Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O-])=[O:11])=O)(C)(C)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.[ClH:41].C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[ClH:41].[NH2:8][C:9]([CH3:14])([CH3:13])[C:10]([N:28]1[CH2:29][CH2:30][N:25]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:26][CH2:27]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.06 g) in N,N-dimethylformamide (40 mL) were added 1-(benzyloxycarbonyl)piperazine (6.6 g), 1-hydroxybenzotriazole (3.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.67 g) and triethylamine (11.2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 25 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added diethyl ether (50 mL), and the insoluble material was collected by filtration. The collected solid was washed with diethyl ether and dried under reduced pressure to give the title compound (4.65 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O.CO.C(Cl)Cl>C(Cl)Cl>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6](/[CH:14]=[C:15](/[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)\[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C)C1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (6 g, 17.91 mmol) was dissolved in DCM (75 mL). DMF (1 mL) was added and the reaction mixture was cooled to 0° C. Thionyl chloride (3.89 mL, 53.73 mmol) was diluted with DCM (75 mL) and added to the above reaction mixture dropwise. The reaction mixture was stirred at RT for 3 h. Progress of the reaction was monitored by TLC (10% MeOH-DCM). Upon completion of the reaction, the reaction mixture was evaporated to dryness and the residue was basified with saturated aqueous NaHCO3 with cooling. The product was extracted with EtOAc, the organic layer was washed with water; dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (100-200 mesh) eluting with 2% MeOH-DCM to obtain 1.7 g of product as the free base. 1HNMR (DMSO, Oxalate salt) δ (ppm): 8.70 (s, 1H), 7.69 (d, 2H), 7.46 (m, 1H), 7.31 (s, 1H), 7.13 (d, 1H), 7.06 (m, 1H), 6.85 (s, 1H), 3.70 (m, 2H), 3.10 (m, 2H), 3.0 (s, 3H), 2.66 (m, 1H), 2.40 (s, 3H), 2.20 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(C=O)cs1

Procedure:
(4-Hydroxymethyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.62 g, 6.95 mmol) was dissolved in 30 ml dichloromethane. Mangan(IV)oxid (3.65 g, 41.7 mmol) was added and the reaction mixture stirred at reflux for 2 hrs. The suspension was filtered through a dicalite speed plus pad and washed with dichloromethane. The solvents were evaporated and the desired compound was obtained as a light yellow solid (1.25 g, 78%), MS: m/e=229.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[N:5]2[S:6](=[O:12])(=[O:11])[NH:7][C:8](=[O:10])[N:9]=[C:4]2[N:3]=1.[CH3:16][O:17][NH:18][CH3:19]>C(Cl)Cl>[CH3:16][O:17][N:18]([S:6]([NH:7][C:8]([NH:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:14]=[C:13]([CH3:15])[N:5]=1)=[O:10])(=[O:12])=[O:11])[CH3:19]
Reactant: CC1=CC(C)=NC2=NC(=O)NS(=O)(=O)N12
Reactant: CNOC
Solvent: ClCCl
Product: CON(C)S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
5.7 g (0.025 mol) of 2,3-dihydro-6,8-dimethyl-3-oxopyrimidino-[1,2-b][1,2,4,6]-thiatriazine 1,1-dioxide (cf. Example 1) are suspended in 100 ml of methylene dichloride, and 3.05 g (0.05 mol) of O,N-dimethylhydroxylamine--dissolved in 50 ml of methylene dichloride--are added at -40° C. in the course of one hour. The mixture is stirred for a further 18 hours at room temperature and evaporated to dryness, and the residue is taken up in water and acidified to pH 4--5 with 0.5 N HCl. After extraction with methylene dichloride, the mixture is worked up as under Example 17. 4.9 g (67.8% of theory) of 1-[(N-methoxy-N-methylamino)-sulfonyl]-3-(4,6-dimethyl-2-pyrimidinyl)-urea of melting point 152° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)([CH3:17])([CH3:16])[CH3:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1P(C1C(OC)=CC=CC=1OC)C1C(OC)=CC=CC=1OC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>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].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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: CC(C)(C)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccccc1-c1cc(-c2ccccc2)ncn1
Reaction time: 7 h
Yield: 18 %

Procedure:
First, 1.0 g of 4-chloro-6-phenylpyrimidine, 1.1 g of 2-tert-butylphenylboronic acid, 4.0 g of potassium phosphate, 39 mL of toluene, and 3.9 mL of water were put in a three-neck flask equipped with a reflux pipe, and the air in the flask was replaced with nitrogen. In this container were added 48 mg of bis(dibenzylideneacetone)palladium(0), namely Pd2(dba)3, and 190 mg of tris(2,6-dimethoxyphenyl)phosphine, and heating was performed at 100° C. for 7 hours. Then, 24 mg of Pd2(dba)3 and 46 mg of tris(2,6-dimethoxyphenyl)phosphine were added and heating was performed at 100° C. for 17 hours. After that, 12 mg of palladium acetate and 44 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (abbreviation: S-Phos) were added and heating was performed at 100° C. for 15 hours. Furthermore, 5.9 mg of palladium acetate and 27 mg of S-Phos (abbreviation) were added and heating was performed at 100° C. for 8 hours. Then, 0.10 g of 2-tert-butylphenylboronic acid, 2.0 g of potassium phosphate, 13 mg of palladium acetate, and 12 mg of S-Phos (abbreviation) were added and heating was performed at 100° C. for 21 hours. An organic layer was extracted from the obtained mixture with the use of ethyl acetate and was washed with saturated brine. Magnesium sulfate was added and the mixture was subjected to filtration. The solvent in the filtrate was distilled off to give a residue. The residue was purified by neutral silica gel column chromatography using a mixed solvent of ethyl acetate and hexane in a ratio of 1:4 as a developing solvent, so that 0.27 g of Hppm-tBup (abbreviation) that is an objective substance was obtained as a yellowish white solid in a yield of 18%. A synthesis scheme of Step 1 is shown in (b-1) below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[C:7]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:6][CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
5-Cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid methylester (Example 2a, 163 mg, 517 μmmol) was dissolved in ethanol (5 mL). Palladium (10% on charcoal, 16.3 mg, 517 mmol) was added; the suspension was evacuated, flushed with hydrogen gas 3 times and stirred for 1.5 h at ambient temperature. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (95 mg, quant.) as grey solid that was used in the subsequent reactions without further purification; MS (ESI) 318.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:32]4[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=4)[CH:29]=3)[C:24]2=[O:38])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:39]N1C(=O)CCC1=O>O1CCCC1>[Br:39][C:33]1[CH:34]=[N:35][N:36]([CH3:37])[C:32]=1[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:38])[N:23]([C@@H:10]([CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:11][N:12]1[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:22])[CH2:31]2
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 2-{(2S)-3-(3,5-difluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.39 mmol) [prepared in Example 40] in tetrahydrofuran (5 mL) was added N-bromosuccinimide (72.0 mg, 0.404 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluting with EtOAc/hexane (50-100%). The purification afforded 177 mg (77% yield) of the desired product as white solid. LC/MS found: 591.0 (M+1)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(=O)(O)[O-].[Na+]>C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([NH:18][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)N)cc(C#N)c21
Reactant: FC(F)(F)COc1ccccc1OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1CCc2cc(CC(C)NCCOc3ccccc3OCC(F)(F)F)cc(C#N)c21
Yield: 56.2 %

Procedure:
To a solution of 1-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile (1.37 g) and 1-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene (1.50 g) in ethanol (6 ml) was added sodium bicarbonate (0.47 g), and the mixture was reacted in a sealed tube at 95° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of methylene chloride, diethyl ether and methanol (5/5/1) as eluent, and recrystallized from diethyl ether-hexane to give 1.30 g of 1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile melting at 64°-65° C.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.C[O:9][C:10](=O)[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([C:28]2[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH:19]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)[C:15]1[CH:14]=[C:13]([S:12][CH2:11][C:10]([NH:3][CH3:2])=[O:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CN
Reactant: COC(=O)CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 60 °C

Procedure:
To a solution of methylamine hydrochloride (76 mg) in toluene (2 mL) is added a 2N solution of trimethylaluminum in toluene. The reaction mixture is heated at 60° C. for 1 hour. Then a solution of {3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}acetic acid methyl ester (50 mg) in toluene (1 mL) is added. The reaction mixture is heated at 60° C. for 24 hours. Water is added to the reaction mixture, pH is adjusted to 10 with a solution of sodium hydroxide, and the mixture is filtered on celite. The filtrate is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (toluene/acetone/triethylamine 80/20/0.2) to give 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide.
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)[NH2:2].CCN(C(C)C)C(C)C.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:36]([NH:2][S:1](=[O:26])(=[O:25])[O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (13.4 g, 33.1 mmol) in DCM (330 mL) at r.t. was added DIPEA (11.5 mL, 66.2 mmol) followed by Ph3CCl (9.23 g, 33.1 mmol). The reaction was stirred at r.t. for 4 hours. The mixture was diluted with DCM, the layers were separated, and the organic layer was washed with 1N HCl followed by brine. The combined organic phases were dried (Na2SO4) and concentrated to yield the title compound as a white solid (17.6 g, 82%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][OH:31]>>[C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH2:12][O:31][CH3:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)C=[N+]=[N-])cc1OC1CCCC1
Product: COCC(=O)CC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.08 h
Yield: 4 %

Procedure:
(+/-)-1 -Phenyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxo-6-diazohexyne (120 mg, 0.35 mmol) was added portionwise to a refluxing solution of BF3 ·Et2O (0.5 ml) in MeOH (20 ml). After 5 min, the solvent was concentrated, the reaction diluted with H2O, basified with NaHCO3, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. Purification by flash chromatography (silica gel, 30% Et2O in hexane) gave the titled product (4.8 mg, 4%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.30 (m, 3 H), 6.98 (m, 2 H), 6.84 (d, 1 H), 4.80 (m, 1 H), 4.40 (t, 1 H), 4.06 (d, 1 H), 3.92 (d, 1 H), 3.84 (s, 3 H), 3.38 (s, 3 H), 3.04 (d of d, 1 H), 2.88 (d of d, 1 H), 1.68-2.00 (m, 6 H), 1.58 (m, 2 H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].CO>[N+](C1C=CC=CC=1)([O-])=O.O>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)n1c(N)cc(=O)n1-c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(=O)n(-c2ccccc2)n1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.7 g (0.1 mole) of 1-phenyl-2-ethoxycarbonyl-3-amino-3-pyrazolin-5-one (compound 2) and 30.2 g (0.11 mole) of palmitoylchloride are dissolved consecutively in a solution of 13.3 g (0.1 mole) of anhydrous aluminium chloride in 100 ml of nitrobenzene. The mixture is stirred for 1 h at room temperature and poured out in 500 ml of water. The precipitate is stirred with methanol, filtered off, and recrystallized from ethanol.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][O:16][CH3:17].C[O:19][B:20](OC)[O:21]C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:17][O:16][CH2:15][O:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[B:20]([OH:21])[OH:19]
Reactant: COCOc1ccc(F)cc1Br
Reactant: COB(OC)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(F)cc1B(O)O
Temperature: -78 °C
Yield: 72.7 %

Procedure:
A 500 mL round bottom flask was charged with a 1.6 M solution of n-butyllithium in hexanes (100 mL, 0.16 mol) and flushed with nitrogen. The solution was cooled to −78° C. and a solution of 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g, 0.13 mol) in dry tetrahydrofuran (50 mL) was added dropwise over one hour. The mixture was stirred at −78° C. and then trimethylborate (20 mL, 0.175 mol) was added very slowly via syringe. The reaction was allowed to gradually warm to room temperature and after two hours the mixture was poured into ice. The mixture was acidified to pH 4 with 5% aqueous citric acid and extracted with ethyl acetate (×3). The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. The solvent was evaporation under reduced pressure and the residue was recrystallized from hexanes give 2-methoxymethoxy-5-fluorophenylboronic acid (18.9 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)=[CH:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)=[CH:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)cn2C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: N#CCc1ccc(-c2cn(C3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of (4-(4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)acetonitrile (14.0 mg) in acetonitrile (2 mL) were added sodium iodide (15.7 mg) and chloro(trimethyl)silane (0.053 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (7.2 mg).
Reaction SMILES: O.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Al+3:17].C(OCC)(=O)CC(OCC)=O.[CH3:29][CH:30]([O:34][C:35]([CH3:37])=[O:36])[CH2:31][O:32][CH3:33]>C(O)(C)C>[CH3:29][CH:30]([O:34][C:35]([CH3:37])=[O:36])[CH2:31][O:32][CH3:33].[Al:17]
Reactant: [Al+3]
Agent: CCCC[O-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: COCC(C)OC(C)=O
Product: [Al]
Reaction time: 2 h

Procedure:
A mixture of purified water (1.8 g) and isopropyl alcohol (40 g) was dropped to a mixture of aluminum tributoxide (24.6 g), isopropyl alcohol (60 g) and diethyl malonate (16 g). After completion of dropping, the mixture was agitated for 2 hours, subjected to hydrolytic condensation and heated to reflux for 2 hours. PGMEA (200 g) was added thereto and was concentrated under reduced pressure to obtain a PGMEA solution of an aluminum-containing condensate (B-III) (150 g). The solid content concentration of the aluminum-containing condensate was 9.9%.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.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>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (434 mg), (3-fluorophenyl)boronic acid (227 mg), dichlorobis(triphenylphosphine)palladium (44 mg) and potassium carbonate (518 mg) in DME-water (1:1, 12 mL) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (430 mg, 95%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.4 %

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-methanol (2.75 g, 14.6 mmol) and Et3N (3.10 mL, 22.2 mmol) in DCM (75 mL) at −20° C. under N2 was added methanesulfonyl chloride (1.70 mL, 22.2 mmol) dropwise. After 45 min the reaction was allowed to warm to room temperature and diluted with DCM (75 mL). The reaction mixture was washed with water (75 mL), sat. NaHCO3 (2×75 mL) and brine before drying over Na2SO4. Concentration in vacuo afforded crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester (4.21 g) as an oil. The crude material was used in the next step without purification.