Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([Br:22])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:6])=[O:4].C(O)(=O)C.[O-:32][C:33]#[N:34].[Na+]>O>[Br:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:23]([Cl:26])=[CH:24][CH:25]=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH2:34])=[O:32])[C:8]=3[Cl:27])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(N)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (100 mg), acetic acid (0.5 ml) and water (1.0 ml) was added an aqueous solution (1 ml) of sodium cyanate (138 mg) at 40° C. The mixture was stirred at the same temperature for 1 hour and evaporated in vacuo. The residue was partitioned into dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) followed by crystallization from ethyl acetate--diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(ureidoacetyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (72 mg) as crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:35])[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:16]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:15]=2[O:14]1>ClCCl>[C:33]([C:30]1[CH:31]=[CH:32][C:15]2[O:14][C:13]([CH3:35])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]=3[O-:9])[C:16]=2[CH:29]=1)#[N:34]
Reactant: CC1(C)C=C(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.9 %

Procedure:
450 mg of m-chloroperbenzoic acid were added at room temperature to a solution of 624 mg of 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile in 20 ml of dichloromethane. After stirring at room temperature for 6 hours the mixture was washed with sodium bicarbonate solution and the organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (4:1) for the elution and then chromatographed on silica gel a second time using methanol/ethyl acetate (1:9) for the elution. The product was recrystallized from toluene to give 45 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)quinoline 1-oxide of melting point 177° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].Br[CH2:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]2[S:16][C:40]([C:41](=[O:42])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:18][N:17]=2)[C:7]=1[C:23]([O:25][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 720 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 260 mg of 2-bromo-1-phenylethanone and 90 mg of potassium carbonate in 15 ml of dry acetonitrile was stirred for about 1 hour, then filtered and the filtrate evaporated, giving 526 mg of the desired product.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[N:10]=[N:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc(-n2cccn2)nn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-n2cccn2)nn1
Yield: 26 %

Procedure:
6-(1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (100 mg, 0.53 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile as described in Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: silica, eluent: 0-15% MeOH in DCM) to obtain 54 mg (26%) of the title compound. 1H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.35-4.50 (m, 2H), 4.51-4.64 (m, 1H), 6.75 (dd, 1H), 6.94 (d, 1H), 7.87 (d, 1H), 7.92-7.98 (m, 2H), 8.03 (dd, 2H), 8.30 (m, 2H), 8.87 (d, 1H), 9.38 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:14][CH:15]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)cc(F)c3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cc(F)cc(F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.510 g of tert-butyl 4-{4-[3-(3,5-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.323 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=6.04.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].Br[CH:45]1[CH2:49][CH2:48][O:47][C:46]1=[O:50]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:42][CH2:43]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH:45]5[CH2:49][CH2:48][O:47][C:46]5=[O:50])[CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: O=C1OCCC1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=CCN1CCN(C2CCOC2=O)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.42 ml of triethylamine is added to 608 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline in 3.0 ml of tetrahydrofuran. The mixture is cooled in the ice bath and a solution of 215 mg of 3-bromodihydrofuran-2-one in 1.0 ml of tetrahydrofuran is added dropwise and the mixture is stirred for one hour with cooling. The ice bath is then removed and the mixture is stirred for about 48 hours at ambient temperature. The reaction mixture is chromatographed directly, without further processing, over a silica gel column, with methylene chloride/methanol (95:5 to 90:10) as eluant. The foamy crude product is crystallized by trituration with a little diethylether.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:11][C:10]1[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][C:5]=1[N:4]([CH3:24])[C:1](=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(NC(C)=O)c(C)nc1C(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N(C)C(C)=O)c(C)nc1C(=O)OCC
Reaction time: 1 h

Procedure:
A stirred mixture of 2.94 g of 5-acetamido-6-methylpyridine-2,3-dicarboxylic acid, diethyl ester, and 0.44 g of 60% sodium hydride in 200 mL dry tetrahydrofuran is kept at room temperature for 1 hour, then 0.93 mL of methyl iodide is added, and the reaction is stirred for an additional 4 hours. The reaction is concentrated in vacuo, and the residue is slurried in water, the pH is adjusted to 3 with hydrochloric acid, and the mixture is extracted with methylenechloride. The organic phase is dried, concentrated in vacuo to afford the desired product as an oil.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][N:51]=1>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>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:47])([CH3:48])[CH3:46])=[CH:41][CH:40]=3)[N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:50]4[CH:55]=[CH:54][C:53]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:52][N:51]=4)=[CH:22][CH:21]=3)[N:28]=2)=[CH:34][CH:33]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccc5)cn4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-bromo-5-phenylpyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 35 ml portion of tetrahydrofuran prepared by dissolving 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine synthesized by the method of Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 10 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4-(5-phenylpyridin-2-yl)phenyl]-1,3,5-triazine (1.05 g, yield 91%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:3][N:4]([C:8]1[S:9][C:10]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)C(=O)C.C1COCC1.Cl.[OH-].[Na+]>>[NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:3][NH:4][C:8]1[S:9][C:10]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1
Reactant: COCc1nc(N(C[C@@H](N)Cc2cccc(Cl)c2)C(C)=O)sc1-c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1nc(NC[C@@H](N)Cc2cccc(Cl)c2)sc1-c1nc2ccncc2s1
Temperature: 150 °C
Yield: 38.6 %

Procedure:
A glass microwave reaction vessel was charged with N—((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.090 g, 0.18 mmol), THF (2.0 mL, 24 mmol), and 5 N HCl (2.0 mL, 10.0 mmol). The reaction mixture was stirred and heated in a Smith Synthesizers microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 11 minutes. The solution was then made basic with 10 N NaOH and extracted with EtOAc. The solvent was removed, and the compound was purified by reverse phase HPLC to give the title compound (31 mg, 38%). LCMS (M+H) 445.7 calc. for C20H21ClN5OS2 446.09. 1H NMR (400 MHz, CD3OD): δ ppm 9.12 (s, 1H), 8.50 (d, J=5.7 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.34 (s, 1H), 7.23 (m, 3H), 4.70 (dd, J=12.4, 17.4 Hz, 2H), 4.46 (m, 1H), 3.47 (s, 3H), 3.25 (dd, J=3.7, 13.2 Hz, 1H), 3.15 (dd, J=9.9, 13.2 Hz, 1H), 2.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:8].C1N=CN([C:31](N2C=NC=C2)=[S:32])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:7](=[S:8])[C:9]2[C:10](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:31]1=[S:32]
Reactant: CCOC(=O)CNc1ccccc1C(=S)NCc1ccc(Cl)c(Cl)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of ethyl 2-[2-{N-(3,4-dichlorobenzyl)thiocarbamoyl}anilino]acetate (4.0 g) and N,N'-thiocarbonyldiimidazole (8.97 g) was heated at 120° C. for 15 minutes, and the reaction mixture was chromatographed on silica gel (100 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and hexane to give ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetate (560 mg).
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+:16]>CO>[NH2:16][C:6]([C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)=[CH:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)c1cccs1
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C=C(N)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of 17.83 g (0.09679 mol) of methyl 2-(2-thenoyl)acetate in 180 ml of methanol, 36.62 g (0.5807 mol) of ammonium formate was added, and the resulting mixture was heated under reflux for 38 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated off under reduced pressure. To the residue, 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed with 40 ml of water and with 40 ml of a brine successively and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective methyl 3-amino-3-thiophen-2-yl-acrylate (15.80 g, colorless liquid). The yield was 89.1%.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.[I:24]I>CCOCC.C1COCC1>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([I:24])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1cccnc1Cl
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1nccc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at −78° C., under a nitrogen atmosphere, was added 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol), dropwise. The resulting reaction mixture was stirred at −78° C. for 10 min., and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate compound D10 (8.21 g, 44%) as a pale cream solid.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Br[CH2:20][CH:21]([F:23])[F:22]>CO>[F:22][CH:21]([F:23])[CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1S
Reactant: FC(F)CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1ccccc1SCC(F)F
Reaction time: 16 h
Yield: 94.8 %

Procedure:
A mixture of 145.2 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 79.7 g of 2-bromo-1,1-difluoroethane in 600 ml of methanol is stirred for 16 hours at a temperature of +55° C. to +60° C. The reaction mixture is then evaporated. Triturating the residue with ice water and filtering the suspension thus obtained gives 120 g (95% of theory) of 2-(2,2-difluoroethylthio)-phenylsulfonamide having a melting point of +111° C. to +112° C.
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:23][N:22]([CH3:24])[C:20]([C:19]1[C:18]([CH3:29])=[C:17]([N:16]=[C:1]=[O:2])[C:27]([CH3:28])=[CH:26][CH:25]=1)=[O:21]
Reactant: Cc1ccc(C(=O)N(C)C)c(C)c1N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(C)C)c(C)c1N=C=O

Procedure:
A solution of di-tert-butyl dicarbonate (0.081 g) in methylene chloride (1.6 ml) and a solution of 3-amino-N,N,2,4-tetramethylbenzamide (J. Chem. Soc., Perkin Trans. I, 1973, 1-4; 0.072 g) in methylene chloride (1.0 ml) were added in turn to a solution of 4-dimethylaminopyridine (0.004 g) in methylene chloride (0.4 ml). The resultant mixture was stirred at ambient temperature for 20 minutes. There was thus obtained a solution of 3-(N,N-dimethylcarbamoyl)-2,6-dimethylphenylisocyanate which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([OH:16])=[C:4]([CH:17]=[O:18])[CH:3]=1.I[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([O:16][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:3]=1
Reactant: CC(C)I
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (3.50 g), 2-iodopropane (5.70 g), potassium carbonate (3.09 g), and DMF (15 mL) was stirred at 50 C for 1 hour. The reaction mixture was poured to water, followed by extraction with ethyl acetate twice. The organic layer was separated, then washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g)
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CC(C)=O.O>[CH2:20]([O:19][C:17](=[O:18])[NH:11][C:7]1[N:6]=[C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]2=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(n1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc2c(n1)OCCO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 2,3-dihydro-1,4-dioxino[2,3-b]pyridin-6-amine (commercial; 2.70 g) in acetone/water 1:1 (40 mL) was treated at 0° C. with 1M NaHCO3 (35 mL) and CbzCl (2.63 mL). The reaction mixture was stirred at rt for 3 h, the org. solvent was evaporated under reduced pressure and the residue was partitioned between water and ether/EA. The org layer was dried over MgSO4 and evaporated under reduced pressure, affording a beige solid (5.3 g; 100% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])=[O:4]
Reactant: Cc1ccccc1NCN1C(=O)CSC1=O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1N(CN1C(=O)CSC1=O)C(=O)CCl
Reaction time: 3 h

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a suspension of 7.8 g of N-(2-methylphenylaminomethyl)-2,4-thiazolidinedione and 3 g of pyridine in 80 ml of toluene at -5° C with stirring and kept on an ice bath for 3 hrs. The resulting precipitate was filtered and washed with water to give 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methylphenyl)acetamide, mp 133°-136° C. The toluene filtrate was extracted with two 50 ml portions of 5% hydrochloric acid, 50 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated on a rotary evaporator to give the product which was crystallized from benzene-ether, mp 134°-137° C. The total yield was 6.0 g [M+ = 312 (molecular ion by mass spec.)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:35])=[CH:19][CH:20]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(SC)cc2)cc1F
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)=O)cc2)cc1F
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfanylphenyl)-3-trifluoromethyl-1H-pyrazole (compound No. 14) (790 mg) in chloroform (25 mL), m-chloroperbenzoic acid (55-75%, 464 mg) was added in one portion at −40° C. and stirred at the same temperature for one hour. The reaction mixture was diluted with chloroform (50 mL), washed with saturated solution of aqueous sodium bicarbonate (30 mL), water (2×30 mL), dried over calcium chloride and evaporated under reduced pressure. The product obtained was chromatographed over silicagel using 7:3 ethyl acetate: petroleum ether as eluent to afford 600 mg of product as a thick liquid.