Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:14])=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1CCl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:25]3[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CC(=O)N1CCc2cc(S)c(I)cc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(SCc3ccncc3)c(I)cc21
Reaction time: 65 h

Procedure:
1-Acetyl-2,3-dihydro-6-iodo-1H-indol-5-thiol (D49) (0.346 g, 1.08 mmol) in dry DMF (5 ml) was treated with potassium carbonate (0.374 g, 3.71 mmol) followed by picolyl chloride hydrochloride (0.186 g, 1.13 mmol). After 65 h stirring at room temp. the reaction mixture was evaporated under reduced pressure and was partitioned between dichloromethane and water. The aqueous layer was then extracted with dichloromethane and the combined organic layers were then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a pale brown solid which was dried in vacuo (0.392 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([S:8]([NH:11][C:12]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1.[C:25]([O:28][C:29](=O)[CH3:30])(=[O:27])[CH3:26].[CH:32](Cl)(Cl)Cl>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([S:8]([NH:11][C:12]([NH:14][C:15]2[N:20]=[C:29]([O:28][CH3:25])[CH:30]=[C:17]([CH3:23])[N:16]=2)=[O:13])(=[O:9])=[O:10])[CH:7]=1.[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([S:8]([NH:11][C:12]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: ClC(Cl)Cl
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2Cl)n1
Reactant: CC(=O)OC(C)=O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C)n1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(NC(C)=O)ccc2Cl)n1

Procedure:
To a solution of 37.3 g of 5-amino-2-chloro-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide prepared in a minimum amount of boiling chloroform, is added with vigorous stirring 20.4 g of acetic anhydride. The resulting mixture is then refluxed for 2 hours, the chloroform, excess acetic anhydride and acetic acid are removed in vacuo to yield as residue the desired product, 5-acetamido-2-chloro-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:12])[C:8]([CH3:11])=[CH:9][N:10]=[C:5]2[S:4][C:3]=1O.[C:14](=[O:17])([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30](CBr)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:14][O:17][C:9]3[N:10]=[C:5]4[S:4][CH:3]=[C:2]([CH3:1])[N:6]4[C:7](=[O:12])[C:8]=3[CH3:11])=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cc1cnc2sc(O)c(C)n2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2scc(C)n2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
To a solution of 3,6-dimethyl-2-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (513 mg) and potassium carbonate (741 mg) in DMF (10 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (782 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (76 mg).
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>ClCCCl>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCCl
Product: Clc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
CH3MgBr (3M in diethyl ether, 22.68 mL, 68.03 mmol) was added dropwise over a period of 10 minutes to a stirred solution of 1H-indole (7.97 g, 68.03 mmol) in 1,2-dichloroethane (250 mL) at 0° C. under an atmosphere of N2. The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion. The resulting solution was allowed to warm to r.t. and was stirred for a further 16 h. The reaction was quenched by the addition of CH3OH (25 mL) then the mixture was concentrated in vacuo and absorbed onto silica. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (7.17 g, 46%) as a yellow solid; 1H NMR: 7.20-7.28 (2H, m), 7.49-7.53 (1H, m), 7.91 (1H, d), 8.42 (1H, dd), 8.50 (1H, d), 8.53 (1H, d), 12.06 (1H, s); m/z: ES+ MH+ 230.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N-:11]=[N+:12]=[N-:13].[Na+].[CH2:15](OC(OCC)(OCC)C)C>C(O)(=O)C>[N:10]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH:15]=[N:13][N:12]=[N:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(C)(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cc2cc(-n3cnnn3)ccc2[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 1H-indol-5-amine (0.6 g, 4.52 mmol) in acetic acid (9 mL), sodium azide (0.42 g, 6.2 mmol) and triethoxy ethane (1.0 mL, 6.2 mmol) were added and stirred at 100° C. for 3 h. The reaction was brought to room temperature and stirred for 10-12 h. The reaction was quenched with saturated NaHCO3 and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous NaSO4 and concentrated in vacuo. Resultant residue was purified by flash column chromatography to yield 5-(1H-tetrazol-1-yl)-1H-indole. (0.174 g, 21%); MS: 186 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](=[O:15])[NH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:16](Br)[CH2:17][CH3:18]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCBr
Reactant: CCCCNc1ccc2n[nH]c(=O)n2n1
Product: CCCCNc1ccc2nn(CCC)c(=O)n2n1
Yield: 86 %

Procedure:
By reacting the product of Example 3 with propyl bromide according to the procedure of Example 4, 6-n-butylamino-2-propyl-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one is obtained, yield 86%, m.p. 183°-185° (ethyl acetate with some drops of absolute ethanol). The hydrochloride is obtained by treatment with ethanolic HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N1C=CC=CC=1.Cl[N:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]2[S:30][CH:31]([I:33])[CH:32]=[C:23]12.C(=O)(O)[O-].[Na+]>C(OCCO)C>[I:33][C:31]1[S:30][C:24]2[C:23](=[N:22][CH:27]=[C:26]([C:28]#[N:29])[C:25]=2[NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:32]=1
Reactant: N#CC1=CN(Cl)C2=CC(I)SC2=C1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)cc(OC)c1OC
Yield: 85.7 %

Procedure:
A mixture of 3,4,5-trimethoxyaniline (964 mg, 5.26 mmol), pyridine hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (937 mg, 2.92 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux overnight. The solution is poured into saturated aqueous sodium bicarbonate and the resulting solid is collected by filtration, washed with water and dried under reduced pressure. The resultant solid is purified by flash column chromatography eluting with 2% methanol in dichloromethane. The fractions containing product are combined and concentrated to provide 1.17 g of 2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-256° C.; 1H NMR (DMSO-d6) δ 3.70-3.78 (m, 9H), 6.66 (s, 2H), 7.72 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][NH:30][CH2:29]2)[CH:25]=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][N:30]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=3[NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])=[O:7])[CH2:29]2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1nccc(C2(O)CNC2)n1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc(C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)n1
Yield: 7.9 %

Procedure:
A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (22 mg, 7%). 1H NMR (400 MHz, CD3OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63 (t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H), 3.04-3.99 (t, 1H); MS (EI) for C20H15F3IN5O2: 542 (MH+).
Reaction SMILES: S([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)(=O)(=O)N.NC1C=CC(S(NC2SC(S(N)(=O)=O)=NN=2)(=O)=O)=CC=1.C(N(CC)CC)C.[C:59](Cl)(=[O:69])CCCCCCCCC>C(#N)C>[OH:69][CH2:59][C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
N-(4-(N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)decanamide 139). 5-(4-Aminophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide (7, 50 mg, 0.15 mmol) was suspended in anhydrous acetonitrile (5 mL). Triethylamine (17.1 mg, 0.17 mmol) was added with stirring at 0° C. A solution of decanoyl chloride (32.4 mg, 0.17 mmol) dissolved in anhydrous acetonitrile (1 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 h and overnight at room temperature. Volatiles were removed in vacuo and the residue was washed with water (5 mL). The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1, giving the pure product as a solid (42 mg, 0.09 mmol, 60% yield), mp 242-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.9 Hz), 1.24 (m, 12H), 1.56 (m, 2H), 2.32 (t, 2H, J=7.5 Hz), 7.66 (s, 4H), 7.91 (s, 2H), 10.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 22.3, 25.2, 28.8, 29.0, 31.5, 36.6, 118.6, 127.0, 137.4, 142.2, 157.8, 170.8, 172.1; LRMS (LCQ, ESI−) calcd for C18H26N5O5S3 488.1, found 488.1 (M−H)−; HRMS (ESI−, m/z) calcd for C18H26N5O5S3 488.1102, found 487.1101 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>COCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:37]=[CH:36][C:25]4[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4c(Cl)cccc4C(=O)NC)n3)ccc21
Yield: 10.3 %

Procedure:
Combined 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (91 mg, 0.275 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (64 mg, 0.275 mmol), DL-10-Camphorsulfonic acid (82 mg, 0.353 mmol) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2.5 hours. Evaporated off solvent, dissolved residue in methylene chloride and washed with saturated sodium bicarbonate solution, then brine. Dried with magnesium sulfate, filtered and purified with normal phase chromatography using basic alumina silica gel to yield a yellow solid, 3-Chloro-2-[5-chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (15 mg, 10%). LCMS: m/z=527.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=1.0 Hz), 8.02 (br s, 1H), 7.59 (d, 1H, J=8.1 Hz), 7.51 (m, 2H), 7.28 (m, 1H), 7.21 (m, 2H), 7.02 (d, 1H, J=8.6 Hz), 6.25 (d, 1H, J=4.6 Hz), 4.13 (m, 2H), 3.76 (m, 2H), 2.82 (d, 3H, J=4.3 Hz), 2.22 (m, 2H), 1.27 (m, 9H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:11]=1)(=[O:8])=[O:7].O>CN(C)C=O>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:12]=2[CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC1(C)COc2ccc(OS(C)(=O)=O)cc21
Temperature: 15 °C

Procedure:
Thionyl chloride (83 parts) was added dropwise with cooling to dimethyl formamide (260 parts). To this mixture was then added dropwise a solution of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (180 parts) (from Example 1) in dimethyl formamide (190 parts) with stirring at about 15° C. The mixture was then stirred for one hour at room temperature and for five hours at 100° C. Addition to water (2000 parts) caused precipitation of an off-white solid which was filtered off and recrystallised from aqueous ethanol to give 2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (65.2 parts) identical with the product of Example 37(a) above.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[CH:19][N:18]=[C:17]3[N:24](C(OC(C)(C)C)=O)[CH:25]=[C:26]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:16]=23)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:48]>>[ClH:48].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:22][CH2:23]3)=[CH:19][N:18]=[C:17]3[NH:24][CH:25]=[C:26]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[C:16]=23)[CH2:10]1
Reactant: ClCCl
Reactant: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(C3CC3)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)Nc1c[nH]c2ncc(C3CC3)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.150 g, 0.277 mmol) was placed in DCM (5 mL). TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting product was dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.085 g, 74% yield) as a solid. 1H NMR (400 MHz, D2O) δ 7.88 (s, 1H), 7.25 (s, 1H), 3.96-3.93 (m, 1H) 3.53-3.49 (m, 1H) 3.42-3.37 (m, 2H), 3.32-3.27 (m, 1H), 3.22-3.17 (m, 1H), 2.70-3.63 (m, 1H), 2.14-2.12 (m, 1H), 1.89-1.86 (m, 1H), 1.80-1.77 (m, 1H), 1.69-1.66 (m, 1H), 1.54-1.52 (m, 1H), 1.12-1.09 (m, 6H), 0.99-0.96 (m, 2H), 0.66-0.62 (m, 2H); LCMS (APCI+) m/z 342 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(O)c(F)c3)ccc2c1

Procedure:
The title compound was prepared by reacting 6-(3-fluoro-4-methoxyphenyl)-2-naphthol (600 mg, 2.24 mmol) with boron tribromide (6.27 mL of 1.0 M solution in CH2Cl2, 6.27 mmol) according to method D to yield 385 mg (68%) of a yellowish solid: mp 216-219° C.; 1H NMR (DMDO-d6): δ 7.03-7.13 (3H, m), 7.43 (1H, dd, J=8.37 Hz, J=1.77 Hz), 7.58 (1H, dd, J=12.92 Hz, J=2.13 Hz), 7.68 (1H, dd, J=8.68 Hz, J=1.61 Hz), 7.74 (1H, d, J=8.68 Hz), 8.03 (1H, s), 9.79 (1H, s), 9.98 (1H, s); MS (ESI) m/z 253 (M−H)−. Anal. for C16H11FO2.0.13H2O:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:15][CH3:16].O>C(Cl)Cl>[CH3:10][O:11][CH2:12][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: CCCc1ccc(O)cc1
Reactant: COCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc(OCOC)cc1
Reaction time: 0.25 h

Procedure:
Ethyldiisopropylamine (10.3 mL) and chloromethyl methyl ether (4.5 mL) were added to a solution of 4-propylphenol (4.09 g) in methylene chloride (60 mL) under ice cooling to form a reaction solution. This reaction solution was stirred for 15 minutes under ice cooling, and then left overnight at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target product (4.50 g) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([NH:36][NH:37]C(OC(C)(C)C)=O)=[O:35])=[CH:32][CH:31]=1)=[O:28]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:37][NH:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:47])=[CH:46][CH:45]=1)=[O:35]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl)hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 496 mg of the title compound (82%) as a yellow solid in 99.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:9][CH2:8]1.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[C:19]([C:3]1[C:2]([NH:1][S:21](=[O:24])(=[O:23])[NH2:22])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:8][CH2:9]1)#[N:20]
Reactant: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Reactant: NS(=O)(=O)Cl
Product: CCCNC(=O)C1(COc2cccc(NS(N)(=O)=O)c2C#N)CC1
Yield: 78 %

Procedure:
Prepared as in Example 158a from 1-((3-amino-2-cyanophenoxy)methyl)-N-propylcyclopropanecarboxamide (Example 183b) and sulfamoyl chloride in 78% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.45 (broad s, 1H), 7.51-7.61 (m, 2H), 7.26 (broad s, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=7.6 Hz, 2H), 1.08-1.14 (m, 2H), 0.83-0.88 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10](Br)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:24]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[OH:25])[CH:26]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Brc1cnn(-c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 1-phenyl-4-bromopyrazole (see M. A. Khan, et al., Can. J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad cooled to −78° C. under argon atmosphere, and added dropwise thereto was n-butyl lithium (1.59 M hexane solution, 6.9 ml). The mixture was stirred at −20° C. to −10° C. for 5 hours, and added dropwise thereto at the same temperature was a solution of 5-bromo-2-chlorobenzaldehyde (2.19 g) obtained in Reference Example 16-(1) in diethyl ether (30 ml). The mixture was stirred at the same temperature for 30 minutes, and added thereto was tetrahydrofuran (30 ml), and the mixture was stirred at 0° C. for further 30 minutes. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=83:17-80:20) to give 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol (831 mg) as yellow oil. APCI-Mass m/Z 363/365 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:10].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[O:7]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1Cl
Temperature: 90 °C

Procedure:
To a solution containing 1.0 g 4-fluoro-3-chlorobenzaldehyde and 45 ml DMSO, was added 1.93 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H-NMR (DMSO-d6, 400 MHz): 3.45 (s, 3H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).