Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[CH3:15][C:16]1[C:17]([NH2:22])=[N:18][CH:19]=[CH:20][CH:21]=1>C(#N)C>[CH3:15][C:16]1[C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]=4[CH:14]=3)[N:22]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccnc1N
Reactant: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Solvent: CC#N
Product: Cc1cccn2cc(-c3ccc4sc(=O)[nH]c4c3)nc12
Yield: 65.2 %

Procedure:
A solution of 5-bromoacetyl 2-benzothiazolinone (1.75g) and 3-methyl-2-aminopyridine [2.07 g] in acetonitrile [100 ml] was refluxed for 4 hours and the reaction mixture was evaporated in vacuo. To the residue was added a mixture of water, ethyl acetate and tetrahydrofuran. The resulting mixture was adJusted to pH 8.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to afford a crystalline residue, which was recrystallized from a mixture of tetrahydrofuran and diethyl ether to give 5-(8-methylimidazo-[1,2-a]pyridin-2-yl)-2-benzothiazolinone (1.18 g). mp. 272° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](SC2C=CC=CC=2)[N:3]=1.C([CH:30]([C:34](N)=[O:35])C(N)=O)C.[CH3:37][C:38](C)([O-:40])C.[K+].O>CN(C=O)C>[CH2:38]([O:40][C:34](=[O:35])[CH2:30][C:4]1[C:5]([C:19]#[N:20])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:7]([C:8]#[N:9])=[C:2]([NH2:1])[N:3]=1)[CH3:37]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: CCC(C(N)=O)C(N)=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Amino-4-(1,3-benzodioxol-5-yl)-6-(phenylsulfanyl)-3,5-dicyanopyridine (5.00 g, 13.43 mmol) [preparation analogously to J. M. Quintela, J. L. Soto, Anales de Quimica 79, 368–372 (1983)] is initially charged with ethyl malonamide (4.23 g, 23.22 mmol) in absolute DMF (30 ml) under an atmosphere of argon. Potassium tert-butoxide (3.01 g, 26.85 mmol) is added, and the solution is then stirred at room temperature for 22 hours. The mixture is poured into water (300 ml). The mixture is then extracted three times with ethyl acetate (300 ml each) and the combined organic phases are dried over magnesium sulfate, filtered and concentrated to about 100 ml. The precipitated crystals are filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[N:32]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)n1

Procedure:
Example 67 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.78 (br s, 1H), 7.65 (t, 1H, J=8.0 Hz), 7.40–7.38 (m, 2H), 7.30–7.27 (m, 2H), 6.88 (d, 2H, J=7.6 Hz), 3.29 (dd, 2H, J=6.0, 11.6 Hz), 2.96 (m, 2H), 2.56–2.49 (m, 2H), 2.36–2.30 (m, 4H), 2.00–1.75 (m, 8H), 1.64–1.59 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.Cl[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=3)=[N:25][CH:24]=2)=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)s2)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in 14 b], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester (example 2 c]) was reacted with 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (prepared from [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/62774 A1] and methanesulfonyl chloride, triethylamine in dichloromethane) in N,N-dimethylformamide in the presence of cesium carbonate to give [rac]-2-ethoxy-3-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25](O)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([N:32]3[CH2:33][C:30]([CH3:29])([OH:34])[CH2:31]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Reactant: CC1(O)CNC1
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CC(C)(O)C3)cc2n1C
Yield: 76 %

Procedure:
The title compound was prepared as a colorless amorphous in 76% yield (71 mg) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (80 mg, 0.21 mmol, STEP 2 of Example 21) and 3-methylazetidin-3-ol hydrochloride (crude 135 mg, STEP 1) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.CO.[OH-].[Na+].Cl>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1OC
Yield: 23.3 %

Procedure:
A solution of methyl 6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylate (75 mg, 0.22 mmol), methanol (2.2 mL), and aqueous sodium hydroxide (1 M, 0.75 mL, 0.75 mmol) was heated at 75° C. for 24 hours. The reaction was acidified with 1 M HCl to pH=2 then diluted with ethyl acetate. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude solid. The crude product was dissolved in methylene chloride and methanol and silica gel was added. The solvent was removed in vacuo and the crude material adsorbed onto silica was loaded onto a column of silica gel and eluted with ethyl acetate (with 0.2% formic acid)/heptanes (1:1 to 1:0) to provide the title compound (17 mg, 24%) as a tan solid.
Reaction SMILES: [N:1]([C:4]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-].FC(F)(F)C1C=CC(C2(O)C3C(=CC=CC=3)OCC2)=CC=1.[Si](N=[N+]=[N-])(C)(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:4]2([NH2:1])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][CH2:6][CH2:5]2)=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NC1(c2ccc(C(F)(F)F)cc2)CCOc2ccccc21
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Agent: OC1(c2ccc(C(F)(F)F)cc2)CCOc2ccccc21
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: NC1(c2ccc(C(F)(F)F)cc2)CCOc2ccccc21
Reaction time: 0.08 h

Procedure:
4-azido-4-(4-(trifluoromethyl)phenyl)chroman. To a solution of 4-(4-(trifluoromethyl)phenyl)chroman-4-ol (112 mg, 0.381 mmol) in toluene (4 mL), was added an ice bath and TMS azide (0.101 mL, 0.761 mmol). After 5 min., the solution was treated with BF3.OEt2 (0.048 mL, 0.381 mmol) dropwise. The solution turned from clear to light yellow during the addition. After 20 min, the reaction was quenched with MeOH (2 mL) and diluted with EtOAc (20 mL). The organic solution was washed with water (2×10 mL) and the organic layer concentrated in vacuo to give the title compound as a light yellow oil. MS (ESI pos. ion) m/z: 277.0 (M−N3). 1H NMR (CDCl3) δ: 7.57-7.65 (m, J=8.3 Hz, 2H), 7.41-7.52 (m, J=8.2 Hz, 2H), 7.26-7.33 (m, 1H), 6.81-7.03 (m, 3H), 4.30-4.44 (m, 1H), 4.21-4.30 (m, 1H), 2.23-2.34 (m, 1H), 2.12-2.23 (m, 1H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:28]2[CH2:27][CH2:26][CH:25]([C:22]3[C:21]4[CH:31]=[CH:32][C:18]([F:17])=[CH:19][C:20]=4[O:24][N:23]=3)[CH2:30][CH2:29]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)NCc1ccc(C(=O)CCCCl)s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(C(=O)CCCN2CCC(c3noc4cc(F)ccc34)CC2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
A mixture of 2-acetylaminomethyl-5-(4-chlorobutyryl)thiophene (2.6 g), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.7 g), potassium carbonate (3.0 g), potassium iodide (1.6 g), dimethylformamide (20 ml), and toluene (20 ml) was stirred at 60° C. for 6 hours. The reaction mixture was poured into water, and the precipitated crystals were filtered off, followed by recrystallization from ethanol to give 0.9 g of 3-(1-(4-(5-acetylaminomethyl -2-thienyl)-4-oxobutyl)piperidin-4-yl)-6-fluoro-1,2-benzisoxazole as white crystals, m.p. 140-142° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[CH:12](=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(OC(C)(C)C)(=O)C>>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH2:10][CH2:15][CH:14]=[CH:13][CH:12]=[O:16]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: C/C=C/C=O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)=CCCC(C)=CCCC=CC=O
Yield: 78 %

Procedure:
110 parts of geraniol, 50 parts of crotonaldehyde and 3.2 parts of t-butyl acetate are heated for six hours at 30 atmospheres pressure and at 150°C in an agitated autoclave having a capacity of 250 parts by volume. Working up gives 85 parts of 7,11-dimethyldodeca2,6,10-trien1-al having a boiling point of 93° to 96°C at 0.2 mm. The yield is 78% of theory at a conversion of 74% (based on crotonaldehyde).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[C:19]1([CH:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:48]CCCl>>[ClH:48].[C:19]1([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC3c3ccccc3)cc2)nc1
Reaction time: 24 h
Yield: 3.9 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.150 g, 0.619 mmol), 2-phenyl-pyrrolidine (0.095 g, 0.64 mmol), sodium triacetoxyborohydride (0.194 g, 0.915 mmol), and acetic acid (0.051 mL, 0.891 mmol) in 1,2-dichloroethane (9.0 mL). After about 24 hours, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and concentrate. Dissolve the residue in 1,4-dioxane and treated with 4 N hydrochloric acid in dioxane. Isolate the white precipitate by vacuum filtration. The solid became a yellowish syrup after approximately 3 min. on vacuum. Dissolve the residue in 1,4-dioxane and concentrate to provide 0.0100 g (3.9%) of the title compound as a white/yellow foam: high resolution mass spectrum (electrospray): m/z calc for C23H24N3O2 374.1869, found 374.1877; 1H NMR (methanol-d4): 8.63 (s, 1H), 8.35 (dd, 1H, J=1.5, 7.8 Hz), 7.64-7.44 (m, 7H), 7.24 (d, 2H, J=8.8 Hz), 7.11 (d, 1H, J=8.8 Hz), 4.69-4.60 (m, 1H), 4.28 (s, 2H), 3.75-3.66 (m, 1H), 3.58-3.47 (m, 1H), 2.71-2.60 (m, 1H), 2.45-2.22 (m, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13](/[CH:16]=[N:17]/[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:12]=2)=[CH:7][CH:6]=1>C(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C@@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH3:1])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(-c2ccc(Cl)cc2)on1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(-c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A solution of methylmagnesium bromide (3.0 M in diethyl ether, 12.8 mL, 38.4 mmol, 4 equiv) was added to a solution of (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.98 g, 9.6 mmol) in DCM (96 mL) at 0° C. The solution became orange, then faded to yellow. The reaction was stirred at 0° C. for 30 min and then carefully quenched with saturated aqueous ammonium chloride (100 mL). The layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, white solid) in 32% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 4.75 (m, 1H), 3.47 (m, 1H), 1.70 (d, J=6.8 Hz, 3H), 1.25 (s, 9H). MS m/z 327.0 (M+H)+; Rt-0.94 min.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([N:17]1[C:21](=[O:22])[C:20](Cl)=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:18]1(=[O:31])=[O:30])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:18]1(=[O:30])=[O:31])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCCOc1ccccc1
Product: CC(C)(C)N1C(=O)C(NCCCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 80 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of (4-phenoxybutyl)amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA at 100° C. The residue was purified by silica gel column chromatography (Horizons Biotage) using 10-20% EtOAc in hexane as eluent giving the title compound (0.172 g, 80%) as a solid. 1H NMR (500 MHz CDCl3): 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.44-7.38 (m, 3H), 7.32-7.25 (m, 2H), 6.96 (t, 1H), 6.83 (d, 2H), 5.34 (t, 1H), 3.81 (t, 2H), 2.98-2.90 (m, 2H), 1.75 (s, 9H), 1.64-1.53 (m, 4H); 13C NMR (125 MHz CDCl3): δ 159.9, 158.9, 135.2, 131.8, 129.8, 129.7, 128.8, 125.3, 121.0, 114.6, 107.2, 67.1, 61.7, 43.9, 27.9, 26.6, 26.4; Mass Spectrum: M+H+ 429.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[CH3:10][N:11]([CH3:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](=[S:23])[NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(N)cc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=S)c2ccc(N(C)C)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
13.6 g of p-anisidine were added to a solution of 22.2 g of 4-dimethylamino-benzoic acid chloride in 84 ml of anhydrous pyridine and the mixture was refluxed for one hour and cooled to 30° C. 33 g of phosphorus pentasulfide were added to the mixture which was refluxed for 2 hours and was then poured into an ice water-concentrated hydrochloric acid mixture. The mixture was stirred for one hour and was vacuum filtered and the product was washed with 0.1N hydrochloric acid. A mixture of the product and 300 ml of N sodium hydroxide solution was stirred for one hour and was vacuum filtered. The product was washed with water and dried to obtain 13.5 g of 4-dimethylamino-N-(4'-methoxyphenyl)-benzenecarbothiamide melting at 192° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:12]CC2C=CC=CC=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.Cl.[N:25]([O-])=O.[Na+]>O>[S:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[N:25]1
Reactant: O=N[O-]
Reactant: COC(=O)c1cccc(N)c1SCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A mixture of methyl 3-amino-2-(benzylthio)benzoate (26.9 g, 98.4 mmol), acetic acid (1.00 L, 1.75 mol), water (200 mL) and concentrated hydrochloric acid (172 mL, 2.06 mol) was stirred at room temperature for 30 min. To the reaction mixture was added a solution of sodium nitrite (7.59 g, 110 mmol) in water (200 mL) at 0° C. and the mixture was stirred at 0-5° C. for 2 hr. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.5 g, yield 65%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[N:10]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:12][C:5]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cncc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
To a stirring suspension of NaH (1.3 g) in anhydrous THF (25 ml) at −5° C. was added 4-bromo-1H-pyrrolo[2,3-c]pyridine (prepared for example as described in patent US2005/0090529, 5 g) in anhydrous THF (75 ml) over 10 min. The reaction was stirred at −5° C. for 10 min then benzenesulfonyl chloride (3.6 ml) in anhydrous THF (25 ml) was added over 10 min. The reaction was stirred at 0° C. for 1 h then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The organics were combined, washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a residue that was triturated using methanol (25 ml). The resulting solid was collected by filtration, washed sparingly with methanol then dried in vacuo at 45° C. overnight to give title compound, 7.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)([O-])O.[Na+].O>ClCCl>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Reaction time: 3 h

Procedure:
To 8-amino-2-naphthol (100 mg) were added phenyl chloroformate (87 μl), saturated aqueous sodium hydrogen carbonate (0.5 ml), dichloromethane (1 ml) and water (0.5 ml), and the mixture was stirred for 3 hrs. The reaction mixture was diluted with dichloromethane. After washing with 1N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Diethyl ether and hexane were added to the residue, and the precipitate was collected by filtration to give the title compound (160 mg). NMR data of Example 109: 1H-NMR (300 MHz, DMSO-d6) δ3.49 (2H, m), 4.06 (2H, s), 6.79 (4H, m), 7.10 (2H, m), 7.30 (2H, m), 7.75 (2H, m), 8.34 (1H, s), 9.69 (1H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].[F:21][CH:22]([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH:22]([F:21])[F:31])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccc(Cl)cc2)S1(=O)=O
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccc(Cl)cc2)S1(=O)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
2-Butyl-4-chloro-5-(4-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.20 g, 0.60 mmol) and 4-(difluoromethoxy)-aniline (0.190 g, 1.20 mmol) were mixed in MeCN (2.5 mL). The mixture was heated in a microwave reactor at 130° C. for 15 mins, then additional 60 mins and then at 140° C. for 15 mins, then additional 30 mins. The mixture was evaporated and the residue was purified by column chromatography (ISOLUTE SI 20 g/70 mL), eluting with heptane, then DCM:heptane (25:75, then 50:50), to give the title compound (0.122 g, 45%); 1H NMR (400 MHz, CDCl3): δ 7.28 (s, 1H), 7.12 (d, 2H), 7.04 (d, 2H), 6.81 (d, 2H), 6.70 (d, 2H), 6.37 (t, 1H), 3.76 (t, 2H), 1.87-1.80 (m, 2H), 1.50-1.40 (m, 2H), 0.97 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 158.9, 148.0, 135.6, 133.1, 131.3, 130.3, 128.4, 123.7, 123.1, 120.1, 115.5 (t), 110.1, 40.3, 30.1, 20.0, 13.4; Mass Spectrum: M−H+ 455.