Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A light brown suspension of 4-bromo-1-methanesulfonyl-2-nitro-benzene (8.65 g, 30.9 mmol) in methanol (300 mL, not completely dissolved in methanol even at hot condition) was treated sequentially with ammonium chloride (24.8 g, 463.5 mmol), zinc dust (20.2 g, 309 mmol), and water (100 mL). Initially, the reaction was exothermic, and the brown color disappeared. The reaction mixture was stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 6/1 to 4/1 hexanes/ethyl acetate) afforded 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 74%) as a white solid: mp 107-109° C.; EI-HRMS m/e calcd for C7H8BrNO2S (M+) 248.9459, found 248.9451.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccc(C#N)cc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-cyanobenzyl bromide (40 mmol, 7.84 g), methyl 3-hydroxybenzoate (40 mmol, 6.08 g) and potassium carbonate (60 mmol, 8.29 g) in 50 mL DMF was stirred at 60° C. overnight and the solution was cooled to room temperature. To it was added dilute citric acid followed by ethyl acetate. The organic layer was separated, washed with brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give a solid. The solid was washed with ether two times to give 6.2 g (60%) product. NMR (DMSO-d6): δ7.88 (d, 2H); 7.66 (d, 2H); 7.58 (m, 2H); 7.46 (t, 1H); 7.32 (dd, 1H); 5.30 (s, 2H); 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].O[CH2:36][CH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:36][CH2:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(C#N)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 4-(2-hydroxyethyl)benzonitrile (0.063 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 16 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(4-cyanophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0327 g, 0.055 mmol, 64.1% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.17 (dd, J=8.5, 2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.96 (qd, J=4.2, 2.4 Hz, 2H), 6.07 (s, 1H), 4.31-4.24 (m, 3H), 4.18 (dq, J=10.8, 7.1 Hz, 1H), 3.22 (t, J=6.5 Hz, 2H), 3.18 (br. s., 1H), 2.86 (t, J=12.2 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J=11.3 Hz, 1H), 2.19 (s, 3H), 2.05 (t, J=11.6 Hz, 1H), 1.54 (br. s., 1H), 1.42-1.33 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.20-1.16 (m, 1H), 1.07 (d, J=10.7 Hz, 1H), 0.91 (s, 3H), 0.65 (s, 3H). LCMS (M+H)=598.4.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15](Cl)[N:14]=[C:13]4[C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[O:25][C:12]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]1[O:44][C:43]2[CH:42]=[CH:41][C:40]([OH:45])=[CH:39][C:38]=2[O:37]1>CN(C=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:45][C:40]4[CH:41]=[CH:42][C:43]5[O:44][CH2:36][O:37][C:38]=5[CH:39]=4)[N:14]=[C:13]4[C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[O:25][C:12]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1c(Cl)nc2c(oc3ccccc32)c1-c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Oc2ccc3c(c2)OCO3)nc2c(oc3ccccc32)c1-c1ccc2c(c1)OCCO2
Reaction time: 8 h

Procedure:
A solution of 3.8 g of ethyl 4-(1,4-benzodioxan-6-yl)-2-chlorobenzofuro[3,2-b]pyridine-3-carboxylate and 3.1 g of caesium carbonate in 40 ml of DMF is treated with a solution of 1.7 g of 3,4-methylenedioxyphenol in 20 ml of dichloromethane and stirred overnight. The mixture is worked up in the customary manner and ethyl 4-(1,4-benzodioxan-6-yl)-2-(3,4-methylenedioxyphenoxy)benzofuro[3,2-b]pyridine-3-carboxylate is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.Cl[C:32]([O:34][CH3:35])=[O:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:35][O:34][C:32]([NH:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:33]
Reactant: COC(=O)Cl
Reactant: CN(CCC(OCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
To a 0° C. solution of tert-butyl 3-(2-aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (6 g, 4.11 mmol), Et3N (1.25 g, 12.3 mL), DMAP (0.25 g, 2.06 mmol) in dry CH2Cl2 (100 mL), methyl chloroformate (1.9 g, 20.6 mmol) in dry CH2Cl2 (30 mL) was added drop wise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid and brine, then dried over Na2SO4, filtered and concentrated to the crude product. The crude product was purified by silica gel to afford tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (600 mg, 40%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.83 (m, 2H), 2.80 (s, 3H), 3.31 (m, 7H), 3.65 (s, 3H), 4.13 (m, 1H), 7.26 (m, 4H).
Reaction SMILES: O[CH:2]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH:2]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1cc2ccccc2cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
3-(1-Hydroxyethyl)-isoquinoline (1.32 g, 7.6 mmole) is dissolved in 20 ml dichloromethane in a 100 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated dropwise with thionyl chloride (835 μl, 11.4 mmole), and is stirred 3 h at 0° C. followed by 1 h at room temperature. The mixture is recooled to 0° C., is quenched with 50 ml saturated sodium bicarbonate, and the layers are separated. The aqueous layer is extracted with 3×25 ml dichloromethane and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to a pale amber oil. The crude material is chromatographed over 60 g silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 9 ml fractions. Fractions 17-26 are combined and concentrated to afford 1.39 g (95%) of 3-(1-chloroethyl)-isoquinoline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][NH:5][C:6]=1[CH:7]([CH3:9])[CH3:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:10]([F:11])([F:13])[F:12])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Reactant: CC(C)c1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C(C)C)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-isopropyl-3-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=5.5/4.5, Rf=0.52) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.19–7.22 (d, 2H), 6.42–6.48 (m, 2H), 5.18 (s, 2H), 3.88 (s, 3H), 3.56–3.78 (m, 4H), 3.22–3.44 (m, 4H), 3.04–3.14 (m, 1H), 1.44–1.48 (d, 6H). 13C NMR (400 MHz, CDCl3): 164.2, 154.8, 151, 130, 109.8, 102, 56.2, 54, 50.5, 50, 45.2, 42.6, 26.2, 22.1
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][S:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:20])=[CH:15][CH:16]=2)[N:11]([CH3:21])[CH:10]=1)=O>N1C=CC=CC=1>[Cl:5][CH:6]([Cl:3])[S:7][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:20])=[CH:15][CH:16]=2)[N:11]([CH3:21])[CH:10]=1
Reactant: Cn1cc(S(=O)CCl)c(=O)c2ccc(F)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cc(SC(Cl)Cl)c(=O)c2ccc(F)cc21
Reaction time: 0.02 h

Procedure:
To an efficiently stirred and gently cooled 4.2 ml mixture of thionyl chloride (“SOCl2”) and 1.05 ml of pyridine (“Py”) at −3° C. was added 1.015 g (3.708 mmol) of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (monochloroflosequinan)(Compound 1 of FIG. 1). This addition was made in multiple alloquots over a period of approximately 1 min. During this addition, cooling was applied to keep the temperature in the range 0-5° C.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6](=[N:13][OH:14])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])(=[O:3])[NH2:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(#N)C>[CH3:15][NH:16][C:17]([O:14][N:13]=[C:6]([S:5][CH2:4][C:1](=[O:3])[NH2:2])[C:7]([N+:10]([O-:12])=[O:11])([CH3:9])[CH3:8])=[O:18]
Reactant: CC(C)(C(=NO)SCC(N)=O)[N+](=O)[O-]
Reactant: CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(SCC(N)=O)C(C)(C)[N+](=O)[O-]
Yield: 71.5 %

Procedure:
A mixture of 10 g (0.045 m) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldoxime, 150 ml. acetonitrile, 8.0 g (0.14 m) of methylisocyanate and three drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for twenty hours. The acetonitrile and excess methyl isocyanate was removed from the product under reduced pressure. The solid residue was recrystallized from isopropanol and then dried at room temperature to give 9.0 g (72% yield) of 1-(carbamoylmethylthio)-2-nitro-2-methylpropionaldehyde O-(methylcarbamoyl)oxime; melting point=125-127° C. The nmr spectra confirmed the structure.
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O>>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: OCc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3cccc(CO)c3)nc2)CC1
Yield: 70.3 %

Procedure:
By a method similar to Production Example 108, step 4, [3-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.675 g, 3.998 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.165 g, 4.000 mmol) were condensed to give tert-butyl 4-(6-{2-[3-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (1.111 g, yield 70.2%, E/Z mixture) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9](=[O:11])[CH3:10].[CH3:34][I:35]>>[I-:35].[C:9]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[CH3:34])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCOc1ccccc1CN(Cc1ccccn1)C(C)=O
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccccc1CN(Cc1cccc[n+]1C)C(C)=O
Product: [I-]

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.90 g of product from Example 75 and 6.19 ml of methyl iodide. The residue is purified by crystallization from methyl alcohol to give 1.135 g of the desired product as yellow crystals. The spectral data indicates the presence of 2 rotomers.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:33]([C:35]([CH3:38])([CH3:37])[CH3:36])#[C-:34]>CO>[Br:12][C:13]1[CH:14]=[C:15]([C:16]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]3[C:34]=2[NH:33][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(-c2cccc(Br)c2)nc2ccc(C(F)(F)F)cn12
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (0.5 g, 3.08 mmol, Eq: 1.00), 3-bromobenzaldehyde (599 mg, 378 μL, 3.24 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (176 mg, 925 μmol, Eq: 0.3) were dissolved in MeOH (4 mL) and the intensive yellow solution was stirred for 10 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (256 mg, 351 μL, 3.08 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 14 h. The solvent was removed and the crude product was purified by flash column chromatography (hexane/AcOEt 100/0 to 0/100) to yield a light yellow solid (865 mg, 68.0%). MS: 414.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.90 (s, 1H), 8.48 (s, 1H), 8.26 (d, 1H), 7.72 (d, 1H), 7.53 (d, 1H), 7.46 (d, 1H), 7.40 (t, 1H), 4.96 (s, 1H), 1.05 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.N1C=CN=C1.[C:41]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Si:45]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.68 g) and imidazole (0.74 g) in N,N-dimethylformamide (20 mL) was added tert-butyl(chloro)dimethylsilane (1.1 g), and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.89 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH2:9].[OH:10]S(O)(=O)=O>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)nn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a stirred solution of 3-chloro-6-methylpyridazine (12.8 g, 100 mol) in concentrated H2SO4 (100 mL) was added powered K2Cr2O7 (35.3 g, 120 mmol) slowly at 50° C. The reaction mixture was stirred at 50° C. for 4 h, and poured into the iced water carefully. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under vacuum to afford the 6-chloropyridazine-3-carboxylic acid (9.25 g, 59%), which was used directly in the next step. 1H NMR (DMSO-d6, 400 MHz): δ8.21 (d, J=4.8 Hz, 1H), 8.06 (d, J=4.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:8][CH2:7]2.CN(C)C=O.[CH2:34](I)[CH3:35]>O.C1C=CC=CC=1>[CH2:34]([O:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:8][CH2:7]2)[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g of a 55% w/w suspension of sodium hydride in mineral oil was added to a mixture of 11 g of 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman and 100 ml of dimethylformamide, and the reaction mixture was stirred for 1 hour at room temperature. Then a mixture of 5.7 g of ethyl iodide and 5 ml of benzene was added dropwise, whilst ice-cooling, and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. This extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled from the extract under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 3:7 by volume mixture of cyclohexane and benzene, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)=[C:8]([CH3:29])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=2)[CH2:16][O:17][C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)=[C:8]([CH3:29])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=2)[CH2:16][O:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(OCc2cccc(Cn3c(C)c(C(=O)c4ccc(C)cc4)c4ccc(OC)cc43)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(C)cc3)c(C)n(Cc3cccc(COC4(C(=O)O)CC4)c3)c2c1
Reaction time: 20 h

Procedure:
The compound of Example 66-1 (10 mg, 0.02 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 1N aqueous sodium hydroxide solution (1 ml), followed by stirring for 20 hours. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (quant.).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][CH:14]=[C:15]([O:18][CH3:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21]OS([O-])=O.[K+].[OH2:27]>CO>[CH2:1]([S:8]([C:9]1[S:20][C:12]2=[N:13][CH:14]=[C:15]([O:18][CH3:19])[C:16](=[O:17])[N:11]2[N:10]=1)(=[O:21])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cnc2sc(SCc3ccccc3)nn2c1=O
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: COc1cnc2sc(S(=O)(=O)Cc3ccccc3)nn2c1=O
Reaction time: 0.83 h
Yield: 50 %

Procedure:
In 155 ml of methanol, 5.1 g of 2-benzylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. A suspension of 46.2 g of OXONE® in 160 ml of water was added to the methanol solution, and the mixture was stirred at 60°-65° C. for 50 minutes. After cooling, the mixture was extracted with chloroform, and the organic layer was washed with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogen carbonate solution and water. After the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off and the residue was recrystallized from a toluene/ethanol mixture, and thus 2.8 g of 2-benzylsulfonyl-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 204°-206° C. Yield 50%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([N:17]([CH3:19])[CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:21].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:21])=[N:13][C:14]([N:17]([CH3:19])[CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: CN(C)c1ncc(C(=O)NCc2ccccc2)c(Cl)n1
Agent: [Na]
Product: CN(C)c1ncc(C(=O)NCc2ccccc2)c(S)n1
Yield: 43.9 %

Procedure:
Using the procedure of Preparation 34, 14.3 g (0.045 mol) of 4-chloro-2-dimethylamino-pyrimidine-5-carboxylic acid benzylamide and 12 g (0.21 mol) of sodium hydrogen sulfide were reacted to give 5.7 g of the title compound, mp 175-178° C.