Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:8][CH:9]=1
Reactant: OCCc1ccc(OC(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-ethanol (0.582 g, 3.09 mmol, from step (iii) above) in methylene chloride (8 mL) was cooled to 0° C. Triethylamine (0.52 mL, 3.7 mmol) was added followed by a solution of methanesulfonyl chloride (0.26 mL, 3.4 mmol) in methylene chloride (2 mL) and the reaction mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with methylene chloride (40 mL) and the organic phase was washed with water (2×30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give 0.78 g (95%) of the title compound as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: Cc1cc(C#N)nc(CCC(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 28.3 %

Procedure:
tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.69 g, 2.8 mmol) and 4-chlorothiosalicylic acid (1.05 g, 5.7 mmol) were dissolved in pyridine (10 ml). The mixture was refluxed for 22 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.33 g, 28%) as white crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:3]1[CH2:4][CH2:5][CH2:6][O:1][C:2]1=[O:7]
Reactant: O=C1NCCCO1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCCOC1=O
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A solution of 0.20 g (2.0 mmol) of 1,3-oxazinan-2-one from step A in 2 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.13 g (3.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.37 g (2.4 mmol) of methyl brornoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 5% methanol in ethyl acetate mixture to afford the title compound as a clear oil (0.068 g, 20%). 1HNMR (500 MHz, CDCl3) δ: 4.28 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.70 (s, 3H), 3.36 (t, J=6.2 Hz, 2H), 2.08-2.04 (m, 2H). LC-MS: m/z (ES) 174 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:11]2=3)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:11]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2C#Cc2ccc(F)cc2)C1
Temperature: 50 °C

Procedure:
Methyl 5-((4-fluorophenyl)ethynyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (0.280 g) was dissolved in MeOH (10 mL) and added 10% aq. KOH solution (5 mL). The reaction mixture was heated at 50° C. for 48 h. Progress of the reaction was monitored by TLC and LCMS. The solvent was evaporated and the residue acidified with 1% aq. HCl solution. The solid was filtered and the residue was washed with water (2-3×). The product was washed with hexane. The product was obtained as a white solid. 1H NMR (CD3OD, freebase) δ (ppm): 8.30 (d, 1H), 8.10 (m, 1H), 7.70 (m, 3H), 7.20 (m, 2H), 4.60 (m, 2H), 3.80 (m, 2H), 3.38 (m, 2H), 3.15 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([S:34]([CH3:37])(=[O:36])=[O:35])[C:12]1[C:13]([O:32][CH3:33])=[CH:14][C:15]2[C:19]([CH:20]=1)=[N:18][N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:16]=2[C:28]([NH:30][CH3:31])=[O:29])(C(C)(C)C)(C)C.[F-].[NH4+].O>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[C:16]([C:28]([NH:30][CH3:31])=[O:29])=[C:15]3[C:19]([CH:20]=[C:12]([N:11]([CH2:10][CH2:9][OH:8])[S:34]([CH3:37])(=[O:35])=[O:36])[C:13]([O:32][CH3:33])=[CH:14]3)=[N:18]2)=[CH:22][CH:23]=1
Reactant: CNC(=O)c1c2cc(OC)c(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1c2cc(OC)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 60 °C
Yield: 33.1 %

Procedure:
To a stirred solution of Compound (11) (250 mg, 0.45 mmol) in MeOH (20 mL) was added ammonium fluoride (166 mg, 4.5 mmol) and water (5 mL). The reaction mixture was heated to 60° C. for 5 h (monitored by TLC and LCMS). MeOH was removed in vacuo and the residue was diluted with water. The resulting precipitate was filtered, washed with ethanol and dried in vacuo at 40° C. to give Compound (12) (65 mg, 33%). ESI-MS m/z calculated for [M+Na]+: 459.11; found: 459.11; 1H NMR (400 MHz, d6-DMSO) δ 8.65 (s, 1H), 7.77 (s, 1H), 7.65-7.52 (m, 2H), 7.46-7.32 (m, 2H), 7.15 (s, 1H), 4.80-4.70 (m, 1H), 3.92 (s, 3H), 3.78-3.39 (m, 4H), 3.08 (s, 3H), 2.88-2.77 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[NH:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:29][C:27](=[NH:28])[CH2:26][O:25][CH2:24][CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-(2-naphthalen-2-yl-ethoxy)-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-[1-imino-2-(2-naphthalen-2-yl-ethoxy)-ethyl]-nicotinamide as yellow oil. MS: m/e=402.3 [M+H+].
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][C:5]=2[O:4]1.Cl[CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>COCCOC>[CH:20]([O:19][CH2:18][CH2:17][C:16]([CH3:23])=[CH:15][CH2:14][O:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)([CH3:22])[CH3:21]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=CCCl)CCOC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=CCOc1ccc2c(c1)OCO2)CCOC(C)C
Reaction time: 18 h

Procedure:
1.7 g (0.03 mol) of pulverised potassium hydroxide are added to a solution of 4.1 g (0.03 mol) of 3,4-methylendioxy-phenol and 6.2 g (0.035 mol) of 1-chloro-5-isopropoxy-3-methyl-2-pentene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 60° for a period of 18 hours, is subsequently filtered and evaporated at reduced pressure. The residue is dissolved in ether, washed with 5% solution of sodium hydroxide and subsequently with saturated salt solution, dried with sodium sulphate and evaporated.
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].S(Cl)(Cl)=O>CC(O)C>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])=[CH:5][CH:6]=1)(=[O:16])[CH3:15]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(C=C(C(C)=O)C(C)=O)cc1)C(C)=O

Procedure:
To a mixture containing 1.34 g of 1,4-benzenedicarboxaldehyde and 2.1 g of 2,4-pentanedione in 20ml of 2-propanol was gradually added 3.0 g of thionyl chloride with stirring and cooling below 20° C. The mixture was stirred over night at room temperature, filtered and washed with 2-propanol. Yield 1.1 g (55%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)=[O:4].[Cl:19]N1C(=O)CCC1=O>CN(C=O)C>[Cl:19][C:8]1[C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH:7]=1
Reactant: O=C1COc2ccc(NC(=O)C(F)(F)F)cc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1COc2c(Cl)cc(NC(=O)C(F)(F)F)cc2N1

Procedure:
2,2,2-Trifluoro-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetamide was treated with N-chlorosuccinimide in DMF to obtain N-(8-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-trifluoroacetamide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2]>C(O)C.[C].[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C(C)(C)C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(C)(C)C(=O)O)cc1
Yield: 96.4 %

Procedure:
2-(4-Vinylphenyl)-2-methylpropanoic acid (58 g) was dissolved in ethanol, and then stirred for 3 hrs under atmospheric hydrogen pressure in the presence of 10% palladium carbon (5.8 g). The catalyst was removed by filtration, and the filtrate was concentrated to obtain a crude product, which was then suspended and washed with hexane to give the title compound (56.5 g, 94.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH2:12][CH2:13][CH3:14])=[O:5])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:8][C:7]=1[CH2:12][CH2:13][CH3:14])=[O:5])[CH3:2]
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCCc1nc(N)sc1C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(=O)OCC
Temperature: 65 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
2-Amino-4-propyl-thiazole-5-carboxylic acid ethyl ester (0.50 g, 2.3 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (0.48 g, 2.3 mmol) were dissolved in acetonitrile (15 mL) containing triethylamine (0.66 mL, 4.7 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.89 g, 2.3 mmol) was added and the solution was allowed to stir at 65° C. for four hours. The crude product was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 10-99% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.58 g, 1.4 mmol, 61%). ESI-MS m/z calc. 402.1. found 403.3 (M+1)+. Retention time of 3.78 minutes. 1H NMR (400 MHz, CD3CN) δ 0.84 (t, J=7.4 Hz, 3H), 1.25-1.35 (m, 5H), 1.50-1.68 (m, 4H), 2.91 (t, J=7.5 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 6.00 (s, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.95-6.98 (m, 2H), 9.22 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[C:13]([O:18][CH3:19])[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][NH2:30].C(=O)(O)[O-].[Na+].CN1CCCC1=O>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([NH:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[Cl:20])[N:14]=[C:13]([O:18][CH3:19])[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(c2cc(Cl)nc(OC)n2)CC1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1CCN(c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)CC1
Temperature: 140 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
In a tube is combined 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid methyl ester [103 mg, 0.36 mmol], 2-(2,4-dichloro-phenyl)-ethylamine (0.163 mL, 1.08 mmol), sodium bicarbonate (181 mg, 2.16 mmol) and N-methylpyrrolidinone (2 mL). The mixture is heated at 140° C. for 12 h. Additional 2-(2,4-dichloro-phenyl)-ethylamine (0.2 mL, 1.33 mmol) is added and heating at 140° C. is continued for another 12 h. The mixture is diluted with water (30 mL) and extracted twice with EtOAc (30 mL). The organic extracts are washed twice with water (40 mL) and once with brine (30 mL), combined, dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-4-carboxylic acid methyl ester [70 mg, 44%] as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:36]3[S:32][C:33](=[O:38])[NH:34][C:35]3=[O:37])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 81.5 %

Procedure:
To a stirred suspension of 16 (1.81 g, 4.3 mmol) in anhydrous toluene (25 mL), 2,4-thiazolidinedione (0.56 g, 4.74 mmol), benzoic acid (0.68 g, 5.60 mmol) and piperidine (0.60 mL, 6.03 mmol) was added sequentially and heated at reflux temperature with continuous removal of water using a Dean-Stark apparatus for 2 h. Solvent was evaporated to dryness under reduced pressure. The residue obtained was purified by silica gel chromatography, eluted with hexane-ethyl acetate (1:1) to yield 17 (1.82 g, 81%): mp 104-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (br s, 1H), 7.76 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.07 (d, J=4.8 Hz, 2H), 7.03 (d, J=4.8 Hz, 2H), 6.33-6.28 (m, 3H), 4.01 (t, J=7.5 Hz, 1 Hz), 3.66 (s, 6H), 3.56 (s, 3H), 3.22 (dd, J=13.8 and 8.4 Hz, 1H), 2.90 (dd, J=13.5 and 7.2 Hz, 1H); MS (EI) m/z 520[M]+; Anal. (C28H25NO7S) C: calculated, 64.73; found, 65.89; H: calculated, 4.85; found, 5.08, N: calculated, 2.70; found, 2.56.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:13]>CC(C)=O.CO>[NH2:13][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: N
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 216 h
Yield: 148.1 %

Procedure:
Performed in duplicate on identical scales in two pressure vessels, methyl 2,6-dichloronicotinate (4.5 g, 22 mmol) was dissolved in NH3 solution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85±5) ° C. for 9 days. The two reaction mixtures were allowed to cool to 25° C., then combined and concentrated under reduced pressure to yield a white solid. Dissolution of the solid in 1:1 acetone-MeOH (˜500 mL), followed by adsorption onto silica gel (25 g) and then purification by flash column chromatography (25:10:1 hexane-CH2Cl2-Et2O), gave 6.08 g (75%) of methyl 2-amino-6-chloronicotinate.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:8]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]2[CH:24]=[CH:22][CH:8]=[C:7]2[C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=CC=O
Product: Cc1ccc(-n2cccc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a pale brown powder (yield 28%), melting at 131-134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:36][O:35][C:33]1[N:32]=[C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([CH:50]5[CH2:52][CH2:51]5)(=[O:49])=[O:48])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(OC)nc(-c5ccccc5)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCNC(=O)N3C2)nc(-c2ccccc2)n1
Yield: 8 %

Procedure:
Compound 6g was dissolved in a 1:2 mixture of TFA:DCM (24 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was separated of, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (19 mg, 8% over two steps), MS (M+H)+639.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23][S:24](=[O:45])(=[O:44])[NH:25][C:26](=[O:43])[CH2:27][C:28]2[C:33]([CH:34]([CH3:36])[CH3:35])=[CH:32][C:31]([CH:37]([CH3:39])[CH3:38])=[CH:30][C:29]=2[CH:40]([CH3:42])[CH3:41])=[C:16]([CH:46]([CH3:48])[CH3:47])[CH:15]=1>ClCCl>[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:46]([CH3:47])[CH3:48])[C:17]([O:23][S:24](=[O:44])(=[O:45])[NH:25][C:26](=[O:43])[CH2:27][C:28]2[C:29]([CH:40]([CH3:41])[CH3:42])=[CH:30][C:31]([CH:37]([CH3:38])[CH3:39])=[CH:32][C:33]=2[CH:34]([CH3:36])[CH3:35])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: COC(=O)c1cc(C(C)C)c(OS(=O)(=O)NC(=O)Cc2c(C(C)C)cc(C(C)C)cc2C(C)C)c(C(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(CO)cc2C(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
3.9 mL of a 1 M solution of diisobutyl aluminum hydride in dichloromethane was added to a solution of 3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl)-acetyl]sulfamoyloxy}-benzoic acid methyl ester (1.0 g, 1.8 mmol) in 125 mL dichloromethane at -78° C. After 3 hours, the reaction was warmed to room temperature and then quenched with a saturated aqueous sodium sulfate solution. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give a white foam. Triturated with 10% diethyl ether/hexanes to give 0.29 g of the title compound as a white solid; mp 163-168° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:33]([CH3:42])[C:32]=2[CH:43]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:39]2[CH2:40][CH2:41][N:36]([C:34]3[N:33]([CH3:42])[C:32]4[CH:43]=[C:28]([F:27])[CH:29]=[CH:30][C:31]=4[N:35]=3)[CH2:37][CH2:38]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2ccc(F)cc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccc(F)cc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([O:15]C)[C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)Cl>[C:11]([C:9]1[CH:8]=[C:7]([OH:15])[C:6]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1-c1ccc(Cl)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(O)c(-c2ccc(Cl)cc2)c(C(C)(C)C)c1
Temperature: 0 °C

Procedure:
A solution of 4.9 g (14.8 mmol) of the product of Step A in 30 mL of CH2Cl2 was placed in an external cooling bath containing dry ice and acetone and stirred under a nitrogen atmosphere. A 1.0 M solution of boron tribromide (20 mL, 20.0 mmol) in CH2Cl2 was added dropwise. After the addition was complete, the reaction mixture was stirred an additional 5 min then allowed to warn to room temperature. After stirring 1 h the reaction mixture was poured into 500 mL ice water and was stirred for 30 min. The aqueous layer was separated and extracted with 100 mL CH2Cl2. The organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 3% EtOAc-hexanes. Evaporation of the purified fractions and drying in vacuo afforded the title compound.