Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:37])[CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)CCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxy-phenyl)-3-phenyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C28H30O6 [M+NH4]+: 485 [M+H]+: 463.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[C:16]1([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.C(OCC)C>[C:16]1([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH:30]([C:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[S:10][CH:11]=3)[OH:31])[CH2:26][CH2:25]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CC1CCN(CCc2ccccc2)CC1
Reactant: Brc1csc2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve n-butyllithium (9.4 mL of a 2.5M solution in hexane, 23.46 mmol) in anhydrous ethyl ether (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, a solution of 3-bromobenzo[b]thiophene (5.0 g, 23.46 mmol) in anhydrous ethyl ether (50 mL). Stir at -78° C. for 30 minutes then add, by dropwise addition, a solution of 1-(2-phenylethyl)-4-piperidinecarboxaldehyde (5.10 g, 23.46 mmol) in anhydrous ethyl ether (50 mL). Stir for 5 hours at -78° C., remove the ice bath and stir for an additional 1 hour. Quench with saturated ammonium chloride (150 mL) and stir overnight. Separate the organic phase and extract the aqueous phase with ethyl ether and methylene chloride. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by recrystallization (isopropanol) to give the title compound as an off-white solid.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:16](=[O:28])[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[NH:27])[NH2:26])[CH2:21][CH2:20]1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:8][C@@H:9]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:16]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[NH:26])[NH2:27])[CH2:21][CH2:20]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1

Procedure:
A solution of (S)-{[(1-Carbamimidoyl-piperidin-4-ylmethyl)-carbamoyl]-cyclohexyl-methyl}-carbamic acid tert-butyl ester hydrochloric acid salt (20.0 g, 46.3 mmol) in trifluoroacetic acid (100 ml) was stirred for 12 hours at room temperature. The reaction mixture was evaporated and the residue was purified by Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined to give the desired products. MS m/z: 296.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[CH:49][C:50](=[NH:52])[NH2:51])=[CH:44][CH:43]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=[CH:49][C:50](=[NH:51])[NH2:52])=[CH:44][CH:43]=2)=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CNC(=O)OCc3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid in 50 ml of dried pyridine, while being cooled in ice, was added 4.2 g of DCC. After 30 minutes of stirring, to the mixture was added 4.4 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The mixture was stirred overnight at room temperature. The DCU precipitated from the reaction mixture was separated by filtration and washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate a white substance which was collected by filtration, washed with ethyl ether, and recrystallized from ethanol to yield 5.7 g of colorless needle crystals of 4-(β-amidinoethenyl)pnenyl trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:20])[CH2:19][CH2:18][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCC2)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of 2-bromo-5-iodoanisole (400 mg, 1.28 mmol) in tetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5M in hexane, 0.62 mL, 1.55 mmol) dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then treated with neat cyclobutanone (0.1 mL, 1.3 mmol) dropwise over 10 minutes and stirred at −78° C. for an additional 1.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 27 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (40 mg, 12% yield). GCMS 256/258 (M)+; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.29 Hz, 1H), 7.09 (d, J=1.95 Hz, 1H), 6.98 (dd, J=8.17, 1.83 Hz, 1H), 3.94 (s, 3H), 2.51-2.61 (m, 2H), 2.35-2.46 (m, 2H), 2.02-2.10 (m, 1H), 1.66-1.79 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](O)=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10]C(=O)OC.C1(C)C=CC(S([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1.[OH-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:9])[C:5]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:4][C:3]=1[NH2:10]
Reactant: COC(=O)Nc1ccc(Cl)c(O)c1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
Methyl N-(2-fluoro-4-chloro-hydroxyphenyl)carbamate (2.03 g, 9.23 mmol), cyclohexyl p-toluenesulfonate (2.51 g, 9.85 mmol) and N,N-dimethylformamide (30 ml) were charged into a 100 cc round-bottom flask, and then potassium hydroxide (1.0 g, 17.8 mmol) in a powder form was added thereto. The mixture was stirred for 4 hours on an oil bath at 80° C. After completion of the reaction, the reaction solution was cooled to room temperature, 1N hydrochloric acid (100 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a etude product. The product was isolated and purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain 2-fluoro-4-chloro-5-cyclohexyloxyaniline (574 mg, 2.36 mmol, 264 yield) and the unreacted starting material, methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.22 g, 5.54 mmol, 60% recovery ratio). The spectral data and the like are as shown in Reference Example 11.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[I-:29].[Na+].I>CC(CC)=O.O1CCOCC1>[I:29][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc(C)nc(Cl)c3)nc12
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc(C)nc(I)c3)nc12
Temperature: 100 °C
Yield: 6.6 %

Procedure:
To a stirred suspension of 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-methyl-isonicotinamide (1.00 g, 2.39 mmol) in ethyl methyl ketone (10 ml) and dioxane (20 ml) were added sodium iodide (2.0 g, 13.3 mmol) and hydriodic acid (0.95 ml, 7.2 mmol, 57% aqueous). The mixture was then heated at 100° C. for 96 hours. The mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed sequentially with saturated sodium bicarbonate solution, 0.1 M sodium thiosulfate solution, and saturated brine. The organic phase was then dried over Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2MeOH (99:1 then 98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a brown solid (80 mg, 7% yield), MS: m/e=511 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[NH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Indomethacin (500 mg, 1.40 mmol) was taken up in 10 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (223 mg, 1.40 mmol) and EDC (295 mg, 1.54 mmol). The resulting reaction mixture was stirred at room temperature for 18 and diluted with CH2Cl2 (10 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 550 mg of tert-butyl 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethylcarbamate (79% yield).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A mixture of 3-{[1-Cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (36 mg), TFA (1 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (21 mg). LC MS ESI+: 442 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18]([O-])([O-])([O:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH2:5][O:6][C:18]([O:20][CH3:21])([CH3:19])[O:4]1
Reactant: COC(C)([O-])[O-]
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C)OCC(CO)O1
Reaction time: 18 h
Yield: 97 %

Procedure:
A 1-liter round-bottomed flask equipped with a pressure equalizing addition funnel was flushed with nitrogen and charged with 41.5 grams (451 mmol.) of glycerol, 750 ml. of methylene chloride and 100 mg. of p-toluenesulfonic acid. Methyl orthoacetate, 56.9 grams (473 mmol.), was added over 5 minutes at room temperature, with stirring; stirring was continued for 18 hours after which 1 gram of anhydrous sodium carbonate was added and the mixture was stirred for one additional hour and filtered. The solvent was stripped under vacuum to yield 65 grams (97% of theoretical) of 4-hydroxymethyl-2-methoxy-2-methyl-1,3-dioxolane as a clear oil. Its molecular structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:34]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=2[S:32][CH:31]=1>CN(C)C=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[S:32][CH:31]=[C:30]([CH2:29][N:17]3[C:9]4=[N:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][C:11](=[O:13])[N:10]4[CH2:14][CH2:15][C@H:16]3[C:18]([F:20])([F:21])[F:19])[C:34]=2[CH:35]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1csc2ccc(Cl)cc12

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 95 mg of 3-(bromomethyl)-5-chloro-1-benzothiophene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 72 mg of (8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].[CH3:14][S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16].C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[C:19]#[N:20])=[C:3]1[Cl:13]
Reactant: CS(=O)(=O)CC#N
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(Cl)c(C=C(C#N)S(C)(=O)=O)c2ccccc21
Reaction time: 144 h

Procedure:
To 550 mg of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 730 mg of methylsulfonylacetonitril and 1.2 g of triethylamine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (3a). Yield 630 mg of (3a), m.p. 180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)NCc1ccccc1
Yield: 82 %

Procedure:
Amide coupling of 4-Bromophenylacetic acid with benzylamine was done according to procedures in Step 10A for Example 3.60 to give N-Benzyl-2-(4-bromo-phenyl)-acetamide in 82% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.5 (s, 2 H) 4.3 (d, J=5.8 Hz, 2 H) 7.2 (dd, J=7.8, 5.6 Hz, 5 H) 7.3 (m, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 8.6 (t, J=5.9 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(O[CH:27]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]1[O:29][C:30](=[O:32])[CH3:31])(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:6]([C@@H:27]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]2[O:29][C:30](=[O:32])[CH3:31])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2-Chlorobenzimidazole (7.5 g) and N,O-bis(trimethylsilyl)acetoamide (18.3 mL) were suspended in acetonitrile (150 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. To the mixture was added trifluoromethanesulfonic acid trimethylsilyl ester (17.9 mL), and the mixture was stirred for 15 minutes. To the reaction mixture was added 1,2,3,5-tetra-O-acetyl-D-ribofuranose (17.3 g), and the mixture was stirred at room temperature for 6 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10) to give the title compound (12.4 g).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.O.O.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:23]1([S:29]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound b, 10 g, 15 g of sodium benzenesulfinate dihydrate and 25 ml of trifluoroacetic anhydride were treated in a manner similar to Example 109 to give 14.3 g of the objective compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[CH:7]=1>>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][C:17]=2[Cl:18])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: FC(F)(F)c1cc(Cl)c(-c2cccc(Cl)c2)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To 50 ml of fuming nitric acid, 5.0 g (15.4 mmol) of 1-chloro-3-(2,6-dichloro-4-trifluoromethylphenyl)benzene was added dropwise at −30° C. After 15 minutes of stirring at the same temperature, the reaction mixture was warmed to 5° C., poured into about 200 ml of ice-cold water and extracted with 100 ml of diethyl ether twice. The diethyl ether layer was washed with 200 ml of water twice and dried over anhydrous magnesium sulfate, and the diethyl ether was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 3.0 g of 1-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrobenzene (yield 52.6%) as a pale yellow liquid (nD20 1.5744), which was used in Example 8 (2) as the starting material.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.S(Cl)([Cl:19])=O>ClCCl>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([Cl:19])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Br
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
The crude benzhydryl alcohol from above (31.8 g, 107 mmole) was dissolved in 150 ml of dichloromethane and 11.7 ml (1.5 equiv.) of thionyl chloride was added dropwise over ten minutes. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 100 ml of toluene and the solvent was again removed under vacuum in order to eliminate excess thionyl chloride, providing crude product as a dark oil. The material was purified by short path distillation (Kugelrohr apparatus, 150° C., 0.5 mm) to give 25.8 g (76%) of (2-bromophenyl)chloro(4-chlorophenyl)methane as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:8]([NH2:13])[C:9]([F:12])([F:11])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:1][CH:8]([C:9]([F:10])([F:11])[F:12])[N:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(Cc1ccccc1)C(F)(F)F
Product: CC1=NC(C(F)(F)F)Cc2ccccc21

Procedure:
(The starting material N-(1-benzyl-2,2,2-trifluoro-ethyl)-acetamide is obtained by reacting 1-benzyl-2,2,2-trifluoro-ethylamine with acetic anhydride.)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19](O)=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:26])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]([Cl:26])=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)cc3cccnc32)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)c(C(=O)Cl)cc3cccnc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.35 g (4.5 mmol) of 1-(6-methoxy-3-pyridinyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 2.5 mL (30 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(6-methoxy-3-pyridyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (50 mL), and 0.56 g (5.0 mmol) of 1,3-cyclohexanedione and 1.54 mL (10.8 mmol) of triethylamine were added to the above solution under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 1.78 g (yield: quantitative) of the title compound was obtained as a light yellow solid.