Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[C:27]([Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40]Br)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:32])[CH3:33]
Reactant: C#CCOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A tetrahydrofuran solution (15 ml) of propargyl alcohol tetrahydropyranyl ether (1.44 g, 10.3 mmol) was cooled to -78° C., and butyllithium (factor=1.5, 6.9 ml, 10.3 mmol) was added thereto. Fifteen minutes later, the temperature was raised to 0° C. Hexamethylphosphoric triamide (3.76 ml, 21 mmol) was added thereto, and the mixture was stirred for 15 minutes. A tetrahydrofuran solution of 2-(2-bromoethyl)cyclopropylmethyl t-butyldimethyl silyl ether (2.73 g, 10.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added thereto, and the product was extracted with ethyl ether. The crude product was purified by silica gel column chromatography to obtain 2-(5-tetrahydropyranyloxy-3-pentynyl)cyclopropylmethyl t-butyldimethylsilyl ether (3 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[CH:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 99.2 %

Procedure:
(7-Benzenesulfonyl-chroman-4-ylidene)-acetonitrile (395 mg, 1.27 mmol) was dissolved in 4 mL EtOAc and placed in a Parr flask containing 40 g of Pd (10% wt) on carbon. The flask was sealed and shaken overnight under 50 psi of hydrogen. The Pd/C was removed by filtration and the solvent was evaporated under reduced pressure to afford 397 mg (1.26 mmol, 99%) of (7-benzenesulfonyl-chroman-4-yl)-acetonitrile. MS: 314 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.0500 g, 0.125 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.114 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperidine-1-carboxylate (0.0507 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[N:11]([CH3:12])[N:10]=[N:9][N:8]=1)=[O:5].I[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:26]([N:6]([C:7]1[N:11]([CH3:12])[N:10]=[N:9][N:8]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:22])[F:23])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1])[CH3:27]
Reactant: Cc1c(C(=O)Nc2nnnn2C)ccc(C(F)(F)F)c1S(C)(=O)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C)c1nnnn1C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
100 mg (0.275 mmol) of 2-methyl-3-(methylsulfonyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide and 43 mg (0.275 mmol) of iodoethane are dissolved in 5 ml of N,N-dimethylformamide, and 0.038 mg (0.275 mmol) of potassium carbonate is added. The reaction mixture is stirred at 80° C. for 16 h and taken up in 5 ml of water and extracted twice with 10 ml each time of dichloromethane. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by means of preparative HPLC (acetonitrile, water). Yield 30 mg (26%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:27][C:28]([CH3:34])=[C:29]([C:31](Cl)=[O:32])[N:30]=1.O>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:29]5[N:30]=[C:26]([CH3:25])[O:27][C:28]=5[CH3:34])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) in N,N-dimethylacetamide (4.0 mL) was added 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (127 mg, 0.79 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (198 mg, 72%) as a white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22](O)=[O:23])[CH:10]=1.Cl.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@H:33]([NH2:35])[CH3:34])[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22]([NH:35][C@H:33]([CH3:34])[CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:23])[CH:10]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cccc(F)c3F)c2)nc1
Reactant: C[C@@H](N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cccc(F)c3F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′,3′-difluoro-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30 mg, 0.092 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (20 mg, 0.11 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (88 mg, 0.23 mmol), N,N-diisopropylethylamine (64 μL, 0.37 mmol), N,N-dimethylformamide (0.5 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to afford the title compound as a light orange solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nccc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1nccc(NC=O)n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of formic acid (100 g) and acetic anhydride (204 g) was stirred for half an hour at ambient temperature. To the solution was added ethyl 4-aminopyrimidine-2-carboxylate (30 g) and the mixture was stirred for 1.5 hours at 70° to 75° C. and then evaporated to dryness. The residue was triturated with ethanol, collected by filtration and washed with ethanol to give ethyl 4-formamidopyrimidine-2-carboxylate (20.0 g), mp 205°-206° C.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 57.3 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.5 g, 1.66 mmol) in dry DMF (5 mL) is added potassium carbonate (1.15 g, 8.3 mmol) and 1-bromo-4-chlorobutane (1.4 g, 8.3 mmol). The mixture is heated at 85° C., under argon, for 4 h. The mixture is then cooled to room temperature and water (50 mL) is added. The mixture is transferred to a separatory funnel and partitioned between water and ether. The ether layer is washed with water (50 mL) then dried over anhydrous sodium sulfate. The ether filtrates are then concentrated. Column chromatography (50 mL silica) using hexanes followed by hexanes/methylene chloride (1:1) gave 0.373 g (57%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][CH2:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:10][C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:3]1.C(O)(=O)C.[CH3:41][C:42]([CH3:44])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:42]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][CH2:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:10][C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([S:35][CH3:36])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH2:3]1)([CH3:44])[CH3:41]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](NC(C)C)CC[C@@H]2N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of (±) 1-[(1S*,2R*,4R*)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one (0.36 mmol) in dichloroethane (6 mL) was added acetic acid (0.1 mL, 1.8 mmol), acetone (0.08 mL, 1.1 mmol), and sodium triacetoxyborohydride (0.23 g, 1.1 mmol). The mixture was heated at 80° C. for 1 h, cooled to rt, and quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. A portion of the crude residue was purified by reverse-phase HPLC to provide two fractions, one of which contained the title. MS found: (M+H)+=581.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:29][CH2:28]4)[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.452 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (77.8 μL, 1.13 mmol), and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with tetrahydrofuran to give the title compound (140 mg, 61%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].S([O-])([O-])(=O)=O.[Mg+2].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[N+:37]([CH3:40])([O-:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:40][N+:37]([O-:39])=[O:38])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-chloro-benzaldehyde (20 g, 0.142 mol) in nitromethane (100 mL) were added magnesium sulfate (37.6 g, 0.312 mol) and phosphazene base P1-t-bu-tris(tetramethylene) (4.43 g, 0.014 mol). The reaction mixture was stirred at room temperature for 2 h. After concentration in vacuo, the residue was purified by flash chromatography (25% EtOAc/hexane) to yield the title compound (26.4 g, 100%) as a green-yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (1H, s), 7.35-7.42 (3H, m), 6.23 (1H, broad s), 5.32-5.33 (1H, m), 4.90 (1H, dd, J=3.2, 12.4 Hz), 4.60 (1H, dd, J=1.2, 12.4 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]3[CH2:49][C:50](O)=[O:51])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[CH:40]([CH2:49][C:50]([N:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)=[O:51])[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:47]3=[O:48])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)O)ccc12
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)N3CCC4(CC3)OCCO4)ccc12
Temperature: 0 °C
Yield: 90.2 %

Procedure:
With ice-cooling and stirring, 1.6 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2 ml of triethylamine and 2.2 g of diethyl phosphorocyanidate were successively added to a solution of 3.5 g of 2-(7-chloro-5-methyl-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an additional 2 hours and 200 ml of ice-water was added thereto. The mixture was allowed to stand, and the resulting crystalline precipitate was collected by filtration, washed with water and dried. Recrystallization from dichloromethane-ether (1:4) gave 4.23 g of colorless crystals melting at 259°-262° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Reactant: BrCc1ccc2ccccc2c1
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccc4ccccc4c3)C1)CC2

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-bromomethyl-naphthalene analogously to Example 1.
Reaction SMILES: [CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[CH:17][N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1.FC(F)(F)C(O)=O.Br[CH2:40][CH2:41][CH2:42][OH:43].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:40][CH2:41][CH2:42][OH:43])[N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1
Reactant: COc1ccc2c(cnc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Reactant: OCCCBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c(CCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 80 °C
Yield: 15 %

Procedure:
2,3-(Methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (prepared by the process described in Japanese Patent KOKAI No. 5-208959, 1.228 g, 3.00 mmols) was suspended in acetonitrile (48 mL), and trifluoroacetic acid (231 μL, 3.00 mmols), 3-bromo-1-propanol (271 μL, 3.00 mmols) and tris(trimethylsilyl)silane (1.85 mL, 6.00 mmols) were added to the suspension. The mixture was stirred at 80° C. on an oil bath. After the suspension was dissolved, azobis(isobutyronitrile) (0.985 g, 6.00 mmols) was added to the solution followed by heating under reflux. 90 minutes later, the reaction mixture was cooled to room temperature. By separating the precipitated crystals through filtration, the starting material, 2,3-(methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine, was recovered as the trifluoroacetate (0.680 g). The filtrate was concentrated in vacuo, and a saturated sodium hydrogencarbonate aqueous solution (40 mL) was added to the residue followed by extraction with methylene chloride (50 mL). After the organic layer was washed with water (50 mL) and dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (eluted with 10% ethyl acetate-toluene) to give 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (0.210 g, yield 15%) as light brown powders.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[C:12](=O)(O)[O-].[Na+].C[Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])O
Reactant: O=C(O)C1CNCCN1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CNCCN1
Reaction time: 4 h
Yield: 28119.6 %

Procedure:
piperazine-2-carboxylic acid dihydrochloride (750 mg, 3.7 mmol) was suspended in MeOH (15 mL) and sodium bicarbonate (620 mg, 7.4 mmol) was added and stirred for 4 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and cooled to 0° C. (Trimethylsilyl)diazomethane (15 mL, 2M in hexane) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, eluent 5-6% MeOH in CHCl3) to get methyl piperazine-2-carboxylate (150 g, yield 28%). 1H NMR (300 MHz, CDCl3) δ 3.74 (s, 3H), 3.51-3.47 (dd, J=8.0 Hz, 3.4 Hz, 1H), 3.24-3.19 (dd, J=12.1 Hz, 3.3 Hz, 1H), 3.04-2.99 (m, 1H), 2.96-2.86 (m, 3H), 2.83-2.77 (m, 1H)
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([O:37]C)=[O:36])[C:28]=4[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CO.[ClH:41]>C1COCC1>[ClH:41].[ClH:41].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=4[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cccc2sc(-c3ccnc(NCCCN4CCN(C(=O)OC(C)(C)C)CC4)n3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCNc2nccc(-c3cc4c(C(=O)O)cccc4s3)n2)CC1
Reaction time: 0.03 h

Procedure:
Aqueous LiOH solution (2.5 N, 2.0 mL) is added to a stirred solution of 4-{3-[4-(4-methoxycarbonyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.49 mmol) in THF (7 mL)/MeOH (4 mL), the resultant mixture is stirred at 40° C. for 4 hours. At 40° C., 5 N HCl (2.1 mL) is added in one shot to the reaction mixture. Within 2 minutes the mixture becomes a suspension. After filtration and drying, the title compound is obtained as a yellow solid (950 mg, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[S:18]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:24](=[O:25])[CH2:23][C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccsc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccsc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 20.3 %

Procedure:
Example 32 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and thien-3-ylacetic acid (0.028 g) to give the title compound (0.016 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][C@@H:13]([CH2:22][CH2:23][CH3:24])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([C@@H:13]([CH2:22][CH2:23][CH3:24])[CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC[C@@H](CN1CCC(O)CC1)NC
Solvent: ClCCl
Product: CCC[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.4 %

Procedure:
4-Chlorobenzoyl chloride (1.683 mL, 13.12 mmol) was added to a solution of (S)-1-(2-(methylamino)pentyl)piperidin-4-ol (Compound J6) (2.629 g, 13.12 mmol) and TEA (3.66 mL, 26.25 mmol) in DCM (25 mL) at 0° C. A white slurry was formed. The reaction was stirred for 45 min at 0° C. and was then allowed to attain rt. The reaction was stirred overnight and was then quenched by addition of NaHCO3 (8% aq., 25 mL). The aqueous phase was extracted with DCM. The organic phases were pooled, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was chromatographed to give the title product (3.13 g, 70.3%) as a colourless glue. 1H NMR (400 MHz, CD3OD) 0.87, 0.99, 1.17-1.33, 1.35-1.63, 1.71-1.90, 1.95-2.15, 2.15-2.36, 2.43-2.51, 2.52-2.68, 2.71-2.80, 2.89, 2.99-3.08, 3.51-3.64, 3.68-3.77, 4.87-4.97, 7.08-7.24, 7.37-7.51. HRMS (M+H)+: calculated 339.1839. found 339.1827.