Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:24][C:25]2[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=2)[CH2:10]1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN2CC(C(=O)c3ccc(C)c(C)c3)C(=O)c3ccccc32)c1

Procedure:
Compound 4m was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.4 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 74.0 mg (0.40 mmol) of 3-methylbenzylbromide. The crude product 4m was purified by flash chromatograph to yield 55 mg of colorless solid: LC-MSD, m/z for C26H23NO2, [M+H]+: 382.5, [M+H]+: 383.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.628 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.3-2.4 (t, 9H), 5.4 (s, 2H), 7.0 (d, 2H), 7.12 (d, 1H), 7.18 (d, 1H), 7.25 (d, 1H), 7.4 (t, 2H), 7.58 (m, 2H), 7.65 (s, 1H), 8.26 (s, 1H), 7.48 (s, 1H).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:14]([OH:16])=[O:15])[NH:5]1.[C:17](Cl)(=[O:19])[CH3:18]>CC(C)=O>[C:17]([N:5]1[CH:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1)(=[O:19])[CH3:18]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)N1Cc2ccccc2CC1C(=O)O
Reaction time: 0.17 h

Procedure:
To a mixture of acetone (75 mL) and 2N NaOH (100 mL) was added portionwise 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid hydrochloride (10.00 g, 46.8 mmol). After stirring for 10 min, acetyl chloride (7.38 g, 94 mmol) in acetone (50 mL) was added slowly into the above solution, followed with 2N NaOH at room temperature. The reaction mixture was maintained at a pH>10 and stirred for 1 hour. The acetone was evaporated in vacuo and acidified the residue by adding 3N HCl. The separated solid was collected by filtration, washed several times with water, and dried to afford the known 2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as an enantiomeric mixture, 7.90 g, (76.9%); mp 178-180° C. (170-171° C.):21 1H NMR (DMSO-d6) δ 2.15 (3H, s, Me), 3.02-3.24 (2H, m), 4.29-4.75 (2H, m), 4.98-5.17 (1H, m), 7.17-7.21 (4H, m, 4×ArH), 12.70 (1H, brs, exchangeable, OH); m/z219.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[O:14][CH3:15])([CH3:3])[CH3:2].[ClH:16]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:14][CH3:15])([CH3:3])[CH3:2].[ClH:16]
Reactant: COc1cc(NC(C)=O)ccc1C(C)C
Agent: Cl
Product: COc1cc(N)ccc1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Isopropyl-3-methoxy-phenyl)-acetamide (14.5 g, 69.9 mmol) in 200 ml 6 N HCl was heated to 95° C. for 3.0 hours. The reaction mixture was cooled to room temperature, and allowed to sit for 72 hours at room temperature, during which time crystals formed. The reaction mixture was filtered, and the crystals were washed 1 N HCl and dried under vacuum to give 4-Isopropyl-3-methoxy-phenylamine as an HCl salt (7.6 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:10])[F:11])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: Cc1cc(C(F)(F)F)cc(=O)n1C
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(F)(F)F)c(I)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
A mixture containing 1,6-dimethyl-4-(trifluoromethyl)-2-pyridone (2.1 g, 10.98 mmol), trifluoroacetic acid (18 mL) and trifluoroacetic anhydride (3.5 mL) was refluxed for 5 min. Then, NIS (3.15 g, 14 mmol) was added and the reaction mixture was stirred for 15 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with ethyl acetate (100 mL), was washed with saturated sodium bicarbonate solution (2×100 mL) and brine solution (100 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave a crude product, which was purified by silica gel chromatography on a Biotage (40m) column to afford 2.15 g (62% yield) of 1,6-dimethyl-3-iodo-4-(trifluoromethyl)-2-pyridone as an amorphous white solid. EI-HRMS m/e calcd for C8H7F3INO (M+) 316.9524, found 316.9527.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:11][C:12]([F:29])([C:25]([F:28])([F:27])[F:26])[C:13]([N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:14][C:13]([C:12]([F:11])([F:29])[C:25]([F:26])([F:27])[F:28])=[N:15][C:16]([C:17]([F:18])([F:20])[F:19])([C:21]([F:24])([F:23])[F:22])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C#N)c1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Product: COc1cccc(C2=NC(C(F)(F)F)(C(F)(F)F)N=C(C(F)(F)C(F)(F)F)O2)c1
Temperature: 60 °C
Yield: 8127 %

Procedure:
3-Methoxybenzonitrile (1.31 g. 0.01 mole) and 2,2,3,3,3-pentafluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl)ethylidene}propanamide (4.67 g., 0.015 mole) were dissolved in diethyl ether and heated in a glass ampoule to 60° C. for six hours. Solvent was evaporated off and the residue distilled at 119° to 120° C./13 min to give a colorless oil (361 g, 82 percent). PMR (CDCl3), 3.85 s (3H), 7.18 d (1H), 7.40 t (1H), 7.55 s (1H), 7.65 d (1H), 19F NMR, −45.74 (2F), −5.47 (3F), −1.12 (6F).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:2].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]([NH:12][OH:13])=[NH:7])[CH3:2]
Reactant: NO
Reactant: CCc1cccc(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(C(=N)NO)c1
Yield: 46 %

Procedure:
3-Ethyl-benzonitrile (400 mg, 3.05 mmol) with 5 M hydroxylamine hydrochloride (0.61 mL) and 1 M sodium hydroxide (3.05 mL) in ethanol (3 mL) were stirred at room temperature for 60 h. Work up as in example 4 afforded 230 mg (46%) of 3-ethyl-N-hydroxy-benzamidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31]
Reactant: Cc1ccn2cc(-c3ccc(CCCCO)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(-c3ccc(CCCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 0 °C
Yield: 125.6 %

Procedure:
The product of Step A (0.33 g) in dichloromethane (20 mL) was treated with triethylamine ( 0.36 g) and cooled to 0° C. The cold solution was treated with methanesulfonyl chloride (0.338 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with water (50 mL), saturated sodium bicarbonate solution (25 mL), water (50 mL), dried over sodium sulfate, filtered and evaporated to give the crude title compound (0.53 g). The crude product was used, Step C, without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1

Procedure:
The title compound was prepared by treating 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (0.3 g, 1.04 mmol) with 4-methylsulfanyl-phenylamine (0.14 g, 1.04 mmol) according to the procedure described above.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12](N)=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][OH:23])=[CH:18][CH:17]=1>>[OH:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[C:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:13]
Reactant: NC(=O)c1cnc2ccccc2c1O
Reactant: ONc1ccc(Cl)cc1
Product: O=C(c1cnc2ccccc2c1O)N(O)c1ccc(Cl)cc1

Procedure:
Using the procedure of Step A of Example 6, 9.45g of 4-hydroxy-3-quinoline carboxamide and N-(4-chlorophenyl)-hydroxylamine acid were reacted to obtain 14.4 g of crude N,4-dihydroxy-N-(4-chlorophenyl)-3-quinoline carboxamide
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2ccc(F)cc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (251 mg, 1.13 mmol), 4-(4-fluorophenyl)piperidin-4-ol (215 mg, 1.13 mmol) and DIPEA (0.20 mL, 1.13 mmol) in DMF (3 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to ambient temperature, and quenched with water (10 mL). The precipitated solid was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to give 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (320 mg, 74%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O[C@@H]1CNC[C@H]1N1CCCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of trans-3-[4-(4-Chloro-phenyl)-[1,4]diazepan-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.820 g, 2.08 mmol) in methylene chloride (1 mL) was added 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, upon which a brown precipitate formed. The reaction was concentrated in vacuo to yield 0.930 g (˜100%) of the title compound. ESI-MS m/z: 296 (M+1), FAS method rt: 0.83 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: OCCc1ccccc1Br
Product: COC(=O)CCc1ccc(C#Cc2ccccc2CCO)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (107 mg, 0.57 mmol) and 2-bromophenethyl alcohol (100 μL, 0.74 mmol) according to the general procedure IF to give 83 mg (47%) of a dark orange oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:1). Rf=0.19 (EtOAc:PE, 1:1); 1HNMR (CDCl3): δ 7.46-7.44 (m, 1H), 7.38-7.36 (m, 2H), 7.21-7.20 (m, 2H), 7.18-7.14 (m, 1H), 7.13-7.10 (m, 2H), 3.91-3.87 (m, 2H), 3.60 (s, 3H), 3.06 (t, J=5.1 Hz, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.56 (t, J=5.4 Hz, 2H); 13CNMR (CDCl3): δ 173.1, 141.1, 140.4, 132.4, 131.7, 131.7, 129.7, 128.5, 126.6, 123.2, 121.2, 93.2, 87.6, 62.9, 51.7, 38.1, 35.4, 30.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1F
Yield: 44.2 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (190 mg, 44%) was provided after purification. MS (ESI) m/z 294. HPLC purity 98.6% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N)n1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100° C. via a Biotag microwave for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50% yield). MS (ES+) m/z 126.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:8]=[C:9]([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C(=O)O)c2)c1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2ccc(OC)c(CO)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
894 mg of 2-Methoxy-5-[3-(methoxycarbonyl)phenyl]benzoic acid was dissolved in 7 ml of tetrahydrofuran, 0.36 mg of triethylamine and 0.55 ml of ethyl chlorocarbonate were added successively, and the mixture was stirred at room temperature for 15 minutes. The precipitated crystals were filtered, and the filtrate was filtered. 2 ml aqueous solution of 180 mg sodium borohydride was added thereto, and the mixture was stirred at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by a silica gel column, to give 496 mg of the title compound in the 5:3 hexane-ethyl acetate fraction.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
Dinitrobenzoyl chloride is caused to react with aniline so as to give dinitrobenzanilide. Thereafter, the resulting product is caused to react with Ar--N(R)2 and oxyphosphorous chloride and to the resulting product concentrated hydrochloric acid is added to prepare a compound having the formula: ##STR5##
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=O.[CH3:20][C:21]([S@@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[N:26]/[S@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C@@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: O=C(CCCCl)c1cc(F)ccc1O[C@H]1CCOC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C(/CCCCl)c1cc(F)ccc1O[C@@H]1CCOC1
Temperature: 27.5 °C
Yield: 296.7 %

Procedure:
Titanium (IV) ethoxide (17.5 g, 76.92 mmol) was added to a solution of (S)-4-chloro-1-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)butan-1-one (11 g, 38.46 mmol) and (S)-2-methylpropane-2-sulfinamide (9.32 g, 76.92 mmol) in THF (170 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethyl acetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colorless liquid. MS (ESI): 390.2 (M+H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.Br[C:48]1[C:56]2[S:55][N:54]=[N:53][C:52]=2[CH:51]=[C:50]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)[CH:49]=1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16]([C:48]3[C:56]4[S:55][N:54]=[N:53][C:52]=4[CH:51]=[C:50]([C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=4)[CH:49]=3)[O:15][C:14]=12
Reactant: Fc1cccc(-c2cc(Br)c3snnc3c2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cc(-c4cccc(F)c4)cc4nnsc34)oc12

Procedure:
The title compound was prepared from {7-[bis(tert-butoxycarbonyl)amino]-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}boronic acid and 7-bromo-5-(3-fluorophenyl)-1,2,3-benzothiadiazole by a procedure analogous to Example 368. 1H NMR (400 MHz, CD3OD): δ 1.48-1.57 (m, 2 H), 1.94-2.05 (m, 2 H), 2.11-2.22 (m, 4 H), 3.67-3.75 (m, 1 H), 4.21-4.29 (m, 1 H), 7.19-7.26 (m, 1 H), 7.53-7.63 (m, 2 H), 7.72-7.77 (m, 2 H), 7.89 (s, 2 H), 8.08 (s, 1 H), 8.70 (s, 1 H), 8.90 (s, 1 H); MS (ESI): 527.60 [M+H]+; HPLC tR=1.07 min (TOF: polar—2 min).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[F:1][CH:2]([F:5])[CH2:3][O:4][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: OCC(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2,2-difluoro-ethanol (6 g, 73.12 mmol) and mesyl chloride (6.26 ml, 80.43 mmol) in CH2Cl2 (40 ml) was added triethylamine (12.66 ml, 87.74 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was then washed two times with water and with brine and dried with Na2SO4. Evaporation of the solvent yielded the title compound (10.7 g, 92%) as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.O[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[O:9][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: Cn1nccc1C(O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nccc1C(OC1CCNCC1)c1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
A mixture of 2.074 g of (±)-(4-chlorophenyl)(2-methyl-2H-pyrazol-3-yl)methanol synthesized in Production Example 174, 942 mg of 4-hydroxypiperidine, 1.949 g of p-toluenesulfonic acid monohydrate, and 100 mL of toluene was heated under reflux for 40 minutes while removing water using a Dean-Stark. To the mixture, 1.949 g of p-toluenesulfonic acid monohydrate was added, and the resulting mixture was further heated under reflux for 4.3 hours while removing water. After the mixture was allowed to cool down, toluene and 22 mL of a 1-N sodium hydroxide aqueous solution were added thereto, and the organic layer was collected by separation. The organic layer was washed with 22 mL of a 1-N sodium hydroxide aqueous solution and with a saturated saline solution in this order. The organic layer was dried over sodium sulfate, and then the solvent was distilled off. Thus, the title compound (2.487 g (87%)) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[C:4]([CH2:5][N:6]2[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:17])[F:15])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:7]2)[CH:3]=1
Reactant: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
Product: O=c1n(Cc2cc(F)cc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of the compound from Example 103A were reacted with 28 mg (0.18 mmol) of 2-chlorophenylboronic acid. This gave 34 mg (54% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.[Cl:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCn1cc(Br)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 140 °C
Yield: 54.1 %

Procedure:
A mixture of 5-bromo-1-ethylpyridin-2(1 H)-one (1.9 g, 9.45 mmol), 6-chloropyridin-3-ylboronic acid (1.8 g, 11.46 mmol), Cs2CO3 (9.9 g, 30.37 mmol) and tetrakis(triphenylphosphine)palladium (0) (543 mg, 0.55 mmol) were suspended in dioxane:water (15:1, 20 ml). After degassing, the mixture was heated in a microwave at 140° C. for 30 min. The reaction was then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was purified by LCMS to provide the title compound, 5-(6-chloropyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 51% yield).