Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:35][O:34][C:32]([C:31]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:19][N:20]=1)[N:7]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:33]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCCC1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
5-Bromo-1-cyclopentylmethyl-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.76 g, 4.85 mmol) was dissolved in 90 mL of MeOH and placed in ice bath. NaOMe solution (3.3 mL, 14.6 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% EtOAc/CH2Cl2) to give 1.61 g of the title compound as an off-white solid. MS: (+) m/z 381.21, 383.16 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:4])=[O:3].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=1)[C:26](O)=[O:27]>>[CH3:1][S:2]([CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[N:31]=[C:23]([C:22]([F:37])([F:21])[F:36])[CH:24]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NCCS(C)(=O)=O
Product: Cc1ccccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Yield: 10 %

Procedure:
The title compound was prepared in analogy to example 90, from (2-methanesulfonyl-ethyl)-(4-o-tolyl-pyridin-3-yl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 17 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A second chromatography (preparative HPLC (phenomenex gemini column), gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2)) yielded the desired product as an off-white solid (10%). MS (ESI): m/z=532.11 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CO>[NH2:15][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (700 mg, 3.23 mmol) in 6-7 mL of 7 N NH3 in MeOH is stirred at 100° C. in a sealed tube for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is suspended in H2O, filtered, washed with H2O, and dried, yielding-4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 8.15 (br s, 2H), 5.70 (d, J=0.9 Hz, 1H), 2.58 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:20][CH:21]=2)=[O:26])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added biphenyl-4-carboxylic acid (100 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (116 mg), 1-hydroxybenzotriazole (82 mg) and triethylamine (84 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (methanol/ethyl acetate) to give the title compound (131 mg).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>ClCCl>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)c(OC2CCNCC2)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl-amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (0.3 g, 0.48 mmol) and anisole (0.26 mL) in dichloromethane (10 mL) was added TFA (1 mL). After 2 h, the solvent was removed in vacuo and the residue was suspended in diethyl ether and concentrated in vacuo twice and then again suspended in diethyl ether with vigorous stirring. The solid was washed with diethyl ether, filtered and dried in vacuo to give 0.28 g (90%) of off-white solid,
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Br[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>C(O)C.CCOCC>[CH2:2]([O:1][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:3]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCC(OCC)C(=O)OCC

Procedure:
To a solution of sodium ethoxide in ethanol, prepared from sodium (1.46 g) and ethanol (35 ml) a solution of ethyl 2-bromohexadecanoate (20.3 g) in ethanol (25 ml) was added. After refluxing for 3 h water was added and the product was taken up in ether. After evaporation of the ether and fractionation of the residue there was obtained 10.8 g ethyl 2-ethoxyhexadecanoate b.p. 112°-114° (0.01 mm), nD23 1.4393.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]=2[O:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:15]([CH2:14][C:10]2[C:9]([O:24][CH3:25])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: COc1c(CNCc2ccc(F)cc2)cccc1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1-c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of 1-(4′-chloro-2-methoxybiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (590 mg, 1.684 mmol, 1.0 eq) in dry DCM under nitrogen at 0° C. and treated slowly with triethylamine (492 mg, 4.8 mmol, 3 eq). The reaction mixture was stirred for 10 minutes and treated with a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (527 mg, 2.018 mmol, 1.2 eq) dissolved in DCM. The resulting mixture was stirred for 12 h at ambient temperature and concentrated under reduced pressure. The residue was further diluted with water and extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 15-20% ethyl acetate/hexane to afford the title compound (0.400 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 4.52-4.53 (d, 4H), 7.04-7.08 (m, 3H), 7.17-7.24 (m, 4H), 7.43-7.52 (m, 5H), 7.77 (s, 1H). MS (ESI): 577.8 (M−H)−.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:15][C:16]1[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>COCCOC>[F:15][C:16]1[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=[CH:21][C:17]=1[C:18]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:19]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OCC)c(F)c1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 2-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 2-fluoro-4-(hexadecylamino)benzoylmalonate.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([O:15][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 130 °C
Yield: 13.5 %

Procedure:
To a solution of tert-butyl 4-fluorobenzoate (392 mg, 2 mmol) in dimethyl formamide (20 mL) was added 4-hydroxybenzonitrile (240 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol), the mixture was heated to 130° C. for 0.5 hour by microwave (pressure: 3.2 bar, equipment power: 150 W). The solvent was evaporated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 14%). LRMS (M+H+) m/z: calcd 295.12. found 295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ClCCl.CO.N>>[N:19]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [5-(4-chlorophenyl)pyridin-2-yl]propynoic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.2 g (48% of theory); C26H24ClN3O (M=429.95); calc.: molecular ion peak (M+H)+: 430/432; found: molecular ion peak (M+H)+: 430/432; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14]([O:16]C)=[O:15])[CH:5]=1)(=[O:3])[NH2:2].[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:4]1[N:9]=[C:8]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Reactant: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(NC[C@H](O)C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 8.7 %

Procedure:
To a mixture of the (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate (0.408 g, 1.49 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.517 g, 1.65 mmol), 2M aqueous Na2CO3 (1.50 mL, 3.00 mmol) and PdCl2(dppf) (0.066 g, 0.081 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was diluted with acetone and decanted. Water was added to the insoluble residue to make a suspension. The solid was filtered, washed successively with water, acetone, 1N aqueous HCl then MeOH. The solid was dried under vacuum at 40° C. to give the product (S)-3-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)-2-hydroxypropanoic acid as a light tan powder (0.053 g, 0.13 mmol, 9% yield). 1H NMR (400 MHz, DMSO-d6): 12.61 (1H, s), 8.53 (2H, d, J=8.3 Hz), 8.27 (1H, s), 7.99-7.93 (1H, s), 7.73 (1H, s), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.08-7.01 (3H, m), 5.60 (1H, s), 4.26 (1H, s), 3.90-3.80 (1H, s), 3.64-3.54 (1H, m). LC/MS: m/z=413.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[K].[CH3:14]I>CN(C)C=O>[CH3:14][N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11]
Reactant: CI
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Agent: [K]
Solvent: CN(C)C=O
Product: CN1Cc2cccc(Cl)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.6 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 85 mls of dry dimethylformamide was cooled and treated with 10 g of potassium t-butoxideat such a rate that the temperature remained below 6° C. The resulting suspension was stirred at 5° to 10° C. for 30 minutes, treated with 6.1 mls of methyl iodide at 10° to 15°C. and stirred at room temperature for 16 hours. The mixture was poured into ice water and the resulting solid was filtered, washed with water anddried in vacuo at 50° C. for 1.5 hours to give 15.4 g of the title compound as a pinkish solid, m.p. 95°-97° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([Cl:34])(=O)=O)=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][Cl:34])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NCCCCl)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 2-tert-butyl-4-[(3-hydroxypropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 49) (0.14 g, 0.42 mmol 4-methylbenzenesulfonyl chloride (0.089 mg, 0.46 mmol) and TEA (0.065 ml, 0.46 mmol) in DCM (2 ml) was stirred at rt for 2 h, after which more TEA (0.065 ml, 0.46 mmol) and cat. DMAP were added. After a further 18 h more 4-methylbenzenesulfonyl chloride (0.16 mg, 0.84 mmol), TEA (0.059 ml, 0.42 mmol) and DMAP (0.052 g, 0.42 mmol) were added. After 5 h the reaction mixture was warmed to reflux for 18 h and evaporated to dryness. The residue was purified by silica gel column chromatography (Horizons Biotage) using 10% EtOAc in hexane as eluent to give the title compound (0.097 g, 64%). 1H NMR (500 MHz, CDCl3): δ 7.56-7.50 (m, 2H), 7.50-7.44 (m, 3H), 5.32 (t, 1H), 3.35 (t, 2H), 3.08 (q, 2H), 1.80-1.72 (m, 11H); 13C NMR (125 MHz, CDCl3): δ 159.8, 135.0, 131.8, 130.0, 128.9, 124.9, 107.8, 61.8, 41.7, 41.3, 32.0, 27.8; Mass Spectrum: M+H+ 357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:17]([O-])=O)[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].C([O-])(O)=O.[Na+]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: [H][H]
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
6-chloro-7-methoxy-8-nitro-9H-β-carboline (510 mg, 1.84 mmol) was suspended in 50 ml of methanol and 100 mg of Pd/C (10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained. This residue was suspended in methanol (15 ml) and added, with vigorous stirring, to a solution of saturated NaHCO3 (100 ml). The light brown solid that precipitated out was collected by filtration and dried thoroughly in vacuo to give the desired product (512 mg, quantitative yield). 1H-NMR (300 MHz, methanol-d4): 63.90 (s, 3H), 7.63 (s, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 8.84 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.12 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[O:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][C:27]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:28][CH2:29]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (4.15 g) was added and stirred at 80° C. for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as a yellow solid.
Reaction SMILES: Br/[C:2](/[Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[CH2:4][CH3:5].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:16][C:17]1[CH:22]=[CH:21][C:20](/[C:2](/[Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)\[CH2:4][CH3:5])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC/C(=C(\Br)[Si](C)(C)C)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC/C(=C(\c1ccc(F)cc1)[Si](C)(C)C)c1ccccc1
Yield: 90.8 %

Procedure:
To a solution of (E)-1-bromo-2-phenyl-1-(trimethylsilyl)-1-butene (Miller R. B., Al-Hassam, M. I. J. Org. Chem. 1985, 50, 2121-2123) (1) (4.4 g, 15.5 mmol) in DME (50 mL) was added 4-fluorobenzene boronic acid (2.63 g, 18.9 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol), and 2N aqueous sodium carbonate(9.5 mL, 19 mmol). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, hexanes) to give (2) as a white solid (4.2 g, 91%): 1 H NMR (CDCl3) δ 7.30 (m, 3 H), 7.19 (m, 2 H), 7.00 (m, 4 H), 2.12 (q, J=7.7 Hz, 2 H), 0.72 (t, J=7.7 Hz, 3 H), −0.35 (s, 9 H).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[C:7](/[N:9]=[C:10](\SC)/[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)#[N:8]>C(O)C>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([NH:11][C:10]2[N:9]=[C:7]([NH2:8])[O:6][N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CS/C(=N\C#N)Nc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Nc2cccc(C(F)(F)F)c2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium methanolate (9.26 ml, 4.63 mmol, Eq: 3.00) was added into a solid hydroxylamine hydrochloride (322 mg, 4.63 mmol, Eq: 3.00) at rt. Stirred at rt for 0.5 hrs, a solution of (Z)-methyl N′-cyano-N-(3-(trifluoromethyl)phenyl)carbamimidothioate (400 mg, 1.54 mmol, Eq: 1.00) in ethanol was added and the mixture was heated to 63° C. overnight.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:31](C=O)C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([NH2:31])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (205 mg) was dissolved in THF (5 ml) and thionyl chloride (0.06 ml) and DMF (0.01 ml) were added. The mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated under reduced pressure and re-dissolved in THF (5 ml). 28% Aqueous ammonia (3 ml) cooled to 5° C. was gradually added. The reaction mixture was stirred at room temperature for 30 min. and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→ethyl acetate) for purification and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (130 mg) as colorless powder crystals.