Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:13]([CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:26][CH:25]=2)[N:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1cc2ccccc2cn1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc3ccccc3cn2)cc1
Yield: 17.9 %

Procedure:
3-Chloroisoquinoline (33 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using general procedure A to afford tert-butyl (4-(isoquinolin-3-yl)phenyl)(methyl)carbamate as a clear oil (12 mg, 18%). 1H NMR (400 MHz, CDCl3): δ 9.33 (s, 1H), 8.09 (m, 2H), 8.05 (s, 1H), 7.99 (m, 1H), 7.87 (m, 1H), 7.69 (m, 1H), 7.58 (m, 1H), 7.38 (m, 2H), 3.32 (s, 3H), 1.48 (s, 9H); MS (ESI): 335 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([OH:16])[CH2:18]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1CCCNC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-hydroxypiperidine (6.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (0.6 mg). HRMS calcd for C16H18N2O3: 286.1317, found 286.1315.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.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>[Cl:14][C:15]1[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-(2-ethynylphenyl)propanamide K7 (2.5 g, 14 mmol) and 2,4,5-trichloropyrimidine (2.2 mL, 19 mmol) in 1,4-dioxane (27 mL) and Et3N (8.1 mL, 58 mmol) containing CuI (0.055 g, 0.29 mmol) was added PdCl2(PPh3)2 (0.10 g, 0.14 mmol). The reaction mixture was heated at 60° C. for 2.5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% Et2O in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound A29 as a light brown solid (4.52 g, 98%). LCMS-C: rt 5.10 min; m/z 320 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2]
Reactant: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(OS(=O)(=O)c2ccc(C)cc2)cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester (19.00 g, 59 mmol) in 118 mL AcOH was added 236 ml fuming HNO3 over 20 min. After 16 h the solution was pouring into a rapidly stirring slurry of 2 l of ice/H2O. After 15 min the precipitate was filtered, washed with H2O and dried under vacuum (50° C.) to give toluene-4-sulfonicacid 2-isopropyl-4-methoxy-5-nitro-phenyl ester (21.27 g, 98%) and toluene-4-sulfonic acid 2-isopropyl-4-methoxy-3-nitro-phenyl ester and as a pale yellow solid (7:1 inseparable mixture).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:16][CH2:15][CH2:14][O:13][CH3:12])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COCCO
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: CN(C)C=O
Product: COCCOc1cccc(F)c1[N+](=O)[O-]
Yield: 49.9 %

Procedure:
A solution of 1,3-difluoro-2-nitro-benzene (1.0 g), 2-methoxyethanol (480 mg), and CsCO3 (3.6 g) in DMF (20 mL) was heated at 60° C. for 16 hours. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography to afford 675 mg of 1-fluoro-3-(2-methoxy-ethoxy)-2-nitro-benzene: 1H NMR (300 MHz, CDCl3) δ 7.4 (dd, 1H), 6.8 (m, 2H), 4.2 (t, 2H), 3.7 (t, 2H), 3.4 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30].C(O)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
In a sealed tube N-(tert-butoxycarbonyl)ethylenediamine (5 mL) was added to a solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (3 g) in DMSO (6 mL). The reaction mixture was stirred at 110° C. for 15 h. The reaction mixture was allowed to cool at 50° C. and was poured into ice, acetic acid was added to reach pH=5. A precipitate appeared and was separated by filtration and washed with ether to afford a 40:60 mixture of title compounds (4.4 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:13]([CH:16]=[N:17]O)([CH2:14][OH:15])[O:12][C@@H:11]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][C:29]([O-])=[O:30].[Na+].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[Si:1]([O:8][C@@H:9]1[C@@:13]([C:16]#[N:17])([CH2:14][O:15][C:29](=[O:30])[CH3:28])[O:12][C@@H:11]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@@]1(C#N)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 4703.9 %

Procedure:
A solution of 3'-O-t-butyldimethylsilyl-4'-hydroxyiminomethylthymidine (1.98 g, 4.95 mM) the compounds of Formula 13, prepared, e.g., as described in Preparation 9) with NaOAc (7 mg, 0.09 mM) in Ac2O (7 ml) was stirred at 80° C. for 72 hours, allow to cool and treated with 10 g of ice followed by sat. NaHCO3. The solution was extracted CH2Cl2 (3×100 ml), and the organic phases were combined and dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by flash column chromatography silica gel eluting with (20% acetone/CH2Cl2) affording 3'-O-t-butyldimethylsilyl-4'-cyano-5'-O-acetylthymidine (1.7 g, 4.0 mM). MP 67°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH2:35]([N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43])[C:36]#[CH:37].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:37]#[C:36][CH2:35][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCN1CCCC1=O
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#CCN4CCCC4=O)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 39.3 %

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (250 mg, 0.42 mmol) and 1-prop-2-yn-1-ylpyrrolidin-2-one (103 mg, 0.84 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (30 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (84 mg, 0.84 mmol). The reaction was allowed to warm to room temperature and stirred 46 hr. then filtered through Celite and evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution, the organic layer separated, dried over magnesium sulphate and evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (98 mg, 40%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.12 (m, 4H), 2.44 (t, 2H), 2.49 (m, 4H), 2.57 (t, 2H), 3.55 (t, 2H), 3.72 (m, 4H), 4.00 (s,3H), 4.25 (t,2H), 4.35 (s,2H), 6.08 (s,2H), 7.03 (s,1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 594/596.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:14]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)[C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(N)cc2)cc(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(NC(=O)c3ccccc3)cc2)cc(OC)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(4-aminophenyl)-3-(3,5-dimethoxyphenyl)-N,N-dimethylacrylamide, 43, (0.49 g, 1.2 mmol) and benzoyl chloride (0.26 g, 1.8 mmol) in anhydrous benzene (18.0 mL) was heated at 90° C. for 2 h. Solvent was evaporated and crude product was purified by silica gel chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:28][CH:29]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Reactant: BrCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
In a 100 mL round-bottom flask, a suspension of 6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol (Example 39B, 0.190 g, 0.643 mmol) and 4-(bromomethyl)-2-phenylthiazole (Table of bromides, 0.180 g, 0.708 mmol) in DMF (5 mL) was purged under vacuum and N2 for 10 min. The reaction was treated with potassium carbonate (0.24 g, 1.737 mmol) and stirred at 22° C. for 18 hours, then diluted with DCM and washed with water (1×), brine (1×). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 0% to 50% EtOAc in CH2Cl2) to give the impure title material (0.198 g, 66%). The solid was triturated in hot ethyl acetate to provide the pure title material (0.176 g). LC (Method A): 2.414 min. HRMS (ESI) calcd for C26H21N4O3S [M+H]+ m/z 469.1329, found 469.1379. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.57 (s, 3H), 3.84 (s, 3H), 5.39 (s, 2H), 6.46 (d, J=1.96 Hz, 1H), 6.74 (broad d, 1H), 6.91 (d, J=9.1 Hz, 1H), 7.34 (s, 1H), 7.36 (s, 1H), 7.39-7.46 (m, 3H), 7.80 (d, J=9.1 Hz, 1H), 7.90-8.0 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[C:30]([Cl:32])=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOCC>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[C:30]([Cl:32])=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1
Reactant: Cn1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1cc(C(=O)c2cncc(N)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of [5-(benzhydrylidene-amino)pyridin-3-yl]-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 229, 30 g, 0.066 mol) in THF (200 mL) was added aq. citric acid (200 mL), the mixture was stirred for 30 min at room temperature. Ether was added and the layers were separated. The aqueous layer was adjusted to pH7 by aqueous Na2CO3. Then the mixture was filtered. The filter cake was evaporated with toluene and the residue was washed with EtOAc (200 mL) to give the title compound as a brown solid in 95% yield, 18 g.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CC1(C)[O:41][CH:40]([CH2:42][CH2:43]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:39][O:38]1.O>CN(C=O)C>[CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:43][CH2:42][CH:40]([OH:41])[CH2:39][OH:38])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC1(C)OCC(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC(O)CO)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.26 mmol) in DMF (3 mL) is added K2CO3 (43.2 mg, 0.312 mmole) and 4-nitrobenzenesulfonic acid 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (129 mg, 0.39 mmole) and the reaction is stirred for 18 h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with EtOAc/hexane and dried in vacuo to afford 96 mg, 84% of the desired product, (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}carbamic acid isopropyl ester, compound 1428.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:28](=[O:30])[CH3:29])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (1.0 g) in dichloromethane (10 ml), acetic anhydride (0.56 g) is added; and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.92 g) as an oil. The free base thus obtained is converted to the fumarate 1/4 hydrate of the title compound in a usual manner, m.p. 166°-168° C. (recrystallized from ethanol).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(C=O)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(c2ccc(CO)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 6-(4-ethylpiperazin-1-yl)pyridine-3-carbaldehyde (6.9 g, 31.46 mmol) in anhydrous ethanol (80 mL) was added at 0° C. sodium borohydride (2.38 g, 62.93 mmol). The reaction mixture was stirred at room temperature for 1 hour and then quenched with water. The solvent was evaporated, and the mixture was extracted with ethyl acetate (2×200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to provide [6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methanol as a syrup (6.61 g, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.31 (q, 2H), 2.39 (m, 4H), 3.42 (m, 4H), 4.32 (s, 2H), 4.98 (s, 1H), 6.78 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 8.01 (s, 1H); LRMS (ES+) m/z 221.3.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]\[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Solvent: COCCOC
Solvent: O
Product: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2Z,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2Z,6Z)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated with 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6Z,10Z)-2,3-epoxy-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours. After cooling to room temperature the reaction mixture is poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6Z,10Z)-2,6,10-trimethyl-12 -[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3449 cm-1, 1647 cm-1, 1449 cm-1, 1377 cm-1, 901 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: NC(CO)(CO)CO
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c[nH]1
Temperature: 60 °C
Yield: 48.4 %

Procedure:
Ethylpyrrole-2-carboxylate (1.0195 g, 7.33 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (1.934 g, 14.5 mmol) and 4-chlorobenzeneacetyl chloride (2.7841 g, 14.73 mmol) in dichloroethane (10.9 mL, 0.67 M) under N2. After stirring 10 min, the ice bath was removed, and the reaction was stirred at room temperature for 60 minutes, with little change by TLC (9:1 Hexanes:EtOAc): After heating to 60° C. for an additional hour, only a small quantity of starting material was left by TLC. The reaction was cooled to room temperature, PS-Trisamine™ resin (6.3954 g, 24.30 mmol) and dichloroethane (10 mL) were added, and the reaction was stirred for 3 hours. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 to 50:50 Hexanes:EtOAc) to obtain 1.0345 g (48.4%) 37 as a pale orange solid. Note: A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.07 (1H, broad s), 7.55-7.52 (1H, m), 7.33-7.30 (1H, m), 7.27 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 4.35 (2H, q, J=7.0 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.55, 160.97, 133.10, 132.75, 130.76, 128.69, 126.80, 126.25, 124.30, 114.95, 61.06, 45.79, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 61.06, 45.79; CH carbons: 130.76, 128.69, 126.80, 114.96 ppm. HPLC: 10.049 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:19]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([N:27]1[CH2:32][CH2:31][N:30]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[O:16][CH3:17])[NH:9][CH:8]=2)=[O:15])[CH2:29][CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12

Procedure:
Precursor 5b, 1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 4d, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C21H20ClN4O4: 427.12; found 427.12. HPLC retention time: 1.28 minutes (column A).