Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:39][S-:40].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:29][N:26]1[CH2:25][CH2:24][CH:23]([O:22][CH:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([S:40][CH3:39])[C:15]=3[CH2:14][CH2:13][N:12]3[C:8]2=[N:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11]3)[CH2:28][CH2:27]1
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Reactant: C[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1cccc2c1CCn1cc(-c3ccccc3)nc1C2OC1CCN(C)CC1
Temperature: 95 °C

Procedure:
To a solution of compound 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (150 mg) in toluene (2 mL) in a screw-capped vial under argon are added diisopropylethylamine (0.2 mL), sodium thiomethoxide (29 mg), bis(dibenzilideneacetone)palladium(0) (50 mg) and Xantphos (50 mg). The reaction mixture is heated at 95° C. for 19 hours. The mixture is then diluted with water and extracted with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 17% (B) to 27% (B) in 10 minutes) to afford 4-(1-methylpiperidin-4-yloxy)-8-methylsulfanyl-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 134° C.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=[CH:10][N:9]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].C1COCC1>[N:9]1[C:8]2[NH:18][CH2:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCCCOc1cccnc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: c1cnc2c(c1)OCCCN2
Temperature: 60 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
Potassium tert-butoxide (18 mL, 18 mmol) was added to a THF (120 mL) solution of 3-(2-bromo-pyridin-3-yloxy)-propylamine (2.75 g, 11.9 mmol). The solution was purged with an Ar stream for 10 min, bis(dibenzylideneacetone)palladium (342 mg, 0.6 mmol) and tri-tert-butylphosphine (2.1 mL, 0.7 mmol, 10% in hexane) were added and the mixture was stirred at 60° C. for 5 h. The solvent was evaporated, the residue was dissolved in CH2Cl2. This solution was washed with water, dried and evaporated. Chromatographic purification (silica, 0-2% MeOH in CH2Cl2) afforded 0.75 g (42%) of the title compound. 1H NMR (300 MHz, DMSO-d6, 8): 7.70 (dd, J=4.8, 1.4 Hz, 1H), 7.09 (dd, J=7.7, 1.4 Hz, 1H), 6.60 (dd, J=4.8, 7.7 Hz, 1H), 6.02 (s, br, 1H), 4.06 (t, J=5.5 Hz, 2H), 3.21 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[K+].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:30]([CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: O=C(Cl)Cc1ccccc1
Agent: [H-]
Agent: [K+]
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)Cc1ccccc1

Procedure:
Starting from 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,3-dimethyl-2H-indol-2-one (Example 3), this compound was synthesised according to the method described for Example 23 using only one equivalent of potassium hydride and phenylacetyl chloride instead of isonicotinoyl chloride. If an excess of potassium hydride is used in this reaction (2 equivalents) a by-product (described in Example 28) is obtained as the major fraction.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]2[CH:16]=[C:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([C:29](OCC)=[O:30])#[C:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[C:24]([C:23]1[N:3]2[C:4]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:5]=3[C:6]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)=[N:7][CH2:8][C:2]2=[N:1][C:29](=[O:30])[CH:22]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1cc2c(cc1C)C(c1ccc(F)cc1)=NCC(N)=N2
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1-c1cc(C)c(C)cc1C(c1ccc(F)cc1)=NC2

Procedure:
In the manner given in Example 27, 2-amino-7,8-dimethyl-5-(p-fluorophenyl)-3H-1,4-benzodiazepine was heated in ethanol with diethyl acetylenedicarboxylate to give 1-carboethoxy-9,10-dimethyl-7-(p-fluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>CC(C)=O>[CH2:1]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCNCc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a solution of piperonylamine (2.5 mL, 19.8 mmol) in acetone (30 mL) was added 1,3-propane sultone (2.52 g, 20.8 mmol). The mixture stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid was collected by filtration and dried in vacuo. This allowed the isolation of compound AW, 2.56 g (45%).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH3:15][C:12]1[N:9]2[C:10]3[C:5]([C:6]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][C:8]2=[N:14][N:13]=1)=[CH:4][CH:3]=[C:2]([S:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1)[CH:11]=3
Reactant: OC1(c2cccc(S)c2)CCOCC1
Reactant: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(Sc4cccc(C5(O)CCOCC5)c4)cc3n12
Temperature: 70 °C

Procedure:
5u (100 mg, 0.26 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (5v, 65 mg, 0.31 mmol), iPr2NEt (0.1 mL, 0.52 mmol), Pd2dba3 (6 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 5 minutes. The mixture was heated to 70° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 5y.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>CC(O)C>[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Reactant: N#Cc1cccc(N)c1
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1cccc(C#N)c1
Yield: 50.3 %

Procedure:
The reaction mixture of 106.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 51.5 mg (0.44 mmol) of 3-amino-benzonitrile in 2.0 mL of 2-propanol was refluxed for 2 h and cooled down. The pale yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 40° C. overnight to give 65.7 mg (50%) of the title compound.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:4]=1[CH2:21]O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:4]=1[CH2:21][Cl:1]
Reactant: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: Cl
Solvent: Cc1ccccc1
Product: ClCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 4 h

Procedure:
Hydrogen chloride gas is introduced into a mixture of 15 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenylpyrazole and 25 ml of concentrated hydrochloric acid and heating is carried out for 4 hours at boiling point. Following this 25 ml of toluene are mixed in. The layers are separated and the aqueous phase with toluene is removed. The organic layers are reduced in bulk by evaporation in vacuo, toluene is again added and reduction in bulk is repeated. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a quantitative yield; F 96.5°-97° (from petroleum ether).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
30 ml of 50% by volume aqueous dimethylamine were added to a solution of 19.68 g of 2-[2-(4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 300 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature overnight. At the end of this time, the solvent was removed by distillation under reduced pressure, and the pale yellow oily residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 20.6 g (yield 90.4%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([NH:12][C:13]3[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])=[O:18])=[CH:15][C:14]=3[O:45][CH3:46])=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:47]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:47][N:1]1[C:9]2[C:4](=[C:5]([C:10]([NH:12][C:13]3[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])=[O:18])=[CH:15][C:14]=3[O:45][CH3:46])=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 4-[(indol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (160 mg) in N,N-dimethylformamide (3.0 ml) was added portionwise potassium tert-butoxide (37.3 mg) at 0° C. and the mixture was stirred at 0° C. for 1 hour. Methyl iodide (47.2 mg) was added to the mixture and the solution was stirred at 0° C. for 1 hour. The reaction was quenched with water and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; 2% methanol in chloroform) to give 4-[(1-methylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (65 mg) as a white syrup.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][C@H:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][O:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 120 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (238.2 mg, 0.8157 mmol) and tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge, 203.9 mg, 0.7600 mmol) was added EtOH (3.0 mL), followed by DIPEA (539.5 mg, 4.174 mmol). The mixture was stirred at 120° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (227.1 mg, 69%). LCMS calc. for C18H24F3N4O5 (M+H)+: m/z=433.2. found 433.2.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:8]=3[NH:9]2)=[CH:5][CH:4]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][C:37]=1[S:45](=[O:48])(=[O:47])[NH2:46]>O1CCCC1.C(Cl)Cl.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([C:3]2[CH:11]=[C:10]3[C:6]([C:7]4[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:8]=4[NH:9]3)=[CH:5][CH:4]=2)=[O:41])=[CH:38][C:37]=1[S:45]([NH2:46])(=[O:48])=[O:47]
Reactant: C[Sn](C)(C)c1ccc2c3c([nH]c2c1)C(=O)NCC3
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3c4c([nH]c3c2)C(=O)NCC4)ccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.8 %

Procedure:
7-Trimethylstannanyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one (0.66 g, 1.88 mmol) and 1,8-bis(dimethylamino) naphthalene (0.210 g, 0.94 mmol) in tetrahydrofuran (25 mL) is treated with 4-chloro-3-sulfamoyl-benzoyl chloride (0.48 g, 1.88 mmol). After a few minutes, allylpalladium chloride dimer (0.057 g, 0.15 mmol) is added. The reaction mixture is stirred for 5 min at room temperature and then refluxed for 2 h. After cooling to room temperature the reaction mixture is diluted with methylene chloride and washed with a saturated sodium chloride solution then concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (ethanol-ethyl acetate) provides 0.014 g (1.8%) of the title compound as a pale yellow solid. 1H NMR (DMSO): δ 12.00 (s, 1H), 8.30 (s, 1H), 8.00 (m, 1H), 7.90 (m, 6H), 7.60 (m, 1H), 3.40 (m, 2H), 3.00 (m, 2H). MS (m/z): 402.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13]1([CH:23]=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Yield: 78 %

Procedure:
2-Amino-5-chlorobenzoic acid methyl ester (1.85 g, 10.0 mmol) was treated with 1-napthaldehyde (1.56 g, 10.0 mmol) and sodium triacetoxyborohydride (4.23 g, 20.0 mmol) in 1,2-dichloroethane as described in general procedure E to give 5-chloro-2-[(napthalen-1yl-methyl)-amino]-benzoic acid methyl ester (2.54 g, 78%). This methyl ester (2.0 g, 6.13 mmol) was treated with LiOH (2 eq, 1N aqueous solution) according to the general procedure C gave 5-chloro-2-[(napthalen-1yl-methyl)-amino]-benzoic acid (1.64 g, 86.0%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[N:23]1)[C@H:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@@H](C(=O)OC(C)(C)C)c1ccccc1)N=C2c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@@H](C(=O)O)c1ccccc1)N=C2c1cccc(F)c1
Reaction time: 3 h

Procedure:
A solution of (2R,3R)-tert-butyl 6,6,6-trifluoro-3-((5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamoyl)-2-phenylhexanoate (168 mg, 0.275 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL) and allowed to stand at room temperature for 3 hours. The mixture was diluted with DCM and evaporated to dryness. The residue was dissolved in DCM and washed with water and concentrated to give (2R,3R)-6,6,6-trifluoro-3-((5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl) carbamoyl)-2-phenylhexanoic acid as a light-yellow off-white solid. MS(ES):m/z=556.1 [M+H+].
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:7]=[N:6][CH:5]=[N:4]1>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([OH:10])[CH:8]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1Cl)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Yield: 80 %

Procedure:
Sodium borohydride (0.42 g) was added in small portions to 2-(1,2,4-triazol-1-yl)-2-(2',4'-dichlorobenzyl)-4'-chloroacetophenone (4.2 g) in methanol (40 ml). When the effervescence ceased, the mixture was refluxed for 1 hour, cooled to room temperature and the methanol removed at the water pump. The residue was acidified with 1N-hydrochloric acid to give a solid which was filtered and washed. Recrystallisation from ethanol/water gave white crystals of the title compound (yield 80%).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[NH:22][C:23](=O)[CH:24]=[CH:25][CH3:26])[CH2:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5].CC(N(C)C)=O.[H-].[Na+].Cl>O>[OH:1][C:2]1[C:12]2[C:13](=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:16][CH:17]=2)[N:22]=[C:23]([CH:24]=[CH:25][CH3:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5]
Reactant: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC=Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 120 °C
Yield: 100 %

Procedure:
17.5g of the product of Step A were added to a solution of 175ml of dimethylacetamide and a mixture of 2.11 g of sodium hydride as a 50% dispersion in oil and 100 ml of dimethylacetamide and the mixture was heated at 120° C. for 30 minutes and was then cooled. The mixture was poured into a mixture of water and 2N hydrochloric acid and the mixture was vacuum filtered. The product was washed with water and dried under pressure at 80° C. to obtain 16.7g of 4-hydroxy-2-(1-propenyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 265° C.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:30][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.820 g, 8.70 mmol), 3,4-dimethoxy phenol (1.347 g, 8.74 mmol) and cuprous oxide (647 mg, 4.52 mmol) in 2,4,6-collidine (20 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 106.85° C. (DSC).
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:13]C(OCC[Si](C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[C:1]([O:5][C:6]([C@:8]1([NH2:13])[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@]1(NC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@@]1(N)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the product of Step 3 (3 g, 9 mmol) was added a 1.0 M TBAF solution in THF (9.3 mL, 9.3 mmol) and the mixture heated to reflux for 1.5 h, cooled to rt and then diluted with 500 mL of EtOAc. The solution was successively washed with water (2×100 mL), brine (2×100 mL), dried (MgSO4), concentrated in vacuo to provide the title intermediate
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]2[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]2)[CH2:24][CH2:23]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:33]3[CH:32]=[N:31][N:30]([CH2:29][CH2:28][N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH:34]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cnn(CCN5CCOCC5)c4)nc32)c1Cl

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 1-(2-Morpholinoethyl)-1H-pyrazole-4-boronic acid, pinacol ester using Suzuki coupling conditions as described in Example 1.