Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1[C:13]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:13]2[C:12]([CH3:11])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 2-fluoro-benzoyl chloride (1.74 g, 11.0 mmol) dropwise to a solution of 3-methyl-5-nitro-2-(piperidin-4-yloxy)-pyridine in dichloromethane (50 mL) and triethylamine (1.21 g, 12 mmol) and stir under N2 at room temperature for 2 hours. Wash the reaction mixture with distilled water (3×20 mL) followed by saturated aq. sodium chloride solution (1×20 mL). Dry the organic phase over sodium sulfate and concentrate to give (2-fluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([N:10]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]3=[O:18])[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1ncc(C(F)(F)F)cc1Oc1ccccc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(-n2cc(C(F)(F)F)cc(Oc3ccccc3)c2=O)c1

Procedure:
The title compound is prepared according to Example 8 by using 3-phenoxy-5-trifluoromethyl-pyridin-2-ol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 37 mg (7%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24O5NF3 523, found 524 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:29][C:30]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CN1CCCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and pyrrolidin-1-yl-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(pyrrolidin-1-yl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 425; RT=4.954 min; LCMS Method III
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:14].Cl.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccc2cccnc2c1
Yield: 71.1 %

Procedure:
Prepared in analogy to the method for Example 1 starting from 183 mg of quinoline-7-carboxylic acid (Seibert et al. J. Am. Chem. Soc. 1946, 68, 2721) and 200 mg of 3-aminoquinuclidine dihydrochloride. 227 mg (71% yield) of the hydrochloride were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(N(CC)CC)C.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH2:22][CH2:23]2)[N:3]=1
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1
Yield: 60.8 %

Procedure:
To a solution of [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (19.2 mg, 0.0611 mmol, Example 9) in methylene chloride (1.5 mL) were added triethylamine (12.6 mg, 0.124 mmol, Aldrich) in methylene chloride (0.2 mL) and a solution of ethanesulfonyl chloride (8.66 mg, 0.066 mmol, Aldrich 99+%) in methylene chloride (0.2 mL) at room temperature. After ˜30 mins the reaction mixture was concentrated and purified by reversed phase HPLC as described in Example 11 to give [2-Amino-6-(1-ethanesulfonyl-piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone as a white solid (15.1 mg, 60 % yield). HRMS, observed: 407.1533, calcd for (M+H)+: 407.1548.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[K].[I-].[K+].O>CN(C=O)C>[O:37]=[C:35]1[C:34]2[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32](=[O:42])[N:36]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate (20 g, 45.8 mmol), potassium phthalimide (9.33 g, 50.4 mmol) and potassium iodide (1.52 g, 9.15 mmol) were stirred in DMF (81 mL) at 50° C. overnight. Room temperature was attained, H2O was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in MeOH to give 1,1-dimethylethyl {3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate as a pale yellow solid.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH:8]1([CH2:7][N:27]2[CH2:28][CH2:29][N:25]([C:17]3[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=3)[C:26]2=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CCCCC1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCCC3)C2=O)nc1C
Yield: 76 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclohexane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 76% yield: 1H NMR (300 MHz, CDCl3) δ 4.27 (q, J=7.2 Hz, 2H), 4.09-3.99 (m, 2H), 3.57-3.40 (m, 2H), 3.11 (d, J=6.9 Hz, 2H), 2.59 (s, 3H), 1.86-1.55 (m, 5H), 1.31-1.11 (m, 7H), 0.97-0.82 (m, 2H); MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]=2[N:20]=1
Reactant: Oc1cccnc1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF (1.67 ml) was added NaH (0.027 g, 55% dispersion in mineral oil, 0.630 mmol) at 0° C. After stiffing for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture. After stiffing for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 70%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.46 (1H, dd, J=8.0 and 4.8 Hz), 7.66-7.69 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=4.4 Hz), 8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O1CCCC1>[N:31]1([CH2:30][C:21]2[C:22]([C:26]([F:27])([F:29])[F:28])=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][CH2:18][C@H:17]3[O:16][C:14]2[CH:13]=[CH:12][C:11]3[C@H:7]([CH2:6][C:5]([OH:37])=[O:4])[CH2:8][O:9][C:10]=3[CH:15]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M aqueous NaOH solution (0.20 mL) is added to a solution of {(S)-6-[(R)-4-morpholin-4-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (91 mg) in methanol (1 mL) and tetrahydrofuran (1 mL) at room temperature. The mixture is stirred at room temperature for 3 h. The organic solvent is evaporated, water is added to the residue, and the resulting solution is neutralized with 1 M aqueous HCl solution. The solution is stirred at room temperature for 1 h. The precipitate formed is separated by filtration, washed with water, and dried to give the title compound (if the title compound does not precipitate, the solution is concentrated, and the residue is purified by HPLC on reversed phase using acetonitrile and water as eluent). LC (method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: N(C1CCCC1)=C=S.[CH:9]1([NH:14][C:15]([NH2:17])=[S:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O>N.CO.C1COCC1>[CH:9]1([NH:14][C:15]2[S:16][CH:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NC1CCCC1
Agent: N
Agent: S=C=NC1CCCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isothiocyanato-cyclopentane (4 g) in ammonia (37% in water, 8 mL) and methanol (32 mL) was stirred for 16 hours, filtered of and dried. The Cyclopentyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.05 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (5.0 g, 32.03 mmol), 2-fluoro-5-trifluoromethyl-benzonitrile (6.07 g, 32.03 mmol) and lithium hydroxide monohydrate (4.03 g, 96.08 mmol) in methyl sulfoxide (DMSO, 60 ml). Heat the resulting mixture to 70° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 400 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate to obtain 9.995 g of the title compound (30.73 mmol, 96% yield) as an orange amorphous solid. Product used as is with no further purification: Mass Spectrum (m/e): 326(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl>CCOCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.6 %

Procedure:
Formation of compound (b): To a mixture of 3,5-dimethylphenol (a) (25 g, 205 mmol) and NaNO3 (26.1 g, 307 mmol) in ether (200 mL) and water (200 mL), at 0° C., 250 mL of conc.HCl solution was added dropwise within 1 hour under stirring. The reaction mixture was kept under stirring overnight and the temperature was allowed to warm to room temperature. The organic phase was seperated and the aqueous phase was extracted with ether (3×100 mL). The combined organic phase was washed with 3N HCl (2×100 mL), saturated NaHCO3 solution (3×100 mL) and finally with brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. The obtained residue was purified by chromatography over silica gel by using ethyl acetate and hexane (2:8) as eluent. The collected fractions were further recrystalized in ether/hexane to afford compound (b), 3,5-dimethyl-4-nitrophenol (6.7 g, 19% yield) as a yellow solid. MS: m/e 167
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17](F)[CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Cl)cc1Sc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Mercaptopyridine (1.1 1 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room temperature for 15 min. The mixture was treated with 4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at 50° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted 3 times with ethyl acetate. The organic layer was combined the ethyl acetate and then reduced in vacuo. The residue was dissolved in DMF (30 mL) and treated with SnCl2.2H2O. The mixture was heated at 50° C. for 16 hr. The DMF was distilled off under vacuum and the reduction product was purified by flash chromatography on silica gel column (50-100% EtOAc/hexane) to afford 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow solid. The title sulfonamide compound was prepared according to the general procedure using 118 mg of 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([N:28]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(NS(C2C3C(=CC=CC=3)C(N3C(=O)C4C(=CC=CC=4)C3=O)=CC=2)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:28])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)CC1
Agent: COc1ccc(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1

Procedure:
4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20) was prepared according to the general procedure in Scheme 3 substituting 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester for 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonic acid(4-methoxyphenyl)-amide.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:39])[CH3:38]>>[Cl:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:38])[CH3:39])=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CC(C)NCCC(O)CCN
Reactant: NC(=O)c1c(OCc2c(F)cc(Cl)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CC(C)NCCC(O)CCNC(=O)Nc1snc(OCc2c(F)cc(Cl)cc2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H), 3.34 (t, 2H, J=6.4 Hz), 2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]+.
Reaction SMILES: N#N.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[O-:15]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].O>CS(C)=O>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:3]=[O:15])=[CH:5][NH:6]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1c[nH]c(=O)c2ccccc12
Agent: N#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c[nH]c(=O)c2ccccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In an apparatus equipped with a mechanical stirrer (N2 gas), 135 g (848 mmol) of 4-methyl-2H-isoquinolin-1-one in 2.0 l of DMSO are heated to 50° C. After removing the oil bath, 108 g (447 mmol) of Cu(NO3)2.3H2O are added. Then, whilst cooling, 432 g (1.81 mol) of Na2S2O8 are added in portions, and finally 162 g (1.91 mol) of NaNO3. After stirring for 2 h at 50° C., the mixture is cooled to 10° C., mixed with 4 l of water and stirred for 10 min. 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde can be filtered from the light green suspension and washed with water; m.p. 222-223° C. The filtrate is extracted 3 more times with EtOAc. The EtOAc phases are washed with water (3×) and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography of the residue (SiO2, methylene chloride/toluene/acetone 2:2:1) yields further 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CCOC(C)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH2:14][CH2:13]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 4-bromo-2-chloro-5-fluorobenzoic acid (50 g, 0.25 mol) in 200 mL of EtOAc at 0° C. (ice/water bath) was added triethyl amine (237 mL, 0.50 mol), pyrrolidine (41.2 mL, 0.5 mol), followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (CAS #68957-94-8) (237 mL, 0.37 mol, 50 wt %, EtOAc). After 1 hr, the reaction was quenched with a saturated solution of NaHCO3, and extracted with EtOAc, and CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75 L column, eluting with a gradient of 2%-50% EtOAc/hexanes. The product containing fractions were collected and concentrated to give the title compound (52 g, 68% yield) as a white solid: Rf=0.23 (40% EtOAc/hexanes); LRMS m/z Calcd for C11H10BrClFNO, 306.6, found, 306, 308, 310 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J=6.2 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.54 (apt t, J=6.6 Hz, 2H), 3.13 (apt t, J=6.6 Hz, 2H), 1.92-1.83 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 164.5, 158.1 (d, JC-F=249.5 Hz), 138.2, 134.3, 126.0, 115.5 (d, JC-F=25.5 Hz), 110.3 (d, JC-F=22.5 Hz), 47.0, 45.8, 26.0, 24.6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:23]([O:21][C:20](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Finely divided t-butoxycarbonyl-D-tryptophan (3 g, 10 mmol) was suspended in methylene chloride and benzyl alcohol (1.08 mL, 10 mmol) and 4-dimethylaminopyridine (0.12 g, 1 mmol) were added and stirred at room temperature. Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) was then added in three roughly equal portions over 5 minutes. The reaction mixture was stirred for 3 hours at room temperature during which time the reaction mixture became a homogeneous solution. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (2×50 mL). The combined methylene chloride layers were washed with 5% aqueous citric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL). The resulting methylene chloride layer was dried over magnesium sulfate, filtered and evaporated under vaccum to give an off-white solid. This solid material was chromatographed on silica gel using ethyl acetate/hexanes (2:3 v/v) as eluant. This afforded 3.56 g (91%) of the desired benzyl ester as a white amorphous powder.