Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].[NH:18]([C:20](=[S:22])[NH2:21])[NH2:19]>O=P(Cl)(Cl)Cl>[CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[S:22][C:20]([NH2:21])=[N:18][N:19]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3]
Reactant: NNC(N)=S
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(-c2nnc(N)s2)cc1C(F)(F)F
Temperature: 90 °C
Yield: 120.3 %

Procedure:
To a suspension 4-[(1-methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (D2) (3 g) in POCl3 (11.27 mL) was added hydrazinecarbothioamide (1.652 g). The reaction mixture was heated at 90° C. for 3 h. The reaction was quenched with ice water, the pH value was adjusted to about 9 with NaOH solid. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated to afford 5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-amine (D3) (4.41 g). MS (ES): C12H12F3N3OS requires 303. found 304.1 (M+H+).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:26](=[O:33])[CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:26](=[O:33])[CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of 0.190 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)-acetyl]valerohydrazide in 5 mL of methanol was treated with 0.020 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.152 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)acetyl]valerohydrazide in the form of a white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].CO>CN(C=O)C>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
83.6 g (0.5 mol) of carbazole are dissolved in 250 ml of dry DMF. This solution is added dropwise at 0° C. to a suspension of 12.0 g (0.4 mol) of sodium hydride in 500 ml of DMF. An 80% oil suspension of NaH is used. After stirring for a further 2 hours at 0° C., 38 ml (0.45 mol) of allyl bromide are added dropwise. After the end of the addition, the mixture is warmed to room temperature within one hour, with stirring. To decompose residual NaH, 100 ml of methanol are also added. The solvent mixture is then removed in vacuo in a rotary evaporator and the residue is extracted with 400 ml of petroleum ether (40°-60° C.). Finally, the petroleum ether extract is filtered and evaporated in a rotary evaporator. The remaining brownish oil is distilled in a high vacuum. This gives 65.1 g of a pale yellow, microcrystalline solid. Melting point: 52°-54° C., boiling point: 112° C./13 Pa. Yield 78.5% of theory.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](#[N:25])[CH:23]=[CH2:24]>N1C=CC=CC=1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:24][CH2:23][C:22]#[N:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: C=CC#N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC#N
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of Example 109A (65 mg, 0.200 mmol) in pyridine (1 mL) and water (1 mL) was added acrylonitrile (0.185 ml, 3.00 mmol) and the reaction heated at 90° C. for 7 hr. The reaction was concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexane) to afford the title compound (65 mg, 86%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.36 (s, 9H) 3.05 (t, J=6.44 Hz, 2H) 3.90 (s, 3H) 4.40 (t, J=6.44 Hz, 2H) 6.74 (s, 1H) 6.92 (d, J=8.81 Hz, 1H) 7.35 (dd, J=8.81, 3.05 Hz, 1H) 7.90 (d, J=3.05 Hz, 1H); MS (DCI/NH3) m/z 378 (M+H)+. Anal. calcd C18H20ClN3O2S: C, 57.21; H, 5.33; N, 11.12. Found: C, 56.93; H, 5.42; N, 10.92.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1>C1C=CC=CC=1>[CH3:17][C:18]1[C:22]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:23][C:21]=2[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccncc1
Reactant: Cc1cc(N)n(C(C)C)n1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccncc2)nc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 64 using ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (766 mg, 2.87 mmol), benzene (6 mL), and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 2.87 mmol). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 30% MeOH/DCM) to give 95 mg (10%) of product. LCMS E-S (M+H)=325.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.56 (m, 3H), 1.61-1.73 (m, 6H), 2.77 (s, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.37-5.50 (m, 1H), 8.02-8.16 (m, 3H), 8.76-8.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:42][CH2:43][N:38]3[CH2:37][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)C2CCCc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)(3-methyl-4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (345 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), and 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 ml) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give title compound of formula I. Yield 324 mg (72%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([S:35]([CH3:34])(=[O:37])=[O:36])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(S(C)(=O)=O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 369 mg (0.758 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide (Example 2) and 176 mg (1.67 mmol) sodium methanesulfinate in 4 ml N,N-dimethylformamide was heated at reflux over night. After cooling to room temperature the mixture was diluted with dichloromethane and treated with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate, concentrated and and dried in high vacuo. Flash column chromatography gave 118 mg (29%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:49]1(C(OC(C)(C)C)=O)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:49]6[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (40 mg, 0.062 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (115.37 mg, 0.619 mmol, 10 eq) and acetic acid (3.55 μL, 0.062 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in a VX-2500 Multi-Tube Vortexer overnight at room temperature. MP-triacetoxyborohydride (195 mg, 0.482 mmol, 7.78 eq) was then added and the mixture was stirred again in the VX-2500 Multi-Tube Vortexer overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock (Artisian Scientific, Champaign, Ill., USA, http://www.artisan-scientific.com/51413.htm) in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) and hydrochloric acid (5 μL) were then added and the vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator over the weekend at 60° C. The reaction mixture was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on a Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 16.4 mg (41.1%) of the title compound. LC-MS m/z 716 (M+H)+, 1.25 min (ret time).
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=C=O.[CH3:8][NH:9][C:10]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>O>[CH3:8][N:9]1[C:10]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:1][CH2:4][C:5]1=[O:6]
Reactant: CNc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: O=C=NCC(=O)Cl
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 95 °C

Procedure:
2-Milliliters of 2-isocyanatoacetyl chloride was cooled, and 0.20 g. of powdered 2-methylamino-5-nitrobenzophenone was added thereto with stirring. After stirring the resulting mixture at room temperature for one hour, excess 2-isocyanatoacetyl chloride was removed by reduced pressure distillation. To the residue was added 4 ml. of pyridine, whereby a reaction took place with generation of heat. The reaction liquid was heated at 95° C, for 1.5 hours, diluted with water and then extracted with chloroform. The chloroform layer was washed with a 5% aqueous hydrochloric acid solution and then with an aqueous sodium chloride solution in this order, dried over Glauber's salt, and evaporated by reduced pressure distillation. Subsequently, the residue was chromatographically purified (solvent: chloroform→ethyl acetate) by use of a column packed with 10 g. of silica gel to obtain 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one having a melting point of 154° to 156° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]1([CH:2]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(c1ccccc1)[Si](Cl)(Cl)Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Into a 2-liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged styrene (410 g, 3.94 mols) and Bis(triphenylphosphine)palladium (II) dichloride (1.2 g, 0.3% wt). The reaction mixture was heated to 70° C. and then trichlorosilane (532.8 g, 3.94 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 110° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, >98% pure (1-phenylethyl)trichlorosilane (840 g, 99% purity) was obtained (collected at 78° C./3 mmHg). The product structure was characterized by GC-MS.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:15]1[O:20][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:17]=2[N:16]=1)[CH2:12][CH2:13][CH3:14]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH2:12][CH2:13][CH3:14])[C:15]([NH:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[O:21])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:20]
Reactant: CC(=O)Nc1nccs1
Reactant: CCCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 72.6 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 6.94 g of N-(2-thiazolyl)-acetamide in 280 ml of tetrahydrofuran and 70 ml of a butyllithium-hexane solution and a solution of 7.8 g of the product of Step A in 40 ml of tetrahydrofuran were reacted to obtain 8.3 g of 2-[(2-chloro-1-oxo-pentyl)-amino]-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene propanamide melting towards 184°-186° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Solvent: c1ccncc1
Product: OCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 41.6 %

Procedure:
To a solution of 45 g of butane-1,4-diol in 0.25 l of pyridine, cooled to 0° C., were added 139.4 g of triphenylchloromethane and the mixture was stirred at room temperature for 26 h. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in 0.5 I of ethyl acetate and the solution was washed successively with 200 ml portions of water, 1N hydrochloric acid, water, 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane afforded 69.0 g of 4-trityloxy-1-butanol as white crystals of m.p. 73°-74° C.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([OH:16])=O)([CH3:4])[CH3:3].C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([Cl:1])=[O:16])([CH3:4])[CH3:3]
Reactant: CC(C)C1=C(C(=O)O)SC2=NCCCN21
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)C1=C(C(=O)Cl)SC2=NCCCN21
Yield: 201.3 %

Procedure:
In 50 ml of thionylchloride was suspended 6.5 g of 3-isopropyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained in Example 46, followed by reflux under heating for 1 hour. To the reaction mixture was added dry diethylether. The precipitated crystals were collected by filtration and washed with diethylether to obtain 7.0 g of 3-isopropyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride. In the mixture 5 ml of pyridine and 5 ml of dimethylformamide was dissolved 500 mg of this compound. To the solution was added 291 mg of 2,5-dimethoxyaniline, followed by stirring at 80uÅ for 12 hours. The solvent was removed under reduced pressure. The residue was crystallized from isopropylalcohol and diethylether. The resulting crystals were recrystallized from isopropylalcohol and saturated hydrogenchloride diethylether solution to obtain 200 mg of the titled compound.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])(=[O:8])=[O:7])C.Cl[C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1>>[CH3:16][C:11]([CH3:15])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][CH2:13][O:14][C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CCO
Reactant: Cc1cc2ncnn2nc1Cl
Product: Cc1cc2ncnn2nc1OCCC(C)(C)CCS(N)(=O)=O

Procedure:
Using 5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethyl-1-pentanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 143°-144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27](=[O:29])[CH3:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:25])[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27]([O:29][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH2:28])=[CH:11][C:12]=1[S:13](=[O:25])(=[O:26])[N:14]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.5 h

Procedure:
To a solution of (5-acetyl-3-{[2-(4-fluorophenyl)ethyl]methylsulfamoyl}thiophene-2-yl)-carbamic acid t-butyl ester (the compound of Preparation Example 111) (946 mg) in dichloromethane (8 mL) was added triethylamine (0.58 mL) and 0.71 mL of t-butyldimethylsilyltrifluoromethane sulfonate (0.71 mL) on an ice bath. After stirring for 30 minutes, an aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate) and, the title compound (985 mg) was obtained as a colorless oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:23]([CH3:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[C:23]([CH3:24])[C:22]([CH3:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1C
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1ccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c2c1C
Yield: 53.3 %

Procedure:
365 mg (1.68 mmol) of 4-chlorobenzenesulfonylisocyanate and 230 mg (1.40 mmol) of 2-amino-3,4-dimethylbenzoic acid were treated in the same way as in Example 1 to obtain 272 mg of the above-identified compound (yield 53.6%). Properties: colorless crystal, Melting point; 241°-245° C., PMR (δppm, DMSO-d6): 2.21 (3H,s), 2.32 (3H,s), 7.06 (1H,d), 7.63 (1H,d), 7.75 (2H,d), 8.18 (2H,d), 10.64 (1H,br).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:9][C:8]=1[CH3:23])(=O)=O.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:17]([NH:16][C:14](=[O:15])[C:13]([CH3:22])([C:10]1[CH:11]=[CH:12][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:8]([CH3:23])[CH:9]=1)[CH3:21])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1cc(C(C)(C)C(=O)NCC(C)C)ccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: Cc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1ccccc1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 1 from 4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)-2-methylphenyl trifluoromethanesulfonate (example 50a) and phenyl boronic acid. Yield: 75%. 1H NMR (400 MHz, dMSO): δ 0.76-0.77 (d, 6H), 1.46 (s, 6H), 1.72-1.73 (m, 1H), 2.21 (s, 3H), 2.84-2.87 (m, 2H), 7.13-7.21 (m, 3H), 7.30-7.37 (m, 4H), 7.41-7.45 (m, 2H); MS+H (310).
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C=CC=CC=1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cc1ccccc1)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
In a 500-ml four-necked flask were placed 22.4 g (0.10 mole) of 1,3-diphenylpropanedione, 20.0 g (0.13 mole) of p-nitrophenylhydrazine, and 200.7 g of toluene. The mixture was then heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by reslurrying by adding 300 ml of methanol. Thereafter, the residue was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 26.0 g of 1-(p-nitrophenyl)-3,5-diphenylpyrazole.