Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Br:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>O>[Br:26][CH:27]([CH3:31])[C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:13])=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])=[O:29]
Reactant: CC(Br)C(=O)Cl
Reactant: Cc1ccc(C)c(NCC=O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)c(N(CC=O)C(=O)C(C)Br)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2,3,6-trimethylanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-bromopropionyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-bromopropionyl-2,3,6-trimethylanilino)acetaldehyde.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][CH:50]([C:52]1[CH:57]=[C:56]([CH:58]([CH3:60])[CH3:59])[CH:55]=[C:54]([CH:61]([CH3:63])[CH3:62])[C:53]=1[CH2:64][CH2:65][C:66](O)=[O:67])[CH3:51]>>[O:67]=[C:66]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH2:65][CH2:64][C:53]1[C:52]([CH:50]([CH3:49])[CH3:51])=[CH:57][C:56]([CH:58]([CH3:60])[CH3:59])=[CH:55][C:54]=1[CH:61]([CH3:63])[CH3:62]
Reactant: CC(C)c1cc(C(C)C)c(CCC(=O)O)c(C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1cc(C(C)C)c(CCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3-[2,4,6-tris(1-methylethyl)phenyl]propionic acid, mp 138°-141° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].C(N(CC)CC)C.[C:15](=[S:17])=[S:16].[CH3:18]I>C(O)C>[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:15](=[S:17])[S:16][CH3:18])(=[O:7])[CH3:6]
Reactant: CC(=O)NCCN
Reactant: CI
Reactant: S=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSC(=S)NCCNC(C)=O
Temperature: 25 °C

Procedure:
To a solution of 20.4 g (0.20 mol) of N-(2-aminoethyl)acetamide in 200 ml of 95% ethanol was added 27.9 ml (0.20 mol) of triethylamine and 12.0 ml (0.20 mol) of carbon disulfide. The exothermic reaction reached reflux and then cooled to ambient temperature over a 1.5 hour period. Methyl iodide (28.4 g, 0.20 mol) was added which again produced an exothermic reaction. After 1.75 hours the reaction mixture was evaporated to dryness and the solid residue was dissolved in 200 ml of water. The aqueous solution was extracted twice with 250 ml portions of ethyl acetate. The extracts were combined, shaken with sodium thiosulfate, dried (MgSO4) and evaporated to dryness to give methyl 2-acetamidoethyldithiocarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: Oc1ccnc2cc(Br)cnc12
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Temperature: 90 °C

Procedure:
A mixture of 7-bromo[1,5]naphthyridin-4-ol (33 g, 0.147 mol) and fuming nitric acid (350 mL) was heated at reflux (90° C. internal reaction vessel temperature) for 3 hours. The reaction mixture was cooled to 50° C., poured over 1 L of ice and neutralized to pH 2-3 with a solution of 50% aqueous NaOH. The resulting precipitate was filtered, washed with water, and dried over vacuum for 3 days to yield 25.1 g of 7-bromo-3-nitro[1,5]naphthyridin-4-ol as a yellow crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:57])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:56])[C@@H:17]([NH:42][S:43]([C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)(=[O:45])=[O:44])[CH2:18][CH2:19][CH2:20][NH:21]/[C:22](/[NH2:41])=[N:23]/[S:24]([C:27]2[C:28]([CH3:40])=[C:29]([CH3:39])[C:30]3[O:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]=3[C:37]=2[CH3:38])(=[O:26])=[O:25])[CH2:12][CH2:11]1)=[O:9].[Li+].[OH-]>C1COCC1.O>[NH2:41]/[C:22](/[NH:21][CH2:20][CH2:19][CH2:18][C@H:17]([NH:42][S:43]([C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)(=[O:45])=[O:44])[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:57])=[O:2])[CH2:15][CH2:14]1)=[O:56])=[N:23]\[S:24]([C:27]1[C:28]([CH3:40])=[C:29]([CH3:39])[C:30]2[O:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]=2[C:37]=1[CH3:38])(=[O:25])=[O:26]
Reactant: COC(=O)CCCCC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)CCCCC(=O)O)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of compound O (2.1 g, 2.08 mmol) in THF (5 mL), H2O (5 mL) was added 2 M aq LiOH (6 mL). The reaction mixture was stirred at room temperature for 2 h. Solvents were removed in vacuo, then the residue was dissolved in water (˜50 mL), acidified with saturated aqueous NaHSO4 (˜100 ml) and extracted with EtOAc (2×100 ml). The organic layer was dried over Na2SO4 and removal of the solvent gave compound P (1.72 g, 2.08 mmol). LC-MS [M+H] 813.5 (C39H52N6O9S2+H, calc: 813.3). Compound P was used without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:7]1=[NH:19].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:19])=[N:6][CH:15]=[CH:14]2)([O-:18])=[O:17]
Reactant: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6-nitroisoquinolin-1(2H)-imine (11.9 g, 35 mmol) in anisole (24 mL) was added TFA (24 mL). The reaction mixture was stirred at 90° C. for 6 h and the solvent was removed under reduced pressure. The residue was suspended in MeOH (30 mL) and then treated with NaOH (1.0 N, 38 mL). The mixture was stirred at rt for 10 min and pH was checked to be 9-10. The precipitate was collected by filtration and washed with water to afford 6-nitroisoquinolin-1-amine (6.0 g). 1H NMR (400 MHz, DMSO-d6) ppm 7.20 (d, J=5.72 1H) 7.36 (s, 2H) 7.95 (d, J=5.72 Hz, 1H) 8.15 (dd, J=9.24, 2.64 Hz, 1H) 8.43 (d, J=9.24 Hz, 1H) 8.67 (d, J=2.64 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:24]CC2C=CC(OC)=CC=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:22])([F:23])[F:21])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(c2ccc(OCc3ccccc3)c(Cl)c2)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1ccc(OCc2ccccc2)c(Cl)c1)(C(F)(F)F)C(F)(F)F
Yield: 9.5 %

Procedure:
82 mg (0.2 mmol) of crude 1-benzyloxy-2-chloro-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-benzene were treated with 3 mL of a mixture of dichloromethane/trifluoroacetic acid (1:3) at room temperature for 1 h. The solvent was evaporated and the residue was redissolved in a mixture of diethyl ether and a solution of Na2CO3. The inorganic phase was extracted with diethyl ether and the combined organic phases were washed with brine and dried (Na2SO4). After filtration and evaporation of the solvent, the crude product was purified by column chromatography to give 7.3 mg (12%) of 2-(4-benzyloxy-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol as a yellow gum, MS: 383 (M−H, 1Cl)−.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (126 mg) and triethylamine (0.119 mL) in anhydrous dichloromethane (20 mL) was added acetyl chloride (33.5 mg). After stirring for 2 hours at ambient temperature, the mixture was washed with an aqueous saturated sodium bicarbonate solution, water and brine. The resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4-acetamidobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as yellow powders (135 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:20]1[CH:21]=[C:22]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH3:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]([N:29]1[CH2:28][CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH:17]([CH3:19])[CH3:18])[CH:21]=2)[CH2:31][CH2:30]1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cccc(C2=CCNCC2)c1
Reactant: CC(C)(C)OC(=O)C1CCCNC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C2=CCN(C(=O)C3NCCCC3C(=O)OC(C)(C)C)CC2)c1

Procedure:
To a 0° C. solution of piperidine-2,3-dicarboxylic acid 3-tert-butyl ester (100 mg) in DMF (0.6 mL) was added sequentially, 4-(3-isopropyl-phenyl)-1,2,3,6-tetrahydro-pyridine (97 mg), PyBOP (232 mg), and diisopropylethylamine (0.152 mL). The resultant mixture was stirred at rt overnight. The reaction solution was diluted with EtOAc and washed with saturated NaHCO3 solution (×3), water, and brine. The organic layers were dried over MgSO4, filtered, and concentrated to dry under reduced pressure. The residue was used in next step without further purifications. MS (ESI): 413.2 (M+H+)
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH:4]=1
Reactant: OCCCCc1cc2ccccc2o1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzo[b]furanbutanol (2 g), 1,6-dibromohexane (7.7 ml), TAB (500 mg) in 50% w/v sodium hydroxide solution (100 ml) was stirred at room temperature overnight. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil. Purification by FCC eluting with hexane:ethyl acetate, 100:0→95:5) gave the title compound as a clear oil (2.1 g), t.l.c. (ether) Rf 0.83.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@H:12]3[O:13]C(=O)C3C=CC=CC=3)[C:6]=2[C:5]([F:44])=[CH:4][N:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]3[OH:13])[C:6]=2[C:5]([F:44])=[CH:4][N:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)ncc(F)c32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncc(F)c32)[C@H](O)[C@@H]1O

Procedure:
To a suspension of 4-chloro-7-fluoro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)imidazo[4,5-c]pyridine (45, 0.73 g, 1.2 mmol) in dry methanol (50 mL) was added sodium methoxide until pH 10 was reached. The reaction mixture was refluxed for 30 min, cooled, neutralized with glacial acetic acid, and evaporated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2/EtOH, 10:1, v/v) to give 0.29 g (78%) as a white solid: mp 187-189° C.; 1H NMR (DMSO-d6) δ3.58 (m, 1 H, 5′-HA), 3.70 (m, 1 H, 5′-HB), 3.99 (m, 1 H, 4′-H), 4.13 (m, 1 H, 3′-H), 4.36 (m, 1 H, 2′-H), 5.16 (t, 1 H, 5′-OH, D2O exchangeable), 5.28 (d, 1 H, OH, D2O exchangeable), 5.63 (d, 1 H, OH, D2O exchangeable), 6.03 (d, 1 H, 1′-H, J=5.1 Hz), 8.27 (d, 1 H, 6-H, J=2.1 Hz), 8.88 (s, 1 H, 2-H). Analysis calculated for C11H11ClFN3O4: C, 43.50; H, 3.65; N, 13.84. Found: C, 43.43; H, 3.26; N, 13.81.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.Cl.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:21][CH2:20]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(CC)CC)C>CN(C)C=O.C(N(CC)CC)C>[C:28]1([CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:20][CH2:21]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.2 g), 4-amino-1-(3-phenylpropan-1-yl)piperidine dihydrochloride (1.5 g), triethylamine (1.5 ml), 1-hydroxy-1H-benzotriazole monohydrate (0.8 g), and 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at 50° C. for 2 hours. After spontaneous cooling, this reaction mixture was extracted with ethyl acetate/tetrahydrofuran (4/1; 90 ml). The organic layer was washed with 1N-aqueous solution of sodium hydroxide (10 ml) and water (30 ml) and concentrated. The resulting crystal crop was rinsed with diisopropyl ether (20 ml) and dried to provide the title compound (2.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][NH:15]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][N:15]4[C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CC4CC3CN4)ccnc2c1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CC2CC1CN2c1ccnc2cc(Cl)ccc12

Procedure:
7-Chloro-4-(2,5-diazanorborn-2-yl)quinoline (110 mg, 0.42 mmol) and 4-fluorophenyl isocyanate (67 μL, 0.59 mmol) are reacted according to method C yielding the title product as a colorless solid after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:10]([F:16])=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH2:4]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:25])=[O:24])=[CH:21][CH:20]=1>O1CCOCC1>[ClH:25].[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:10]([F:16])=[C:11]([NH:15][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCO1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3)c2F)CC1
Product: Cl
Yield: 64.9 %

Procedure:
Reflux a mixture of 3-(4-dimethylamino-cyclohex-1-enyl)-2-fluoro-phenylamine (preparation 8, 0.115 g, 0.49 mmol) and 4-fluoro-benzoyl chloride (93 mg, 0.586 mmol) in dioxane (20 mL) for 2 hrs. Filter the reaction mixture through a SCX column (Bond Elut™, 10 g), wash with MeOH, elute the product with 2M NH3 in MeOH, evaporate the solvent, and further purify on a silica gel column (DCM:2M NH3 in MeOH, gradient) to give the free base of the title compound (0.125 g, 72%): MS (ES): m/z=357 (M+H)+. 1H NMR (CDCl3): δ 8.30 (m, 1H), 8.00 (m, 1H), 7.91 (m, 2H), 7.18 (m, 2H), 7.12 (m, 1H), 6.99 (m, 1H), 5.90 (m, 1H), 2.68 (m, 1H), 2.50 (m, 3H), 2.43 (s, 6H), 2.26 (m, 1H), 2.15 (m, 1H), 1.64 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:5]5[CH2:4][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:7][CH2:6]5)=[CH:14][CH:13]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: CC1(C)CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
A degassed mixture of 4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]piperidine (836 mg, 2.5 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (109 mg, 0.13 mmol) in 1N aqueous potassium fluoride solution (25 mL) and acetonitrile (25 mL) was heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (190 mg, 33%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].Cl>C(NCC)C.CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:7][C:6]=1[CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: C#C[Si](C)(C)C
Reactant: N#CCCCc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(F)c(CCCC#N)c1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-(5-Bromo-2-fluoro-phenyl)-butyronitrile (0.37 g, 1.52 mmol) in diethyl amine (6 mL) and DMF (2 mL) was added triphenylphosine (0.08 g, 0.31 mmol), trimethylsilylacetylene (0.23 ml, 1.7 mmol), CuI (0.015 g, 0.076 mmol), and dichlorbis(triphenylphospine)palladium (0.054 g, 0.076 mmol). The reaction was heated at 85° C. for 12 h and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and then poured into 0.1 N HCl (20 mL) and extracted with ethyl acetate (3×50 ml). The extracts were washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave the title compound as a clear oil (0.28 g, 70%), identified by NMR and mass spectral analyses; MS (ES+): 260 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([NH:19][C@:20]12[CH2:28][N:27]([C@@H](C3C=CC=CC=3)C)[CH2:26][C@@H:25]1[CH2:24][CH:23]=[CH:22][CH2:21]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH2:5]([O:4][C:2]([N:27]1[CH2:28][C@@:20]2([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[C@@H:25]([CH2:24][CH:23]=[CH:22][CH2:21]2)[CH2:26]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@@H]2CC=CC[C@@]2(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@]12CC=CC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.9 %

Procedure:
Benzyl chloroformate (0.600 mL, 4.20 mmol) was added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene (479 mg, 1.40 mmol) in dichloromethane (4.66 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→75:25→66:34) to give 401 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>O1CCOCC1.CCOC(C)=O>[CH2:20]([NH:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=[C:2]([NH:3][CH2:4][CH2:5][CH2:6][CH3:7])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3c2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCNc1nc(NCCCC)c2cc(-c3ccc(F)cc3)ccc2n1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 2,4-Dichloro-6-(4-fluoro-phenyl)-quinazoline (20 mg, 0.068 mmol) in 1,4-dioxane was added n-butylamine (20 mg). The solution was heated to 60° C. for 2 hours, and subsequently cooled, diluted with EtOAc and washed with brine. The organic layer was dried and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (8 mg). The product was characterized as follows: MS (m/z): 367 ([M+H]+, 100); HPLC Rt=1.69 minutes (Method A).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=2[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:17][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=[C:11]2[C:16]=1[NH:8][CH2:9][CH2:10]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1N(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])ccc2c1NCC2
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-2,3-dihydro-7-methyl-6-nitroindole (5.00 g, 17.9 mmol), as prepared above (Example 1C), in methylene chloride (75 mL) is slowly added trifluoroacetic acid (15 mL). The reaction is stirred for 1.5 hours then partitioned between 200 mL of methylene chloride and 200 mL of 1 M aqueous sodium hydroxide solution. The methylene chloride layer is collected, dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator to afford 3.1 g of 2,3-dihydro-7-methyl-6-nitroindole as an orange solid (97% yield).