Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30]
Reactant: [H][H]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluoro phenyl)amino)benzoate (19.43 g, 45.56 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (18.06 g, 99.0%). 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.78 (s, 1H), 7.11 (m, 9H), 4.65 (s, 2H), 3.88 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][CH:41]=1)[CH2:17][N:18]([CH2:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[CH2:29][N:18]([CH2:17][C:16]1[CH:15]=[C:14]([CH:41]=[CH:40][CH:39]=1)[CH2:13][NH:12][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccnc(C)c1C(=O)NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (56 mg, 0.37 mmol) in SOCl2 (˜3 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.0 mL) and added to a stirring mixture of (3-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (147 mg, 0.37 mmol), Et3N (0.26 mL, 1.85 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred ovemight at room temperature. Purification of the crude yellow foam by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 200:1:1) afforded the desired amide (85 mg, 43%) as a light yellow foam.
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([O:18]CC)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].Cl>>[CH2:1]([C:4]1([C:13]([C:16]([OH:18])=[O:17])([CH3:14])[CH3:15])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)(C)C(=O)OCC)C(=O)NC(=O)NC1=O
Agent: Cl
Product: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Reaction time: 8 h

Procedure:
A mixture of 50 g. of 5-allyl-5-(1-ethoxycarbonyl-isopropyl)barbituric acid and 400 ml. of 1N hydrochloric acid was heated under reflux for 4 hours. The solution was allowed to stand at room temperature overnight and the precipitate was collected to yield 42.5 g. (94%) of the acid, m.p. 202°-203°.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[C:3]([CH3:39])[CH:4]=2)[CH3:15])=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NS(C)(=O)=O)c(C)c4)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methanesulfonyl chloride (0.03 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. Methanesulfonyl chloride (0.03 ml) and triethylamine (36 mg) were further added thereto, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and the residue was dissolved in methanol. To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 3 hours at ambient temperature and concentrated. To the residue were added dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-(4-methanesulfonamido-3-methylcinnamoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (185 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.C(=O)([O-])[O-:13].[K+].[K+].C(=NO)C.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:13])[CH:7]=1
Reactant: CC(=O)c1ncc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC=NO
Product: CC(=O)c1ncc(O)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
To a solution of 3.8 g of the 1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 1 in Synthetic Example 2 and 13.8 g of potassium carbonate in 20 ml of dimethylsulfoxide, 5.9 g of acetaldoxime was added, and the mixture was stirred at 80° C. for 4 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 50 ml of water and washed with diethyl ether (30 ml×1), the resulting aqueous layer was acidified with 6N aqueous hydrochloric acid and extracted with ethyl acetate (25 ml×2). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.0 g of desired crude product as brown crystals. The crystals were used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>N#N>[CH2:22]([O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[NH2:14])[CH3:23]
Reactant: CCO
Reactant: N[C@@H](Cc1ccc(O)c2ncccc12)C(=O)O
Agent: N#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred slurry of DL-3-(8-hydroxyquinolin-5-yl)alanine (HLM8) (2.19 g, 7.04 mmol) in absolute ethanol (26 ml) at 0° C., with protection from atmospheric moisture by CaCl2 tube in N2, thionyl chloride was added dropwise (1.1 ml, 14.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and then refluxed overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in absolute ethanol and reevaporated to dryness. To ensure completeness of the esterification, the whole operation was repeated. The ester HLM9 (yellow solid, 1.67 g, 92% yield), which was shown by HPLC to contain about 1% of free amino acid, was further purified by FC(CH2Cl2:MeOH:AcOH 9:1.5:1.5). 1H NMR (250 MHz, D2O) 0.94 (dd, J=7.2, 7.2 Hz, 3H), 3.63 (m, 2H), 4.01 (m, 2H), 4.34 (dd, J=7.7, 7.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 8.01 (dd,J=8.7, 5.4 Hz, 1H), 8.93 (d, J=5.4 Hz, 1H), 9.08 (d, J=8.7 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:22]1([C:5]2[C:4]3[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[N:15][O:16][C:3]=3[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Temperature: 100 °C
Yield: 19.8 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.72 mmol), cyclopropylboronic acid (74 mg, 0.87 mmol), K3PO4 (505 mg, 2.38 mmol) and Pd(PPh3)4 (83 mg, 0.072 mmol) were added to a flask, and the flask evacuated. After refilling with nitrogen, toluene (4 mL) and water (43 μl, 2.38 mmol) were added, and the resulting suspension was heated in an oil bath (T=100° C.) for 18 h. After the mixture was cooled to room temperature, the mixture was diluted with EtOAc (50 mL) and the solid was removed by filtration. The filtrate was concentrated and the residue was purified first by flash chromatography (0-40% EtOAc/hexanes), then by preparative TLC (eluted with 40% EtOAc/hexanes), to afford 47 mg of the title compound. MS: (+) m/z 331.24 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6](Cl)[N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:24])=[O:23])[NH2:18].CN1C(=O)CCC1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1>C(OCC)(=O)C.C(O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([NH:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]3)[N:7]=2)[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(N)cc1Cl
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(S(C)(=O)=O)c(Cl)c2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 230 °C
Reaction time: 1 h

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at 230° C. for 1 hour using a microwave reaction system. Thereafter, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190° C. for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 30:1) to give a crude product. This product was heated with ethanol and washed to give a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and insoluble materials were separated by filtration and the filtrate was concentrated. After the filtrate was concentrated, the residue was heated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a light yellow solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH2:28]([N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O)[CH3:29]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:35]([C:31]2[N:30]([CH2:28][CH3:29])[CH:34]=[CH:33][CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: CCn1cccc1C=O
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Product: CCn1cccc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 1-ethyl-1H-pyrrole-2-carbaldehyde. 479 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([N:64]1[CH2:71][C@@H:70]2[C@@H:66]([CH2:67][NH:68][CH2:69]2)[CH2:65]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:64]3[CH2:71][C@@H:70]4[C@@H:66]([CH2:67][NH:68][CH2:69]4)[CH2:65]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (3.35 g, 7.25 mmol) was dissolved in DMF (30 mL) and HATU (2.85 g, 9.42 mmol) was added. cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (2.0 g, 9.42 mmol) and DIPEA (1.63 mL, 9.42 mmol) were added and the mixture was stirred at room temperature for 17 hours. The volatiles were evaporated and the resultant residue azeotroped with toluene. The solid was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4) and evaporated. The residue was dissolved in DCM (10 mL) and TFA (10 mL) was added. The solution was stirred at room temperature for 4 hours and then evaporated. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The solvent was evaporated and the product was crystallised from MeOH/Et2O. The desired product was obtained as an off-white solid (3.7 g, 90%). LCMS (Method 5) [M+H]+=556.9, RT=2.83 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 9.38-9.22 (m, 2H), 8.69 (dd, 2H, J=1.7, 4.2 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.30 (dd, 2H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.4 Hz), 5.15 (s, 2H), 3.80-3.67 (m, 2H), 3.65-3.53 (m, 2H), 3.49-3.32 (m, 3H), 3.16-2.94 (m, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[S:13][C:14]2[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:11][C:12]1[S:13][C:14]2[C:20]([CH:21]=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Cc1nc2cccc(CO)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc2cccc(C=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (3.78 mL, 44.6 mmol) in dichloromethane (20 mL) was added dimethyl sulfoxide (4.75 mL, 66.9 mmol) at −78° C. and the mixture was stirred for 30 min. To the reaction mixture was added (2-methyl-1,3-benzothiazol-7-yl)methanol (4.00 g, 22.3 mmol) at −78° C. and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (18.8 mL, 134 mmol) at −78° C. and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and the mixture was further stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (dichloromethane/hexane) to give the title compound (3.54 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([C:9]([OH:15])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran (10.4 gm.) in acetone (200 ml.) cooled to 20° C. is added an oxidizing solution prepared from chromium trioxide (6.0 g.), concentrated sulfuric acid (5.3 ml.) and water (43 ml.) over a one-half hour period. The reaction mixture is stirred at 25° C. for 18 hours. The acetone layer is separated from the precipitated chromium salts, added to water (600 ml.) and extracted with ether (2×150 ml.). The ether extract is washed with water then extracted with aqueous sodium bicarbonate. Acidification of the basic solution gives 3.4 g. of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid which is purified by reprecipitation from aqueous sodium hydroxide with aqueous hydrochloric acid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].CO>[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: OCc1ccccc1
Product: c1ccc(CN(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 110 °C
Yield: 1.8 %

Procedure:
Into an inertised reactor with a capacity of 150 ml provided with a turbine agitator were successively introduced 41.9 g benzaldehyde (395.3 mmol), 20.1 g CH3OH, 0.08 g 5% palladium/carbon (Degussa; E10 R/W 50% H2O w/w) and 3.8g NH3 (223.5 mmol). The reactor was then pressurized to 70 bar with hydrogen. Next, the temperature was raised to 110° C. and the pressure in the reactor increased to 85 bar with hydrogen. After approximately 15 minutes no further hydrogen was absorbed. The reactor contents were cooled to room temperature and the reactor was then depressurized and flushed with N2. After the catalyst had been filtered off, the reaction mixture was found to be a 2-phase system. This 2-phase system was homogenized after the addition of the CH3OH which was used for flushing of the autoclave. The homogenous reaction mixture obtained in this way was analyzed by means of gas chromatography. All the benzaldehyde had been completely converted. The selectivity to dibenzylamine was 95.1%. In addition, small amounts of benzylalcohol (sel. approx. 1.8%) and tribenzylamine were formed.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6].O.Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:1])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methylmagnesium bromide (60 mL of a 3.0 M solution in diethyl ether) at 0° C. was added dropwise a solution of 3-bromoacetophenone (29.8 grams) in 75 mL of diethyl ether. Once the addition was complete, the mixture was stirred for 0.5 hours and poured into water. The aqueous phase was acidified with 1M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate, concentrated to afford 30.4 grams of the title compound. 1H NMR δ7.72 (br s, 1), 7.49 (d, 1, J=7.8), 7.37 (d, 1, J=7.9), 7.25 (dd, 1, J=7.8, 7.9), 4.19 (s, 1), 1.50 (br s, 6).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[CH:15]=[O:16].O>CN(C)C=O>[CH3:3][O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (23.34 g, 0.165 mol) and potassium carbonate (22.73 g, 0.165 mol) are added to a solution of 5-hydroxy-2-nitrobenzaldehyde (25 g, 0.149 mol) in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 18 hours and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown solid, mp 89°-90° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.CCCCCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: OCC=Cc1ccc(-c2ccc(F)cc2)nc1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
520 mg (2 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)acrylic acid methyl ester were dissolved in 40 ml of dichloromethane and cooled to −70° C. Under argon, 4.65 ml of a 1M solution of diisobutylaluminum hydride in hexane were slowly added. The mixture was stirred at −70° C. for 3 h, quenched with a solution of sodium sulfate, and warmed to room temperature. After filtration over Celite, the organic phase was separated and evaporated. Yield: 430 mg (93%)
Reaction SMILES: OC1C=CC(C=O)=CC=1.BrCC1CCC1.[OH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:16][C@@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]2)=[CH:31][CH:30]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Clc1ccc(CBr)cc1
Agent: BrCC1CCC1
Agent: O=Cc1ccc(O)cc1
Product: CCOC(=O)[C@H]1CC[C@@H](OCc2ccc(Cl)cc2)CC1
Product: CCOC(=O)[C@H]1CC[C@H](OCc2ccc(Cl)cc2)CC1

Procedure:
Instead of 4-hydroxybenzaldehyde and (bromomethyl)cyclobutane, ethyl 4-hydroxycyclohexanecarboxylate (2.00 g) and 4-chlorobenzylbromide (2.86 g) were respectively used and treated by the same technique as in Reference Example 9-1 to give ethyl cis-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate as a colorless oil (0.33 g) and ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate as a pale yellow oil (0.47 g).