Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+].C(Cl)Cl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (907.2 mg, 2.16 mmol) was added 4 mL of 1:1 TFA:CH2Cl2. The mixture was stirred at room temperature for 5 hours. The reaction was diluted with a solution of saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol. To this free amine (640 mg, 2 mmol) was added 8 ml of CH2Cl2 and triethylamine (335 μL, 2.4 mmol). After cooling the mixture to 0° C., (S)-tetrahydrofuran-3-yl chloroformate (271 mg, 1.8 mmol) was added, and the reaction was allowed to stir for 30 minutes. Purification on silica gel using 30-100% ethyl acetate/hexanes gave (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, CDCl3) δ 14.8 (bs, 1H), 8.34 (d, J=6.4 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (bs, 1H), 7.27 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 5.21 (s, 1H), 5.06 (s, 1H), 4.37 (s, 1H), 4.15 (m, 1H), 4.02 (s, 1H), 3.97 (d, J=5.6 Hz, 1H), 3.87-3.77 (m, 5H), 2.42 (s, 3H), 2.24 (t, J=6.0 Hz, 1H), 2.15-2.06 (m, 1H), 1.98 (q, J=9.3 Hz, 2H) ppm.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52]C(OC(C)(C)C)=O.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:16])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NCCCCNC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
3-(Phenylsulfonyl)aminobenzoic acid as prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) (221 mg, 0.5 mmol), tert-butyl 4-aminobutylaminocarboxylate (100 mg, 0.6 mmol) and triethylamine (0.2 mL) were mixed in dry DMF (5 mL) and stirred at room temperature for 3 hours. The mixture was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was mixed with 1:1 trifluoroacetic acid (TFA):CH2Cl2 (10 mL), stirred at room temperature for 2 hours and the solvent evaporated to give the title compound (140 mg, 81%) as the TFA salt. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (m, 4H), 2.79 (t, 2H), 3.23 (d, 2H), 7.23 (d, 1H), 7.30 (t, 1H), 7.57 (m, 5H), 7.60 (d, 2H), 8.50 (t, 1H). Mass spectrum (MALDI-TOF) calcd. for C17H21 N3O3S: 370.4 (M+Na), Found: 370.7.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17](O)[CH2:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.ClCCl>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=1)[CH2:16]2
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: OC1CN2CCC1CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc2c(c1)[nH]c1cc(OC3CN4CCC3CC4)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a 0° C. mixture of 2-hydroxy-9H-carbazole (369 mg, 2.02 mmol; Aldrich), quinuclidin-3-ol (260 mg, 2.05 mmol; Aldrich), and triphenylphosphine (646 mg, 2.47 mmol; Aldrich) in THF (10 mL) was added diethylazodicarboxylate (320 μL, 2.03 mmol; Lancaster). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred for 3 d. The mixture was diluted with dichloromethane, washed with saturated aq. NaHCO3, dried over MgSO4, and purified by flash chromatography (80 g silica gel, eluting with 1-16% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound as an oil (350 mg, 1.20 mmol, 59% yield). Trituration of the oil with ethyl acetate produced a solid. 1H NMR (300 MHz, methanol-d4) δ 7.92 (1H, d, J=6 Hz), 7.90 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.26 (1H, ddd, J=7, 7, 1 Hz), 7.10 (1H, ddd, J=8, 8 ,1 Hz), 6.92 (1H, d, J=2 Hz), 6.78 (1H, dd, J=8, 2 Hz), 4.59 (1H, m), 3.36 (1H, ddd, J=14, 8, 2 Hz), 3.04-2.75 (5H, m), 2.22 (1H, m), 2.11 (1H, m), 1.88-1.65 (2H, m), 1.51 (1H, m). MS (DCl/NH3): m/z 293 (M+1)+. Anal. Calcd. for C19H20N2O.0.1C4H8O2: C, 77.36; H, 6.96; N, 9.30. Found: C, 77.04; H, 7.23; N, 9.45.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]2)=[CH:8][C:7]=1[C:22]#[N:23])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)=[CH:8][C:7]=1[C:22]#[N:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-n2cc(C(=O)OCC)cn2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a solution (15 ml) of ethyl 1-(4-butoxy-3-cyanophenyl)pyrazole-4-carboxylate (1.5 g) in ethanol was added 1.5 N aqueous sodium hydroxide solution (4 ml) with stirring, and the mixture was heated at 80° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.75 g of 1-(4-butoxy-3-cyanophenyl)pyrazole-4-carboxylic acid, melting point 200-202° C.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[C-:13]#[N:14].[Na+].[Cl-].[NH4+:17].[OH-].[NH4+]>O>[C:1]([N:6]1[CH2:11][CH2:10][C:9]([NH2:17])([C:13]#[N:14])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-carboethoxy-4-piperidone (88.6 g, 517.2 mmol), sodium cyanide (30.0 g, 612.1 mmol) in water (54 mL), ammonium chloride (34.0 g, 635.5 mmol) in water (72 mL), and ammonium hydroxide (76 ml) is heated to 60°-65° C. for 5 hours, and then stirred at room temperature overnight. The resulting solid is filtered off, dissolved in methylene chloride, and washed with a small amount of brine. The organic layer is dried (MgSO4), concentrated in vacuo to 1/2 volume, and triturated with hexane. The resulting precipate is collected by filtration and dried under vacuum, to give N-carboethoxy-4-amino-4-cyanopiperidine.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[C:16]([CH3:27])=[N+:17]([O-])[CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:27][OH:4])=[N:17][CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(Cl)cc(C2OCCO2)c[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1ncc(C2OCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
Trifluoroacetic anhydride (231 μl, 1.635 mmol) was added to a solution of 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine 1-oxide (225 mg, 1.043 mmol) in DCM (4 ml) at 0° C. and the mixture was stirred at room temperature for 48 h. Full conversion was observed by HPLC. MeOH (0.5 ml, 12.36 mmol) was added and, after stirring for 10 min, DCM and 10% Na2CO3 solution were added. Extraction, drying (MgSO4), and filtration afforded 223.2 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded [3-chloro-5-(1,3-dioxolan-2-yl)-2-pyridinyl]methanol (142.7 mg, 63%) as a yellow oil.
Reaction SMILES: Br[C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[BH4-].[Na+]>CO.CS(C)=O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:3]2[C:4]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=3[S:6](=[O:8])(=[O:7])[CH:2]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc2c(c1)S(=O)(=O)C=C2Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol) in MeOH (10 mL) and DMSO (30 mL) was added NaBH4 (0.789 g, 20.85 mmol). The mixture was stirred at room temperature for 3 h after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol, 97% yield) as an off white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.85 (s, 3H), 5.38 (s, 1H), 7.02-7.08 (m, 3H), 7.22 (d, J=2.53 Hz, 1H), 7.47-7.60 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([CH2:30][NH2:31])[CH:28]=C.[CH3:32]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:31]([CH2:30][CH:27]=[CH2:28])[CH3:32])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CCCCCOS(C)(=O)=O)ccc21
Reactant: C=CCCN
Product: C=CCN(C)CCCCCc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Yield: 94 %

Procedure:
1.5 g (0.4 mmol) crude 5-(5-Methanesulfonyloxy-pentyl)-indole-1-carboxylic acid tert-butyl ester in 3 ml DMF were treated with 1.15 ml (12 mmol) N-allylmethylamine at 60° C. for 1 h. The solution was concentrated in vacuo and, the residue was dissolved in water and ether, 0.5M NaOH was added and the inorganic phase was extacted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel yielded 1.35 g (94%) 5-[5-(Allyl-methyl-amino)-pentyl]-indole-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 357 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:34])[OH:33])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH2:39]([Sn:43]([CH2:57][CH2:58][CH2:59][CH3:60])([CH2:53][CH2:54][CH2:55][CH3:56])[C:44]1[N:45]=[N:46][N:47]([CH2:49][CH2:50][CH2:51]O)[CH:48]=1)[CH2:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:33])[O:34][CH2:51][CH2:50][CH2:49][N:47]4[CH:48]=[C:44]([Sn:43]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:57][CH2:58][CH2:59][CH3:60])[N:45]=[N:46]4)=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
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: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO[PH](=O)CCCCc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinic acid (Compound 74B, 0.370 g, 0.599 mmol), 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propan-1-ol (Compound 64B, 0.299 g, 0.719 mmol) and DIPEA (0.313 mL, 1.80 mmol) in 1,2-dichloroethane (10.0 mL) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (0.936 g, 1.80 mmol). The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (20 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an off-white solid (352.1 mg, 57.8%). MS (ESI): m/z 1016.90 [M+H]+. UPLC: tR=1.44 min (UPLC-SQD: analytical_non-polar 2 min).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N+:26]([O-])=O)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].C1COCC1.NN>C(O)C.[Pd]>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[C:19]([NH2:26])=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
([8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-(4-methoxy-2-nitro-phenyl)-amine C (21.9 g, 51.3 mmol) was dissolved in 200 mL ethanol (EtOH) and 70 mL of THF under an atmosphere of dry N2. To this solution was added 10% palladium on carbon (2.18 g) followed by the dropwise addition of 10 mL of anhydrous hydrazine. The reaction mixture was stirred at ambient temperature for 2 hours after which time it was filtered through Celite™ and the Celite™ washed with DCM. The combined filtrates were concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was then washed again with saturated NaHCO3 and then brine, dried over Na2SO4, filtered and concentrated under vacuum to give 18.3 g of a tan solid as the title compound D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][CH:36]2[CH2:37][C:38]([CH3:45])([CH3:44])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC(C)(C)NC(C)(C)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 4-Amino-2,2,6,6-tetramethylpiperidine (79 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (27 mg, yield 17%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:29]=[O:30])=[CH:23]2.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:24]([CH:29]=[O:30])=[CH:23]2
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
p-Toluenesulfonyl chloride (2.445 g, 12.82 mmol), N,N-dimethyl-4-aminopyridine (0.196 g, 1.603 mmol) and triethylamine (2.253 ml, 16.03 mmol) were added to a solution of 5-fluoro-1H-indole-2-carbaldehyde (0.523 g, 3.21 mmol) in dichloromethane (10 ml) and stirred at room temperature for 20 hours. After reaction, the mixture was poured into saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to give 823 mg (81% yield) of the title compound as a white crystal:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.[H][H].[CH3:16][O:17][C:18](=O)[O:19]C>C(COC)OC>[C:18]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=2)[C:9]1=[O:13])([O:17][CH3:16])=[O:19]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: COC(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 60 °C
Yield: 44.5 %

Procedure:
To a mixture of sodium hydride (2.4 g, 60% in mineral oil, 0.06 mole) and 50 ml. dry dimethoxyethane, 5-chloroindanone (50 g, 0.03 mole) in 50 ml dimethoxyethane was added dropwise at room temperature. The mixture was stirred at room temperature until hydrogen evolution ceased. Then dimethylcarbonate (27 g, 0.3 mole) was added dropwise at room temperature and the reaction was heated to 60° C. for one hour. The reaction was cooled to room temperature, quenched with 100 ml H2O, acidified to pH 5 with concentrated HCl and extracted with ethyl ether (3×100 ml). The ether extract was washed with brine (100 ml), dried over anhydrous MgSO4 and stripped to yield 3.0 g (45%) of the desired product as a tan solid.
Reaction SMILES: CN(C)C=CC1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1.O=[O+][O-].OO.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH3:11][C:7]1[CH:6]=[C:19]([CH:10]=[CH:9][N:8]=1)[C:18]([OH:21])=[O:20]
Reactant: Cc1cc(C=CN(C)C)ccn1
Reactant: CC(=O)O
Agent: O=[O+][O-]
Agent: OO
Product: Cc1cc(C(=O)O)ccn1
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
1.63 g Dimethyl-[2-(2-methyl-pyridin-4-yl)-vinyl]-amine (10 mmol) were dissolved in 19 ml acetic acid containing 1 ml H2O. To the red solution maintained and stirred at ca. 15-20° C. was passed O3 (˜85 mmol/hour) for 1 hour. The reaction was mildly exothermic, changing in appearance from an orange (10 min) to a yellow solution (15 min) then from a yellow (20 min) to a white suspension (30 min). Excess ozone was purged with argon until a peroxide test was essentially negative. 1.02 ml 30% aqueous H2O2 (10 mmol) was added in one portion, and the resulting yellow suspension was stirred at 50° C. for 2 hours during which time a white suspension was formed. With the aid of toluene, the aqueous acetic acid solvent was removed under reduced pressure (45° C./100-50 mbar). The white residue was briefly digested in 25 ml tert. butyl methyl ether (TBME) at 40° C. then at ambient temperature for 30 min. The product was filtered, washed with TBME and dried for 2 hours at 45° C./25 mbar: 1.17 g (85%) biege crystals (GLC 98 area %, as trimethylsilylester).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:30]1([O:36][C:37](=[O:38])[NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (30 mg, 0.097 mmol) was dissolved in dry DCM (1 mL) under nitrogen atmosphere. Triethylamine (0.018 mL, 0.126 mmol, 1.3 eq) and phenylchloroformate (0.015 mL, 0.117 mmol, 1.2 eq) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water, dried over Na2SO4 and concentrated to dryness. The residue was taken up with ethylether and filtered to give 27 mg (65%) of [3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-carbamic acid phenyl ester as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: Cc1ccc(Br)cc1C(N)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Temperature: 120 °C

Procedure:
To a mixture of 5-bromo-2-methylbenzamide (I69) (0.292 g, 1.36 mmol), PdCl2(PPh3)2 (0.049 g, 0.070 mmol), triphenylphosphine (0.054 g, 0.21 mmol) and copper iodide (0.036 g, 0.19 mmol) in DMF (3 mL) was added triethylamine (0.570 mL, 4.09 mmol) and trimethylsilylacetylene (0.210 mL, 1.49 mmol) and the resulting mixture heated under microwave irradiation at 120° C. for 25 minutes. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-20% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I70) (0.190 g, 60%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.40 (m, 3H), 7.24 (d, J=7.9 Hz, 1H), 2.36 (s, 3H), 0.22 (s, 9H).