Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].CN1CCOCC1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 0.120 g (purity: 76% corresponds to 0.25 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 1E) in 2 ml N,N-dimethylformamide was treated at room temperature with 0.052 g (0.27 mmol, 1.1 eq.) of 3,4-dichlorophenyl isocyanate and 0.136 ml (1.24 mmol, 5 eq.) of 4-methylmorpholine. The reaction was stirred at room temperature overnight. To the solution was added 5 mg (0.02 mmol, 0.1 eq.) of 3,4-dichlorophenyl isocyanate. After 1 h, no starting material was left; the solution was slowly added to a solution of sat. aq. sodium hydrogencarbonate, followed by extraction with ethyl acetate (3 times). The organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum. The crude product was purified by flash chromatography (20 g SiO2-column, dichloro-methane/methanol 2:98, 5:95, 1:9, 1:4) to give 0.061 g (51%) of the title compound as white solid. MS: 483.4 (MH+, 2Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:24][CH:23]2[OH:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:24][C:23]2=[O:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-methylsulfonylphenyl)piperidin-3-ol (0.49 g, 0.91 mmol) obtained in Step 3 in 3 ml of dimethyl sulfoxide (DMSO), was added dropwise 0.5 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.5 g, 0.31 mmol) was added to the reaction mixture, which was then stirred for 2 hours, diluted with 20 ml of ethyl acetate, and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 210 mg of the titled compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:19]=[N:20][C:21]([CH:25]3[CH2:27][CH2:26]3)=[C:22]([Cl:24])[CH:23]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:19]=[N:20][C:21]([CH:25]3[CH2:27][CH2:26]3)=[C:22]([Cl:24])[CH:23]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoate (Preparation 26, 1.24 g, 3.01 mmol) in dichloromethane (22 mL) was added TFA (10.0 mL, 0.02 mol). The mixture was stirred under nitrogen at room temperature for 18 hours. Additional TFA (2.50 mL, 32.0 mmol) was added and stirring continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue dissolved in EtOAc (25 mL) and washed with 2M aqueous solution of HCl (25 mL). The resulting solid was filtered to afford the title compound (1.4 g, crude quant.) which was used with no further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([NH:20][CH3:21])[CH:17]=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[O:12])=[CH:6][CH:5]=1)[CH3:2].ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]([NH2:40])([CH3:39])[CH3:38]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:21][N:20]([C:29]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:35])[C:18]1[CH:17]=[CH:16][C:15]([N+:22]([O-:24])=[O:23])=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)[CH:19]=1
Reactant: CC(C)N
Reactant: CCOc1ccc(CC(=O)Nc2cc(NC)ccc2[N+](=O)[O-])cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)NC(C)C)ccc2[N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-ethoxy-N-[5-(methylamino)-2-nitrophenyl]-benzeneacetamide (2.20 g, 6.69 mmol) in 1,2-dichloroethane (100 mL) was stirred at room temperature under nitrogen as triphosgene (1.99 g, 6.69 mmol) and TEA (0.93 mL, 6.69 mmol) were added. After 30 minutes, DMAP (817 mg, 6.69 mmol), and isopropylamine (3.42 mL, 40.0 mmol) were added, and the contents were stirred for 16 hours at 45° C. The mixture was quenched with saturated aqueous NaHCO3 (40 m L) and the layers were separated. The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic layers were combined and washed with brine (50 mL), and dried with Na2SO4. The solids were filtered off and the filtrate concentrated in vacuo to a residue which was purified by column chromatography (75% EtOAc, 25% heptane on silica gel) to give the title compound (2.44 g, 88%), 1HNMR (400 MHz, CDCl3): δ 1.14 (d, J=6.4, 6H), 1.38 (t, J=7.1 Hz, 3H), 3.29 (s, 3H), 3.71 (s, 2H), 4.01 (q, J=7:1 Hz, 2H), 4.70 (s, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.00 (dd, J=2.5, 9.2 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 8.13 (d, J=9.2 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H). MS (ESI) (M+H)+=415.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[I:8][CH2:9][CH3:10]>C(OCC)(=O)C>[I-:8].[CH2:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:9][CH3:10])[CH:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCn1ccnc1
Solvent: CCOC(C)=O
Product: CCn1cc[n+](CC)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
1-ethylimidazole (4.81 g, 50 mmol, Sigma-Aldrich, 99%) in 50 mL ethyl acetate was cooled to 0° C. in an ice bath. Once cool, iodoethane (8.69 g, 55.7 mmol, Sigma-Aldrich, 99%) was added dropwise via an addition funnel. The solution was allowed to warm slowly to room temperature then stirred overnight. The precipitate was filtered off and washed with diethyl ether. The filtrate was collected and an additional 8.96 g (57.4 mmol) iodoethane was added and stirring continued at room temperature for 6 days. The solution was filtered again and the residue was washed with diethyl ether. The combined solids were dried overnight under high vacuum yielding 9.76 g white solids (38.7 mmol, 77% yield) that were used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: BrCCCCBr
Reactant: O=C1COc2ccccc2N1
Product: O=C1COc2ccccc2N1CCCCBr

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4H-benzo[1,4]oxazin-3-one and 1,4-dibromobutane.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:38])OC(C)(C)C)[CH2:19][N:20]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:30])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][C:69]=1[O:70][CH:71]([CH3:73])[CH3:72])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:38])[C:52]4[CH:67]=[CH:68][C:69]([O:70][CH:71]([CH3:72])[CH3:73])=[C:50]([Cl:49])[CH:51]=4)[CH2:19][N:20]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:30])=[CH:15][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2 yl)methyl]ethyl}carbamate (3.5 mmol) and hydrogen chloride in 1,4-dioxane (20 mL, 4.0 M) was stirred for 1 h at RT. The reaction was concentrated to dryness and redissolved in N,N-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (3.8 mmol), followed by stirring at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3×50 mL) and brine (1×50 mL). To the separated organic layer was added hexanes (150 mL) upon which a precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+H]+: 672.2.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].[C:8]([O:12]CC)(=[O:11])[CH:9]=[CH2:10].C(OC1CCCCC1)(=O)C(C)=C>C1(C)C(C)=CC=CC=1.C(O)CCC.C1(C)C(C)=CC=CC=1.C(O)CCC.O>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OCC
Reactant: C=CC(=O)O
Agent: C=C(C)C(=O)OC1CCCCC1
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: CCCCO
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 95 °C

Procedure:
A zinc acrylate polymer was prepared by the reaction of zinc oxide and naphthenic acid (acid value 200 mgKOH/g) with a carboxylic acid functional acrylic copolymer based on the monomers; Acrylic acid (25.0 mol %), Ethyl acrylate (62.9 mol %), Cyclohexyl methacrylate (9.6 mol %) and methoxy polyethyleneglycol methacrylate (MPEG350) (2.5 mol %). These components were mixed at a 1:1:1 molar ratio (zinc oxide:naphthenic acid:polymer carboxylic acid groups) in xylene/n-butanol (4:1 weight ratio) and heated and stirred at 95° C. until a clear solution was obtained resulting in a solution of zinc acrylate polymer of 45 wt % in xylene/n-butanol/water (41.7:12.3:1.0 wt %).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([OH:27])=O)[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].C[N:29]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([NH2:29])=[O:27])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CN1CCOCC1
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(=O)O)c2c(Cl)nc(C)nc21
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(Cl)nc(C)nc21
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
In 4 ml of tetrahydrofuran, 0.47 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetic acid was dissolved. After the reaction mixture was cooled to −15° C., 0.14 g of N-methylmorpholine and 0.19 g of isobutyl chloroformate was added thereto. After the reaction solution was stirred for 5 minutes, 0.085 ml of 28% aqueous ammonia was added thereto. The reaction mixture was warmed up to room temperature and was subsequently stirred overnight. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to yield 0.41 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide as an oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21].Cl>C1COCC1>[OH:22][CH:20]([CH3:21])[CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CC(O)CN
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80g, 10 mmol) in 100 ml of THF was cooled in an ice-bath and stirred while a solution of 1-amino-2-propanol (1.65g, 22 mmol) in 10 ml of THF was added dropwise over a period of 50 minutes. After stirring an additional 30 minutes in the ice-bath, the reaction mixture was acidified by the addition of 3 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting with 4×20 ml of saturated NaCl solution, the ethyl acetate solution was dried over Na2SO4 and the solvent evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give 2.02g (63.5%) of yellow crystalline product, m.p., 93.5-95°.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C([CH2:28][CH2:29][C:30](Cl)=[O:31])C=CC=1.[Al+3].[Cl-:34].[Cl-].[Cl-].Cl>C(=S)=S>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:30](=[O:31])[CH2:29][CH2:28][Cl:34])=[CH:17][CH:18]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: O=C(Cl)CCc1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCc1ccccc1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: S=C=S
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(C(=O)CCCl)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl(dimethyl)[(6-phenylhexyl)oxy]silane (21.00 g), 3-chlorophenylpropionyl chloride (9.14 g) and CS2 solvent (100 mL) were placed in a two neck flask equipped with a reflux condenser. The mixture was then cooled to −78° C. and AlCl3 (19.20 g) was added. The reaction mixture was stirred at −78° C. for 15 min., followed by: 0° C. for 20 min., 25° C. for 30 min., 40° C. for 40 min., 25° C. for 14 h. During the course of the temperature ramping, gas evolution (presumably HCl) was noted. The reaction was then quenched with several portions of 100 mL water/30 mL conc. HCl and the resulting mixture was transferred to a separatory funnel. The organic products were extracted into chloroform (4×200 mL). The chloroform fractions were combined and dried over MgSO4. The solvent was then removed by roto-evaporation to give a tan oil which solidified on standing overnight. 1H NMR shows the presence of resonances consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[OH:10][S:7]([OH:11])(=[O:9])=[O:8].[O:8]=[S:7](=[O:10])=[O:9].[C:3]([NH2:4])(=[O:8])[C:2]([CH3:6])=[CH2:1]
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Product: C=C(C)C(N)=O
Product: O=S(=O)=O

Procedure:
reacting acetone cyanohydrin with sulphuric acid or an oleum, in order to obtain methacrylamide;
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]([O:27]C)=O)[CH2:16][CH2:17][NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:25]2=[O:27])=[CH:11][CH:10]=1
Reactant: COC(=O)N(CCNc1cccnc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(Cl)cc2)CCN1c1cccnc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A 10 ml toluene solution of 4.54 g (14.8 mmol) of N-(4-chlorophenyl)-N-methoxycarbonyl-N'-(3-pyridyl)ethylenediamine in a 100 ml round-bottomed flask was heated gradually and, while distilling off toluene, it was heated for 1.5 hours at 190° to 210° C. The amorphous reaction mixture was cooled to room temperature and methylene chloride was added to dissolve. This was purified by column chromatography (silica gel, ethyl acetate:n-hexane=5:1) to obtain 2.28 g (yield 56%) of 1-(4-chlorophenyl)-3-(3-pyridyl)-2-imidazolidinone as brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)([CH3:32])([CH3:31])[CH3:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.8 %

Procedure:
N-Benzyloxycarbonyl-L-valine (121.3 g), 1-hydroxybenzotriazole (130.5 g) and dry dimethylformamide (DMF) (800 ml) were placed in a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a calcium sulfate drying tube, under nitrogen atmosphere. The mixture was cooled to 0° for 15 min and proline t-butyl ester (82.6 g) in dry DMF (800 ml) was added at a fast dropwise rate over 2 h while the temperature of the reaction mixture was maintained at 0°. Dicyclohexylcarbodiimide (109.4 g) in dry DMF (400 ml) then was added in one portion to the reaction mixture. The reaction was stirred at 0° for 3 h, allowed to warm to room temperature gradually over 1 h, and stirred for 48 h, whereupon the reaction was shown to be complete by TLC [Rf =0.55, chloroform:ethyl acetate (85:15)]. The reaction mixture was chilled in ice/water and filtered cold to remove the precipitated dicyclohexyl urea. The DMF was evaporated using a mechanical vacuum pump and at a maximum bath temperature of 40°. The remaining oil was diluted with ethyl acetate (2 liter), chilled, and refiltered to remove additional dicyclohexyl urea. The ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium chloride solution, saturated sodium bicarbonate solution (twice), and saturated sodium chloride solution), dried (MgSO4), and evaporated to afford crude benzyloxycarbonyl-L-valyl-L-proline t-butyl ester as an amber oil (208.3 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:20]([Si:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)Cl)([CH3:23])([CH3:22])[CH3:21].C(Cl)(Cl)Cl>ClCCl>[O:1]([CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCC1(CCO)CCCCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (6.41 g) in dichloromethane (170 mL) were added triethylamine (6.74 mL) and tert-butyldiphenylchlorosilane (11.1 mL) at room temperature. After stirring the solution at room temperature for 18 hours, chloroform was added to the solution, and it was washed in turn with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=85:15) to give the title compound (10.97 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[C:28](Cl)[N:27]=1>C(#N)C>[NH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:26]2[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccnc(NCC2CCNCC2)n1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared as follows: A 40 mL round-bottomed vial was charged with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1 equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), methyl 2,6-dichloropyrimidine-4-carboxylate (1.58 mmol, 1 equiv.), and then shaken at 85° C. for 72 h. The reaction mixture was concentrated under reduced pressure and purified on SiO2 using a Biotage and a 10-50% EtOAc/hexanes gradient to provide the desired protected amine (233 mg, 552 mg theoretical, 42%). Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared using the general TFA de-protection procedure and used directly in the general displacement procedure to provide the title compound (4 mg, 73.4 mg theoretical, 5%). LC-MS m/z 456.1 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:4]=2[CH:16]=1
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 3-bromomethyl-5-chlorobenzo[b]thiophene-2-carboxylate (11.0 g, 0.033 mol), methylaminoacetaldehyde dimethyl acetal (4.76 g, 0.04 mol) and potassium carbonate (11.4 g, 0.8 mol) in dry acetone (200 ml) was stirred for 48 hours, filtered and the filtrate concentrated to give 11.8 g (96%) of ethyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylate.