Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[BrH:40].N([O-])=O.[Na+]>C(#N)C.[Cu]Br>[Br:40][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
A suspension of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.6 g, 2.70 mmol) in acetonitrile (30 mL) and hydrogen bromide (25 mL, 2.70 mmol) was treated with aqueous sodium nitrite (0.205 g, 2.97 mmol) at 0° C. and the mixture was stirred for 30 min, copper(I) bromide (0.464 g, 3.24 mmol) was added in portions at the same temperature. It was allowed to warm up to room temperature and then heated to 55° C. overnight. The mixture was cooled down to room temperature and partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by flashing chromatography on silica gel eluted with 0-50% EtOAc in hexane to give the product (0.92 g, 55%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (q, J=4.23 Hz, 1H) 8.14 (s, 1H) 7.97 (dd, J=8.78, 5.46 Hz, 2H) 7.80 (d, J=2.93 Hz, 1H) 7.75 (d, J=8.78 Hz, 1H) 7.50 (dd, J=8.88, 2.83 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.22 (s, 1H) 3.84 (s, 3H) 3.44 (s, 3H) 2.84 (d, J=4.68 Hz, 3H) 2.05-2.15 (m, 1H) 0.92-1.05 (br. s, 1H) 0.87 (br. s., 2H) 0.40 (br. s., 1H). LCMS (m/z, ES+)=617 (M+H+).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:19][O:20][C:21]1[C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COc1ncccc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1ncccc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-methoxypyridine-3-amine as the starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(C(F)(F)F)cc1Br
Yield: 78 %

Procedure:
Compound 55.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-4-trifluoromethylbenzyl bromide. 4-[3-(2-Bromo-4-trifluoromethylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 78%. 1H NMR: 8.36, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 8.05, s, 1H; 7.85, d, 1H, 7.73, d, 1H, 4.7, s, 2H, 1.48, s, 6H.
Reaction SMILES: F[B-](F)(F)F.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[FH:17].[FH:18].F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]([CH:10]1[CH2:15][CH2:14][C:13]([F:18])([F:17])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (593 mg, 2.6 mmol) in dichloromethane (10 mL) at room temperature is added 4-tert-butylcyclohexanone (200 mg, 1.3 mmol) and triethylamine trihydrofluoride (266 μl, 1.3 mmol). The reaction mixture is stirred for 4 hours, then an aqueous solution of sodium bicarbonate (5%) is added and stirring is continued for 30 minutes. The organic phase is isolated and dried with magnesium sulphate. The solution is diluted with pentane (10 mL) and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuo to provide 4-t-butyl-1,1-difluorocyclohexane (120 mg, 53%) as a clear liquid, admixed with 3% of the corresponding vinyl fluoride. Major compound: 1H NMR (CDCl3) 2.09-1.95 (m, 2H), 1.76-1.67 (m, 2H), 1.65-1.51 (m, 2H), 1.30-1.15 (m, 2H), 1.02-0.97 (s, 1H), 0.80 (s, 9H); 19F NMR (CDCl3)-91.9 (d, J=232.6 Hz, 1F), −103.5 (dm, J=232.6 Hz, 1F).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[N:5][N:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc(CCOCCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnnc1-c1cccc(CCOCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(1-methyl-1H-tetrazol-5-yl)phenethoxy)propanoate [Example 7, Step iii)] (135 mg), DCM (4 mL) and TFA (4 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to afford the subtitled compound as a gum. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.53-7.41 (m, 3H), 4.18 (s, 3H), 3.78-3.72 (m, 4H), 2.96 (t, J=5.9 Hz, 2H), 2.59 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](Cl)[C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1.Cl(O)(=O)(=O)=O.C(O)C>[H][H].C(OCC)(=O)C.[C].[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1
Reactant: [H][H]
Reactant: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture of 7.0 g of 1-(3,4-methylenedioxyphenyl)-1-chloro-2-methyl-2-nitropropane, 7.7 g of 70% perchloric acid, 2.8 g of 10% palladium-carbon and 100 ml of ethanol is shaken at room temperature for 3 hours in hydrogen gas atmosphere under 3 atmospheres. After the reaction, insoluble materials are removed by filtration, and the filtrate is condensed. The residue is dissolved in ethyl acetate, and the solution is washed with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, successively. The washed solution is dried and then evaporated to remove solvent. 5.4 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane are thereby obtained as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C1(OC)C=CC=CC=1>O1CCOCC1>[CH3:24][O:23][C:21](=[O:22])[C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: COC(=O)c1cc(Cl)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 4-4 (40 mg, 0.11 mmol), dioxane (3 mL), 4N HCl in dioxane (3 mL) and a drop of anisole were added and stirred at rt for 2 hrs. The reaction mixture was concentrated, triturated with ether and dried in vacuo. Compound 4-5 was isolated as a white solid (33 mg, 100%). MS (ES+) m/z 253.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[C:3]=1[Br:10].C1COCC1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)c(Br)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1c(F)ccc(Br)c1Br
Temperature: 40 °C
Reaction time: 40 h
Yield: 79.4 %

Procedure:
A thick-walled glass vessel was charged with 1,2-dibromo-4-fluoro-3-iodobenzene (8.31 g, 21.88 mmol), Pd(PPh3)2Cl2 (0.768 g, 1.094 mmol), and CuI (0.292 g, 1.532 mmol) and sealed with a rubber septum. Anhyd THF (30 mL) and DIPA (30.8 mL, 219 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (3.40 mL, 24.07 mmol) was added via syringe and the septum was replaced with a PTFE bushing. The mixture was stirred in an oil bath at 40° C. After 40 h, the mixture was cooled, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed (satd NH4Cl×2, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording ((2,3-dibromo-6-fluorophenyl)ethynyl)trimethylsilane (6.08 g, 17.37 mmol, 79% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=8.9, 5.4 Hz, 1H), 6.95 (dd, J=8.9, 8.1 Hz, 1H), 0.29 (s, 9H); MS (GCMS EI) m/z 348 ([M]+, Br isotopes, 18%), 350 ([M]+, Br isotopes, 34%), 352 ([M]+, Br isotopes, 18%), 333 ([M-CH3]+, Br isotopes, 56%), 335 ([M-CH3]+, Br isotopes, 100%), 337 ([M-CH3]+, Br isotopes, 54%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 74.9 %

Procedure:
A suspension of 0.80 g (2.69 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.08 g (10.8 mmol) of 2-methylpiperazine, and 20 ml of acetonitrile was refluxed for three hours, then cooled in an ice bath. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.76 g of the title compound, mp 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:15]([CH3:16])[C:14]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-(4-Chlorophenyl)-2-oxo-4-oxazoline (3.0 g) was dissolved in methanol (30 mL) and methyl acrylate (1.66 mL) and triethylamine (2.14 mL) were added. The obtained mixture was stirred with reflux for 6 h, and the solvent was concentrated under reduced pressure. Isopropanol (9 mL) and isopropyl ether (21 mL) were added, and the mixture was allowed to stand at room temperature overnight and was cooled to not higher than 5° C. and stirred for 1 h. The precipitated crystals were collected by filtration and washed with isopropyl ether to give the title compound (2.81 g; yield 65.0%).
Reaction SMILES: C1CCCCC=1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=1[C:12]#[N:13])([O-])=O>[Pd]>[NH2:7][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=1[C:12]#[N:13]
Reactant: CCCCCOc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CCCCCOc1cccc(N)c1C#N

Procedure:
2-amino-6-pentyloxybenzonitrile is prepared by Pd/C, cyclohexene reduction of 2-nitro-6-pentyloxybenzonitrile as in example 27, m.p. 70°-73° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16]
Reactant: O=CC=Cc1cccc(CO)c1
Reactant: NNC(N)=S
Product: NC(=S)NN=CC=Cc1cccc(CO)c1
Yield: 25 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-hydroxymethylcinnamaldehyde (3 mmoles) et de thiosemicarbazide (3 mmoles). Yield 25%.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Temperature: 100 °C
Yield: 39.2 %

Procedure:
6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 27 Step 3, 57 mg, 0.14 mmol) in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) was heated in a microwave reactor for 40 min at 100° C. The mixture was concentrated, re-dissolved in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) and heated with MW for 40 min at 100° C. The mixture was concentrated. Purification of the crude product by flash chromatography using a gradient of CHCl3/MeOH 40:1-30:1-20:1 gave the title compound (21 mg, 39% yield): 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.15-1.29 (m, 1 H), 1.47 (m, 2 H), 1.61-1.73 (m, 1 H), 1.73-1.97 (m, 4 H), 2.18 (s, 3 H), 2.98 (d, 1 H), 3.08 (d, 1 H), 6.67 (m, 3 H), 7.26 (d, 1 H), 7.37 (dd, 1 H); MS (ES+) m/z 382 [M+H]+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>O.C(O)(=O)C>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(N)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.3 %

Procedure:
A solution of potassium cyanate (9 mg) in water (0.5 ml) was added to a solution of N-[2-(3-aminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (40 mg) in water (2 ml) and acetic acid (1 ml). The mixture was stirred at ambient temperature for about 72 hours and then basified to pH 9 with 10% sodium hydroxide. The solution was extracted with dichloromethane, and the organic phase dried over sodium sulfate, filtered, evaporated in vacuo to give N-[2-(3-carbamoylaminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (35 mg), M+H 411.2
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH2:38])=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH:38][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1ccccc1NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3ccc(F)cc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-(4-fluorobenzylamino)benzoic acid (Step A, 0.7 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.71 g, 2.57 mmol), TBTU (0.917 g, 2.86 mmol), and DIEA (0.5 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, and brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), and the titled compound was obtained as oil. MS (ES+): 504 (M+H)+. Calc'd for C30H34FN3O3-503.26.
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32].[Li]>C1COCC1>[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[N:24]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of nBuLi, 1.6 m in hexane (21.49 mL, 34.4 mmol) in THF (80 mL) at −50° C. was added 2,2,6,6-tetramethylpiperidine (5.80 mL, 34.4 mmol). The mixture was warmed to 0° C. and stirred for 20 min. The mixture was then cooled to −78° C. In another flask, 2-chloropyrazine (0.974 mL, 10.91 mmol) and tributyltin chloride (2.96 mL, 10.91 mmol) were dissolved in THF (50 mL) and cooled to −78° C. The cooled solution was transferred to lithium solution through cannula and the resulting orange mixture was slowly warmed up to −40° C. in 3 h, and was quenched with sat. HCl:EtOH:THF (1:4:5, 50 mL) and warmed to RT. The mixture was neutralized with sat. NaHCO3 and the volatiles were removed. The residue was diluted in H2O and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-30% DCM in Hex) to give 2-chloro-6-(tributylstannyl)pyrazine (3.15 g, 7.81 mmol, 71.5%) as a clear oil. MS (ESI, pos. ion) m/z: 405 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.42 (1H, s), 8.38 (1H, s), 1.50-1.62 (6H, m), 1.27-1.41 (6H, m), 1.14-1.22 (6H, m), 0.89 (9H, t, J=7.3 Hz)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[F:34][C:31]([F:32])([F:33])[C:30]([C:26]1[CH:25]=[C:24]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:29]=[N:28][CH:27]=1)([OH:36])[CH3:35]
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: CC(O)(c1cncc(Br)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 2-(5-bromo-pyridin-3-yl)-1,1,1-trifluoro-propan-2-ol (253 mg, 0.94 mmol.), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (EtOAc/heptane 0 to 100% gradient, then 100%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 65% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and is extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 69 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]>>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN1CCCS1(=O)=O
Yield: 48.9 %

Procedure:
Using the general method of Example 5, chloropropylsulfonyl chloride (0.13 ml, 1.05 mmol) was reacted with 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.3 g, 1.05 mmol). Recrystallization from 2-propanol yielded 0.2 g of 1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, m.p. 186.0-187.0° C.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:31]([CH2:30][CH2:29][O:28][CH3:27])(=[O:33])=[O:32])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: COCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCOC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.11 g, 0.40 mmol) in dichloromethane (1.5 ml) was added pyridine (64 mg) in dichloromethane (0.75 ml) and 2-methoxy-1-ethanesulfonyl chloride (J. F. King, J. Y. L. Lam, S. Kronieczny, J. Am. Chem. Soc., 1992, 114 (5), 1743; 0.96 g, 0.60 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with ethyl acetate:2M ammonia in methanol (99:1).