Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH-].[Na+].O.C([O-])(=O)C.[Ca+2:34].C([O-])(=O)C>C(O)C.O>[Ca:34].[CH2:1]([N:3]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: CCc1cccc2c1c(O)c(C(=O)N(CC)c1ccccc1)c(=O)n2C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [Ca]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide (5.0 g, 14.2 mmol) was dissolved in a mixture of 1M NaOH (14.26 mmol, 14.26 ml) and ethanol (30 ml), and pH was adjusted to 7.5. The solution was heated to 70° C. and calcium acetate hydrate (1.05 eq., 7.5 mmol, 1.335 g) in water (7 ml) was added dropwise during 5 min. The heating was discontinued and the mixture was stirred at room temperature for 1 h, the crystals were filtered, washed with ethanol/water 1/1, and dried under vacuum to afford the title compound (5.16 g, 98% yield). Anal. Calcd for C42H42N4O6Ca: C, 68.3; H, 5.73; N, 7.58. Found C, 68.4; H, 5.72; N, 7.63. EDTA-titriometric determination of calcium gave a content of 5.42% (theoretical content is 5.42%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cccc(F)c1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cccc(F)c3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 3-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (31% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.65-7.59, 7.29, 7.12, 6.99, 4.05-3.99, 3.89-3.72, 3.54, 3.35, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][C:20]1[NH:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:23]2[N:24]=[C:20]([CH3:19])[NH:21][CH:22]=2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 1.63 g, 5.60 mmol), 2-methyl-1H-imidazole-4-carboxylic acid (1.0 g, 6.16 mmol), triethylamine (3.12 mL, 22.4 mmol), EDCI (0.96 g, 6.16 mmol) and HOBt (0.94 g, 6.16 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. To the reaction mixture was added saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution, 1 M HCl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 98:2 to 75:25) to give the title compound (1.63 g, 89%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C@H:60]([OH:62])[CH3:61]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH2:59][C@@H:60]([OH:62])[CH3:61])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@H](O)CN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC[C@H](C)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-aminopropan-2-ol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.1 Hz, 3H) 1.12-1.41 (m, 3H) 1.55-1.87 (m, 8H) 1.70-1.88 (m, 4H) 3.21 (q, J=6.3 Hz, 1H) 3.32 (s, 3H) 3.77 (m, 1H) 3.94 (s, 3H) 4.16 (t, J=13.0 Hz, 2H) 4.49 (quin., J=12.1 Hz, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.58 (s, 1H) 8.14 (d, J=8.3 Hz, 1H) 8.23 (s, 1H) 8.41-8.47 (m, 1H) 8.51-8.57 (m, 1H). [M+H] calc'd for C25H32F2N6O4 519. found 519.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:29][C:30](=O)OCC.[CH:39](=O)C.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[NH:29][CH2:30][CH3:39]
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCNC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 30.7 %

Procedure:
Ethyl 1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (example 3, 60.0 mg, 0.103 mmol) was dissolved in dichloromethane (5 ml) and acetaldehyde (5.45 mg, 0.124 mmol μl) and molsieve 3{acute over (Å)} were added and the mixture was stirred for 3 h. Acetic acid (7.07 mg, 0.118 mmol) was added and the mixture was stirred for another 3 h. MeOH (5 ml) and sodium cyanoborohydride (14.8 mg, 0.236 mmol) were added and it was stirred for another 14 h. Water was added and it was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 solution, washed and evaporated. The residue was purified by column chromatography using SiO2 and CH2Cl2/MeOH 95:5->90:10. The product was precipitated as an HCl salt from 6N HCl in isopropanol and isopropylether to obtain the product as a white salt (17 mg, 25%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>CC(N(C)C)=O>[O:22]=[C:20]([CH3:21])[CH2:19][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)N
Reactant: CC(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(C)NCC(C)=O
Temperature: 0 °C
Yield: 83.9 %

Procedure:
430 g (2.56 mol) of ethyl 2-aminoisobutyrate hydrochloride was dissolved in 2 l of DMAc, and 652 g (6.46 mol) of triethylamine and 373 g (4.03 mol) of chloroacetone were added thereto. The mixture was stirred and reacted under nitrogen stream at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 20 l of ice water and extracted twice with 2 l of ethyl acetate. The extracted solution was treated by a conventional method to obtain 402 g (yield: 84%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7](C(=O)C)[N:6]=[CH:5]2.[OH-].[Na+]>C(O)C.Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2
Reactant: CC(=O)n1ncc2cc(Br)c(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1cc2[nH]ncc2cc1Br
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
To a solution of 22.5 g of 1-(5-bromo-6-fluoro-indazol-1-yl)ethanone in 250 mL of ethanol was added 20.0 mL of 5N sodium hydroxide aqueous solution at room temperature, and stirred at this temperature for 5 minutes. After neutralizing in 5N hydrochloric acid aqueous solution, the solution was diluted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to afford 16.7 g of the title compound as pale brown crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].Cl>C(OCC)(=O)C.CN(C)C(=O)C>[CH2:7]([O:15][C:16]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.9 g) and benzyl bromide (1.2 mL) were sequentially added to an N,N-dimethylacetamide (20 mL) solution of methyl 2-hydroxy-4-iodobenzoate (2.5 g), followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid and ethyl acetate were added thereto. The organic layer was separated, washed with 1 mol/L hydrochloric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 3.3 g of methyl 2-(benzyloxy)-4-iodobenzoate as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:24](=[O:26])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:22]=2)[CH:7]=1
Reactant: CNc1cnccc1-c1cc(F)ccc1C
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 20.5 hours. The compound was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (20%). MS (ESI): m/z=467.10 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][C:12](=[O:19])[N:13]3[CH2:16][CH:17]=O)=[N:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[C:29]2[CH:28]=[C:27]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:26]=[CH:25][C:24]=2[O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:20]1[C:29]2[CH:28]=[C:27]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][N:42]([CH2:17][CH2:16][N:13]4[C:14]5[C:9](=[N:8][CH:7]=[C:6]([N:1]6[CH:5]=[CH:4][N:3]=[CH:2]6)[CH:15]=5)[CH:10]=[CH:11][C:12]4=[O:19])[CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:26]=[CH:25][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(-n3ccnc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(-n4ccnc4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
To a solution of 0.12 g of (7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 1 mL of dichloromethane, a solution of 0.14 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 1.4 mL of dichloromethane, and 23 μL of acetic acid and 0.13 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour 40 minutes. The reaction mixture was charged with chloroform, and a saturated aqueous sodium hydrogen carbonate solution and adjusted to pH 8.6, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=19:1 to 93:7 to obtain 0.12 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([C:14]([OH:16])=[O:15])[CH:18]=3)[NH:22][C:21]2=[O:26])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(C(=O)O)cc21
Yield: 30 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 88.6 mg 5-carboxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven. The crude product was purified by chromatography on a silica gel column using ethyl acetate-hexane-acetic acid as the eluant to give 51 mg(30%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[C:16]([O:15][C:13]([C:10]1([O:9][C:3]2[C:2]([NH:1][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2N)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)cnc2OC2(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 75 °C
Reaction time: 20 h
Yield: 54.7 %

Procedure:
At room temperature, to a 1,2-dichloroethane solution (280 ml) of tert-butyl 1-[(3-amino-5-chloropyridin-2-yl)oxy]cyclopropanecarboxylate (7.88 g) were added tert-butyl 4-oxopiperidine-1-carboxylate (22.1 g) and sodium triacetoxyborohydride (23.5 g), and then temperature was raised to 75° C., followed by stirring for 20 hours. After the temperature was brought back to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[(2-{[1-(tert-butoxycarbonyl)cyclopropyl]oxy}-5-chloropyridin-3-yl)amino]piperidine-1-carboxylate (7.09 g).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:33][CH:32]2[N:17]([C:18](=[O:38])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35](O)=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:16]1.C1(C2N=C(C3N=C(OC4CC5C(C(=O)N(C)CCCCC=CC6C(C([NH:81][S:82]([CH:85]7[CH2:87][CH2:86]7)(=[O:84])=[O:83])=O)(NC5=O)C6)C4)C4C(C=3)=CC(OC)=CC=4)SC=2)CC1>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:33][CH:32]2[N:17]([C:18](=[O:38])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:81][S:82]([CH:85]4[CH2:87][CH2:86]4)(=[O:84])=[O:83])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:16]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCNC(=O)N4C3)nccc2c1Br
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nccc2c1Br

Procedure:
The title compound was prepared from 18-[5-bromo-6-methoxyisoquinolin-1-yloxy]-2,15-dioxo-3,14,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (74) following the procedure reported for synthesis of N-[17-[3-(4-cyclopropylthiazol-2-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]_octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (30): m/z=691 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[N:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:28][CH3:29])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[N:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:28][CH3:29])[CH3:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCOC(=O)COc1cc2ncnc(Cl)c2cc1OC
Product: CCOC(=O)COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OC
Yield: 2 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 2% yield from 1,2,3,4-tetrahydroquinoline and (4-chloro-6-methoxy-quinazolin-7-yloxy)-acetic acid ethyl ester. (film; LC-MS: 393 (MH+)).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:16][C:17]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:21][N:20]=1)[CH3:18].Cl>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[CH3:18][C:17]([N:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:21][N:20]=1)[CH3:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1-c1nnc(C(C)(C)Nc2ccccc2)n1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nnc(C(C)(C)N(C(=O)c2ccccc2)c2ccccc2)n1C
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Benzoyl chloride (0.21 ml) and N,N-dimethylaminopyridine (40 mg) were added to a pyridine (15 ml) solution of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}aniline (500 mg), followed by stirring at 80° C. for 3 days. After the reaction solution and chloroform were added to 1M hydrochloric acid, the reaction solution and chloroform were added to brine and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution successively, dried over anhydrous magnesium-sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=99:1 to 98:2) and then the resulting solid washed with ether to obtain 523 mg of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}-N-phenylbenzamide (colorless solid).
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[C:13]([CH3:16])([CH3:15])[CH3:14].N1CCCCC1>C(Cl)Cl>[C:13]([C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) (1.08 g, 4 mmol) in CH2Cl2 (40 mL) was added piperidine (3.94 mL, 10 mmol). The mixture was stirred at room temperature for 1 h and extracted with 1N NaOH (3×). The aqueous layer was acidified with 1N HCl and extracted with diethyl ether. The ether extract was washed with brine, dried (MgSO4) and concentrated to give 2-tert-butyl-4-fluoro-5-nitrophenol (530 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.25 (d, J=13.7 Hz, 1H), 1.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:28][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
A mixture of 0.61 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene, 0.19 g of 4-chlorophenol, 0.22 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at room temperature. After 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.54 g of 3,5-dichloro-4-(4-(4-chlorophenoxy) butyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (59% yield), m.p. 54.5° C.