Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[C:4](=[O:15])[C:3]=1[C:16](OCC)=[O:17].C(N(C(C)C)C(C)C)C.Cl.[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1.CCOC(C)=O>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:13])([CH3:14])[C:4](=[O:15])[C:3]([C:16]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:17])=[C:2]2[OH:1]
Reactant: CCOC(=O)C1=C(O)c2cc(C)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Ethyl 4-hydroxy-1,1,6-trimethyl-2-oxo-naphthalene-3-carboxylate (750 mg, 2734 μmol) was dissolved in 1,4-dioxane (2734 μL) and N-ethyl-N-isopropylpropan-2-amine (1429 μL, 8202 μmol). tert-Butyl 2-aminoacetate hydrochloride (687 mg, 4101 μmol) was added, and the reaction was stirred at 80° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (266 mg) as a white solid after flash chromatography. MS (m/z)=304 (M+H-tBu)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:47]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:64])[CH2:55][C:56](=[O:63])[N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:49][CH:48]=1>CN(C=O)C.O>[C:47]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:64])[CH2:55][C:56]([N:57]2[CH2:58][CH2:59][N:60]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:21]=3[Cl:20])[CH2:61][CH2:62]2)=[O:63])=[CH:51][CH:52]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-chloro-5-trifluoromethylbenzoic acid (48 mg, 0.21 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 53 mg (48%) of N-biphenyl-4-yl-3-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 530.14 (M+1)+ 98.5%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 8H), 7.43 (t, 2H), 7.33 (t, 1H), 4.0 (m, 2H), 3.7 (m, 4H), 3.5 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C.O>O1CCCC1>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]2[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.21 g, 0.5 mmol) in tetrahydrofuran (10 ml) were added acetyl chloride (0.04 ml, 0.6 mmol) and triethylamine (0.08 ml, 0.6 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(acetylamino)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.19 g, yield 83%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([Cl:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[OH2:17]>>[Cl:9][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: O
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 4-amino-2-chlorophenol (2.0 g; 13.9 mmol) and acetic anhydride (1.77 g, 17.3 mmol) in water (40 ml) was stirred vigorously for 5 minutes. The reaction mixture was then heated with stirring to 60° C. for 30 minutes, and was then allowed to cool. A pink solid was formed and the precipitate was collected by filtration, washed twice with water, and dried to give 1.8 g (70%) of the subtitle compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[C:38]5[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=5)[N:32]=[C:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:30]=4)[CH2:24]3)[C:20](=[O:48])[NH:19][C:18]3([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:54])=[O:53])=[O:50])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1>ClCCl.FC(F)(F)C(O)=O>[CH3:40][O:39][C:35]1[C:34]([CH3:41])=[C:33]2[C:38]([C:29]([O:28][CH:23]3[CH2:22][CH:21]4[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]5[C:18]([C:49]([NH:51][S:52]([CH:55]6[CH2:57][CH2:56]6)(=[O:54])=[O:53])=[O:50])([NH:19][C:20]4=[O:48])[CH2:17]5)[CH2:24]3)=[N:30][C:31]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:32]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccccc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nc(-c3ccccc3)nc2c1C
Yield: 64 %

Procedure:
Compound 173 (150 mg, 0.18 mmol) was stirred for 30 min in a mixture of dichloromethane-trifluoroacetic acid; 2:1. Evaporation and purification by column chromatography (5% methanol in ether) gave the title compound (81 mg, 62%). MS (M−H)+ 703
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14].C(=O)([O-])O.[Na+]>O.CC(C)=O>[CH2:16]([O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (16.4 g) in water (100 ml), isobutyl chloroformate (13.7 g) and acetone (10 ml) are added, and the resulting mixture is stirred at a temperature lower than 20°C. After adjusting pH to 7 with the addition of an aqueous solution of sodium hydrogencarbonate, stirring is continued for 3 hours. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with water, dried and concentrated. The residue is crystallized with the addition of petroleum ether and collected by filtration. Recrystallization from petroleum ether containing a small amount of ethyl acetate affords ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (14.1 g) as scales. M.P. 60 to 62°C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1.[H][H].[CH3:18]I>C1(C)C=CC=CC=1>[CH3:18][O:15][CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: OCCCCSc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCCCSc1ccc(Cl)cc1
Yield: 44 %

Procedure:
To a mixture of 7.2 g of a 57% oil dispersion of sodium hydride and 125 ml of toluene was added a solution of 36.5 g of 4-(p-chlorophenylthio)butanol in 125 ml of toluene. The mixture was stirred and heated under reflux until the evolution of hydrogen ceased. It was then cooled and 25.6 g of methyl iodide was added with stirring. The resulting mixture was heated under reflux for 2 hours, cooled, washed with three portions of water saturated with sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was distilled at reduced pressure to give 17.1 g of product, b.p. 92°-100° at 0.05 mm, ND25 1.5524.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Yield: 44.8 %

Procedure:
As described for Example 9, 0.111 g (1.1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine in 8 ml of dichloromethane is reacted with 0.230 g of (1.1 mmol) of 2,4-dichlorobenzoyl chloride. The product is recrystallized from hexane-dichloromethane to give 0.24 g of crystals, m.p. 212°-215° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N+:33]=2[O-])[C:15](=[O:31])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@@H](NC2C(C)=CC=C[N+]=2[O-])C1)=O)(C)(C)C.B(O)(O)B(O)O.O>C(#N)C>[CH3:38][C:37]1[C:32]([N:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[C:15](=[O:31])[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[CH:20][CH:21]=2)=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc[n+]([O-])c1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc[n+]([O-])c1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: OB(O)B(O)O
Solvent: CC#N
Solvent: O
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from Step 1 (R)-2-(1-(tert-butoxycarbonyl)-piperidin-3-ylamino)-3-methylpyridine 1-oxide (760 mg, 1.44 mmol) in acetonitrile (15 mL) was added tetrahydroxydiboron (387 mg, 4.32 mmol) at room temperature. The reaction was stirred at 60° C. overnight. The resulting mixture was treated with water then extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (760 mg) as a white gum. This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:31])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:31])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[CH3:32])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(/C=C/[C@@H]1CCCN1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of N-(3-Chloro-4-fluorophenyl)-7-{(2E)-3-[(25)-pyrrolidin-2-yl]prop-2-enoyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 13 (60 mg, 0.13 mmol) in DMF (1 mL) was added potassium carbonate (27 mg, 0.20 mmol) and iodomethane (20 mg, 0.14 mmol), and the mixture was stirred overnight at rt. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM/MeOH 10:1) to yield 8 mg (13%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br>>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH:29]3[O:31][CH2:30]3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: BrCC1CO1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(CC3CO3)CC2)c2ccccc2)cc1

Procedure:
Method as described for Example 4, using compound 6 and epibromohydrin (102 mg, 84%):
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13]C(=O)C(C)(C)C)=O.[H-].[Li+].[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>CS(C)=O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[NH:13][CH:24]([C:23]([F:31])([F:32])[F:22])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:1]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(C(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 30 °C
Yield: 1.1 %

Procedure:
To a suspension of N-(2-formyl-4-(trifluoro-methylphenyl)-2,2-dimethyl propanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to 30° C. for 4 hours. After the addition of ethyl acetate (50 mL), the reaction was washed with water (2×30 mL), saturated ammonium chloride solution (2×30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, eluant: ethyl acetate-hexanes, 1:9) to yield, upon concentration of the appropriate fractions, ethyl 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (65 mg, 5%): mp 138–139° C. 1H NMR (CDCl3/300 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H,), 5.14 (m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMS m/z 338.0592 (M−H Calc'd 338.0616). Anal. Calc'd for C13H11F3NO2: C, 49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:17][CH3:16])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 35.1 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the solid which formed was collected by filtration (6.0 g). Recrystallization from benzene yielded 2.0 g (35.1%) of tan crystals, m.p. 134°-135° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[CH:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, white solid (6.2 mg, 17%), MS (ISP) m/z=457.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 3,3,3-trifluoro-2-hydroxypropanoic acid
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:18])=[O:17])[N:9]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]CC)=[O:25])[C:8]=23)=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:18])=[O:17])[N:9]3[CH2:19][CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:8]=23)=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)c1cccc2c1c(Cc1ccc(Cl)cc1)c1n2CCCC1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of the ester of Step 13 (70 mg) in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 h and AcOH was added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc/MeOH to give 35 mg of the desired acid as a white solid.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].I[C:9]1[C:14]2[CH:15]=[CH:16][O:17][C:13]=2[C:12]([NH2:18])=[CH:11][CH:10]=1.[C:19](OCC)(=[O:21])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:19][O:21][CH2:2][C:1]#[C:3][C:9]1[C:14]2[CH:15]=[CH:16][O:17][C:13]=2[C:12]([NH2:18])=[CH:11][CH:10]=1
Reactant: CC(C)NC(C)C
Reactant: Nc1ccc(I)c2ccoc12
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: COCC#Cc1ccc(N)c2occc12
Temperature: 25 °C

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (144 mg), copper iodide (58 mg) and diisopropylamine (208 mg) were added to a stirred solution of (4-Iodo-7-amino-benzfuran) (266 mg) and methyl propargyll ether (144 mg) in ethyl acetate (5 mls) at −20° C. The reaction was allowed to warm to ambient temperature over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organics were washed with saturated NaHCO3, water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using 100% dichloromethane as eluent. [4-(3-methoxyprop-1-ynyl)benzofuran-7-yl]amine was thus obtained as a yellow/brown gum (70 mg); NMR Spectrum: (DMSOd6) 3.34 (s, 3H), 4.34 (s, 2H), 5.74 (s, 2H), 6.50 (d, 1H), 6.80 (s, 1H), 7.05 (d, 1H), 7.96, s, 1H); Mass Spectrum: M+H+ mass ion not observed.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[N:13]2[C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([NH2:24])[C:15]=3[N:25]=[C:12]2[CH2:11][N:10]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:9]1.Cl>FC(F)(F)C(O)=O.C(O)C.[Pt]=O>[OH2:27].[ClH:2].[ClH:2].[NH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[N:13]2[C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([NH2:24])[C:15]=3[N:25]=[C:12]2[CH2:11][N:10]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:9]1
Reactant: CS(=O)(=O)N1Cc2nc3c(N)nc4ccccc4c3n2[C@@H](CCCN)C1
Agent: O=[Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1Cc2nc3c(N)nc4c(c3n2[C@@H](CCCN)C1)CCCC4
Reaction time: 48 h
Yield: 121.7 %

Procedure:
(11S)-11-(3-Aminopropyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride hydrate (1.30 g, 2.80 mmol) was dissolved in 10 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (635 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 2 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with ethanol and the combined filtrates were concentrated under reduced pressure. The resulting residue was concentrated with 2 N HCl in ethanol three times to give white solid. The white solid was treated with hot 2 N HCl in ethanol and the solution was allowed to cool, leaving a white solid. The solid was isolated by filtration and rinsed with ethanol and dried under vacuum at 80° C. to give (11S)-11-(3-aminopropyl)-9-(methylsulfonyl)-1,2,3,4,8,9,10,11-octahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride hydrate (800 mg) as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:35](OCC)(OCC)(OCC)[CH3:36]>>[CH:32]1([CH2:31][O:30][C:3]2[C:2]3[N:1]=[C:35]([CH3:36])[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:9]2[C:10]3[CH:19]=[CH:18][NH:17][C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4OCC4CC4)cn(C)c(=O)c32)cc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nc2c(OCC3CC3)c(-c3cn(C)c(=O)c4[nH]ccc34)ccc2[nH]1

Procedure:
This compound was synthesized according to the procedure of Example 2 using 4-[3,4-diamino-2-(cyclopropylmethoxy)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting material and triethyl orthoacetate instead of ethyl orthoformate. 1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.99 (s, 0.3H), 11.93 (s, 0.7H), 7.33-7.19 (m, 1.2H), 7.18-7.00 (m, 2.8H), 6.17-6.10 (m, 0.3H), 6.10-6.02 (m, 0.7H), 4.37 (d, J=6.8 Hz, 2H), 3.62-3.51 (m, 3H), 1.09-0.89 (m, 1H), 0.41-0.25 (m, 2H), 0.17-0.06 (m, 1.4H), −0.01-−0.12 (m, 0.6H); LCMS calculated for C20H21N4O2 (M+H)+: m/z=349.2. found: 349.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[ClH:1].[O:9]1[C:10]2[CH:2]=[CH:3][CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])[C:6]=2[CH2:7][CH2:8]1
Reactant: N#C/C=C/c1ccc(Cl)c2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cl
Product: NCCCc1cccc2c1CCO2
Reaction time: 72 h

Procedure:
A solution of the (E)-3-(7-chloro-benzofuran-4-yl)-acrylonitrile (intermediate 3) (1.0 g) in acetic acid (30 ml) containing 10% palladium on charcoal (50 mg; 50% wet paste) and 5% platinium on charcoal (50 mg) was hydrogenated at 100 psi and 50° for 3 days. The solution was filtered through hyflo and evaporated to dryness and the residue recrystallised from isopropanol to give the title compound as white plates (583 mg).