Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.NC1N=CC=CN=1>O1CCOCC1>[N:7]([C:8]1[N:9]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[CH:11]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[N:13]=1)=[C:2]=[O:3]
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: O=C(Cl)C(=O)Cl
Agent: Nc1ncccn1
Solvent: C1COCCO1
Product: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
Oxalyl chloride (42.0 mL, 481 mmol) was dissolved in anhydrous 1,4-dioxane (400 mL) under an N2 atmosphere. The resulting solution was heated to 90° C. To the hot solution was slowly added a solution of 2-amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (14.0 g, 48 mmol) in anhydrous 1,4-dioxane (50 mL). After addition of the aminopyrimidine solution was complete, heating was continued for 6 h, the heat removed, and the solution cooled to room temperature. The solution was concentrated and the residue distilled at reduced pressure to afford the product as a clear oil (12.4 g, 82% yield): by 53-54° C. (ca. 0.1 to 0.2 mm Hg): 1H NMR (CDCl3) δ 6.19 (s, 1H), 4.82-4.74 (q, 2H, J=8.2 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:20])[N:9]([CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=1)[C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH3:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(N(Cc2ccc(F)c(F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Sodium hydride (60%, 0.37 g, 9.19 mmol) was added to a solution of compound 125-B (2.2 g, 8.35 mmol) in DMF (30 mL), at 0° C. and the resultant mixture was stirred for 15 minutes. 3,4-Difluorobenzylbromide (1.18 mL, 9.2 mmol) was added, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic extract washed with water (3×), brine, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography, eluting with an ethyl acetate-heptane gradient, to afford compound 125-C as an oil (2.73 g, 84%). 1H-NMR (CDCl3): δ 1.40 (s, 9H), 1.97 (s, 3H), 4.72 (s, 2H), 6.93-7.19 (m, 3H), 7.28-7.39 (m, 2H), 7.61 (d, 1H), 7.70 (d, 1H).
Reaction SMILES: [CH2:1]([C:4](=[CH:7][CH2:8]CCC)C=O)[CH2:2]C.C(#N)C=C.C(CCC(CCC)(C=CCCC)C=O)#N.C([C:34]1([CH:41]=[CH:42][CH2:43]CC)[CH2:40][O:39][C:37](=[O:38])[CH2:36][CH2:35]1)CC>>[CH2:41]([CH:34]1[CH:40]([CH:2]=[CH:1][CH2:4][CH2:7][CH3:8])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1)[CH2:42][CH3:43]
Reactant: CCCC=CC1(CCC)CCC(=O)OC1
Reactant: CCCCC=C(C=O)CCC
Agent: CCCC=CC(C=O)(CCC)CCC#N
Solvent: C=CC#N
Product: CCCC=CC1OC(=O)CCC1CCC

Procedure:
γ-Propyl-δ-1-pentenyl-δ-valerolactone was prepared from 2-propyl-2-heptenal and acrylonitrile analogous to Example 1. Yield of 2-(beta-cyanoethyl)-2-propyl-3-heptenal 38%, boiling at 118°-120° C. at 0.6 mm.; nD20 1.4640. Yield of γ-propyl-γ1-pentenyl-δ-valerolactone from this intermediate 40%, boiling at 107°-110° C. at 0.4 mm.; nD20 1.4749.
Reaction SMILES: O[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH2:23][C:24]([CH3:26])=[CH2:25])[CH2:3][CH2:4][N:5]([C:19]([O:21]C)=[O:20])[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:26][C:24](=[CH2:25])[CH2:23][C@@:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][C:19](=[O:21])[N:5]([C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:4][CH2:3]1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of (3S)-tert-butyl 3-((3-hydroxy-5-methyl-3-phenylhex-5-enyl)(methoxycarbonyl)amino)piperidine-1-carboxylate (5.80 g, 13 mmol) in dry THF (200 mL) was added NaH (60% in mineral oil, 1.04 g, 2 equiv). The mixture was heated to reflux for 2 h. After being cooled down to rt, the mixture was diluted with ether (200 mL), quenched with satd aq NH4Cl solution (25 mL), washed with 1% HCl solution (50 mL), brine (35 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 40-70% EtOAc in hexanes gradient to afford (5)-tert-butyl 3-((R)-6-(2-methylallyI)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (2.98 g, 55% yield). LC-MS Method 1 tR=1.92 min., m/z 437 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.II.[CH3:12][C:13]([CH3:15])=O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[NH:6][CH2:15][CH:13]=[CH:12]2
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)=O
Agent: II
Product: Cc1cc(Br)cc2c1NCC=C2

Procedure:
4-Bromo-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 mmol) and acetone (150 mL) in a sealed tube at 80° C. for 24 h to provide 6-bromo-1,2-dihydro-8-methylquinoline (Compound 85 of Scheme XXII) in 9% yield as a yellow oil (0.70 g). Most of the aniline (>80%) was recovered. A mixture of the 6-bromo-1,2-dihydro-8-methylquinoline (90 mg, 0.33 mmol), 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), K2CO3 (190 mg, 1.38 mmol) in toluene (7 mL) and water (1.5 mL) was heated to 70° C. for 16 h. Standard work-up followed by chromatography afforded 23 mg (23%) of Compound 292 as a yellow oil. Data for Compound 292: IR (neat) 3412, 2966, 1602, 1530, 1348; 1H NMR (400 MHz, CDCl3) 8.38 (t, J=2.0, 1H), 8.08 (dd, J=7.8 and 2.0, 1H), 7.85 (d, J=7.8, 1H), 7.52 (t, J=7.8, 1H), 7.24 (d, J=11.7, 1H), 7.21 (d, J=1.9, 1H), 5.39 (s, 1H), 3.72 (bs, 1H), 2.18 (s, 3H), 2.07 (s, 3H), 1.34 (s, 6H); 13C NMR (100 MHz, CDCl3) 148.9, 143.7, 142.0, 132.2, 129.6, 128.8, 128.7, 128.6, 126.5, 121.3, 121.0, 120.7, 120.6, 120.3, 52.3, 31.9, 19.2, 17.3.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:6][NH3+:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CC(N(C)C)=O>[NH2:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Reaction time: 1 h

Procedure:
3 g of 3-amino4-methoxycarbonylbenzylammonium chloride (18.8 mmol) are dissolved in 50 ml of dimethylacetamide, triethylamine (2.8 g, 27.7 mmol) is added, and the mixture is subsequently reacted at 0-10° C. with a solution of methanesulfonyl chloride (1.6 g, 13.8 mmol) in 20 ml of dimethylacetamide. After 1 h, the solvent is removed in vacuo and the residue is worked up by extraction with water/dichloromethane. The combined organic extracts are washed with water and dried (Na2SO4) and then evaporated on a rotary evaporator. The residue obtained is crystallized from water, whereupon 3 g (84%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 120-121° C. are obtained.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[Na+].CC(O)C.Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([O:20]C)=[O:19])=[N:16][CH:17]=1>C1COCC1>[CH:2]([O:4][C:12]1[N:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1cnc(C(=O)O)cn1
Reaction time: 1.5 h

Procedure:
To a rt solution of sodium t-butoxide (1.41 g, 14.67 mmol) in THF (20 mL) was added 2-propanol (1.250 mL, 16.33 mmol) dropwise. After 10 min a solution of methyl 5-chloro-2-pyrazinecarboxylate (1.70 g, 9.85 mmol, Ark Pharm) in THF (10 mL) was added dropwise. After 1.5 h, the reaction was quenched with saturated aq NH4Cl and extracted with EtOAc (3×). The aqueous layer was concentrated under reduced pressure and the resulting solid was treated with aqueous HCl. The solution was extracted with DCM (3×) and the combined organic layers were purified by flash chromatography, eluting with 0.5% TFA in iPrOH:CH2Cl2 (0:1→1:9) to give a white crystalline solid. (497 mg, 2.7 mmol, 28%). MS m/z=183 [M+H]+. Calculated for C8H10N2O3: 182.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:9][C:10]=1[C:11]([NH:13][O:14]C1CCCCO1)=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[S:9][C:10]=1[C:11]([NH:13][OH:14])=[O:12]
Reactant: O=C(NOC1CCCCO1)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide (153 mg, 0.324 mmol) in methylene chloride (1.50 mL) was added trifluoroacetic Acid (1.50 mL, 19.5 mmol). The reaction was stirred at rt for 12 hrs. The resulting solution was concentrated and distributed between NaHCO3(aq) saturated solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (×2). The combined org layer was washed with water, dried, and concentrated. Purification on a silica gel column (gradient elution, 0-8% MeOH/CH2Cl2) provided 4-(3,4-dichlorobenzyl)-N-hydroxy-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide as a yellow solid (53 mg, 42.1% yield). LCMS: (AA) ES+ 388, 390, 392; 1H NMR (400 MHz, MeOD) δ 7.47-7.41 (d, J=1.8 Hz, 1H), 7.38-7.29 (d, J=8.3 Hz, 1H), 7.25-7.14 (dd, J=8.3, 1.9 Hz, 1H), 4.28-4.21 (s, 2H), 3.79-3.71 (t, J=4.9 Hz, 4H), 3.50-3.43 (t, J=4.9 Hz, 4H), 3.33-3.27 (t, J=1.6 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=[O:21]>CN1C(=O)CCC1>[CH2:1]([O:8][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
To benzyl alcohol (1.1 g, 10 mmol) in NMP (20 mL) was added sodium hydride (60% in mineral oil; 0.44 g, 11 mmol), and the mixture was stirred for 30 minutes at room temperature. The mixture was then added to a vial containing 2-chloro-5-fluorophenylacetic acid (1 g, 4.5 mmol), and the reaction was stirred at 120° C. for 3 hours. Acidic work-up gave the desired product (1.8 g).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[CH:3]=1.[CH3:14][O-:15].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Br)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 4-bromo-2,5-difluorobenzoate (i-7c) (0.5 g, 2 mmol) in DMF (5 mL) at 0° C. was added NaOMe (25% in MeOH, 0.45 mL, 2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then at rt for 30 min. The mixture was then brought back to 0° C. and quenched with EtOAc and 1M HCl. The organic layer was separated, and the aqueous phase was extracted with EtOAc, dried over Na2SO4, concentrated and purified by flash chromatography (Pentane/EtOAc=9:1) to give the title compound. LCMS (ESI) calc'd for C9H8BrFO3 [M+H]+: 263. found: 263
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C.C>C(Cl)Cl>[CH3:9][C:10]1[N:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:12]=[CH:13][N:14]=1
Reactant: C=Cc1ccncc1
Reactant: Cc1ncc[nH]1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nccn1CCc1ccncc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A stirred solution containing 52.5 g (0.50 mol) of 4-vinylpyridine, 36.9 g (0.45 mol) of 2-methylimidazole and 1.1 g of glacial acetic acid was heated to an internal temperature of 130° C. under a nitrogen atmosphere, maintained at this temperature for 5 hours, and then allowed to stand overnight at room temperature. The resultant solidified mass was dissolved in 150 ml of methylene dichloride, treated with charcoal, filtered through Celite and then concentrated in vacuo. The crude residue was crystallized from a mixture of methylene chloride and pentane in a ratio of 1:2.5 as the eluent to yield a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].CC(=CC)C.C1C[O:31]CC1.[O-]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[C:21]([OH:31])=[O:22]
Reactant: C1CCOC1
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4a (335 mg, 1.00 mmol) and 2-methyl-2-butene (1.06 ml, 10.01 mmol) were dissolved into 50 ml THF. A freshly prepared solution of 80% NaClO2 (339 mg, 3.00 mmol) and NaH2PO4.H2O (414 mg, 3.00 mmol) in 55 ml of t-BuOH/H2O 5:1 was added. The reaction mixture was stirred in room temperature for 6 hours. The reaction was quenched with water and extracted CH2Cl2. The organic phase was extracted with sat. NaHSO4. The water phase was then made acidic with HCl and extracted with CH2Cl2. the organic layer was washed with brine and dried over Na2SO2. After filtration the solvent was evaporated ant the product recrystallized from ethanol.
Reaction SMILES: [OH:1][CH2:2][C@@:3]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[CH:2]([C@@:3]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH2:4]1)=[O:1]
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](CO)(NC(=O)OC(C)(C)C)C2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCc1ccc([C@H]2CC[C@@](C=O)(NC(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Tert-butyl (1R,3S)-1-(hydroxymethyl)-3-(4-octylphenyl)cyclopentylcarbamate (3.9 g, 9.66 mmol) was dissolved in dichloromethane (193 ml) under nitrogen to give a colorless solution. Dess-Martin periodinane (4.51 g, 10.63 mmol) (Aldrich) was added and the reaction stirred for about 3 h. LC/MS showed the reaction was complete. Methylene chloride (100 mL) and water (100 mL) were added and the layers separated and extracted with methylene chloride (2×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to an off-white solid. The residue was purified by flash column chromatography (120 g Redi-Sep) eluting with ethyl acetate/heptane and the product fractions combined. Solvents were removed under reduced pressure to provide tert-butyl (1R,3S)-1-formyl-3-(4-octylphenyl)cyclopentylcarbamate (3.40 g, 88%) as an off white solid: LC/MS (method f) Rt=3.58 min.; MS m/z: 401.36 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cl)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH2:19][CH2:20][C:21]1[N:25]2[C:26]3[S:40][C:39]([CH2:41][CH3:42])=[CH:38][C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[C:27]2[CH:38]=[C:39]([CH2:41][CH3:42])[S:40][C:26]=2[N:25]2[C:21]([CH2:20][NH:19][C:16]([C:8]3[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:18])=[N:22][N:23]=[C:24]2[CH2:30][N:29]=1
Reactant: CCOC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc3n2-c2sc(CC)cc2C(c2ccccc2Cl)=NC3)cc2ccccc21
Reaction time: 24 h
Yield: 60.3 %

Procedure:
1-Ethoxycarbonylmethylindole-2-carboxylic acid (1.36 g) synthesized by a known method such as the method described in Japanese Patent Unexamined Publication No. 279374/1991, 9-aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.79 g) and triethylamine (1.4 ml) were dissolved in dimethylformamide (15 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 2.43 g) was added at room temperature, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol and isopropyl ether to give 2.78 g of crude crystals. The crystals were recrystallized from ethanol to give 1.77 g of ethyl 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethylcarbamoyl)indole-1-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1

Procedure:
A mixture of 4.6 g (20 mmol) of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 100 ml of acetic anhydride is stirred at reflux for 2 hrs. The reaction is cooled and the solid filtered, washed with acetonitrile and ether, and dried to give 4.12 of 6-[3(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:21][C:22]1[S:26][C:25]([C:27](SC)=[NH:28])=[CH:24][CH:23]=1>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:21][C:22]1[S:26][C:25]([C:27](=[NH:28])[NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH2:12]3)=[CH:24][CH:23]=1
Reactant: CSC(=N)c1ccc(C)s1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)CCCN3CCCN2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a stirred solution of 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in ethanol (6 ml) was added methyl 5-methylthiophene-2-carbimidothioate hydroiodide (265 mg, 0.887 mmol). The resulting suspension was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane. The combined organics were dried, filtered and concentrated, then chromatographed on silica gel with ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane as eluent to give the desired 5-methyl-N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (98 mg, 0.256 mmol, 57.8% yield). 1H NMR (DMSO-d6) δ 7.45 (d, J=3.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.53 (m, 2H), 6.45 (s, 1H), 6.13 (brs, 2H), 3.26-3.16 (m, 4H), 2.68-2.63 (m, 2H), 2.43-2.39 (m, 6H), 2.41 (s, 3H), 1.86-1.82 (m, 2H), 1.68-1.64 (m, 6H). ESI-MS (m/z, %) 383 (MH+, 39), 272 (49), 192 (100). ESI-HRMS calculated for C22H31N4S (MH+), calculated: 383.2264, observed:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[CH:20].C(N(CC)CC)C.Cl>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.O1CCCC1>[OH:32][C:24]1[CH:23]=[CH:22][C:21]([C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)ccc1O

Procedure:
3-Iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol), ethyl 5-ethynyl-2-hydroxybenzoate (9.5 g, 50 mmol), triethylamine (65 ml) and tetrahydrofuran (65 ml) were stirred at 60° C. Dichlorobis(triphenylphosphine)palladium (250 mg, 0.36 mmol) and copper(1)iodide (140 mg, 0.7 mmol) were added with stirring. After 1 h the solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, treated with activated carbon and the solvent evaporated. The residue was recrystallized from methanol, then from toluene and finally from acetic acid. Yield 12.7 g 58%.