Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C>ClC(Cl)C>[CH3:20][C:17]1[O:16][C:15]([CH2:14][NH2:13])=[CH:19][CH:18]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)=[CH:24][CH:23]=1
Reactant: Cc1ccc(CNc2ccc3c(CN)cccc3n2)o1
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(CNCc4ccc(F)cc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 22 %
Yield: 66 %

Procedure:
A solution of (5-aminomethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (example 126, step B) (95 mg, 0.355 mmol), 4-fluorobenzaldehyde (97 mg, 0.78 mmol) and acetic acid (85.4 mg, 1.42 mmol) in 1,1-dichloroethane (5 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (176 mg, 0.75 mmol) was added, the reaction mixture was allowed to stir for 21 h at room temperature, poured into ice/saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield beside 5-{[bis-(4-fluoro-benzyl)-amino]-methyl}-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (114 mg, 66%) the title compound as light yellow oil (30 mg, 22%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][N:56]1[CH2:62][CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C1C[O:66]CC1>>[CH:46]([OH:47])=[O:66].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:59]3[CH2:60][CH2:61][CH2:62][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: CN1CCCNCC1
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO
Yield: 54 %

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.066 mmol) and N-methyl homopiperazine (39 mg, 0.34 mmol) in THF (1 mL) was heated at 60° C. overnight in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give a white solid of the title compound (28 mg, 54%). LCMS (Method 5): Rt 3.28 min, m/z 775 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.0 Hz), 1.27 (9H, s), 1.47-1.56 (2H, m), 1.62-1.73 (4H, m), 1.75-2.18 (6H, m), 2.28 (3H, s), 2.56-2.63 (4H, m), 2.70-2.77 (4H, m), 2.85 (2H, t, J=6.0 Hz), 2.87-2.95 (1H, m), 3.12-3.20 (1H, m), 3.27-3.35 (1H, m), 4.07 (2H, t, J=5.6 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=3.8 Hz), 6.32 (1H, s), 6.93-6.98 (1H, m), 7.04-7.10 (2H, m), 7.14 (1H, d, J=8.9 Hz), 7.19 (1H, dd, J=9.8 Hz, 2.2 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=4.9 Hz), 7.69 (1H, d, J=1.8 Hz), 8.18 (1H, s), 8.20 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:14]([C:20]5[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.Cl.Cl.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]2[N:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[NH:44][N:43]=2)[CH2:38][CH2:37]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:14]([C:20]5[CH:27]=[CH:26][C:23]([CH2:24][N:36]6[CH2:41][CH2:40][CH:39]([C:42]7[NH:46][C:45]([C:47]8[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=8)=[N:44][N:43]=7)[CH2:38][CH2:37]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C=O)cc5)nc4ccn23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(CN6CCC(c7nnc(-c8ccccn8)[nH]7)CC6)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 13-2 (0.5 g, 1.2 mMol) and 8-5 (0.34 g, 1.3 mMol) in NMP (10 mL) was added triethylamine (0.33 mL, 2.3 mMol) followed by acetic acid (0.13 mL, 2.3 mMol). After stirring overnight at room temperature, sodium triacetoxyborohydride (0.3 g, 1.3 mMol) was added in portions. After stirring for 6 hours, the solution was filtered through a syringe filter and purified on a C18 reverse phase HPLC to give 13-3 as a solid. Mass (M+1) calculated: 644.2993 observed: 644.2988
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][CH:15](N)[CH2:16][OH:17]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:14][CH:15]1[CH2:16][O:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CC(N)CO
Reactant: CCCCCCCCCCCC#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCCC1=NC(C)CO1
Yield: 91.9 %

Procedure:
10.9 g (60 mmoles) of undecyl cyanide was treated with 5 g (66.6 mmoles) of DL-2-amino-1-propanol in presence of 400 mg (1.5 mmoles) of cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 13.2 g (92%) of product was obtained on distillation at 115°-117° C./1-1.5 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: C1COCCN1
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N2CCOCC2)c1I

Procedure:
4-[3-Amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]morpholine [C; R° is CH3CON(CH3), Q is H, Z is morpholino] was prepared from the acid chloride of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and morpholine according to the procedure described in Example 45, part (a). The product obtained was used directly in the procedure described in part (b) below.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10](SC)=[CH:9][CH:8]=2)=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:4][N:3]=1.O[O:22][S:23]([O-:25])=O.[K+].O1CCC[CH2:28]1>CO.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:23]([CH3:28])(=[O:25])=[O:22])=[CH:9][CH:8]=2)=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:4][N:3]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2c(C)noc2-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 3-methyl-4-(4-methylthiophenyl)-5-phenylisoxazole (Step 3) (285 mg, 1 mmol) in tetrahydrofuran and methanol (1:1) was added a solution of Oxone® (900 mg, 1.5 mmol) in water (5 ml). The reaction mixture was stirred rapidly at 25° C. for 3 hours. The reaction mixture was extracted with ethyl acetate and the organic extracts dried. After filtration and solvent removal, the crude residue was recrystallized from ethyl acetate and hexane to give pure product as a crystalline solid (250 mg, 79%): mp 144°-145° C. Anal. Calc'd. for C17H15NO3S (313.38): C, 65.16; H, 4.82; N, 4.47; S, 10.23. Found: C, 65.26; H, 4.78; N, 3.99; S, 10.22.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[CH3:5][C:6](C)=[O:7].C[CH2:10][O:11][Si](OCC)(OCC)OCC.[N+]([O-])(O)=O>C(O)CCC.O>[CH3:1][CH:2]([O:4][C:6]([CH3:5])=[O:7])[CH2:3][O:11][CH3:10]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: CC(C)O
Reactant: CC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCCCO
Solvent: O
Product: COCC(C)OC(C)=O

Procedure:
In another 1-liter flask, 297 grams 2-propanol, 148.560 grams acetone, 139.902 grams TEOS, 19.10 grams MTEOS, 51.7 g PTEOS, 5.624 grams 0.1 M nitric acid and 66.827 grams deionized water were combined. The flask was refluxed and/or heated for 1 to 12 hours. To the solution, 43.93 grams of butanol was added. The solution was filtered to be used in the pH tuning experiments.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)[Br:20]>C(O)(=O)C.O>[Br:20][CH2:19][CH:21]([OH:23])[CH2:22][NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][CH2:22][CH:21]([OH:23])[CH2:19][Br:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: BrCC1CO1
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CBr)ccc(NCC(O)CBr)c21
Temperature: 80 °C
Yield: 209.3 %

Procedure:
1,4-Diaminoanthraquinone (2,5 g, 10.49 mmole) was slurried in 20 ml of glacial acetic acid. Water (1.8 ml) was added, followed by epibromohydrin (0.76 ml, 8.88 mmol). The mixture was heated to 80° C. The remaining epibromohydrin (2.24 ml, 26.18 mmol) was dripped in slowly during 5 hours, while the reaction temperature was held at 80° C. After the addition was complete, the 80° C. temperature was maintained for an additional 2 hours for a total of 7 hours. The reaction mixture was diluted with 20 ml of acetic acid and 28 ml of water. After stirring for a few minutes, the resultant mixture was filtered and the filter-cake was rinsed with 20% aqueous acetic acid followed by water, then air dried. After further drying in vacuo over P2O5, 4.76 g of 1,4-bis(3-bromo-2-hydroxypropylamino)-9,10-anthracenedione was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:18]3[C:17](=[O:19])[N:15]([CH3:16])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=3[N:11]=[CH:10]2)[N:4]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C1(C)C=CC=CC=1>[ClH:1].[CH2:22]([N:24]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:18]3[C:17](=[O:19])[N:15]([CH3:16])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=3[N:11]=[CH:10]2)[N:4]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: Cn1c(=O)c2c(ncn2Cc2noc(CCl)n2)n(C)c1=O
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Product: Cl

Procedure:
9.0 g. of 7-[(5-chloromethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline, 6 cm3 diethylamine and 50 cm3 toluene are heated on water bath for 8 hours under stirring. The mixture is evaporated at reduced pressure and the residue is washed with water, dissolved in 50 cm3 hot ethanol, treated with activated charcoal and treated with ethanol in hydrochloric acid. 8.3 g of 7-[(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline-hydrochloride salt are obtained. M.p.: 207°-210° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:37])(=[N:24]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[O:23])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:37])(=[NH:24])=[O:23])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1OCCCCS(C)(=O)=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(NC(C)C)ncnc2cc1OCCCCS(C)(=N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)-S-methyl-N-[(4-nitrophenyl)sulphonyl]sulphoximide (267 mg, 0.48 mmol) is dissolved in acetonitrile (7 ml), treated with caesium carbonate (266 mg, 0.82 mmol) and thiophenol (86 mg, 0.77 mmol) and stirred at room temperature for 20 hours. The reaction batch is diluted with water and methylene chloride. The organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removal of the solvent and preparative HPLC in 51% yield (126 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][CH2:18][CH3:19])[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:34]([NH:37][CH:38](C)C)(C)[CH3:35].O>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:35]=[CH:34][N:37]=[CH:38][CH:19]=3)[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)NC(C)C
Reactant: CCSc1nc(-c2ccc(OC)c(OC)c2)cc2nccn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2cc3nccn3c(Sc3ccncc3)n2)cc1OC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
7-(3,4-Dimethoxy-phenyl)-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine (335 mg, 1.06 mmol) was dissolved in trifluoroacetic acid (TFA, 5 ml). After 5 min the TFA was evaporated. The residue was dissolved in 10 ml CH2Cl2. The solution was cooled to 0° C. and m-CPBA (70%, 524 mg, 2.12 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 5 h. Diisopropylamine (598 mg, 4.63 mmol) and thiol (254 mg, 2.28 mmol) were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extraction was carried out with CHCl3. The organic layer was washed with brine, sat. NaHCO3, brine and dried over Na2SO4. The organic layer was then concentrated to give the crude product of 7-(3,4-Dimethoxy-phenyl)-5-(pyridin-4-ylsulfanyl)-imidazo[1,2-c]pyrimidine which was purified by column chromatography (160 mg, 41%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:34])[CH:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:14]([CH3:33])=[C:15]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:5]=2[O:4]1.CO.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:2][C:3]1([CH3:34])[CH:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:14]([CH3:33])=[C:15]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:5]=2[O:4]1
Reactant: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 4N hydrogenchloride in ethyl acetate solution (10 ml) was added to a solution of tert butyl 4-(2,2,4,6,7-pentamethyl-3-piperidino-2,3-dihydro-1-benzofuran-5-yl)piperazine carboxylate (1.37 g, 3 mmol) obtained in Example 133 in THF (10 mL)-methanol (10 ml) and the mixture was stirred at 60° C. for 3 hours. After the reaction mixture was cooled to 0° C., the resulting mixture was made weakly alkaline using 1N sodium hydroxide and extracted with ethyl acetate. The organic extract was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain 0.89 g (yield 83%) of the title compound as an amorphous powder.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[CH3:25][S:26]SC>CCCCCC.O1CCCC1>[CH3:25][S:26][CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: CSSC
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CSC)=C21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The starting material is prepared as follows: 36.4 ml of 2.5 M n-butyl lithium in hexane are added dropwise under nitrogen and at room temperature to the stirred suspension of 7.8 g of 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2one in 70 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 45 minutes and cooled in a dry ice-acetone bath. The solution of 5.45 ml of dimethyl disulfide in 60 ml of tetrahydrofuran is added dropwise and the mixture stirred with said cooling for 2 hours. It is quenched by the slow addition of 150 ml of water, the mixture is extracted with chloroform, the extract is dried and evaporated. The residue is crystallized from diethylether and recrystallized from ethyl acetate, to give the 1-methylthiomethyl-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 182°-182°.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][N:33]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: Cc1ccc(C(=O)Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C)nc3)cc2)c2ccccc12
Yield: 72.5 %

Procedure:
Ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (258 mg, 0.83 mmol) and triethylamine (0.4 mL, 2.87 mmol) were dissolved in dichloromethane (15 mL), and in an ice bath, dichloromethane solution (10 mL) of the prepared 6-methylnicotinoyl chloride (about 1.00 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, and chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 258 mg, at a yield of 72.3%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25]N)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(OC)(OC)OC.[CH:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39].[C:42]([BH3-])#[N:43].[Na+]>CO.C(O)(=O)C>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:43]([CH2:42][CH2:14][CH:15]([CH3:28])[CH3:16])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:20])=[CH:17][CH:16]=1)[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(C)CC=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CC(C)CCN(CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)CCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol (0.6 ml). Then, the solution was added with trimethyl orthoformate (30.0 μl), acetic acid (30.0 μl), isovaleraldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (25.3 μl), and sodium cyanoborohydride (14.9 mg), followed by stirring at room temperature for 3 hours.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])(C)C)=[O:11].N1[CH:22]=[CH:21]N=C1.[Si](Cl)([C:26](C)([CH3:28])[CH3:27])(C)C>CN(C=O)C>[OH:9][C@H:7]1[CH2:6][N:5]([C:10]([O:12][CH2:13][C:16]2[CH:22]=[CH:21][CH:28]=[CH:26][CH:27]=2)=[O:11])[C@H:4]([C:3]([OH:2])=[O:17])[CH2:8]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.9 %

Procedure:
Boc-trans-4-hydroxy-L-proline methyl ester (10.35 g, 0.04 mol) was dissolved in DMF (135 mL). Imidazole (13.6 g, 0.20 mol) was added, followed by the addition of tert-butyldimethylsilyl chloride (18.1 g, 0.12 mol) and the solution was stirred overnight at room temperature. DMF was removed via vacuum rotary evaporation and the residue was dissolved in ethyl acetate. The solution was washed with 1M HCl and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (4/1, v/v) to afford 12.83 g (89% yield) of the desired product 1 as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:32])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH:15]([CH3:30])[C:14]1=[O:31].CC(C)=O.CC(O)=O>C1COCC1>[CH3:30][CH:15]1[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH:10]=[O:32])[C:14]1=[O:31]
Reactant: CON(C)C(=O)CCN1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1C(=O)N(CCC=O)CCN1c1cccc(OC(F)(F)F)c1
Temperature: -75 °C
Yield: 80.3 %

Procedure:
Lithium aluminum hydride solution (1 M in THF (0.46 mL, 0.46 mmol) was added dropwise at −30° C. to a solution of N-methoxy-N-methyl-3-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-propionamide (180 mg, 0.46 mmol) in THF (10 mL). The reaction mixture was cooled to −75° C., then acetone (0.59 g, 10 mmol) and AcOH (44 mg, 0.93 mmol) were added dropwise. The reaction mixture was then partitioned between TBME and 1 M aq. KHSO4 solution. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (122 mg, 80%). Light yellow oil, MS: 331.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[OH:19])=[O:13])[C:3]1=[O:21].N1C=CC=CC=1.C(Cl)(Cl)Cl.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[O:19][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[O:13])[C:3]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc(C(=O)c2ccc(C(F)(F)F)n(C)c2=O)c1O
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)c3ccc(C(F)(F)F)n(C)c3=O)cnn2C)cc1
Yield: 90.6 %

Procedure:
To a mixed solution of 4-[1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carbonyl]-5-hydroxy-1-methyl-1H-pyrazole (0.25 g, 0.80 mmol), pyridine (0.13 g, 1.6 mmol) and chloroform (5 mL), p-toluenesulfonyl chloride (0.23 g, 1.2 mmol) was added little at a time. After the stirring for a day at room temperature, the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. After separating the inorganic substance by filtration, the solvent was distilled off under reduced pressure, and thus obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/1.5), to obtain 0.33 g of a subject compound (yield: 92%).