Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCc1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc(F)c2F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,3-difluorocinnamic acid (2.8 g, 15.2 mol) (commercially available from Lancaster) (Intermediate TWENTY-1) in ethanol (100 mL) was hydrogenated with H2 (balloon) and 10% Pd/C (0.3 g) at rt for 16 h. The mixture was filtered through Celite® and the solvent was evaporated to give 3-(2,3-difluorophenyl)-propionic acid as a solid, 2.68 g (98%). A mixture of 3-(2,3-difluorophenyl)-propionic acid (2.7 g, 14.4 mmol) in CH2Cl2 at 0° C. was treated with oxalyl chloride (8.7 mL, 2 M in CH2Cl2) and a few drops of DMF. The reaction mixture was stirred for 2 h at rt. The solution was decanted from the dark colored residues and the solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (20 mL) and added to a mixture of AlCl3 (1.92 g, 14.4 mmol) in CH2Cl2 (25 mL). The mixture was heated at 50° C. for 16 h. The entire mixture was poured into ice water. The aqueous phase was removed and extracted with CH2Cl2. The organic layers were combined, washed with sat. NaHCO3 solution, brine, and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel with 20% EtOAc:hexane to give 4,5-difluoro-indan-1-one (Intermediate TWENTY-2), 1.65 g (68%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([OH:13])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.C[O-].[Na+].CN([CH:26]=[O:27])C>>[CH2:15]([O:27][CH2:26][O:13][C:5]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:14][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCOCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
The temperature is maintained at -20° to -10° C during the addition. When the exotherm subsides, the addition of gas is discontinued and the reaction mixture allowed to warm up to 5°-10° C. The reaction mixture is washed with chilled water (100 ml) and the organic layer separated. The organic layer is filtered through calcium chloride and added to a solution of the sodium salt of 1-methyl-3,5-diphenyl-4-pyrazolol in DMF. The 4-pyrazolol solution is prepared by stirring 1-methyl-3,5-diphenyl-4-pyrazolol (10 g, 0.04 mole) with sodium methoxide (2.16 g, 0.04 mole) and dry DMF (100 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].I[CH2:35][CH3:36]>CN(C)C=O>[CH2:35]([N:13]([C:12]1[C:3]([O:2][CH3:1])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:36]
Reactant: CCI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc2ccccc2nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
1-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(106 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and was sodium hydride(6.0 mg, 0.25 mmol) was added and the solution was stirred at room temperature for 15 min. Iodoethane(35 mg, 0.25 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N)C>CN(C=O)C.C(Cl)Cl>[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([NH:9][CH2:10][CH3:11])=[O:30]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1c(C(=O)O)ccc(F)c1Br
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(F)c(Br)c1N
Temperature: 23 °C
Reaction time: 17 h
Yield: 77.4 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU; Aldrich; 5.36 g, 14.10 mmol) was added to a mixture of 2-amino-3-bromo-4-fluorobenzoic acid (Example 719; 3.00 g, 12.82 mmol), ethylamine (2.0 M in MeOH; Aldrich; 7.05 mL, 14.10 mmol), and TEA (2.68 mL, 19.23 mmol) in a mixture of DMF (10 mL) and DCM (10.00 mL), and the resulting solution was stirred at 23° C. for 17 h. The reaction mixture was then diluted with DCM (100 mL), and the resulting solution was sequentially washed with water (2×80 mL), 0.5 N aqueous NaOH (50 mL), and brine (50 mL), then concentrated in vacuo. The residue was chromatographically purified (silica gel, 0-60% EtOAc/hexanes) to yield 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (2.59 g, 9.92 mmol, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, t, J=4.5 Hz), 7.59 (1H, dd, J=8.8, 6.3 Hz), 6.86 (2H, br. s.), 6.57 (1H, t, J=8.5 Hz), 3.20-3.29 (2H, m), 1.11 (3H, t, J=7.2 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −101.26 (1F, s). m/z (ESI, +ve) 260.9/262.9 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:25]>C(Cl)Cl>[ClH:25].[ClH:25].[CH3:17][C@H:16]1[C:9]2[C:8]([N:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Yield: 99 %

Procedure:
(S)-tert-butyl 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 4 mL) in DCM (20 mL) for 6 hours to provide (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.18 g, 99%). MS (APCI+) [M+H]+ 233.
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[N:4][N:5]([CH3:16])[C:6]=1[CH2:7][NH:8]C(=O)OC(C)(C)C.[ClH:19].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COC(C)(C)C>C(OCC)C>[ClH:19].[NH2:8][CH2:7][C:6]1[N:5]([CH3:16])[N:4]=[C:3]2[C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]=[C:17]2[NH2:18]
Reactant: Cn1nc(C#N)c(Br)c1CNC(=O)OC(C)(C)C
Reactant: Nc1ccccc1B(O)O
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cn1nc2c(N)nc3ccccc3c2c1CN
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 94.6 %

Procedure:
A modification of the method described in Example 1283 was used to couple tert-butyl (4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)methylcarbamate (1.43 g, 4.53 mmol) with 2-aminophenylboronic acid hydrochloride (1.57 g, 9.06 mmol). The reaction was completed in 70 minutes. tert-Butyl methyl ether was used instead of chloroform in the work-up procedure. The coupling product was purified by IFC (silica cartridge, eluting with 40% to 60% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for 24 hours. Diethyl ether (50 mL) was added after the reaction cooled to room temperature. A precipitate was present and was isolated by filtration and dried on the vacuum filter funnel for three hours to provide 1.13 g of 1-(aminomethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride as a white solid, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#CC)[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][CH2:21][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC#CCC(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(CCNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 3-chloroaniline (4.33 mL, 40.9 mmol), the product from Step F (ca. 41 mmol), and crushed 4 Å molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, sat. NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[N:11]=[N:10][C:9]=1[CH2:17]O)[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:9]1[N:10]=[N:11][C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=1[O:7][CH2:5][CH3:6]
Reactant: CCOc1cc(OCC)c(CO)nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(OCC)c(CCl)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Excess SOCl2 is added to a stirred solution of (4,6-diethoxy-pyridazin-3-yl)-methanol (174 mg, 0.88 mmol) in CH2Cl2 (4 mL). The reaction mixture is stirred at room temperature for 4 hours. The solvent is then removed in vacuo and toluene (4 mL) is added and evaporated to dryness. Flash column chromatography purification (eluted with 3:1 Hexane, EtOAc) of the residue provides the title product as a clear oil. H1 NMR δ (CDCl3) 6.28(s, 1H), 4.78 (s, 2H), 4.54 (q, 2H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 1.48 (t, 3H, J=7.2 Hz), 1.41 (t,3H, J=7.2 Hz,) LC-MS (M+1) 217.1.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: COc1ccc(C2CCNCC2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(C2CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (2.2 g) and 4-(2,4-Dimethoxy-phenyl)-piperidine (2.0 g) are dissolved in Acetone (30 ml) and potassium carbonate (3.6 g) is added to the solution. The reaction mixture is stirred for 6 h at room temperature. The mixture is diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and filtrated. Ethyl acetate is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=1:1 (v/v).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1.NC(N)=[S:16]>C(O)C>[SH:16][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2cc3c(cc2s1)OCO3
Reactant: NC(N)=S
Solvent: CCO
Product: Sc1nc2cc3c(cc2s1)OCO3

Procedure:
The product from Step 2 (0.67 g) and thiourea (0.26 g) were mixed in ethanol (20 cm3) and stirred and heated to reflux under an atmosphere of nitrogen for 18 hr. The pale yellow solid which precipitated was filtered from the solution at ambient temperature, washed with ethanol and sucked to dryness to give the required product. 1H NMR (DMSO): δ7.26(1H,s); 6.80(1H,s); 6.02(2H,s); mp 265° C. (dec); M+ =211.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6]O)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][Cl:15])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(C(C)C)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 2-isopropyl-6-methylbenzylalcohol (1.7 g, 10.4 mmol) in methylene chloride (20 ml) was added thionyl chloride (1.7 g, 14 mmol) and the reaction was stirred for 1 h. at room temperature. The solvent was evaporated under reduced pressure and the residue was filrated through silica gel using methylenechloride as eluent. The solvent was evaporated under reduced pressure to give 1.83 g (96%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2.P([O-])(O)(O)=[O:18].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([OH:18])=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(cc1C(=O)O)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a mixture of 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (2.0 g) synthesized by a known method (WO2001/077100), sodium dihydrogen phosphate (1.63 g) and 2-methyl-2-butene (4.3 ml) in tert-butanol (52 mL) and water (8 mL) was slowly added sodium chlorite (2.89 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. After cooling to 0° C., the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, and washed with hexane to give 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (0.72 g, 34%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 53.9 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.718 g, 2.06 mmol) and 4-Butylidenepiperidine (0.301 g, 2.16 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF06) (0.40 g, 54%). 1HNMR (CDCl3) δ 7.01 (dd, J=3.0 Hz, J=10.2 Hz, 1H), 6.90 (dd, J=5.4 Hz, J=8.6 Hz, 1H), 6.89-6.63 (m, 1H), 5.12 (t, J=7.4 Hz, 1H), 4.63-4.51 (m, 2H), 4.02-3.89 (m, 1H), 2.51-2.44 (m, 2H), 2.32-2.23 (m, 5H), 2.21-2.15 (m, 5H), 2.11-2.03 (m, 1H), 1.98-1.93 (m, 2H), 1.39-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 136.2, 130.0 (d, J=10.8 Hz), 122.7, 117.6 (d, J=9.3 Hz), 109.5 (d, J=23.1 Hz), 103.4 (d, J=29.1 Hz), 67.8, 63.7, 56.6, 55.8, 45.7, 36.2, 29.4, 29.3, 28.4, 23.3, 17.0, 13.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH2:29][CH3:30]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:28][CH2:29][CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
tert-Butyl 4-((benzyloxycarbonylamino)methyl)piperidine-1-carboxylate (0.950 g, 2.726 mmol) was dissolved in dry DMF (25 mls). To this was added sodium hydride (0.164 g, 4.090 mmole, 60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 30 minutes. Propyl iodide (0.695 g, 4.090 mmole) was then added and the mixture stirred at room temperature for 16 hours, then diluted with brine (200 mls), extracted twice with EtOAc, extracts washed twice with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (100 g Biotage Snap cartridge, 30% EtOAc/Hexanes) to give 0.280 g (26%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH2:19]([OH:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:19][CH3:20])[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCO
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccc(C)o2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 245 (M+H+, 100), 217 ([M+H—CH2═CH2]+, 80).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:7].Cl.[Cl:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.[I-].[K+]>CN(C)C=O>[ClH:9].[ClH:7].[ClH:9].[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: C1COCCN1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCN4CCOCC4)CC3)nc3ccccc32)cc1
Temperature: 70 °C
Yield: 18.3 %

Procedure:
A mixture of 3.6 parts of morpholine, 4.8 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in methanol. The salt is filtered off and dried, yielding 1 part (18.3%) of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-morpholinyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine trihydrochloride; mp.+300° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])C.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:6]1[CH2:5][C:4](=[O:3])[NH:9][C@@H:8]([CH:10]([CH3:12])[CH3:11])[C:7]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](N)C(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Yield: 0.1 %

Procedure:
A solution of 4.2 gm (14.4 Mol) N-benzyl-N-[(S)-valinyl]glycine ethyl ester and 1.2 mL (0.98 mMol) pyridine in 85 mL toluene was heated at reflux for 3 hours. The reaction mixture was then concentrated under reduced pressure to provide 3.4 gm (96%) of the desired compound as an oily solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.Cl>O.C(#N)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:23]=[C:24]([CH2:25][NH:1][C:2]2[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(O)c1cccc(NCc2cccc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The solution was stabilized at about 70° C. and a solution of 38.92 g (0.20mole) of 3-(trifluoromethyl)benzyl chloride in 75 ml of acetonitrile was added dropwise. The resulting orange solution was refluxed for 4 hrs, then acidified by the dropwise addition of 42 ml of conc. HCl while simultaneously removing 105 ml of acetonitrile by distillation. After standing overnight, a flocculent cream-colored solid crystalized which was removed by vacuum filtration. The collected solids were then slurried in 300 ml of warm (60° C.) water for 20 minutes and then filtered. The slurrying process was repeated using 300 ml of boiling methanol and the solids isolated by vacuum filtration. Air-drying in vacuo at about 60° C. gave 15.4 g (23.2% yield) of purified 3-(((3-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: ClCc1ccccc1Cl
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccccc3Cl)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-chlorobenzyl chloride (0.25 ml), potassium carbonate (309 mg) and DMF (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain methyl 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (413 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (Kruger J, Mann F. G, J. Chem. Soc., 1955, 2755) (700 mg, 4.41 mmol) in ethanol (10 ml) was added 4-methoxyaniline (1.087 g, 8.82 mmol), followed by sodium acetate (362 mg, 4.41 mmol). The mixture was heated under reflux for 16 hours, cooled to room temperature and diluted with water (30 ml). The resulting precipitate was collected by filtration, washed with water (×3) and dried in vacuo to afford the title compound (800 mg, 74%); MS (ES+) m/e 309 [M+H]+.