Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.[OH:29]O>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:13])([CH3:14])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:29]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 5,7-dichloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].O>O1CCOCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reactant: COCCN
Solvent: O
Solvent: C1COCCO1
Product: COCCNc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 55.1 %

Procedure:
12.0 g (0.03 mole) of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-pyrazole and 10 g (0.13 mole) of 2-methoxyethylamine are stirred in 50 ml of dioxane at 50° C. to 60° C. for 12 hours. For working up, the cooled reaction mixture is poured into water and extracted several times with chloroform. The combined organic phases are washed with water, dried over sodium sulphate and concentrated in vacuo and the residue is crystallized with ligroin. 6.6 g (55% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(2-methoxyethylamino)-4-nitro-pyrazole of melting point 85° C.-90° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]([N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[N:29]#[C:30]Br>C(O)C>[NH2:29][C:30]1[N:5]([CH2:6][CH2:7][C:8]([N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17])=[O:9])[CH2:4][C:3]2[C:2](=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=2)[N:1]=1
Reactant: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1N)c1ccccc1
Reactant: N#CBr
Solvent: CCO
Product: CN(C(=O)CCN1Cc2cc(Oc3ccccc3)ccc2N=C1N)C1CCCCC1
Reaction time: 3 h

Procedure:
A solution of 3-(2-amino-5-phenoxy-benzylamino)-N-methyl-N-phenyl-propionamide (diamine) (1.4 g, 0.0037 mol) and cyanogen bromide (0.58 g, 0.0055 mol) in 70 mL of ethanol was refluxed for 3 h. The solvent was evaporated to yield a residue, which was crystallized from EtOAc (100 mL). The resulting precipitate was dissolved in ethanol and stirred for 3 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried to yield the title product, pure 3-(2-amino-6-phenoxy-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CN
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CNc1nc(N)nc2[nH]cnc12
Temperature: 150 °C

Procedure:
A mixture of (8-methyl-2-o-tolylquinolin-3-yl)methanamine (40 mg, 0.15 mmol), 2-amino-6-chloropurine (52 mg, 0.30 mmol), and triethylamine (42 μL, 0.30 mmol) in i-PrOH (0.8 mL) was heated in a microwave reactor at 150° C. four times for 20 min. The mixture was partitioned between saturated aqueous NaHCO3 (15 mL) and EtOAc (15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel, and purified by flash chromatography (Biotage® Si 25+M) eluting with MeOH/CH2Cl2 (5% to 10%) to provide a white solid. The compound was further purified by reversed-phase HPLC (Gilson) eluting with H2O/MeCN/TFA to provide a white solid [PI3Kδ IC50=82 nM]. MS (ESI+) m/z=396.2 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C.I>O>[CH2:1]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:27]4[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=4)=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(Cl)c3-c3ccc(OC)cc3)cc2)CC1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(Cl)c3-c3ccc(O)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
4-(trans-4-heptylcyclohexyl)-3′-chloro-4″-methoxyterphenyl of Intermediate 2 was mixed with 100 ml of acetic acid and 5 ml of 59% aqueous hydroiodic acid. The mixture was refluxed about twelve hours, cooled down to room temperature and poured into water. The product was twice extracted with methylene chloride. The combined organic layers were washed by diluted solution of sodium thiosulphate, water and dried over magnesium sulphate. After removing the solvent, the product was recrystallised from toluene-heptane mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:31]([CH:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[O:32])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: CN1CCC(C(=O)O)CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and 1-methyl-piperidine-4-carboxylic acid; MS: m/e=414.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(ccn2Cc2cccnc2)c1
Yield: 71.7 %

Procedure:
To a stirred suspension of nitroindole (D46) (0.63 g, 2.5 mmol), and iron powder (0.41 g, 7.2 mmol) in methanol (20 ml) was added a solution of ammonium chloride (0.66 g. 12.4 mmol) in water (13 ml). The mixture was then heated under reflux for 12 h, then filtered while hot and evaporate. The residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated to give the title compound (0.40 g, 72%) as a gum.
Reaction SMILES: [NH2:1][C:2]12[CH2:8][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([N:24]1[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]1[C:30]#[N:31])=[O:23]>CN(C)C=O>[CH2:12]([O:11][C:9]([C:5]12[CH2:8][C:2]([NH:1][CH2:21][C:22]([N:24]3[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]3[C:30]#[N:31])=[O:23])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)=[O:10])[CH3:13]
Reactant: CCOC(=O)C12CCC(N)(CC1)C2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)C2
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (50.0 mg) was dissolved in N,N-dimethylformamide (2 mL) and potassium carbonate (40.0 mg) was added to the solution. (2S,4S)-1-(2-Bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (64.2 mg) in N,N-dimethylformamide (1 mL) was then added dropwise at room temperature and the mixture was stirred for 1 hour. The insoluble materials were filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (NH silica, eluant:ethyl acetate) to give (2S,4S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.1]hept-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (89.0 mg).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[O:19])[CH2:11]1)=[O:7])(C)(C)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)=[O:19])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethyl)-1-methyl-1 H-indole-3-carboxamide (2.16 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (1.1 g) to give N-(2-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)ethyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:22])([CH2:20][CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:22])[CH2:20][CH3:21]
Reactant: CCC(C)(N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CCC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-butanol (CAN 10196-30-2) as starting materials and isolated (75 mg, 55%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 313.1322 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]c1=O
Temperature: 0 °C
Yield: 50.6 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (200 mg, 0.869 mmol) was dissolved in 8 mL of concentrated H2SO4 and the yellow-green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (87.8 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice H2O. The product was isolated by vacuum filtration as pale yellow crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 121.1 mg (50.6% yield). 1H NMR (d6 -DMSO) δ7.53 (s, 1H, ArH), 7.80 (s, 1H, ArH), 12.4 (s, 2H, NH). EIMS m/z 275 (81, M+), 217 (36), 201 (100, bp), EIHRMS calc. for C9H4N3O4F3 275.0153, found 275.0170.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[O:3]1>C(O)(=O)C.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13](=[O:14])[NH:15][C:16]2=[O:17])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Temperature: 95 °C
Yield: 77.3 %

Procedure:
A suspension of 51 g (0.105 m) of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine in 500 ml of acetic acid and 120 ml of water is heated at 95° C. for 90 minutes. The solution thus obtained is concentrated under vacuum and the residue is taken up with 2 l of ethyl acetate, then is concentrated to a small volume and, after 15 hours at room temperature, the precipitate is filtered, washed with ethyl acetate and dried to give 35.6 g of 5′-deoxy-5′-iodo-5-fluoro uridine. M.p.=174.5÷175.5° C., purity (HPLC)=99.74% [α]D=+8.96° (c=1.00, CH3OH).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]2[C:2](=[O:3])[C:1](=[O:5])[S:14][C:10]=2[CH:9]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1Sc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
Oxalyl chloride (3.7 mL, 42 mmol) was added dropwise to a solution of 3-bromothiophenol (5.00 g, 26.4 mmol) in ether (20 mL). The mixture was heated at reflux for 1.5 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was taken up in DCM (50 mL) and cooled to 0° C. Aluminum chloride (4.23 g, 31.7 mmol) was added in portions. The resultant mixture was stirred at reflux for 30 minutes, cooled to room temperature and poured into ice water with stirring. The organic layer was separated and successively washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried and concentrated in vacuo to give a solid, which was suspended in 20% EtOAc in hexanes (50 mL) and heated at reflux for 10 minutes. After cooling, the precipitated solid was collected by filtration to afford crude 6-bromobenzo[b]thiophene-2,3-dione (3.22 g, 50%). The 6-bromobenzo[b]thiophene-2,3-dione was added to ammonium hydroxide (35% aqueous solution, 40 mL) at 5-10° C., followed by dropwise addition of hydrogen peroxide (35% aqueous solution, 5.5 mL, 66 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and then filtered to give 6-bromobenzo[b]thiophene-3-carboxamide (1.30 g, 38%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ □8.66 (d, J=8.8 Hz, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([C:9]([O:11]CC)=[O:10])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[CH:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cnc(C(=O)O)s1

Procedure:
A solution of ethyl 5-isopropylthiazole-2-carboxylate (example 54, step a) (0.105 g) in methanol (5 mL) was treated with a solution of lithium hydroxide (0.025 g) in water (3 mL) and the resultant mixture was stirred vigorously at 20° C. for 2 hours. The methanol was evaporated off under reduced pressure and the residual aqueous solution was diluted with brine (10 mL). The aqueous layer was washed with ether, then cooled in an ice bath and acidified by dropwise addition of concentrated aqueous hydrochloric acid. The mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.048 g.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[OH:7][C@H:8]1[CH2:12][NH:11][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:9]1>CCOCC>[C:13]([C@H:10]1[CH2:9][C@@H:8]([OH:7])[CH2:12][NH:11]1)([O:15][CH3:3])=[O:14]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and a reflex condenser were placed dry methanol (40 ml) and cooled in ice bath under argon atmosphere. To this stirred solution was added acetyl chloride (4.32 g, 55 mmol) followed by cis-4-hydroxy-D-proline 34 (5.00 g, 38.17 mmol). The resulting solution was heated at reflex for 7-8 h and cooled to room temperature. The solution was diluted with ether, and the resulting white solid was collected by suction, was with ether and dried under vacuum over solid NaOH. Yield; 6.9 g (100%) . 1HNMR (CDCl3): 2.09 (2 dd, 1H), 2.34 (m, 1H), 3.49-3.73 (m, 3H), 3.79 (s, 3H, CH3), 4.34 (m, 2H)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:20]=[C:21]=[S:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH:14]([CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[S:22])(=[O:10])=[O:11]
Reactant: CCCCCC(C)N=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CCCCCC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Yield: 43 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1-methylhexyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 43%), 1H-NMR (DMSO-d6): δ0.85 (t, 3H, CH3), 1.10 (d, 3H, CH3), 1.25 (m, 6H), 1.45 (m, 2H), 4.25 (m, 1H, CH), 6.50 (br, 2H, NH2), 6.65 (s, 1H, H-4), 7.93 (br, 1H, NH), 11.3 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:29](=[O:30])[CH2:28][Cl:27])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOc1nc(-c2ccc(NC(=O)CCl)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 55 (0.064 g, 0.231 mmol) in THF (4 mL), at 0° C. was added triethylamine (0.035 g, 0.346 mmol) and chloroacetylchloride (0.039 g, 0.346 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22](O)=[O:23])=[CH:16][CH:17]=3)[N:12](C3CCCCO3)[N:11]=2)[CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>CC(OC)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22]([NH:42][CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)=[O:23])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH:3]=1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: NCc1ccccn1
Solvent: COC(C)(C)C
Product: Cc1ccnc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)NCc4ccccn4)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 and Example 7 above except using 2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol -6-ylamino]-benzoic acid and C-Pyridin-2-yl-methylamine. 1H NMR (DMSO-d6, 300 MHz) δ 12.91 (1H, s), 9.77 (1H, s), 9.19 (1H, t, J=5.8 Hz), 8.50 (1H, d, J=4.1 Hz), 8.45 (1H, d, J=5.0 Hz), 8.06 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=16.4 Hz), 7.82–7.70 (2H, m), 7.51–7.25 (7H, m), 7.10 (1H, d, J=4.6 Hz), 6.98 (1H, dd, J=8.8, 1.8 Hz), 6.96–6.91 (1H, m), 4.58 (2H, d, J=5.9 Hz), 2.35 (3H, s). ESIMS m/z 461 (M+H)+. Anal. Calcd. for C28H24N6O×0.3 MTBE: C, 72.71; H, 5.77; N, 17.25. Found: C, 72.38; H, 5.80; N, 16.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([B:18]([OH:21])[OH:19])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COB(OC)OC
Reactant: COc1ccc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2ccccc2cc1B(O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
Under a nitrogen atmosphere, 15.0 g (94.9 mmol) of 2-methoxynaphthalene was dissolved in tetrahydrofuran (300 ml), and the solution was cooled to 0° C. After that, 238 mL (1.6-mol/L solution, 190 mmol) of normal butyllithium were slowly dropped to the solution. After the dropping, the mixture was stirred at 0° C. for 2 hours. After that, the mixture was cooled to −10° C., and 33 mL (340 mmol) of trimethyl borate was dropped over 10 minutes to the mixture. The resultant was heated to room temperature, and was stirred overnight. After that, 0.2N hydrochloric acid was added to the resultant to stop the reaction. Chloroform was added to the resultant to separate an organic layer, and the layer was washed with a saturated aqueous solution of ammonium chloride once and with water four times. After that, the solvent was removed by distillation, and heptane and toluene were added to the resultant residue to purify the residue by recrystallization, whereby 4.81 g of Intermediate Compound 6 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (4.1 g, 0.01 mol) was dissolved in 20% TFA/CH2Cl2 (40 mL). The reaction mixture was stirred at rt for 2 h, tlc showed the reaction was complete. A solution of sat'd aq Na2CO3 was added dropwise to adjust the pH to 8˜9 and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)piperidin-3-yl)pentan-1-ol (3.0 g, 97%), which was used without purification.