Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:17])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2=[O:16])[CH:2]=[CH2:3].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]2=[O:16])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2c1OC(C)(C)CC2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: C=CCc1c(OC)ccc2c1OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
567 mg of 8-allyl-7-hydroxy-2,2-dimethyl-4-oxochroman was dissolved in 15 ml of N,N-dimethylformamide. Thereafter, 0.51 g of potassium carbonate and 0.42 g of iodomethane were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 582 mg of the subject compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:18][C:19]([NH2:21])=[NH:20])#[N:17]>>[NH2:21][C:19]1[N:18]=[C:16]([NH2:17])[C:13]2[CH2:14][CH:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:11][C:12]=2[N:20]=1
Reactant: O=C1CCC(C#Cc2ccccc2)CC1
Reactant: N#CNC(=N)N
Product: Nc1nc(N)c2c(n1)CCC(C#Cc1ccccc1)C2

Procedure:
When n is the bridging group --C(Cl)=CH--, 1,4-cyclohexanedione mono-ethylene ketal is reduced with sodium borohydride in ethanol, yielding the corresponding 1,4-dioxaspiro[4.5]decan-8-ol. The so-prepared alcohol is then treated with methanesulfonyl chloride under basic conditions in methylene chloride, affording 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane, which is in turn treated with sodium hydride in tetrahydrofuran, and then is reacted with trimethylsilylacetylene, yielding 8-(trimethylsilylethynyl)-1,4-dioxaspiro[4.5]decane. This compound is then treated with sodium carbonate in methanol to unprotect the ethynyl moiety, affording 8-ethynyl-1,4-dioxaspiro[4.5]decane. The so-prepared ethynyl compound is reacted with an appropriately substituted or unsubstituted phenyl iodide, for example, 3,5-di(trifluoromethyl)phenyl iodide, under basic conditions in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile, and then is treated with 1N hydrochloric acid, yielding the corresponding 4-(phenylethynyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, as previously described, affording the 2,4-diamino-6-phenylethynyl-5,6,7,8-tetrahydroquinazoline. Chlorination of the 6-phenylethynyl-5,6,7,8-tetrahydroquinazoline, using the methods of J. Cousseau (JCS Faraday II, 1973, 1821, and JCS Perkin I, 1977, 1797), affords the targeted 2,4-diamino-6-[1-chloro-2-phenylethenyl]-5,6,7,8-tetrahydroquinazoline. Example 8 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36](Cl)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([C:23]#[C:22][C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (example B.14) according to general procedure II. Obtained as a yellow solid (44 mg, 30%). MS (ISP) 590.0 [(M+H)+]; mp 220-223° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccc(Br)cc2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(Br)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.0 g) and 2-methylthio-5-(4-bromobenzyl)pyrimid-4-one (1.56 g) were heated together under reflux in pyridine (3 ml) for 18 hr. The mixture was stripped and the residue recrystallised three times from ethanol to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(4-bromobenzyl)pyrimid-4-one, 1.45 g (67%) mp 178°-9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:7]([N:22]([OH:21])[C:13](=[O:15])[C:5]=12)=[O:8])([O-:3])=[O:2]
Reactant: [NH3+]O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1O

Procedure:
Analogous to Example 4, but from 500 mg (2.37 mmol) of 3-nitrophthalic acid and 187 mg (0.947 mmol) of hydroxylammonium phosphate at a bath temperature of 130° C. The yield was 443 mg (90%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: C1CSCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.6 g, 32 mmol), thiomorpholine (10.0 g, 97 mmol) and anhydrous potassium carbonate (4.98 g, 36 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 135° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was washed with diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-thiomorpholin-4-yl-phenylamine (7.0 g, 91.5%) as a brown powder, and used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[NH2:16].Cl.N1C=CC=CC=1>O>[NH2:16][C:7]1[N:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[OH:2])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CN1Cc2ccccc2N=C1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NC1=Nc2ccccc2CN1Cc1ccccc1O
Temperature: 140 °C

Procedure:
120 mg (0.45 mmol) 3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2-amine and 5 g pyridine hydrochloride were combined and heated for 4 hours at approx. 140° C. After cooling the melt, the residue was dissolved in water, extracted three times with dichloromethane and the combined organic phases were dried, filtered and evaporated. The resulting crude product was purified over MPLC (silica gel: Bischoff Prontoprep 60-2540-C18E, 32 μm; mobile phase: CH3CN/H2O+0.1% acetic acid) and subsequent lyophilization yielded the target product as a beige white solid; 110 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]([CH:11]=[CH2:12])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.CC1N=C(C(O)C=C)C=CC=1.[S:24](Cl)(Cl)=O.ClC(C1C=CC=C(C)N=1)C=C.[C-]#N.[Na+].S>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([CH:11]=[CH2:12])[C:9]([NH2:10])=[S:24])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC(C#N)c1cccc(C)n1
Agent: C=CC(Cl)c1cccc(C)n1
Agent: C=CC(O)c1cccc(C)n1
Agent: S
Product: C=CC(C(N)=S)c1cccc(C)n1

Procedure:
2-(6-Methyl-2-pyridyl)-3-butenenitrile [prepared by treating α-(6-methyl-2-pyridyl)-2-propenol with thionyl chloride and reacting the resulting 2-(1-chloro-2-propenyl)-6-methylpyridine with sodium cyanide] is treated with hydrogen sulfide by the procedure described in Example 9, to give 2-(6-methyl-2-pyridyl)-3-thiobutenamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:7]=[C:6]2[C:18]([NH:20][NH2:21])=[O:19].C(N(CC)CC)C.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:6]([C:18]3[O:19][C:29](=[O:30])[NH:21][N:20]=3)=[N:7][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](=[O:11])[C:10]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1scc2c(-c3n[nH]c(=O)o3)nn(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a ice cooled solution of 5-amino-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid hydrazide (2.0 g, 6.64 mmol), triethylamine (0.67 g, 6.64 mmol) in dry tetrahydrofuran (50 ml) was added 1,1′-carbonyidiimidazole (1.3 g, 8.30 mmol). The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (100 ml) was added and the precipitate was filtered off and washed with water (2×25 ml), diethyl ether (20 ml) and dried in vacuo at 50° C. for 16 h affording 1.7 g (78%) of the title compound as a solid.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:41])[C:30](=[O:40])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:41])=[O:40]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)COCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine were added at -15° C. to a solution of 5.52 g of the product of Step B in 55 ml of methylene chloride and the reaction mixture was stirred for one hour at 0° C., then chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 6.22 g of the expected product.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[O:13][C@@:12]([O:36]C)([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[O:13][C@@:12]([OH:36])([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl benzoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CN(CCN)S(C)(=O)=O
Product: CCCCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 55 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (excess) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 55% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.41 (br s, 1 H), 8.55 (s, 1 H), 7.27 (s, 1 H), 7.17-7.13 (m, 2 H), 7.05-7.00 (m, 2 H), 4.13 (s, 2 H), 4.08 (m, 2 H), 3.65 (m, 2 H), 3.39 (m, 2 H), 2.94 (s, 3 H), 2.82(s, 3 H), 1.50 (m, 2 H), 1.33 (m, 2 H), 0.89 (m, 3 H); MS m/z 505 (M+1).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1([O:36][CH3:37])[CH2:35][CH2:34]1)[NH2:32]>>[CH3:37][O:36][C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: COC1(C(N)=NO)CC1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COC1(c2noc(C3CC(c4ccc(CC(F)(F)F)cc4)CN(C(=O)N4CCSCC4)C3)n2)CC1

Procedure:
According to General Method 6A, 93.1 mg (0.224 mmol) of the compound from Example 45A and 32.0 mg (0.246 mmol) of N′-hydroxy-1-methoxycyclopropanecarboximidamide from Example 64A were reacted. Yield: 31.1 mg (27% of theory)
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=O)=[CH:4][CH:3]=1>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[O:19][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)NNC(=O)c2ccc(I)cc2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nnc(-c3ccc(I)cc3)o2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N′-(4-iodobenzoyl)-3-methoxybenzohydrazide (7.0 g, 17.67 mmol) was suspended in POCl3 (40.0 ml) and heating was started. The reaction was kept at 100° C. During heating white solid of starting materials dissolved into a clear solution and the reaction was monitor by thin layer chromatography. After 1 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (500.0 ml). White solid precipitated out was collected by filtration and washed with water. After dry, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 25:1 ratio. After evaporating solvent the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 5.8 g (86.8%) yield. 1H NMR (400 MHz, CDCl3, δ): 7.86 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dt, J1=8.0 Hz, J2=1.2 Hz, 1H), 7.63 (m, 1H), 7.42 (t, J=8 Hz, 1H), 7.07 (m, 1H), 3.88 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.66, 164.00, 159.92, 138.32, 130.23, 128.21, 124.73, 123.26, 119.29, 118.26, 111.56, 98.60, 55.52.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:23])=[CH:5][N:6]=1
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 87.5 %

Procedure:
To a solution of 2-amino-5-(4-aminophenylthio)thiazole (4.0 g) in a mixture of chloroform (140 ml) and N,N-dimethylformamide (20 ml) was dropwise added the solution of 3-chloroperbenzoic acid (4.65 g) in chloroform (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 4 hours. The precipitates were collected by filtration, washed with 10% aqueous sodium bicarbonate and water. The solid was dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (3.75 g, yield: 87.5%). mp: 173°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 ml) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)N1CCCCC1CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
Triethylamine (6.0 ml) and octadecyl isocyanate (11.500 g) were added to a solution of 2-(2-hydroxyethyl)piperidine (5.009 g) in methylene chloride (50 ml). After being stirred for 4 hours at room temperature, the reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 200 g, chloroform:methanol=100:1~80:1), thereby yielding the entitled compound (15.662 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19](=[O:21])(=[O:20])[NH2:22])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Yield: 20.2 %

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (1.34 g, 5.25 mmol), 3-aminobenzenesulfonamide (860 mg, 5.0 mmol) and DIPEA (1.29 g, 10 mmol) in THF (10 mL) was stirred overnight at room temperature. The solvent was then evaporated and the residue purified by chromatography on the SP4 (70 g Silica Isolute II, 0-100% EtOAc/hexane) to and the title compound obtained as a white solid (395 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14]
Reactant: CCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21
Yield: 47.5 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 96 from 1.19 g of 5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one and 1.1 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using a gradient of a hexane/AcOEt mixture (from 95/5; v/v to 90/10; v/v) as the eluent gives 0.9 g of the expected product, which is used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[F:27])=[C:11]([C:28]([F:31])([F:30])[F:29])[S:10][N:9]=2)=[C:4]([F:32])[CH:3]=1.Cl.[CH3:34]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24]([O:26][CH3:34])=[O:25])=[CH:17][C:16]=3[F:27])=[C:11]([C:28]([F:31])([F:29])[F:30])[S:10][N:9]=2)=[C:4]([F:32])[CH:3]=1
Reactant: CO
Reactant: O=C(O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3F)nsc2C(F)(F)F)c(F)c1
Agent: Cl
Product: COC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3F)nsc2C(F)(F)F)c(F)c1

Procedure:
3-(4-((3-(4-Chloro-2-fluorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)propanoic acid (Cpd 74, Example 7; 2 g, 4.04 mmol) in 1 M HCl/MeOH solution (10 mL) was stirred at room temperature for 6 h. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried, and filtered. The crude material was purified on a silica gel column, eluting with 10% ethyl acetate/heptanes to afford the desired product as a clear oil. During storage at room temperature, the compound solidified to a white solid (1.86 g, 90%). 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J=7.5 Hz, 1H), 7.25 (m, J=7.8 Hz, 2H), 6.72 (d, J=6.5 Hz, 2H), 5.10 (s, 2H), 3.70 (s, 3H), 2.82 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([Cl:20])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
A mixture of 2-(2,2-difluoroethyl)oxy-5-nitro-nicotinic acid (310 mg, 1.25 mmol), 2.0 mL thionyl chloride, 5.0 mL DCM and one drop of DMF was refluxed for 4 h and concentrated i.vac. The corresponding acid chloride was directly used for the next step without further purification.