C>[ClH:38].[NH2:24][CH:22]([CH3:23])[C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:33])[CH2:16]1)=[O:32]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: Cl
Solvent: CCO
Product: CC(N)C(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 2.3 g of (4.4 mmol) of 1-Cyclopropyl-7-[3-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]amino]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 25 ml of 1.0M hydrochloric acid and 25 ml of ethanol was heated at reflux for two hours. The mixture was evaporated to dryness in vacuo and the residue was triturated with ethanol/ether (100 ml/1:1). The solid was removed by filtration, washed with ethanol/ether, ether and dried in vacuo to give 1.6 g of the title compound, mp 238°-240°.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2ncnn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In 15 ml of dimethylformamide was suspended 0.42 g of 60% sodium hydride in oil, followed by addition of 0.878 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1 hour. Following addition of 40 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.16 g of the title compound. m.p. 181°-184° C.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[S:12]1[C:11]2[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:15]=2[CH:14]=[CH:13]1
Reactant: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2sccc2[nH]1
Yield: 66.1 %

Procedure:
A solution of ethyl 2-azido-3-(2-thienyl)propenoate (0.45 g) in xylene (10 ml) was heated at reflux for 30 minutes, concentrated in vacuo and the residue purified by column chromatography using isohexane-15% ethyl acetate as eluent to give the product as a pale yellow solid (0.26 g, 66%), NMR d(CDCl3) 1.40 (3H, t), 4.39 (2H, q), 6.98 (1H, d), 7.18 (1H, s), 7.35 (1H, d), 9.30 (1H, bs) M/z (−) 194 (M-H+), 166.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COc1ccc(Br)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(OCC2C=CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1
Yield: 86.4 %

Procedure:
Piperidine (0.42 mL, 4.2 mmol) was added to a suspension of 4-methoxybenzaldehyde (0.51 mL, 4.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.83 g, 3.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(4-Methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.95 g, 86%) was obtained as a pale yellow crystalline solid; mp 194-195° C., lit. [24] 195-198° C.; δH (500 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 6.72 (d, J=15.5 Hz, 1H, CH═CHCO), 6.98 (d, J2′,3′=J5′,6′=9.0 Hz, 2H, H3′, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.57 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.68 (d, J2′,3′=J5′,6′=9.0 Hz, 2H, H2′, H6′), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.60 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C.[C:18]([N:25]1[CH2:28]C(=O)[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.ClCCCl.CC(O)=O>[C:21]([O:20][C:18]([N:25]1[CH2:28][CH:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:26]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)NCCNc1ncccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(NCCNc2ncccn2)C1
Reaction time: 5 h
Yield: 35.7 %

Procedure:
A solution of intermediate 2a (610 mg, 2.56 mmol) in TFA (2 mL) and CH2Cl2 (8 mL) was stirred at room temperature for 2 h. The solution was concentrated. The resulting residue was stirred with N-Boc-azetidin-3-one 1a (526 mg, 3.07 mmol) and Na(OAc)3BH (651, 3.07 mmol) in 1,2-dichloroethane (8 mL) and HOAc (0.8 mL) at room temperature overnight. Additional 1a (175 mg, 1.02 mmol) and Na(OAc)3BH (217 mg, 1.02 mmol) was added. The reaction was stirred for another 5 h before it was quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 6% MeOH/CH2Cl2) gave intermediate 2b as light yellow solid (268 mg).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[C:13]([Cl:28])[C:12]2=[O:29])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[Cl:28][C:13]1[C:12](=[O:29])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=2)[C:16]([CH3:17])=[CH:15][C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 99.2 %

Procedure:
Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate (30.4 g, 70.1 mmol) was suspended in methanol (150 mL) and dioxane (150 mL). 2.5N NaOH (30.8 mL, 77.08 mmol) was added. The resulting mixture was heated to 50° C. for 8.0 hours. The reaction was partially concentrated and the heterogenous mixture was acidified (pH 2) with 1N Hcl. The precipitate was collected by filtration washing with H2O and diethyl ether to afford a white solid (29.2 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31 (dt, J=2.4, 9.9 Hz, 1H), 7.18 (app d, J=8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.60 (s, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 420.0821 (M+H calcd for C21H17ClF2NO4 requires 420.0809).
Reaction SMILES: C([O:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=1)C(C)=C)C=CC.[C:17]1([C:19](=[CH:21][C:22](=[CH:24][CH:25]=1)[CH3:23])C)[CH3:18]>>[CH2:15]([CH:10]([CH2:11][C:12]([CH3:13])=[CH:18][C:17]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:19]=1)[CH:6]=[O:5])[CH3:14]
Reactant: Cc1ccc(C)c(C)c1
Reactant: C=C(C)C(OCC=CC)c1ccc(C)cc1
Product: CCC(C=O)CC(C)=Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
The 1-[1-(2-butenyloxy)-2-methyl-2-propenyl]-4-methylbenzene (50.12 g, 0.232 mol), [RuCl2(PPh3)3] (400 mg), BHT (50 mg) and pseudo-cumene (60 ml) were heated together in an autoclave placed in an oil bath at 180° C. for 5 hours. After cooling to room temperature, the pseudo-cumene was distilled off (40° C./5 mbar) and the residue chromatographed on silica gel (eluent: heptanes/ethyl acetate 50:1 to 25:1), then distilled under vacuum through a 20-cm Widmer column. 18.1 g of the desired product were obtained (yield=36%). B.P.=80° C./0.001 mbar
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CN(C=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][OH:16])[CH3:6]
Reactant: OCCc1ccccc1O
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccccc1CCO)OCC
Temperature: 80 °C

Procedure:
2-bromo-1,1-diethoxyethane (5.13 g) was added to a stirred mixture of cesium carbonate (8.49 g) and 2-(2-hydroxyethyl)phenol (3.00 g) in DMF (20 mL). After 5 minutes the reaction mixture was heated at 80° C. 16 h, the reaction mixture was allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water (×3) then evaporated. Purification by silica gel chromatography eluting with ethyl acetate:iso-hexanes, 1:3 gave the subtitle compound as a green oil. Yield 3.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[NH2:22][CH2:21][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: NCC(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by combining 4,4′-dichlorobenzophenone (5 g, 20 mmol) and zinc iodide (480 mg, 1.49 mmol) in DCM (100 mL). Trimethylsilyl cyanide (2.17 g, 21.9 mmol) is added, and the reaction is stirred at room temperature for 18 hours. The reaction is washed with water (100 mL) and dried over magnesium sulfate, before filtering and removal of the solvent under reduced pressure. The residue is redissolved in dry THF (40 mL), 1.0M borane in THF (40 mL) is added, and the reaction is stirred at reflux for 24 hours. After cooling, the volatile components are removed under reduced pressure, the residue is taken up in methanol (100 mL). Concentrated hydrochloric acid is added, and the reaction is refluxed for a further 2 hours, before once more removing the volatile components under reduced pressure, to give the title compound as a hydrochloride salt.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[NH2:10][C:11](N)=[O:12].O>CN1CCCC1=O>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:11]([NH2:10])=[O:12])=[C:8]([OH:9])[N:1]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1c(O)nc(O)nc1O
Yield: 96.5 %

Procedure:
A mixture of 128 grams of barbituric acid and 120 grams of urea in 200 ml of 1-methyl-2-pyrrolidone was heated at 145° for 15 minutes. Hot water was then added to the reaction mixture; a white solid precipitated and was collected by filtration. The precipitate was washed with hot dimethylformamide and dried to give 165 grams of 2,4,6-trihydroxy-5-pyrimidinecarboxamide; mp, >270°. The mass spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[N+]1([O-])CC[O:22]CC1>C(#N)C>[Cl:1][C:2]1[C:11]([CH:12]=[O:22])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
89.2 g (0.26 mol) of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate are dissolved in 500 ml of acetonitrile and treated at room temperature with 52.0 g (0.444 mol) of N-methylmorpholine N-oxide. The batch is stirred at room temperature for 18 hours, concentrated in a rotary evaporator, taken up in dichloromethane and washed several times with water. After concentration in the rotary evaporator, 57.3 g (80% of theory) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate having a melting point of 104-105° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([O:30][CH2:31][CH2:32][NH2:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:28]([O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:29]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (36 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (39 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (t, 1H), 7.99 (s, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.44 (br, 2H), 7.36 (d, 1H), 7.30 (dd, 1H), 3.61 (s, 3H), 3.46 (q, 2H), 3.41 (t, 2H), 2.82 (m 2H), and 1.07 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O:11][C:12](=O)[CH:13]([CH3:15])[OH:14])(=O)C.N=C=N>O>[C:12]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1)(=[O:11])[CH:13]([CH3:15])[OH:14]
Reactant: Nc1ccncc1
Reactant: CC(=O)OC(=O)C(C)O
Agent: N=C=N
Solvent: O
Product: CC(O)C(=O)c1cc(N)ccn1
Reaction time: 24 h

Procedure:
A mixture of 4-aminopyridine (5 mmol) and lactyl acetate (5 mmol) is added to 0.1M carbodiimide [N-cyclohexyl-N′-2-(4-methyl-morpholinium) ethyl carbodiimide-p-toluene sulphonate or CMC] in distilled water adjusted to pH 4.5, such that the final volume is 200 ml. The reaction is performed for 24 hours at 4° C. The resulting lactyl-4-aminopyridine is collected as an oil and purified to pharmaceutical purity.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:20]([CH3:19])[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (0.3 g, 1.0 mmol) in 1,2-dichloroethane (3.6 mL) was added N,1-dimethylpiperidin-4-amine (1.4 mmol), and AcOH (1.0 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (1.1 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford pure N-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (0.2 g). MS (Q1) 410 (M)+