Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[C:13]([C:24]([N:38]3[CH2:37][CH2:36][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:40][CH2:39]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 96.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(3-fluoro-4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.191 g, 96%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.C(OC(=O)[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][CH2:40][CH3:41])[N:34]=1)(C)(C)C>>[NH2:32][C:33]1[N:34]=[C:35]([N:39]([CH2:40][CH3:41])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCNc1cccc(NC(=O)OC(C)(C)C)n1
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(N)n1

Procedure:
The title compound was prepared by procedure analogous to that described in example 325, step 2 using 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl chloride and (6-ethylamino-pyridin-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:17].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])OC2C=CC=CC=2)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:28](=[O:36])[NH:27][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[C:4]([CH3:17])[CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNc1ccc(OCc2ccccc2)cc1C
Reactant: O=C(Nc1ccc(F)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1N(C)C(=O)Nc1ccc(F)cc1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 62.9 %

Procedure:
After dissolving N-methyl-4-benzyloxy-2-methylaniline (2.64 g, 11.61 mmol) in N,N-dimethylformamide (20 ml), sodium hydride (1.16 g, 29.00 mmol, 60% in oil) was added and the mixture was stirred at 85° C. for 45 minutes under a nitrogen atmosphere. Phenyl N-(4-fluorophenyl)carbamate (3.50 g, 12.76 mmol) was added and the mixture was further stirred at 85° C. for 1 hour under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and subjected to crude purification by NH silica gel column chromatography (hexane-ethyl acetate-ethanol) to obtain N′-(4-benzyloxy-2-methylphenyl)-N-(4-fluorophenyl)-N′-methylurea (2.66 g) as a yellow oil. This was dissolved in methanol (50 ml), and then 10% palladium carbon (0.2 g) was added and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then filtrate was washed with ethanol, and the solvent was distilled off under reduced pressure. The precipitated crystals were suspended in ethanol, the suspension was diluted with diethyl ether and hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (0.83 g, 3.0258 mmol, 41.86%) as brown crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](OCC)(OCC)OCC.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[S:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: Nc1ccccc1S
Reactant: CCOC(CCl)(OCC)OCC
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A solution of 2-chloro-1,1,1-triethoxyethane (5.9 g) and 2-aminothiophenol (2.5 g) was heated at 80° C. for 15 minutes. After cooling to room temperature, it was dissovled in methylene chloride (30 ml) and the resulting solution was washed with 3N HCl (10 ml) and then with water (20 ml). The organic portion was evaporated and the residue chromatographed over silica gel to obtain 2-chloromethylbenzothiazole (3.35 g; 90% yield), m.p. 34° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([C:16](O)=[O:17])[CH:2]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:17][CH2:16][C:3]1[CH:2]=[CH:1][C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccccc1C=C2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of dibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product (m.p., 111°-112° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:14](#[N:16])[CH3:15]>>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])[CH:7]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: O=Cc1cccc(OCCCO)c1
Product: N#CCC(O)c1cccc(OCCCO)c1

Procedure:
Addition of acetonitrile to 3-(3-hydroxypropoxy)benzaldehyde gave 3-hydroxy-3-[3-(3-hydroxypropoxy)phenyl]propionitrile as yellow oil. Yield (1.80 g, 45%): 1H NMR (400 MHz, CDCl3) δ 7.28-7.33 (m, 1H), 6.94-6.99 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.77 (d, J=6.0 Hz, 2H), 2.02-2.09 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(N1CCC(CC2C=CC=CC=2)([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)C1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:20]=[O:29])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.3 mL) was added at room temperature to a solution of 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.092 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into aqueous NaOH (1.0 M), diluted with water and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 10% of MeOH in DCM+0.5% of NH4OH) to give 15 mg (48% yield) of 3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone as a yellow oil. This material was dissolved in DCM and a solution of HCl (1.0 M in Et2O, 1.1 equivalents) was added, the resulting mixture was concentrated under reduced pressure and the residue was triturated with Et2O to give 17 mg of 3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone hydrochloride as a white solid; MS=334 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@H:7]([OH:10])[CH2:8][OH:9])=[O:4].CC(C)([O-])C.[K+].CO.O>C(O)(CC)(C)C>[OH:9][CH2:8][C@@H:7]1[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:10]1
Reactant: O=C(CCl)NC[C@H](O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCC(C)(C)O
Product: O=C1CO[C@H](CO)CN1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
(S)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (4.77 g, 28.45 mmol) in tert-amyl alcohol (75 mL) was added over 2 h to a stirred solution of potassium tert-butoxide (3.59 g, 21.4 mmol) in tert-amyl alcohol (25 mL) at room temperature under nitrogen. After 1 hr, methanol (12 mL) and water (0.7 mL) were added and the reaction mixture was stirred for an additional 20 min. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (2/8), to give the title compound as a white solid (1.26 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:8].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[CH:6][C:7]=1[O:8][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
In 70 ml of N,N-dimethylformamide was dissolved 7.1 g (0.028 mol) of 4-chloro-2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone, and thereto were added 4.5 g of p-chlorobenzyl chloride and 5.4 g of anhydrous potassium carbonate. The resulting reaction mixture was heated under stirring on an oil bath at 120° to 130° C. for 2 hours. After allowing to cool, the reaction mixture was poured into 500 ml of water. The solid thus precipitated was taken out by filtration, washed with water, dried and then recrystallized from an ethyl acetate-benzene mixture to give 6.3 g of the intended compound.
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[C:24]([NH:36][CH3:37])[N:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[C].[Pd].O1CCCC1>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[C:24]([NH:36][CH3:37])[N:23]=[C:22]2[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:39][CH:38]=2)[CH:17]=1
Reactant: [H][H]
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(OCc4ccccc4)cc3)c2)c2cc(OC)c(OC)cc2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(O)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
388 mg of 4-[3-(4-benzyloxybenzoylamino)phenyl]-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 20 and 200 mg of 10% palladium-carbon powder (hydrate) were suspended in a mixed solvent of 10 ml ethyl acetate and 10 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 3 days at ordinary pressure at room temperature. The reaction solution was filtered, and the filtrate was evaporated. Then, the crude product was recrystallized from hexane-ethyl acetate to give 278 mg of the title compound as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].[OH-].[K+]>O>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=[C:7]1[CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 99.4 %

Procedure:
A mixture of 4-piperidine carboxylic acid (5.30 g, 40 mmol), 1,2-diaminobenzene (4.32 g, 40 mmol) and polyphosphoric acid (40 g) were heated to 190° C. for 14 hours. Cooled, diluted with water (150 ml) and basified with 50% KOH to pH 8. Solution cooled in an ice/salt bath to give a precipitate which was collected by filtration and washed with water. Solid dried in vacuo to afford the title compound (8.0 g, 100%).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][C:23]1([CH3:37])[C:27]([CH3:29])([CH3:28])[O:26][B:25]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[O:24]1.C([O-])([O-])=O.[K+].[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl.C(Cl)Cl>[OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH:36][C:33]2[CH:32]=[CH:31][C:30]([B:25]3[O:26][C:27]([CH3:29])([CH3:28])[C:23]([CH3:37])([CH3:22])[O:24]3)=[CH:35][CH:34]=2)=[O:12])[C:6](=[O:13])[N:5]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A flask was charged with 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.500 g, 1.72 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.377 g, 1.72 mmol), K2CO3 (0.476 g, 3.44 mmol), HATU (0.982 mg, 2.58 mmol) and CH2Cl2 (10 mL) and the mixture stirred at rt for 14 h. The mixture was diluted with CHCl3 (100 mL), washed with water and sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated. The title compound was obtained as a white solid (873 mg). MS (ESI pos. ion) m/z: 492 (MH+). Calc'd exact mass for C27H34BN3O5: 491.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:23])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:12](=[O:23])[CH:13]([CH2:16][C:17]3[N:18]=[CH:19][N:20]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:21]=3[CH3:22])[CH2:14][CH2:15][C:4]=12)[CH3:2]
Reactant: CCc1c2n(c3ccccc13)C(=O)C(Cc1nc[nH]c1C)CC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A mixture of 8,9-dihydro-10-ethyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6-(7H)-one (0.84 g), trityl chloride (1.0 g) and triethylamine (515 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with chilled water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (2% methanol-chloroform) gave 8,9-dihydro-10-ethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (690 mg).
Reaction SMILES: [CH2:1]([N:3](C)[CH2:4][CH2:5][CH2:6]O)[CH3:2].[CH2:9]([NH:11][C:12]([NH:14][CH3:15])=[S:13])[CH3:10].Br>>[CH2:9]([NH:11][C:12](=[N:14][CH3:15])[S:13][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])[CH3:10]
Reactant: CCN(C)CCCO
Reactant: CCNC(=S)NC
Agent: Br
Product: CCNCCCSC(=NC)NCC

Procedure:
A mixture of 3-(ethylmethylamino)propanol, N-ethyl-N'-methylthiourea and aqueous hydrobromic acid is boiled under reflux to give the dihydrobromide salt of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13]C3)[CH:10]=[C:6]2[CH:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH2:11]([C:9]1[CH:10]=[C:2]2[N:3]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=3)[CH:5]=[C:6]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]2[N:8]=1)[CH3:13]
Reactant: C1COCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3cc(C4CC4)nn3c(Cl)n2)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 50 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-c]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and morpholine (36 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAC to give the titled compound (43 mg, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.87 (s, 2 H), 8.05-7.92 (m, 2 H), 7.59 (d, J=8.6 Hz, 2 H), 7.36 (s, 1 H), 6.19 (s, 1 H), 5.18 (s, 1 H), 3.91-3.79 (m, 4 H), 3.77-3.69 (m, 4 H), 2.74 (q, J=7.6 Hz, 2 H), 1.45 (s, 6 H), 1.35-1.23 (m, 3 H); ESI-MS: m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH:16]1([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2([CH3:15])[CH3:1])[CH2:19][CH2:18][CH2:17]1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C(C)(C)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (413 mg, 1.65 mmol) was dissolved in DCE (15 mL). TEA (1.148 mL, 8.23 mmol) was added, followed by cyclobutanone (231 mg, 3.29 mmol) and sodium triacetoxyborohydride (524 mg, 2.47 mmol). The reaction mixture was stirred for 5 h and a few drops of acetic acid were added. The reaction mixture was heated at 40° C. for 4 days, cooled to rt, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give a dark yellow oil. The crude title compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=CC=CC=1B(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:30])=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: OB(O)c1ccccc1Cl
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1Cl

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 2-chlorophenylboronic acid, the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Mercapto-5-methoxybenzimidazole (1.8 g, 10.0 mmol) is suspended into 25 mL of tetrahydrofuran (THF) under argon. Then, 575 mg (12.0 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. A solution of 5-nitro-2-furaldehyde (1.4 g, 10.0 mmol) in 30 mL of THF is then added dropwise and the reaction mixture is stirred at room temperature for 2 h, upon which it is poured on ice and extracted 3 times with 50 mL of ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated in diisopropyl ether and the resulting suspension is stirred for 1 h. The solid is filtered, washed twice with diisopropyl ether and dried. 0.75 g of 5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow powder. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.92 g of additional 5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow powder. mp: 94-99° C.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].S([O-])([O-])(=O)=O.[Mg+2].SC(O)C>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: CC(O)S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The stoichiometry of our immobilized aspartase, prepared as described in the previous examples, was determined using a 1 g column of immobilized aspartase, approximately 5,000 units per gram activity, operating at 40° C. The feedstock was 1.5 molar ammonium fumarate at pH 8.5 containing 10-3 molar each of magnesium sulfate and mercaptoethanol. The contents of the flask was circulated upflow through the jacketed column with the effluent being returned to the feed flask. The amount of fumaric acid consumed and aspartic acid formed was measured at various times using high-pressure liquid chromatography with results being summarized in Table 3.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:12][C:5]1([O:6][CH3:7])[C:8]([OH:9])=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[CH2:4]1
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: COC1(Cl)CC(C=O)=CC=C1O
Yield: 94 %

Procedure:
Vanillin (100 g) is dissolved in chloroform (800 ml), and thereto is blown with stirring chlorine gas at room temperature for about one hour to give the white solid. The compressed air is blown into the mixture to remove the chlorine being dissolved therein, and the precipitated solid is collected by filtration, washed, and dried. The mother liquor is concentrated, and triturated with diethyl ether, and the precipitates are collected by filtration, washed, and dried. The former precipitated solid and the powder thus obtained are combined to give 3-chlorovanillin (115.25 g).