Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 61.9 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoyl]morpholine (0.290 g, 0.533 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.731 g, 1.33 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.170 g, 0.330 mmol, 62%).
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@H:11]2[N:12]=[C:13]([N:15](C(OC(C)(C)C)=O)[CH2:16][CH3:17])[S:14][C@H:10]2[O:9][C@@H:8]2[CH2:25][O:26]C(C3C=CC=CC=3)[O:28][C@@H:7]12)(=[O:4])=[O:3].FC(F)(F)C(O)=O.CO.C(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([O:5][C@@H:6]1[C@H:11]2[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[S:14][C@H:10]2[O:9][C@H:8]([CH2:25][OH:26])[C@H:7]1[OH:28])(=[O:3])=[O:4]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OS(C)(=O)=O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC1=N[C@@H]2[C@@H](OS(C)(=O)=O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-yl methanesulfonate (30.00 mg; 0.06 mmol; 1.00 eq.) in DCM (100.00 μl) was added trifluoroacetic acid (10.00 μl; 0.13 mmol; 2.31 eq.). The reaction was stirred at room temperature for 3 h. The desired product was isolated by flash chromatography (KPNH, 0 to 50% MeOH/DCM). To afford (3aR,5R,6R,7R,7aR)-2-(ethylamino)-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-7-yl methanesulfonate (19.2 mg, 64%) as a white solid (once lyophilized).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH:7]([C:15]([O:17][CH3:18])=[O:16])[CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([O:17][CH3:18])=[O:16])=[CH:6]2
Reactant: COC(=O)C1Cc2cc(OC)c(OC)cc2CN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Yield: 47.3 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, methyl ester (19.77 g, 78.7 mmol) in 400 ml of tetrahydrofuran, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (39.3 g, 173.1 mmol) was added. The dark solution was heated under reflux overnight. The resulting precipitate was filtered off, dissolved in 500 ml dichloromethane/water 1:1, and the pH was adjusted to 10 by means of 1N sodium hydroxide. The phases were separated, the aqueous phase extracted once with dichloromethane and the combined organic phases washed twice with 100 ml of water containing a few drops of 1N sodium hydroxide. After the drying and evaporating of the solvent, 9.20 g of the title compound was obtained; melting point 214.9° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.8 %

Procedure:
Using general procedure H, 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 77) (612 mg, 2.00 mmol) and benzyl bromide (410 mg, 2.40 mmol) gave 4-[benzyl-(4-methoxyphenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (688 mg, 87%).
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)=CC=1.BrC1C=C[C:25]([O:28]CC)=[CH:24]C=1>>[CH2:25]([O:28][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:24]
Reactant: CCOc1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccc(-c3ccc(F)cc3)cc2)CCN1
Product: CCOc1ccc(N2CCN[C@H](C)C2)cc1

Procedure:
The title compound was prepared following the procedure of Intermediate 22 but starting from 1-bromo-4-ethoxybenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a brown solid. M+(ESI): 221.3. HPLC (Condition A), Rt: 1.5 min (HPLC purity: 97.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.Cl.[OH:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:22]2[CH2:23][CH:20]([OH:19])[CH2:21]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC1CN(c2cc(Cl)nc3cc(-c4ccccc4)nn23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (64.5 mg, 0.244 mM), then 3-hydroxy-azetidine hydrochloride (29.4 mg, 0.268 mM) and potassium carbonate (74.2 mg, 0.537 mM) were added to the solution and the mixture was stirred at room temperature for 3 hours. The solvent was removed from this reaction mixture through distillation, the resulting residue was diluted with water and then extracted with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (42.4 mg, yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)N1CCOCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCOCC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and 4-morpholinesulfonyl chloride (142 mg, 0.766 mmol) the title compound of Step A was obtained as a yellow foam (96 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78-10.01 (m, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.58 (td, J=7.4, 2.4 Hz, 1H), 7.17-7.41 (m, 2H), 6.57-6.68 (m, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.42-3.63 (m, 8H), 2.91-3.11 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Temperature: 120 °C
Yield: 60.9 %

Procedure:
6-Chloronicotinoyl chloride (35, 17.6 g, 100.0 mmol) was added to p-anisidine (33, 12.3 g, 100.0 mmol) dissolved in pyridine (150 mL) solution and the resulting reaction mixture was heated for 3 hours at 120° C. After cooling to room temperature and adding water, the produced gray precipitate was filtered and washed with 5% sodium bicarbonate aqueous solution. Then, the solvent was removed under reduced pressure to obtain the target compound 6-chloro-N-(4-methoxyphenyl)nicotinamide (37, 16.0 g, 60%).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[CH:16]([NH2:18])=[O:17]>C(O)=O>[CH:16]([NH:18][CH:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2])=[O:17]
Reactant: NC=O
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: O=CO
Product: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 180 °C

Procedure:
1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (9.1 g) prepared as above, formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180° C. for sixteen hours to give N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethlyamine. Concentrated hydrochloric acid (20 ml) was added and the mixture heated under reflux for three hours. The solution was then cooled, washed with ether and sodium hydroxide solution added. The product was extracted with ether, and the ether extract washed with water, dried and evaporated. 1-[1-(3,4-Dichlorophenyl)cyclobutyl]ethylamine (b.p. 112°-118° at 0.2 mm Hg) was isolated by distillation. The amine was dissolved in propan-2-ol and concentrated hydrochloric acid and the solution evaporated to dryness to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 185°-195° C.). (Formula I R1 =M3; R2,R3 and R4 =H; R5 =4-Cl; R6 =3-Cl).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a 250 ml flask fitted with reflux condenser, thermometer, and nitrogen inlet were added 4-nitrobenzil (10.83 g, 42.49 mmol), 3-bromophenol (7.35 g, 42.49 mmol) and dimethylsulfoxide (150 ml). After stirring at room temperature for 20 minutes under a nitrogen atmosphere, potassium carbonate (11.73 g, 84.98 mmol) was added to the flask and the flask was heated to an internal temperature of 95° C. for 19 h under nitrogen. When cooled to room temperature the solution was very slowly poured into 12N HCL (500 ml) and extracted with methylene chloride (2×100 ml). The organic layer was washed with water (3×500 ml), dried over anhydrous magnesium sulfate, and evaporated to dryness by rotary evaporation. The light orange oil was then dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 211.94 g, 5 cm dia×24 cm H). The purified product was recrystallized twice from methylene chloride:methanol (25 ml:150 ml) to afford light yellow crystals (11.08 g, 69%): mp 75°-76° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7](=[O:11])[O:6]1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2cc(Br)ccc21

Procedure:
To a suspension of 5-bromoisobenzofuran-1(3H)-one (5 g, 23.5 mmol) in anhydrous carbon tetrachloride (50 mL) was added N-bromosuccinimide (4.18 g, 23.5 mmol) and a catalytic amount of benzoyl peroxide. The reaction mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtered off, and the filtrate was concentrated on a rotary evaporator. The residual solid was partitioned between methylene chloride and water. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes to yield the title compound. MS (ESI) m/z 290 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([NH:14]C(=O)CCC)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[C:10]([C:9]1[NH:14][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCC(=O)Nc1ccc(Cl)nc1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2nc(Cl)ccc2[nH]1
Temperature: 70 °C
Yield: 90.2 %

Procedure:
To a solution of crude N-[6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-butyramide (16 g) in DMF (150 mL) was added t-BuOK (12.4 g, 110 mmol) at room temperature. The mixture was heated at 70° C. for 1 hour. The solvent was removed by evaporation under vacuum. Water (100 mL) and ethyl acetate (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-tert-butyl-5-chloro-1H-pyrrolo[3,2-b]pyridine (10.8 g, two steps: 94%). 1H NMR (CDCl3, 400 MHz) δ 8.52 (brs, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]O.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][Br:17]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (0.203 g, 1.0 mmol; European patentapplication 177353) and CBr4 (0.662 g, 2.0 mmol) were dissolved in 10 mL of ether and cooled to 0° C. Triphenylphosphine (0.524 g, 2.0 mmol) was added and the mixture stirred for 3 hours at room temperature. The mixture was filtered, the filtrate was stripped of solvent and the residue filtered through a plug of silica gel using CHCl3 as eluant to yield 0.16 g of present title product as a white solid; mp 59°-61° C.; tlc Rf 0.22 (CHCl3).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][P:8](OC)(=[O:11])[O:9][CH3:10]>C(O)C>[CH3:10][O:9][P:8]([CH3:7])([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:11]
Reactant: COP(C)(=O)OC
Reactant: C=CC(=O)OC
Solvent: CCO
Product: COC(=O)CCP(C)(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 86 g of methyl acrylate and 80 g of ethanol is added dropwise in the course of 30 minutes at 60° C. under nitrogen to a solution of 108 g of dimethyl methanephosphonate. The reaction mixture is then stirred at 60° C. for one hour. A total of 55 g of methyl ethyl ether are collected in the cooling trap. Excess ethanol is then removed by vacuum distillation. The crude product is obtained in a yield of 184 g with a 95.4% purity, which corresponds to a theoretical yield of 97.5%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>CO>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1nccnc1SCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nccnc1SCc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
3-(4-Pyridylmethylthio)pyrazine-2-carboxylic acid methyl ester (0.21 g, 0.80 mmol, Reference compound No. 16-1) was dissolved in methanol (4.0 mL), a 1 N aqueous sodium hydroxide solution (4.0 mL) was added thereto, and then the mixture was stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and then the mixture was adjusted to approximately pH 5 with 1N hydrochloric acid under ice-cooling. The precipitated solid was filtered off to give 0.17 g of the title reference compound as a red solid. (Yield 85%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)SC=1)=[O:9].BrC1C=[C:30](C(O)=O)[S:31]C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:10]1[S:31][CH:30]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:14]=1)=[O:9]
Reactant: COc1cccc(CNC(=O)c2csc(-c3c[nH]c4ncccc34)c2)c1
Reactant: O=C(O)c1cc(Br)cs1
Product: COc1cccc(CNC(=O)c2cc(-c3c[nH]c4ncccc34)cs2)c1

Procedure:
The above compound was made by the same procedure as N-(3-methoxybenzyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-3-carboxamide starting with the regioisomer, 4-bromothiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])[C@H:4]([O:6][Si](C)(C)C)[CH3:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=1[F:19])([OH:11])[CH:4]([OH:6])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.7 g (3.6 mmol) of (R)-1-chloro-3-(trimethylsilyloxy)butan-2-one in 5 mL of THF was cooled to 0° C., 5.4 mL (3.8 mmol) of a 0.7 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 10 minutes. After the completion of the dropwise addition, stirring was continued for another 5 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). As a result, the yield was determined to be 87% ((2S,3R)/(2R,3R)=41/59).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3C#N)CC2)c(C)c1
Yield: 64.8 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (2.48 g) described in Preparation Example 246 and 1-acetylimidazolidin-2-one (923 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.79 g) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[NH2:24][NH2:25]>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: NN
Reactant: CCOC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a stirred solution of ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoate (0.59 g, 1.951 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.306 mL, 9.76 mmol) and the reaction was heated at 80° C. overnight. The solid which formed was filtered and dried to afford 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) propanehydrazide (0.56 g, 82%), used without further purification. 1HNMR: 400 MHz, DMSO-d6: δ 1.58-1.59 (m, 2H), 1.92-1.96 (m, 1H), 1.97-2021.00 (m, 1H), 2.34-2.42 (m, 3H), 2.90-2.92 (m, 2H), 3.72-3.76 (m, 1H), 3.86-3.89 (m, 1H), 4.14 (s, 4H), 5.79-5.79 (m, 1H), 7.25-7.26 (m, 1H), 7.54 (s, 1H), 7.62 (d, J=8.80 Hz, 1H), 8.01 (s, 1H), 8.94 (s, 2H). LCMS: RT 0.64 min; LCMS (ES-API), m/z 205 (M-THP).
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH2:15][CH:16]=[C:17]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1>C(O)C>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH:17]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=2)[CH2:16][CH2:15][CH2:14][C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(C(=CCCc2cncn2Cc2ccccc2)c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C(CCCc2c[nH]cn2)c2ccc(C#N)cc2)cc1

Procedure:
1-benzyl-5-[4,4-bis(4-cyanophenyl)-3-butenyl]-1H-imidazole hydrochloride is hydrogenated in ethanol using 10% Pd/C as a catalyst to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.55 mmol) in anhydrous DMF (5 mL) were added chlorotrimethylsilane (1.95 mL, 15.37 mmol) and triethylamine (4.18 mL, 30.0 mmol). The resulting milky mixture was heated at 80° C. for 17 h, then cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a pale yellow oil (1.86 g, 55%). To a solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.86 g, 6.852 mmol) in acetonitrile (80 mL) was added Selectfluor™ (2.7 g, 7.622 mmol) and the mixture was stirred at RT for 2 h. The resulting solution was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a colourless oil (1.13 g, 76%).