Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([OH:8])=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C[Si](C)(C)NC(=O)C.O.O.Cl.[Cl-].[NH2:35][CH:36]1[C:53](=[O:54])[N:38]2[C:39]([C:50]([OH:52])=[O:51])=[C:40]([CH2:43][N+:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:41][S:42][C@H:37]12>ClCCl.O1CCCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([NH:35][CH:36]1[C:53](=[O:54])[N:38]2[C:39]([C:50]([O-:52])=[O:51])=[C:40]([CH2:43][N+:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:41][S:42][C@H:37]12)=[O:8])[CH3:2]
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 1 h
Yield: 39.3 %

Procedure:
2-Ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (2.2 g) was added to a solution of phosphorus pentachloride (2.0 g) in dichloromethane (40 ml) at -10° C., and stirred at -5° C. to -10° C. for 1 hour. After the addition of triethylamine (2.0 g), the resulting mixture was stirred at -5° C. for 5 minutes [Solution A]. N-trimethylsilylacetamide (9.8 g) was added to a stirred suspension of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate (3.0 g) in dry tetrahydrofuran (60 ml), and the mixture was stirred for 20 minutes at 35° C. to 40° C. To the solution was added the solution A at -10° C. and the resulting solution was stirred at the same temperature for 40 minutes. Water and ethyl acetate were added to the reaction mixture at -10° C. and the separated aqueous layer was washed with ethyl acetate and adjusted to pH 4.0 with 10% aqueous solution of sodium hydroxide. The resulting solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: Prepared by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and concentrated and lyophilized to give 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1

Procedure:
[5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-phenyl]-(4-fluoro-phenyl)-methanone was prepared by titanium tetrachloride-catalyzed Friedel-Crafts acylation of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene with p-fluorobenzoyl chloride according to the procedure described in the J. Med. Chem., 1995, 695-707.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[S:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5cccs5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5cccs5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of [4-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (100 mg, 0.193 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by prepara-HPLC to give N-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 30 mg). 1HNMR (300 MHz, CD3OD): δ 8.59-8.56 (m, 1H), 8.38 (brs, 1H), 7.82 (d, 1H, J=9.0 Hz), 7.42-7.34 (m, 1H), 7.16-7.04 (m, 2H), 6.98-6.85 (m, 2H), 6.43-6.39 (m, 1H), 4.70 (d, 2H, J=5.1 Hz), 3.89-3.85 (m, 1H), 3.23-3.07 (m, 1H), 2.20-2.05 (m, 4H), 1.60-1.37 (m, 4H). LC-MS: [M+H]+ 420.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1>ClCCCl>[Br:3][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A solution of phosphorus oxybromide (14.4 g, 50 mmol) in 1,2-dichloroethane (50 mL) was added to a stirred suspension of 2-hydroxy-4-methyl-5-nitropyridine (5 g, 32.4 mmol) in 1,2-dichloroethane (50 mL) and the resulting mixture was heated to reflux. After 4 h, the reaction was cooled and quenched with water. The organic layer was dried (Na2SO4), filtered through a pad of silica eluting with chloroform and evaporated in vacuo to give the title compound as a yellow solid:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)c1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), benzoyl chloride (0.44 g, 3.1 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 20 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.13 g, 38%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[OH-].[Na+].[C:39](OC(=O)C)(=[O:41])[CH3:40]>S(=O)(=O)(O)O>[C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:41])[CH3:40]
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), acetic anhydride (20 ml) and two drops of conc. sulfuric acid is stirred at room temperature for 3 hours. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution under ice-cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=200:1), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-acetylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) as colorless needles, m.p. 171-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:27][C:24]3[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:10]=2[N:11]=1
Reactant: COc1ccc(N)cn1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc(Cl)nc23)cn1
Yield: 59.1 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), 6-methoxypyridin-3-amine (0.155 g, 1.250 mmol) and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H2O=1:1) was refluxed for 1 hour. The reaction mixture was diluted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to get 6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (0.085 g, 59%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 3.97 (3H, s), 6.85 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.8, 8.8 Hz), 8.55 (1H, d, J=2.8 Hz), 8.67 (1H, br s), 8.73 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:10][CH:9]=3.C[Li].C([Li])CCC.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[CH:19]1([CH2:18][CH2:17][O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][C:30]([CH3:32])([OH:33])[CH3:31])=[CH:15][C:14]3=2)[CH2:21][CH2:20]1
Reactant: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Reactant: CC1(C)CO1
Agent: FB(F)F
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of 3-bromo-6-(2-cyclopropylethoxy)phenanthrene (11 mmol) from Step 1 above in THF (75 mL) at −78° C. was successively added methyllithium (1.6 M in diethyl ether, 1 mL) and butyllithium (2.5 M in hexanes, 5.3 μL). The mixture was stirred at −78° C. for 30 minutes, after which isobutylene oxide (2.9 mL, 33 mmol) was added, followed by BF3.OEt2 (4.2 mL, 33 mmol). The reaction mixture was stirred at −78° C. for 1 h, then quenched with 1 M HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (10% ethyl acetate in hexanes) to afford 1-[6-(2-cyclopropylethoxy)-3-phenanthryl]-2-methylpropan-2-ol (1.33 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[C:37]([O:41][C:42](=[O:52])[NH:43][C:44]1[C:45]([Cl:51])=[N:46][CH:47]=[CH:48][C:49]=1[I:50])([CH3:40])([CH3:39])[CH3:38].CI>CCCCCCC.CCOC(C)=O>[C:37]([O:41][C:42](=[O:52])[N:43]([C:44]1[C:45]([Cl:51])=[N:46][CH:47]=[CH:48][C:49]=1[I:50])[CH3:2])([CH3:40])([CH3:38])[CH3:39]
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1c(I)ccnc1Cl
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)OC(C)(C)C)c1c(I)ccnc1Cl

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from (2-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (CAS RN 855784-39-3) and methyl iodide and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (88%). MS (ESI): m/z=368.99 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:12]=[C:13]4[S:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:14]4=[CH:15][C:16]=3[C:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:18]=2[CH:19]=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([C:26]1[CH:25]=[C:24]2[C:29]([S:30][C:13]3[C:14]2=[CH:15][C:16]2[C:17]([CH2:20][CH3:21])([CH2:22][CH3:23])[C:18]4[CH:19]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=4[C:11]=2[CH:12]=3)=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CCC1(CC)c2cc(OC)ccc2-c2cc3sc4ccccc4c3cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(CC)c2cc(OC)ccc2-c2cc3sc4ccc(C(C)=O)cc4c3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (100 mL) in which were dissolved 2-methoxy-12,12-diethyl-6,12-dihydro-6-thia-indeno[1,2-b]fluorene (6.60 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. Dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=5)[CH2:45][CH2:44]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=622.01 (M+H+); retention time=0.97 minutes.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][C:17]=4[CH3:35])[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[C:17]([CH3:35])=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCNCC2)cnc1Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
Compound 78 (0.100 g, 0.189 mmol) was dissolved in DCM (3 mL) followed by TFA (1 mL) and stirred at 40° C. in a water bath for 30 min. Concentration under vacuum provided a yellowish oil which was partially dissolved in water and then filtered. The filtrate was purified by preparative RP-HPLC eluting with a gradient of 5% MeCN/water/0.1% TFA-30% MeCN/water/0.1% TFA to yield compound 76 as a yellow solid (33 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.18 (1H, s), 9.51 (1H, s), 9.31 (1H, s), 8.95 (2H, br s), 8.65 (1H, d, J=6.2 Hz), 8.55 (1H, d, J=6.1 Hz), 8.12 (1H, d, J=3.0), 7.58 (1H, d, J=2.4 Hz), 5.25 (1H, p, J=8.3 Hz), 3.46 (4H, t, J=5.4 Hz), 3.30 (4H, m), 2.24 (3H, s), 2.18 (2H, m), 2.01 (2H, m), 1.70 (2H, m), 1.55 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 429.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:46][CH:45]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
First, 3.4 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 3.3 g of 2,3-difluoro-4'-[16-hydroxyhexadecyl]oxybiphenyl, 2.3 g of triphenylphosphine, and 50 ml of tetrahyrofuran were placed in a 100 ml flask. Then, 1.5 g of diethyl azodicarboxylate was added dropwise to the reaction mixture at 5° C. Thereafter, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 5.9 g of 16-[2,3-difluorobiphenyl-4'-yl]oxyhexadecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 92.1%). The compound thus obtained had a purity of 98.3% by HPLC.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.CCOCC>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
To a solution of methyl quinoline-6-carboxylate (14 g, 74.8 mmol) in THF (80 mL) was added LiAlH4 (2.84 g, 74.8 mmol) in portions. The reaction was stirred at rt for 20 min. Then water (2.84 mL) and aqueous NaOH (10%, 4.26 mL) were added dropwise to quench the reaction. After stirring for additional 20 min, ether was added and the resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by column chromatography with hexane/EtOAc to afford quinolin-6-ylmethanol (7.6 g, 64%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH2:2][CH3:3].Cl>O1CCOCC1>[NH:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(=O)Nc1cccc(C2CCNCC2)c1
Yield: 99880.7 %

Procedure:
Into a stirred solution of tert-butyl 4-[3-(propionylamino)phenyl]-1-piperidinecarboxylate (18.8 g, 0.0543 mmol) in dioxane (100 mL) at 5° C. was bubbled HCl gas for 2 h. The solvent was removed in vacuo, the residue was dissolved in water (100 mL) and neutralized by adding 10% KOH aqueous solution. The aqueous layer was extracted (3×200 mL) with a mixture of CHCl3/isopropyl alcohol (3:1), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to afford the desired product (12.6 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.32 (d, 1H, J=7.2 Hz), 7.28-7.21 (m, 1H), 7.09 (s, 1H), 6.97 (d, 1H, J=7.6 Hz), 3.18 (d, 2H, J=12.6 Hz), 2.73 (dt, 2H, J=2.2, 11.2 Hz), 2.65-2.57 (m, 1H), 2.38 (q, 2H, J=7.4 Hz), 1.83 (d, 2H, J=12.1 Hz), 1.70-1.61 (m, 3H), 1.25 (t, 3H, J=7.5 Hz); ESMS m/e: 233.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]2[C:9]=1[NH:8][C:7](=[S:10])[NH:6]2.[CH2:15](I)[CH3:16].[OH-].[Na+]>CO>[CH2:15]([S:10][C:7]1[NH:8][C:9]2[C:5](=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:3][C:2]=2[CH3:1])[N:6]=1)[CH3:16]
Reactant: CCI
Reactant: COC(=O)c1sc(C)c2[nH]c(=S)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2,3-dihydro-4-methyl-2-thioxothieno[3,4-d]imidazole-6-carboxylate (1.1 g), ethyl iodide (0.75 g), 2N NaOH (2.4 ml) and methanol (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and there was added water to give crystals. Recrystallization from ethyl acetate--hexane afforded colorless prisms (1.0 g, 83%), m.p. 159°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][N:38]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:39][CH2:40][CH2:41]N>C1COCC1>[CH3:37][N:38]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:39][CH2:40][CH2:41][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: CN(CCCN)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCCN(C)c3ccccc3)cc21
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with N1-Methyl-N1-phenyl-propane-1,3-diamine (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-12 as an oil in 78% yield.