Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH:22]=O)=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](C=O)C1
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (150 mg) and pyridin-2-amine (79 mg) in THF (1.3 mL) and methanol (0.1 ml) was added borane-2-picoline complex (90 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was stirred in 1 M aqueous hydrochloric acid solution, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (112 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([N+:23]([O-:25])=[O:24])=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[NH:10][CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]1[C:11]2[C:6](=[C:5]([N+:23]([O-:25])=[O:24])[C:4]([F:3])=[C:13]([F:14])[C:12]=2[O:15][CH3:16])[C:7](=[O:22])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
A solution of NaH (1.17 g, 29.3 mmol, 60% in oil) in DMF (50 mL) was cooled to 0° C. and treated dropwise with ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (8.0 g, 24.4 mmol) in DMF (50 mL). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. To the solution was added benzyl bromide (4.4 mL, 36.9 mmol) and stirred over night. The reaction mixture was poured into ice-water and extract with CH2Cl2. The organic layer washed with water, brine, and then dried. The solvent was removed and the crude product was purified by column chromatography (Hexane:EtOAc 3:1 →1:1) to yield ethyl 1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.74 g, 27%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[BH4-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2cnccc2c1
Agent: [BH4-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCNC2

Procedure:
In close analogy to the procedure described above, 6-Bromo-isoquinoline is reacted with sodium borohydride to provide the title compound.
Reaction SMILES: [C:1]1(=[CH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CC(=O)C)CCCC=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CCCCCCC.C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:23][C:21]1[CH:20]([C:19]([O:25][CH2:26][CH3:27])=[O:24])[C:1]2([CH2:6][C:7](=[O:9])[CH:8]=1)[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: CC(=O)C=C1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)CC1=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C1C(C)=CC(=O)CC12CCCC2
Yield: 12.1 %

Procedure:
A mixture of 1-cyclopentylidenepropan-2-one/1-cyclopentenylpropan-2-one (25:75, 100 g, 0.805 mol), ethyl acetoacetate (105 g, 0.805 mol), and zinc chloride (16.5 g, 0.12 mol) in heptane (100 ml) and benzene (100 ml) was refluxed for 6 days using a Dean-Stark apparatus. The resulting mixture was cooled, washed with water (250 ml), with a 5% aqueous solution of NaHCO3 (250 ml), with water, dried (MgSO4) and concentrated. Vigreux-Distillation (0.1 mbar, bath temperature 150° C., head temp. 106-130° C.) of the crude product (174 g) followed by FC (SiO2, hexane/MTBE 10:1 to 5:1) gave ethyl 7-methyl-9-oxospiro[4.5]dec-7-ene-6-carboxylate (23 g, 12%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13](O)=[O:14].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:14]
Reactant: CC(C)(N)CC(=O)O
Reactant: c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(N)CC(=O)N1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2,3-Dihydro-1H-isoindole (543 mg) and 3-amino-3-methylbutanoic acid (700 mg) were dissolved in N,N-dimethylformamide (30 ml). N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (876 mg) and hydroxybenzotriazole (698 mg) were added thereto at 0° C., and then the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The organic phase was separated, and the aqueous phase was adjusted to pH 9 by adding a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.60 g, Y.:60%) as a brown oily matter.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH2:9][C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1.[CH:27]1([NH:30][C:31](=[O:48])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]1([NH:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]3[CH:26]=[CH:25][C:5]4[C:6]([CH2:9][C:10]([N:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]5)=[O:11])=[N:7][O:8][C:4]=4[CH:3]=3)[CH:33]=2)=[O:48])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2noc3cc(Br)ccc23)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 58.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[(6-bromo-1,2-benzisoxazol-3-yl)acetyl]-1-piperazinecarboxylate (Intermediate 33) (0.045 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.03 g) and 2M aqueous sodium carbonate (0.65 ml) in isopropanol (2.5 ml) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (1 mg) then stirred at reflux for 18 h. On cooling the mixture was absorbed onto silica (Merck 7734) and applied to a Varian Bond-Elut SPE cartridge (silica, 5 g). Sequential elution with dichloromethane, chloroform, ether, ethyl acetate, acetonitrile and acetone yielded the title compound as a white solid (0.03 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:10][N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: Cn1cc(Br)cc(N(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(N(C(=O)OC(C)(C)C)c3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 2.45 mmol) in DCM (49 ml) was added 1-methylpiperazine (491 mg, 4.9 mmol), sodium triacetoxyborohydride (1.3 g, 6.12 mmol) and acetic acid (294 mg, 4.9 mmol). The reaction mixture was heated to 40 degrees centigrade and stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 20% methanol in DCM to give 1.08 g (89.5%) of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH:11]([CH3:25])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.NN>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH:11]([CH3:25])[NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC1NCC(c2ccc(Cl)cc2)c2ccc(-c3ccc(Cl)nn3)cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC1NCC(c2ccc(Cl)cc2)c2ccc(-c3cccnn3)cc21
Yield: 57.8 %

Procedure:
To a solution of the product from Step F of Example 6, (190 mg, 0.51 mmol) in ethanol (15 mL) was added hydrazine (1 mL, 20.6 mmol) and 10% Pd/C (100 mg). The reaction mixture was heated at reflux for 1 hour. The mixture was then filtered through celite and the celite bed was washed with methanol. The filtrate was concentrated and purified by column chromatography (silica gel, 1% to 5% MeOH/CH2Cl2) to provide 4-(4-Chloro-phenyl)-7-(pyridazin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline (99 mg, 57%): 1H NMR (CDCl3, 500 MHz) δ 9.15 (dd, J=4.9, 1.6 Hz, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.83 (dd, J=8.6, 1.6 Hz, 1H), 7.69 (dd, J=8.1, 1.8 Hz, 1H), 7.53 (dd, J=8.6, 4.9 Hz, 1H), 7.29-7.26 (m, 2H), 7.08-7.05 (m, 2H), 6.98 (d, J=8.1 Hz, 1H), 4.35-4.33 (m, 1H), 4.19 (dd, J=7.9, 5.8 Hz, 1H), 3.49 (dd, J=12.8, 5.5 Hz, 1H), 3.02 (dd, J=12.8, 8.3 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H). ESI MS m/z=336 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:5]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][C:14]([O:16]C)=[O:15])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:5]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCOc1c(OC)cccc1-c1cccc(C=CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCOc1c(OC)cccc1-c1cccc(C=CC(=O)O)c1
Yield: 60.6 %

Procedure:
Methyl 3-(3-methoxy-2-pentyloxyphenyl)cinnamate (1.47 g, 5.28 mmol), ethanol (10 ml) and a 1N aqueous sodium hydroxide solution (10 ml) were mixed, and this solution was refluxed under heating for 0.5 hour. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make the mixture acidic (pH=1). The precipitated crystals were extracted 3 times with ethyl acetate (20 ml). The organic layers were combined, washed 3 times with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by recrystallization from ethanol to give 3-(3-methoxy-2-pentyloxyphenyl)cinnamic acid (1.09 g, 78%) as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1>C1C=CC=CC=1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)Cl
Reactant: OCCBr
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
2-Bromoethanol (4 g, 32 mmol) was added dropwise to a solution of octanoyl chloride (7.8 g, 48 mmol) and pyridine (5 mL) in benzene (50 mL). The reaction mixture was stirred at room temperature for 24 hours. After evaporation of benzene and pyridine under high vacuum, the residue was redissolved in benzene (100 mL). The solution was washed with water (50 mL), sulfuric acid solution (3×25 mL, 0.5N), sodium bicarbonate solution (25 mL, 1N), and water (2×75 mL). The benzene layer was dried over Na2SO4. The drying agent was suction filtered, and the benzene was evaporated. The resulting oil was purified by silica gel chromatography using chloroform/methanol (9:1) to give 6.5 g of pure product. Yield 81%; liquid; IR (neat) 2930 and 2850 (aliphatic CH), 1730 (CO ester) cm-1 ; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)4), 1.20-1.40 (m, CH3 (CH2)4), 1.55-1.70 (m, CH2 CH2 CO), 2.25-2.40 (t, CH2 CH2 CO), 3.50-3.60 (t, O CH2 CH2 Br), 4.35-4.40 (t, O CH2 CH2 Br).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.51 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.21 g, 42%). MS (ISP) 506.1 [(M+H)+]; mp 204° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([CH3:10])=[N:3]1.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:1][N:2]1[C:6]2[S:7][C:8]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:5]=2[C:4]([CH3:10])=[N:3]1
Reactant: Cc1nn(C)c2sccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a cold (−78° C.) mixture of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole (1.0 g, 6.57 mmol) and THF (50 mL) was added n-butyllithium (4.52 mL, 7.23 mmol) dropwise and allowed under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 hour. To this solution was added tributylchlorostannane (2.13 mL, 7.88 mmol) and the mixture was stirred at −78° C. for 1 hour and then warmed to room temperature over a period of 2 hours. The reaction was quenched with brine (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel flash chromatography, eluting with 20% EtOAc and hexane to give the title compound as a clear oil (1.60 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.33 Hz, 9H), 1.02-1.06 (m, 6H), 1.30 (dq, J=7.29, 14.75 Hz, 6H), 1.44-1.64 (m, 6H), 2.31 (s, 3H), 3.80 (s, 3H), 6.94 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[SH2:5]>>[Cl:1][CH2:2][CH:3]1[S:5][CH:3]([CH2:2][Cl:1])[S:5][CH:3]([CH2:2][Cl:1])[S:5]1
Reactant: S
Reactant: O=CCCl
Product: ClCC1SC(CCl)SC(CCl)S1

Procedure:
reacting chloroacetaldehyde with hydrogen sulfide to obtain 2,4,6-tris(chloromethyl)-1,3,5-trithiane;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Yield: 74 %

Procedure:
Following a procedure similar to that described in Example 40, 0.790 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.388 g of potassium t-butoxide and 1.28 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)piperidine were reacted in 15 ml of dimethylacetamide. The mixture was then worked up as described in Example 40, and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.09 g (yield 74%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:12]>CO>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[NH2:12]
Reactant: Clc1cnc2ccccc2n1
Reactant: N
Solvent: CO
Product: Nc1cnc2ccccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
To 2-chloroquinoxaline (1.0 g, 6 mmol) was added ammonia in methanol (8 mL of a 2M solution). The reaction was sealed in a vial, heated to 80° C., and stirred for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in methylene chloride and filtered. Hexane was added until a precipitate formed which was filtered and found to be the desired product (5% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: Cc1ccc(C(C)C)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mL) dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To the solution of methyl 3-[5-(3-{[benzylamino]carbonylamino}propoxy)indolyl]propanoate (80 mg, 0.2 mmol), as prepared in the preceding step, in tetrahydrofuran (5 mL) and water (5 mL) was added sodium hydroxide (20 mg), and the reaction mixture was stirred at ambient temperature for 2 h. After evaporating the tetrahydrofuran, the aqueous solution was acidified (pH 5–6), the white solid formed was collected, washed with water and dried under high vacuum to give the title compound (65 mg, 82%). 1H-NMR (400 MHz, DMSO6) δ 7.21–7.37 (m, 7H), 7.02 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 6.36 (t, J=6.0 Hz, 1H), 6.30 (d, J=2.9 Hz, 1H), 6.06 (t, J=5.7 Hz, 1H), 4.34 (t, J=6.8 Hz, 2H), 4.20 (d, J=6.0 Hz, 2H), 3.96 (t, J 6.2 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 2.71 (t, J=6.8 Hz, 2H), 1.83 (t, J=6.5 Hz, 2H). Mass spectrum (LCMS, ESI) Calcd. for C22H25N3O4 396.4 (M+H), found: 396.1.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[CH:24]=[O:25])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (1.082 g, 5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), sodium carbonate (2.5 mL, 5.00 mmol) in 1,4-dioxane (20 mL) was heated to reflux for 6 h. After cooling to room temperature, the solid was filtered and washed by ethyl acetate and water. After drying under vacumn, yellow powder was collected (1 g). 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=1.68, 8 Hz, 1H), 7.79 (d, J=1.68 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.35 (dd, J=2.24 Hz, 2.04 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.15 (d, J=1.88 Hz, 1H), 10.22 (s, 1H).