Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C(O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[N:29]=[C:13]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9]
Reactant: NNc1ccc(F)cc1
Reactant: CSc1c(F)cc(C(=O)CC(=O)C(F)(F)F)cc1F
Agent: Cl
Solvent: CCO
Product: CSc1c(F)cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[3,5-difluoro-4-(methylthio)phenyl]-4,4,4-trifluoro-butane-1,3-dione (1.09 g, 3.6 mmol) dissolved in ethanol (150 mL). One drop of concentrated hydrochloric acid was added and 4-fluorophenylhydrazine hydrochloride (0.69 g, 4.0 mmol). The reaction was stirred at ambient temperature for 72 hours. Solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL) extracted with water (2×100 mL), saturated ammonium chloride (2×150 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the 5-[3,5-difluoro-4-(methylthio)-phenyl]-1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole was obtained by crystallization from ethyl acetate and hexanes (0.71 g, 50%). 1H NMR (CDCl3/300 MHz) 7.36-7.29 (m, 2H), 7.18-7.13 (m, 2H), 6.81-6.77 (m, 3H), 2.53 (s, 3H). ESHRMS m/z 389.0557 (M+H+, Calcd 389.0547). Anal. Calcd for C17H10F6N2S: C, 52.58; H, 2.34; N, 7.21. Found: C, 52.45; H, 2.34; N, 7.15.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]1([C:15]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO>[OH:5][C:4]1[CH:3]=[N:2][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred suspension of glycinamide hydrochloride (1.1 gm, 10 mmol) in 20 mL MeOH at 0° C. was added 20% NaOH (10 mL, 50 mmol). A clear solution formed and was treated slowly portionwise with benzil (2.1 gm, 10 mmol) as a solid. The yellow solution was stirred at 0° C. for 2 hours and then neutralized to approximately pH=7 with concentrated HCl. The bright yellow color disappeared and a tan precipitate formed. The material was isolated by filtration with MeOH and triturated with EtOAc to give 2-hydroxy-5,6-diphenylpyrazine (2 gm, 80%). 1H-NMR (400 MHz, CDCl3) δ8.24 (s, 1H), 7.42-7.31 (m, 4H), 7.39-7.21 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15](=S)[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2].S1CC(=O)NC1=S.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(COc1ccc(C=C2SC(=S)NC2=O)cc1)OCC
Reactant: C1CCNCC1
Agent: O=C1CSC(=S)N1
Solvent: CCO
Product: CCOC(COc1ccc(C=C2SC(N3CCCCC3)=NC2=O)cc1)OCC
Yield: 69.2 %

Procedure:
A mixture of 5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (which was obtained in Intermediate 37)(1.19 g, 5 mmol), rhodanine (0.67 g, 5 mmol) and piperidine (1.72 g, 20.2 mmol) in ethanol (50 mL) was refluxed for 2 hours. After cooling to room temperature hexanes (70 mL) were added and the solid which was formed was collected to give the title compound as a yellowish solid (1.4 g, 69%); 1H NMR (300 MHz, DMSO-d6) δ 1.14(t, J=7.1 Hz, 6 H), 1.55-1.75(m, 6 H), 3.40-3.80 (m, 6 H), 3.85-3.95(m, 2 H), 4.02(d, J=5.2 Hz, 2 H), 4.82 (t, J=5.2 Hz, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 7.57 (d, J=7.6 Hz, 2 H), 7.58(s, 1 H); MS (ES) m/z: 404.9 (MH+, 100%); HRMS Calcd. for C21H28N2O4S (M+): 404.1770. Found: 404.1780.
Reaction SMILES: N[C:2](N)=[S:3].[F:5][C:6]([F:32])([CH2:29]CI)[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>C(O)C>[F:5][C:6]([F:32])([CH2:29][CH2:2][SH:3])[C:7]([F:27])([F:28])[C:8]([F:25])([F:26])[C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: NC(N)=S
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCO
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Yield: 93.1 %

Procedure:
A mixture of thiourea (105.7 g, 1.39 moles), 2-(perfluorooctyl)ethyl iodide (531.5 g), 0.926 moles) and anhydrous ethanol (1000 mL) was heated at reflux for 6 hours. Approximately half of the alcohol was removed at reduced pressure and replaced with water. Solid sodium hydroxide (37.0 g) was added and the mixture heated under slow nitrogen purge. The volatile liquid products were collected by steam distillation using a modified Dean-Stark apparatus to yield 414 g (93.1 molar yield) of 2-(perfluorooctyl)ethyl mercaptan. After two consecutive water washes the product was suficiently pure by glc (99.3%) and used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].[CH2:17](Br)[CH2:18][CH:19]([CH3:21])[CH3:20]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH2:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCC(C)C)C(=O)OCC
Reaction time: 0.83 h

Procedure:
Sodium ethoxide was prepared from sodium metal (9.1 g) and freshly distilled absolute ethanol (250 ml). Diethyl malonate (63.5 g) was added to sodium ethoxide in ethanol, and the mixture was stirred at 60°-70° C. for 50 min. Isoamyl bromide (60 g) was added, and the reaction mixture was heated under reflux overnight. After the usual work-up, the resulting crude product was distilled under reduced pressure to give diethyl isoamylmalonate. Yield : 71.7 g (78%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (2.5 ml) was added potassium carbonate (276 mg, 2.0 mmol), and the mixture stirred at room temperature for 5 minutes in a 5 ml Personal Chemistry microwave reaction vial. To the above mixture was added tert-butyl 2-bromoacetate (390 mg, 2.0 mmol), the vial was sealed, and subjected to microwave irradiation at 120° C. for 5 min, and then at 140° C. for 40 min until most of the 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one was converted. The reaction mixture was cooled, poured into water (40 mL), extracted with ethyl acetate (2×40 mL), the combined organic phase was washed with water (40 mL), 2N sodium carbonate (10 mL), brine (40 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was dissolved in a mixture of N,N-dimethylformamide-methanol (1 and 2 mL respectively), subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate (247 mg, 0.61 mmol, 61%). LCMS mz 350.0 (M−56+H), 428.0 (M+Na), anal HPLC>98% in purity, 1H NMR (400 MHz; CDCl3) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.86 (d, J=8.6 Hz, 1H); 4.63 (s, 2H); 3.04 (t, J=7.4 Hz, 2H); 2.76 (t, J=7.4 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Br:36])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:19]([NH:28]C(=O)OC(C)(C)C)[NH:20]C(=O)OC(C)(C)C)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[ClH:37]>O1CCOCC1>[ClH:37].[NH2:28][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[Br:36])=[CH:13][CH:14]=1)=[NH:20]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Br)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Di-tert-butyl {[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (113 mg) and 4N hydrochloric acid in 1,4-dioxane solution (2 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was washed with ethyl acetate to give N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-5-bromo-1,3-thiazol-2-yl}acetamide hydrochloride (16.8 mg) as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]12[NH:22][C:18]([CH3:23])([CH2:19][CH2:20][CH2:21]1)[CH2:17][C:16](=[O:24])[CH2:15]2.N1C=CC=CC=1.[C:31]([OH:35])([CH3:34])([CH3:33])[CH3:32]>O.ClCCl>[C:31]([O:35][C:2]([N:22]1[C:18]2([CH3:23])[CH2:19][CH2:20][CH2:21][C:14]1([CH3:13])[CH2:15][C:16](=[O:24])[CH2:17]2)=[O:4])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)O
Reactant: CC12CCCC(C)(CC(=O)C1)N2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C2(C)CCCC1(C)CC(=O)C2
Reaction time: 0.5 h
Yield: 113.5 %

Procedure:
Triphosgene (1.33 g, 4.48 mmol) was added in several portions to a dichloromethane solution (50 ml) of 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (1.87 g, 11.2 mmol) and pyridine (2.3 ml, 28 mmol) under ice-cooled condition. After stirring the mixture for 30 min under ice-cooled condition, tert-butanol (2.2 ml, 22.4 mmol) was dropped, and the mixture was stirred for 8 h. The reaction was stopped by adding water to the reaction liquid. The reaction liquid was then extracted with diethyl ether, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and N-tert-butoxycarbonyl-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (0.37 g, 13%), and 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (1.1 g, 59%) were collected. The collected 1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one was subjected to the same procedure twice to give N-tert-butoxycarbonyl-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (1.36 g, 44%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[C:10]([CH3:11])=[CH:9]C(C#N)=[CH:5][N:4]=1.[OH-].[Na+].Cl.C1C[O:19]CC1.[CH2:21]([OH:23])[CH3:22]>>[CH3:1][N:2]([CH3:12])[C:3]1[C:10]([CH3:11])=[CH:9][C:22]([C:21]([OH:19])=[O:23])=[CH:5][N:4]=1
Reactant: Cc1cc(C#N)cnc1N(C)C
Reactant: CCO
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)cnc1N(C)C
Temperature: 25 °C

Procedure:
The above prepared 6-dimethylamino-5-methyl-nicotinonitrile (0.435 g, 2.70 mmol) was dissolved in 13.6 ml of THF/ethanol=1/1 and treated with 6.75 ml of 2N NaOH (5 eq.). The mixture was refluxed for 30 h; aliquots were taken from time to time and analyzed by MS to follow the disappearance of the amide intermediate. After cooling down to room temperature, the pH was adjusted with HCl to 3. Careful evaporation of the solvents and drying under HV left 1.45 g of the title acid as white solid, contaminated with NaCl, which was used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:20]I.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -75 °C
Reaction time: 3.75 h

Procedure:
In heat-dried argon purged 4-neck flask was placed a solution of pyridin-3-yl-carbamic acid tert-butyl ester (10 g, 51.5 mmol, CAS RN 56700-70-0) in THF (100 mL). After cooling down to −75° C., tert-butyllithium (1.7M solution in n-pentane, 66.6 mL, 113 mmol) was added dropwise over 15 min keeping the temperature below −60° C. The resulting light brown suspension was stirred at −75° C. for 3.75 h. A solution of iodine (28.7 g, 113 mmol) in THF (50 mL) was added dropwise over 20 min. below −63° C. The reaction mixture was stirred at −75° C. for 1.5 h and then poured on saturated aqueous NH4Cl solution (1000 mL) and EtOAc (500 mL). The layers were separated. The organic layer was washed once with 10% aqueous Na2S2O3 solution (300 mL) and once with brine (250 mL), dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 120 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (11.7 g; 71%). MS (ESI): m/z=321.1 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:49])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[N:25]=[C:26]([C:34]5[CH:35]=[C:36]([CH:46]=[CH:47][CH:48]=5)[CH2:37][NH:38]C(=O)OC(C)(C)C)[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:11]=2[O:10]1>C(Cl)Cl.[OH-].[Na+]>[NH2:38][CH2:37][C:36]1[CH:35]=[C:34]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:33]=[C:24]([NH:23][C:21]([C:18]3([C:16]4[CH:15]=[CH:14][C:12]5[O:13][C:9]([F:49])([F:8])[O:10][C:11]=5[CH:17]=4)[CH2:19][CH2:20]3)=[O:22])[N:25]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
TFA (500 μL) was added to a solution of tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzylcarbamate (115 mg, 0.200 mmol) in CH2Cl2 (1.5 mL). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with CH2Cl2 and 1N NaOH was added until the mixture become basic. The organic layer was dried over MgSO4, filtered and concentrated to yield N-(1-(3-(Aminomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (95 mg, 99%). ESI-MS m/z calc. 473.2. found 474.2 (M+1)+. Retention time 1.62 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C=CC(S([C:47]#[N:48])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([C:47]#[N:48])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A cooled (−78° C.) solution of 3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.040 g; 1.833 mmol) in anhydrous THF (50 ml) was treated dropwise with 1.6M n-BuLi in hexanes (1.6 ml; 2.560 mmol). The resulting reaction mixture was further stirred at −78° C., under nitrogen, for 3 min., and a solution of para-toluenesulfonyl cyanide (0.576 g; 3.025 mmol) in anhydrous THF (5 ml) was then added dropwise. Stirring at −78° C. was continued for 20 min. before aq. sat. NH4Cl (2 ml) was added. The resulting mixture was allowed to warm-up to rt, and water (50 ml), followed by ether (50 ml) were added. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH, 25/1) afforded 1-cyano-3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (0.233 g; 27%). LC-MS: tR=1.12 min.; [M+H]+=467.23 g/mol.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c(OC)c1
Yield: 59 %

Procedure:
Prepared from VII and 2,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 59%; orange solid; mp 255-257° C.; IR (KBr) νmax/cm−1 3401, 3081, 2948, 2837, 2233, 1600, 1565, 1540, 1525, 1505, 1443, 1417, 1329, 1278, 1231, 1203, 1159, 1132, 1088, 1030, 959, 915; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 7.98 (s, 1H), 7.83 (d, 1H, J=9.0 Hz), 6.95 (m, 1H), 6.67 (s, 1H), 6.58 (d, 1H, J=9.0 Hz), 3.78 (s, 3H), 3.73 (s, 3H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: [C:1]([CH:3]1[CH2:21][CH2:20][C:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]=2[CH2:4]1)#N.[OH2:22].C(O)C[O:25]CCO>[OH-].[K+]>[C:1]([CH:3]1[CH2:21][CH2:20][C:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]=2[CH2:4]1)([OH:25])=[O:22]
Reactant: N#CC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Reactant: OCCOCCO
Reactant: O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Temperature: 25 °C

Procedure:
1.5 g of 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine ("starting material 6") is suspended in 80 ml diethyleneglycol and 65 ml of an aqueous KOH solution (40%). The mixture is refluxed for 5 hours. After cooling the mixture to ambient temperature, it is poured into 450 ml water. The aqueous mixture is extracted with ether to remove non-acidic material. The water-phase is acidified to about pH 3, whereupon the mixture is extracted with ether. The ether extracts are washed, dried and then evaporated, yielding 0.80 g of the crude 2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. This carboxyl-compound is converted into the dimethylamide in the usual manner and then reduced with LiAlH4, yielding 0.5 g of the title product as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A mixture of 2-thiphenepropanol (5 g), 1,6-dibromohexane (25 g), 50% aqueous sodium hydroxide (25 ml) and TAB (500 mg) was stirred at room temperature overnight. Water (100 ml) was added over and the mixture was extracted with ether (2×100 ml). The organic layer was dried and concentrated to an oil which was purified by FCC eluting with hexane to give the title compound as a colourless oil (6.6 g). T.l.c. (hexane-diethyl ester 9:1) Rf 0.50.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:7]2[S:11][C:10]([CH:12]3[O:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1ccc(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Cc2ccc(C3OCCO3)s2)cc1
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
n-Butyl lithium (2.6N hexane solution, 3.3 mL, 8.47 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (1.8 g, 7.7 mmol) in tetrahydrofuran (20 mL) that had been cooled to from −75° to −70° C., and the solution was stirred for 30 minutes. 4-Fluorobenzyl bromide (1.1 mL, 8.47 mmol) was added dropwise to this reaction solution while keeping it at −70° C. or less. After completion of dropwise addition, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, silica gel was added to the organic layer, which was then evaporated in vacuo for adsorption, purification by silica gel column chromatography (hexane, then hexane:ethyl acetate=20:1, then 10:1) was carried out, and the title compound (560 mg, 2.04 mmol, 26.4%) was obtained as a brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and butyric acid chloride (butyryl chloride)