Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:15][CH2:16][O:17][CH3:18])[CH:3]=1.[OH-].[K+]>CO.O>[OH:1][C:2]1[C:11]([CH:12]([CH3:13])[CH3:14])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][O:17][CH3:18])[CH:3]=1
Reactant: COCOc1cc(O)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCOc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 25 %

Procedure:
The crude methyl 4-hydroxy-5-isopropyl-2-(methoxymethyloxy)benzoate was dissolved in methanol (20 ml) and water (8 ml), aqueous potassium hydroxide (50% w/v, 5 ml) was added and the mixture was stirred and held at reflux for 16 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The organic material was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford a yellow oil that was subjected to column chromatography on a Strata-NH2 cartridge. Elution with 2M ammonia in methanol afforded crude 4-hydroxy-5-isopropyl-2-(methoxymethyloxy)benzoic acid (180 mg, 25%) as a pale grey solid that was used without further purification. MS: [M+Na]+ 263.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][C@@H:2]1[CH:3]=[CH:4][C@@H:5]([OH:7])[CH2:6]1
Reactant: C1=COCCC1
Reactant: O[C@@H]1C=C[C@@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O[C@@H]1C=C[C@@H](OC2CCCCO2)C1
Yield: 57.1 %

Procedure:
Ten milligrams of (S)-trans-3,5-dihydroxycyclopent-1-ene and 8 milligrams of dihydropyran were stirred at room temperature for 24 hours in 1.0 milliliter of methylene chloride in the presence of 0.1 milligram of p-toluenesulfonic acid. Next, the organic solution was washed with an aqueous sodium bicarbonate solution and then with an aqueous sodium chloride solution, after which it was dried with anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. When the resulting crude product was purified by thin-layer chromatography (n-hexane:ethyl acetate = 6:4), 10 milligrams (54%) of (S)-trans-5-tetrahydropyranyloxycyclopent-1-en-3-ol was obtained. The IR and NMR of this product was in complete agreement with those of the product obtained in Example 36.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=O)=O.[C:33]1([N:39]2[C:43]3([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:42](=[O:49])[NH:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:32][C:27]1[CH:26]=[C:25]([C:8]2([CH2:7][CH2:6][N:46]3[CH2:45][CH2:44][C:43]4([N:39]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:40][NH:41][C:42]4=[O:49])[CH2:48][CH2:47]3)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]3[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:9]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cccc(OC)c1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N1CCC(CCN2CCC3(CC2)C(=O)NCN3c2ccccc2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 51.2 %

Procedure:
2-[1-(2,6-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl methanesulfonate (200 mg, 0.398 mmol), and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (100 mg, 0.432 mmol) were dissolved in THF/H2O (4 mL/1 mL) and treated with potassium carbonate (110 mg, 0.796 mmol, 2 eq.) at reflux for 22 hours. The solution was concentrated in vacuo and the aqueous phase was extracted (3x) with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 130 mg (51%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15]([C:17]1[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[C:28]([F:31])([F:30])[F:29])=O)[CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1[O:13][C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])=[N:14][C:8]=1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Yield: 97 %

Procedure:
A solution of N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (Preparation 43A, 135.6 mg, 0.315 mmol) and phosphorous oxychloride (1.468 mL, 15.75 mmol) in anhydrous dichloroethane (5 mL) was heated under an argon atmosphere at 85° C. for 13 hrs. The solvent and excess phosphorous oxychloride were evaporated off and the residue was purified by Combiflash (12 g silica gel) eluting with 2:8 ethyl acetate-hexane to give the desired 7-methoxy-2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazole (126 mg, 97% yield) as an oil. 1H NMR (400 MHz, MeOD) δ ppm 7.62-7.66 (2H, m), 7.53-7.60 (3H, m), 7.48 (1H, d, J=8.14 Hz), 6.94 (1H, d, J=2.20 Hz), 6.89-6.93 (1H, m), 3.84 (3H, s), 3.18 (2H, t, J=8.03 Hz), 2.95-3.01 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[NH:8][C:7]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]1[CH:38]=[C:37]([C:39]2[S:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[O:36][N:35]=1.C(O)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH2:19]2)[N:8]([CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[O:36][N:35]=2)[C:7]=1[CH3:24]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)NC2CCN(C(C)C)CC2)c1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)CCc1c(C)c(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
55 mg (0.16 mmol) of 3-[5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester were dissolved in DMF (5 mL). Subsequently 103 mg (2 equiv.) of Cs2CO3 and 65.8 mg (1.5 equiv.) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 4 h at 800 C. Because of low conversion 206 mg (4 equiv.) of Cs2CO3 were added stirring was continued for 7 h at 80° C. The reaction mixture was acidified by the addition of acetic acid and concentrated. The residue was purified by preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) to give 3-[1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester (34 mg) as a colorless amorphous material. MS (ESI+): m/e=548 [M+H]+, chloro pattern.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COCOc1ccc(I)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(-c2ccccn2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml). Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a white powder.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19](C)[C:20](=O)OC(C)(C)C)[CH2:15][CH2:14]2)=[N:5][N:4]=1>CO>[ClH:2].[ClH:1].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][CH3:20])[CH2:17][CH2:18]2)=[N:5][N:4]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Cl)c3ccccc23)CC1
Agent: Cl
Solvent: CO
Product: CNC1CCN(c2nnc(Cl)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.6 %

Procedure:
Add hydrogen chloride (4.0 N in dioxane, 100 mL; 400 mmol) to a solution of tert-butyl 1-(4-chlorophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (7.60 g; 100 equiv; 20.2 mmol) in methanol (100 mL). Stir at room temperature one hour. Remove the solvent under reduced pressure to obtain the title compound (7.05 g, 100%). ES/MS m/z 277.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[CH3:35][O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:32]=[CH:33][CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][CH:47]([N:50]5[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]5)[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH3:35])[N:7]=2)[CH:19]=1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3c(F)cccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3c(F)cccn23)n1
Temperature: 175 °C
Yield: 76.5 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 188, step A) (80 mg, 0.17 mmol) and 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, step B) (61 mg, 0.17 mmol) in 2,2,2-trifluoroethanol (0.80 mL) was added 4 M HCl in dioxane (84 μL, 0.33 mmol). The mixture was stirred and heated on a microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (111 mg, 0.13 mmol, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.21 (br s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H, J=5.13 Hz), 8.07 (d, 1H, J=7.88 Hz), 7.83 (d, 1H, J=7.70 Hz), 7.62 (t, 1H, J=7.70 Hz), 7.34-7.45 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.92-6.99 (m, 1H), 6.66-6.69 (m, 1H), 6.46-6.50 (m, 2H), 3.79 (s, 3H), 3.71-3.76 (m, 2H), 3.06-3.11 (m, 4H), 2.86 (s, 3H), 2.57-2.71 (m, 5H), 2.38-2.46 (m, 1H), 1.80-1.87 (m, 2H), 1.48-1.60 (m, 2H). MS (ESI): 812 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:26]([OH:35])[C@@H:27]([C@H:29]([C@@H:31](CO)[OH:32])[OH:30])[OH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:26]([C@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:35])=[O:7]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
1.0 g (2.8 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 0.86 g (2.8 mmol) of xylitol and 0.78 g (5.7 mmol) of potassium carbonate in dry N,N-dimethylformamide (2.5 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 24 hours, the potassium carbonate was separated by filtration. The resulting solution was diluted with t-butylmethylether, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain 146 mg of the title compound (12% yield) as a colorless viscous product.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:11]=[C:10]2[N+:32]([O-:34])=[O:33])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C[O:36][C:37]1C(OC)=C(C=C[CH:56]=1)C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(OCC)(=O)C>[C:37]([O:4][C@@H:3]1[C@@H:5]([CH2:7][OH:8])[O:6][C@@H:1]([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:11]=[C:10]2[N+:32]([O-:34])=[O:33])[CH2:2]1)(=[O:36])[CH3:56]
Reactant: O=C(CCCCCNC(=O)C(F)(F)F)NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2cc(C#CCNC(=O)CCCCCNC(=O)C(F)(F)F)cc2[N+](=O)[O-])O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-[3-(6-trifluoroacetamidohexanamido)-1-propynyl]-2-nitropyrrole (394 mg, 803 μmol) was azeotroped three times with anhydrous pyridine in a 50 mL flask and dissolved in anhydrous pyridine (4 mL). To this solution, dimethoxytrityl chloride (286 mg, 844 μmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was added to ethyl acetate/water, and the aqueous layer was removed. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and then evaporated to remove the solvent. The resulting crude product was purified by silica gel column chromatography (0-0.5% CH3OH in CH2Cl2) to give a tritylated product as an amorphous substance (543 mg). 1-(2-Deoxy-5-O-dimethoxytrityl-β-D-ribofuranosyl)-4-[3-(6-trifluoroacetamidohexanamido)-1-propynyl]-2-nitropyrrole (542 mg, 684 μmol) was azeotroped three times with anhydrous pyridine in a 30 mL flask and dissolved in anhydrous pyridine (7 mL). To this solution, acetic anhydride (169 μL, 1.79 mmol) was added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and then evaporated to remove the solvent. The resulting crude product was dissolved in anhydrous dichloromethane (68 mL). To this solution, dichloroacetic acid (680 μL) was added while stirring at 0° C. and further stirred for 15 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and then evaporated to remove the solvent. The resulting oil was purified by silica gel column chromatography (2% CH3OH in CH2Cl2) to give the desired product as an amorphous substance (328 mg, 77%, yield for 2 steps).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:4])=[O:3].BrC1C=CC(F)=CC=1CO[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[Cl:1][S:2]([C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[CH2:7][O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2S(=O)(=O)Cl)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cc(F)ccc2Br)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cc(F)ccc2S(=O)(=O)Cl)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 215, starting from tert-butyl (R)-3-(2-bromo-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 220).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)=O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)OC
Product: COC(=O)c1ccc2[nH]cc(I)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 3-Iodo-1H-indole-5-carboxylic acid (8.0 g, 27.68 mmol) in DMF (80 mL) was added potassium carbonate (4.2 g, 30.44 mmol) and heated at 60° C. for 5 min. Dimethylsulphite (3.5 g, 27.68 mmol) was added and the resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was then added ice cold water and extracted with EtOAc (240 mL). The organic layer was dried over Na2SO4, filtered, concentrated to dryness. The crude solid was washed with n-pentane to obtain the title compound (8.0 g, 95%) as a white solid. MS (ESI, pos. ion) m/z: 299.9 (M−1).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1.O.NN>[Ni].C(O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.5 gm (36.9 mmols) of 5-methyl-6-[3'-nitro-4'-benzylamino-phenyl]-4,5-dihydro-3(2H)-pyridazinone were added to a mixture of 20 ml of 99% hydrazine hydrate and 350 ml of ethanol, and then 10 gm of Raney nickel were added. After 24 hours' stirring at room temperature, the solid components were suction-filtered off, dissolved in dimethyl formamide, the catalyst was filtered off, and the filtrate was evaporated. The crystalline residue thus obtained was digested with ethanol, washed with ether and dried.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29](O)(=[O:35])[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].C1CCC(N=C=NC2CCCCC2)CC1.C(OC)(C)(C)C>C(Cl)Cl>[C:29]([C@:18]1([OH:19])[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:35])[CH:30]=[CH:31][CH2:32][CH2:33][CH3:34]
Reactant: C=CCCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCC=CC(=O)[C@]1(O)CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of cholesterol (2.0 g, 5.17 mM) in methylene chloride (20 mL) was added 5-hexenoic acid (0.68 mL, 5.69 mM) followed by the addition of DCC (1.60 g, 7.76 mM) and 4-PP (0.115 g, 0.78 mM) under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 1 h and worked up with the addition of methyl t-butyl ether (60 mL). The urea was filtered off, and the product was transferred to a separatory funnel, washed with 1N HCl (10 mL), water (30 mL) and brine (30 mL). The product was filtered after drying over MgSO4 and the solvent was evaporated to leave a residue. The product obtained in >95% yield was characterized by 1H NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:18][OH:19])=N)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].C(=O)([O-])O.[Na+].[C:30]([C:32]1[C:33]([NH2:39])=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=1)#[CH:31].C(N(CC)CC)C>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[CH:31]=[C:30]([C:32]3[C:33]([NH2:39])=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=3)[O:19][N:18]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(Cc1ccc(OCc2ccccc2)cn1)NO
Reactant: C#Cc1ccc(N)nc1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cn3)no2)c(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
To a mixture of 2-(5-benzyloxy-pyridin-2-yl)-N-hydroxy-acetamidine (50 mg, 0.19 mmol) described in Manufacturing Example 127-1-5 and a 5 N hydrochloric acid aqueous solution (1 mL) was added sodium nitrite (20 mg, 0.29 mmol) at 0° C., which was stirred for 20 minutes at 0° C. Sodium hydrogencarbonate and water were added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a tetrahydrofuran (3 mL) solution of this residue were added 3-ethynyl-pyridin-2,6-diamine (10 mg, 0.39 mmol) described in Manufacturing Example 13-1-3 and triethylamine (27 μL, 0.19 mmol), which was stirred for 40 minutes at 50° C. under nitrogen atmosphere. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1), and then purified further by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.7 mg, 4.0%) as a ditrifluoroacetic acid salt.