Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])([O:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])=[O:2].I([O-])(=O)(=O)=[O:16].[Na+]>ClC(Cl)(Cl)Cl.C(#N)C.O.C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[S:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])(=[O:16])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COCCCOS(=O)OCCCOC
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COCCCOS(=O)(=O)OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 726.22 mmol of bis(3-methoxypropyl) sulphite in 330 ml of tetrachloromethane, 330 ml of acetonitrile and 830 ml of water is cooled to 15° C., and 18.16 mmol of ruthenium(III) chloride hydrate are added. 1089.34 mmol of sodium periodate are added in small portions, and the reaction mixture is stirred at room temperature overnight. It is diluted with ethyl acetate, and the organic phase is separated off, dried with sodium sulphate and evaporated. The crude title compound is obtained as a beige liquid from the residue and is employed without further purification in the next stage.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), 3-pyridylboronic acid (61 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (207 mg, 82%) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: O=c1c2cc(F)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(F)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2r (118 mg, 0.365 mmol), 6-mercaptopurine monohydrate (68 mg, 0.402 mmol), K2CO3 (56 mg, 0.402 mmol), and DMF (2 mL). The crude product was recrystallized from EtOH to provide 103 mg of an off-white crystalline solid (64%), mp 232.8-233.0° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.81-7.86 (m, 3H); 7.76 (d, J=7.5 Hz, 1H); 7.67 (d, J=7.5 Hz, 1H); 7.40-7.54 (m, 2H); 4.48 (br s, 2H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=247 Hz), 160.2 (d, J=3.3 Hz), 156.9, 152.3 (d, J=1.9 Hz), 151.5, 149.7, 144.0, 143.6, 134.1, 132.1, 131.7, 131.5, 130.5, 130.4, 130.2, 128.8, 124.0 (d, J=24 Hz), 122.0 (d, J=8.7 Hz), 111.7 (d, J=24 Hz), 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.2C2H6O.0.1H2O: C, 54.46; H, 3.00; Cl, 7.88; N, 18.68. Found: C, 54.09; H, 2.73; Cl, 7.80; N, 18.77.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[C:8]([C:16](=[O:18])[CH3:17])=[CH:9][C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1.[C:19]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:34]>CO.C(O)C>[ClH:34].[C:19]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][C:30]3([CH2:17][C:16](=[O:18])[C:8]4[CH:9]=[C:10]5[O:14][CH2:13][O:12][C:11]5=[CH:15][C:7]=4[O:6]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: CC(=O)c1cc2c(cc1O)OCO2
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Solvent: CO
Product: O=C1CC2(CCN(CCc3ccccc3)CC2)Oc2cc3c(cc21)OCO3
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Pyrrolidine (83 ml, 71 mg, 1 mmol) was added to a mixture of 1-(6-hydroxy-1,3-benzodioxol-5-yl)-ethanone [prepared as described by K. Fukui and M. Nakayama, Bull. Chem: Soc. Jap., 1963, 37, 300.] (180 mg, 1 mmol) in methanol (1 ml). The mixture was stirred for 10 minutes, then 1-(2-phenylethyl)-4-piperidinone (203 mg, 1 mmol) in methanol (1 ml) was added and the mixture was heated under reflux for 1.5 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 20 ml) was added. The mixture was extracted with dichloromethane (3×20 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (98:2:0.2) to give a yellow glass which was suspended in ethanol (5 ml) and treated with ethanolic HCl (6N, 0.5 ml). The mixture was stirred for 1 hour, cooled and the precipitate was collected and dried in vacuo to give the title compound as a white solid (153 mg, 38%), m.p.>285° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([OH:26])=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[Cl-].[NH4+].Cl.C[N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CO.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:13]=[C:12]([C:24]([NH2:31])=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid (60 mg, 0.17 mmol), ammonium chloride (15 mg, 0.28 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (43 mg, 0.22 mmol), and 1-hydroxybenzotriazole hydrate (30 mg, 0.22 mmol) in a vial was flushed with nitrogen and dimethylformamide (0.5 mL) followed by triethylamine (38 μL, 0.28 mmol) were added. After stirring overnight, the reaction was diluted with methanol and the product was isolated by preparative HPLC (100×30 mm Luna C18 column, gradient elution starting with A:B=10:90 and ending with A:B=70:30 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) This gave 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (36 mg, 57% yield) as a yellow solid. MS (ESI) m/z 348.0 (M+H). 1H NMR (MeOD) δ ppm 8.27 (1H, d, J=8.85 Hz), 8.09 (1H, s), 8.04 (2H, d, J=8.85 Hz), 7.18 (1H, d, J=2.14 Hz), 7.09 (2H, d, J=8.55 Hz), 6.92 (1H, dd, J=8.55, 2.14 Hz), 3.95 (3H, s), 3.90 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[N:9][NH2:10])=[N:4][CH:5]=[CH:6][N:7]=1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[NH2:1][C:2]1[C:3]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[F:19])[C:25]([OH:26])=[N:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NN=C(Nc1cccc(F)c1F)c1nccnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1nccnc1-c1nnc(O)n1-c1cccc(F)c1F
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-Amino-N-(2,3-difluorophenyl)-N′-aminopyrazine-2-carboxamidine (500 mg, 1.89 mmol) was dissolved in dry THF (10 mL) and CDI (340 mg, 2.10 mmol) was added at RT. The solution was kept at RT for overnight. After the solvent was removed by evaporation, the residue was added to saturated NaHCO3 solution and filtered. After washing with water, the crude yellow solid product (500 mg, 91%) was obtained after drying under vacuum. LC-MS m/e=290.8 (M+H). Using the same procedure, 5-(3-aminopyrazin-2-yl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-ol, 5-(3-aminopyrazin-2-yl)-4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-ol, 5-(2-aminopyridin-3-yl)-4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-ol, 5-(2-aminopyridin-3-yl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-ol, and 5-(2-aminopyridin-3-yl)-4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-ol can be produced from 3-amino-N-(2,3-dichlorophenyl)-N′-aminopyrazine-2-carboxamidine, 3-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyrazine-2-carboxamidine, 2-amino-N-(2,3-difluorophenyl)-N′-aminopyridine-3-carboxamidine, 2-amino-N-(2,3-dichlorophenyl)-N′-aminopyridine-3-carboxamidine, and 2-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyridine-3-carboxamidine, respectively.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.[F:10][C:11]([C:37](F)([F:39])[F:38])([O:15][C:16]([F:36])([F:35])[C:17]([F:34])([C:30]([F:33])([F:32])[F:31])[O:18][C:19]([F:29])([F:28])[C:20]([F:27])([C:25]#[N:26])[C:21]([F:24])([F:23])[F:22])C(F)=O>>[F:38][C:37]([F:39])=[C:11]([F:10])[O:15][C:16]([F:36])([F:35])[C:17]([F:34])([C:30]([F:31])([F:32])[F:33])[O:18][C:19]([F:28])([F:29])[C:20]([F:27])([C:25]#[N:26])[C:21]([F:24])([F:23])[F:22]
Reactant: N#CC(F)(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: N#CC(F)(C(F)(F)F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)=C(F)F
Yield: 92 %

Procedure:
A bed (8 × 90 cm) of finely divided dry sodium carbonate held at 250°-270° C. in a vertical glass tube was fluidized with a minimum flow of preheated (300° C.) nitrogen from the bottom, and the exit gases passed out the top and through a series of three dry-ice cooled traps. Perfluoro(8-cyano-2,5-dimethyl-3,6-dioxanonanoyl) fluoride (215 g) was added at 0.59 ml/minute to the preheated nitrogen entering the bed. After all of the acid fluoride had been added, the traps were washed out with the aid of ethyl ether and the combined trap contents distilled to give 172 g (95%) of perfluoro(8-cyano-5-methyl-3,6-dioxa-1-nonene).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14](=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14]([OH:18])([CH3:27])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Yield: 56 %

Procedure:
To a solution of benzyl-(3R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate (1.61 g, 4.44 mmol) in THF (30 mL) at −78° C. a solution of methylmagnesium bromide in ether (3.0 M, 4.4 mL, 13 mmol) was added. The reaction was then quenched by adding aq. NH4Cl, and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-80% EtOAc in hexanes to give a mixture of the two diastereoisomers of the sub-title compound as a colorless oil (0.95 g, 56%). LCMS calc. for C20H30N2NaO5 (M+Na)+ m/z=401.2. found 401.0.40% of unreacted starting material was also isolated.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:17][C:18]([F:31])([F:30])[C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][CH:20]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH3:15])=[C:9]([C:10]([N:27]2[CH2:28][CH2:29][N:24]([C:22]3[S:23][C:19]([C:18]([F:31])([F:17])[F:30])=[CH:20][N:21]=3)[CH2:25][CH2:26]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CSc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 18 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-methylsulfanyl-benzoic acid (Example A26) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a light brown solid (yield 18%). MS (m/e): 466.0 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7](O)=[O:8].[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([O:32]CC)=[O:31])=[N:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[H-].[Na+]>>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:6]=1[C:7]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=1)=[O:8]
Reactant: O=C(O)c1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Reactant: CCOC(=O)c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(NC(=O)c2c(Oc3ccc(F)cc3Cl)cccc2C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
A solution of 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (33.46 mg, 0.10 mmol), ethyl 5-aminopyridine-2-carboxylate (19.94 mg, 0.12 mmol), HATU (41.83 mg, 0.11 mmol) and N-methylmorpholine (21.99 μL, 0.20 mmol) was stirred at 100° C. for 8 hours. NaH (16.00 mg, 0.40 mmol) was added and the mixture was stirred at 100° C. for 10 min. The mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in Water (1-99%) and HCl as a modifier, to give 5-[[2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylic acid (74) (2.52 mg, 5%) as a white solid. ESI-MS m/z calc. 454.03. found 455.3 (M+1)+; Retention time: 1.42 minutes (3 minutes run).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[C:10]([OH:12])=[O:11])(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)O)cc1

Procedure:
At 50° C. and 0.02 mbar, 1 g (6.1 mmol) of indoline-2-carboxylic acid and 2.5 g (12.2 mmol) of 4-methoxybenzenesulfonyl chloride are kept for 4 hours (h) in a kugelrohr which is rotated slowly and continuously. The brown crystalline product is subsequently taken up in sodium carbonate solution and extracted twice with diethyl ether. The aqueous phase is acidified using 6 N HCl and extracted four times with ethyl acetate. The combined organic phases are extracted with saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. Residual solvent is removed using oil pump vacuum.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:17]=2[CH:43]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:17]=2[CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccc(Cl)cc2)=NC12CCN(Cc1ccccc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1NC2=O
Reaction time: 3 h

Procedure:
20 ml (0.06 mole) of a 50 percent strength solution of benzyl chloroformate in toluene are added to a mixture of 9.5 g (0.02 nole) of 7-chloro-5-(4-chlorophenyl)-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one and 5 g (0.06 mole) of NaHCO3 in 150 ml of methylene chloride. The reaction mixture is boiled for 3 hours, with reflux cooling. It is then poured onto ice and the organic phase is separated off and washed twice with 10 percent strength NaHCO3 solution. After drying over Na2SO4, the organic phase is filtered and the solvent is evaporated off. The oily residue is made to crystallise with petroleum ether. The compound is filtered off with suction, boiled up with n-hexane and dried at 60° C. in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH3:36])[NH:11][C:12](=[O:35])[C@H:13]([CH:23]([C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[C:24]([F:27])([CH3:26])[CH3:25])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH3:36])[NH:11][C:12](=[O:35])[C@H:13]([CH:23]([C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[C:24]([F:27])([CH3:25])[CH3:26])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](N)C(=O)C([C@@H](C(=O)N[C@@H](C)C(=O)OCc1ccccc1)N(C)C(=O)OC(C)(C)C)C(C)(C)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C(=O)[C@@H](N)C(C)C)C(C)(C)F
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A solution of 1.75 g (0.0033 mole) of Boc-4-fluoro-3(R,S)-L-Valyl-N-Methyl-L-Leucyl-L-Alanine benzyl ester in 17 ml of dry methylene chloride was stirred and cooled at -10° C. as 17 ml of trifluoroacetic acid, which was previously cooled at the same temperature, was added. The reaction was stirred and kept at -5° C. for 16 hours, then poured carefully with stirring into a mixture of 21 g of sodium bicarbonate, ice, and 100 ml of methylene chloride. After 5 minutes the organic layer was separated and washed with 3×30 ml of saturated sodium bicarbonate solution. The methylene chloride layer was dried over magnesium sulfate, and evaporated in vacuo to give 1.38 g of a stiff oil as the product. The yield was 99% of theory and the FAB m.s. showed a molecular ion peak at 424.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.C([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)(OC(C)(C)C)=O>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:31]4[CH:32]=[N:28][NH:29][CH:30]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: NC(=O)c1nc2n(c1-c1cn[nH]c1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.14 g) was reacted with 1-Boc-4-pyrazoleboronic acid pinacol ester similar to as described in Example 4 and triturated from water followed by methanol to give 100 mg of 10-bromo-9-fluoro-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol via similar to as described in Procedure E to afford 47.5 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+. 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 8.62 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 5.50 (s, 1H), 4.54-4.41 (m, 2H), 4.38-4.20 (m, 2H), 2.07 (s, 1H), 1.51 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[C:21]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:35][CH2:34]4)[N:22](COCC[Si](C)(C)C)[N:23]=3)[N:9]=[C:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:11]=2[CH:12]=1)#[N:2].S(=O)(=O)(O)[OH:44].N>C1(C)C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[C:10]1[C:11]2[CH:12]=[C:3]([C:1]([NH2:2])=[O:44])[CH:4]=[CH:5][C:6]=2[C:7]2=[N:23][NH:22][C:21]([NH:32][CH:33]3[CH2:34][CH2:35][N:36]([S:39](=[O:41])(=[O:40])[NH2:42])[CH2:37][CH2:38]3)=[C:8]2[N:9]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(C#N)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(N)(=O)=O)CC3)[nH]nc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
54 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 0.5 ml of toluene. After cooling to 0° C. using an ice bath, 90 μl of 95% sulphuric acid are added and the mixture is stirred at RT for 24 h. It is cooled to 0° C. and neutralized with 9 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by volume). This gives 7 mg of 5-(2,6-difluorophenyl)-3-[(1-sulphamoylpiperidin-4-yl)amino]-2H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (yellow solid). 1H NMR: 1.67 (m, 2 H) 2.11 (m, 2 H) 2.67 (m, 2 H) 3.47 (m, 2 H) 3.71 (m, 1 H) 6.01 (d, J=8.2 Hz, 1 H) 6.70 (broad s, 2 H) 7.33 (t, J=7.7 Hz, 2 H) 7.55 (broad s, 1 H) 7.68 (m, 1 H) 8.17 (broad s, 1 H) 8.22 (broad s, 1 H) 8.35 (broad d, J=8.5 Hz, 1 H) 8.45 (d, J=8.5 Hz, 1 H) 12.84 (s, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][NH:28][N:29]=[C:23]2[N:22]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:21]1=[O:34]>CC(C)=O>[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][N:28]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[N:29]=[C:23]2[N:22]([CH2:30][C:31]([CH3:33])=[CH2:32])[C:21]1=[O:34]
Reactant: ClCc1cccc2ccccc12
Reactant: C=C(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Chloromethyl)naphthalene (0.214 ml) and potassium carbonate (0.60 g) were added to a suspension of 5-methyl-7-(2-methyl-2-propenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6[5H,7H]-dione (0.215 g) in acetone (10 ml). The mixture was stirred at room temperature for 16 hours and then heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:hexane (2:1) followed by recrystallisation from ethyl acetate/hexane to give the subtitle compound (0.062 g).