Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](O)=[O:23])=[CH:18]2)(=[O:11])=[O:10].C[N:27](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([NH2:27])=[O:23])=[CH:18]2)(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=O)[nH]c12
Temperature: 25 °C

Procedure:
To a mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxylic acid (3.0 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.65 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.1 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (2.82 g, crude yield 94%) as pale-pink crystals. MS: 360 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[NH:29]1[CH:28]=[C:27]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125° C. for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHz, CDCl3): δ 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES): 316 (M+1).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[NH2:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C=CC=CC=1>[N:39]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:31]=[CH:30][C:29]=2[N:28]=[CH:1]1
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Triethyl orthoformate (12.74 mL, 76.64 mmol) and pyridinium p-toluenesulfonate (0.200 g) were sequentially added to a solution of ethyl 6-[(3-aminoquinolin-4-yl)amino]hexanoate (16.5 g, 54.7 mmol, prepared as described in Part A of Example 8) in toluene (200 mL), and the reaction was heated at reflux under a Dean-Stark trap for four hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 16.4 g of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:19][CH2:20][CH2:21][O:22]4)[CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: Fc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1F
Agent: [Ni]
Solvent: CCO
Product: Fc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1F

Procedure:
A solution of 4.9 g of 8-[4-(3,4-difluorophenyl)-3-cyclohexenyl]-1.4-dioxaspiro[4.5]decane in 670 ml of ethanol was hydrogenated with 1.0 g Raney nickel at 50° C. under normal pressure until the hydrogen uptake came to a standstill. The reaction mixture was filtered and the filtrate was concentrated. Threefold recrystallization of the obtained crude product (5.0 g) from diethyl ether/hexane yielded 2.52 g of 8-[trans-4-(3,4-difluorophenyl)cyclohexyl]-1, 4-dioxaspiro[4.5]decane. The mother liquors were evaporated. Isomerization of the residue (2.2 g) under inert gas with 11 ml of dimethyl sulfoxide and 0.344 g of potassium tert. butylate at 100° C. for 7 hours yielded after twofold recrystallization further 0.7 g of 8-[trans-4-(3,4-difluorophenyl)cyclohexyl]-1,4-dioxaspiro-[4.5]-decane.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(NC2=NCCN2)cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(NC2=NCCN2)cc2cc[nH]c12

Procedure:
A solution of 7-isopropenyl-5-(2-imidazolin-2-ylamino)indole (0.25 g, 1.0 mmol) and 10% Pd/C (100 mg) in 10 mL of MeOH was stirred for 12 h under H2 (18 psi). The reaction mixture was filtered and concentrated in vacuo, yielding an oil which, in NMR analysis, was highly pure and corresponds to the desired product. The product obtained was converted to the succinate salt and recrystallized from isopropanol-CHCl3 to afford 0.13 g of the product as a light brown solid: mp 254-255° C.; H NMR (CD3OD) δ7.28 (d, J=1.8 Hz, 1H), 7.27 (d, J=3.2 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 3.67 (s, 4H), 3.30 (hep, 1H), 2.18 (s, 3H); Anal. Calc. for C14H18N4.1.0C4H6O4 requires C, 60.32; H, 6.19; N, 15.63. Found: C, 60.17; H, 6.25; N, 15.59.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:30](O)=[O:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:34][O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:38][C:30](=[O:31])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To N-Boc-4-(tributylstannyl)-L-phenylalanine (1.67 g, 3.00 mmol, 1.00 equiv) and L-phenylalanine methyl ester hydrochloride (647 mg, 3.00 mmol, 1.00 equiv) in CH2Cl2 (30 mL) at 0° C. was added EDCI (1.15 g, 6.00 mmol, 2.00 equiv), HOBt (810 mg, 6.00 mmol, 2.00 equiv), n,n-diisopropylethyl amine (1.56 mL, 9.00 mmol, 3.00 equiv) and 4-(Dimethylamino)pyridine (36 mg, 0.30 mmol, 0.10 equiv). After stirring for 1 hr at 0° C., the reaction mixture was allowed to stirred at room temperature for 12 hr. The reaction mixture was quenched with water (20 mL), and CH2Cl2 (10 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with brine (10 mL) and dried (Na2SO4). concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane/EtOAc 3:1 (v/v) to afford 1.72 g of the title compound as a white foam (80% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[NH2:25][C:23]([C:22]1[C:21]([CH3:29])=[C:20]([CH:28]=[CH:27][CH:26]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17])=[O:24]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(C(N)=O)c3C)c2cc1OC
Temperature: 100 °C
Yield: 63.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-amino 2-metylbenzamide (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 18 h. After cooling the reaction mixture was diluted with water (20 ml) and made alkaline with 1 M NaOH. The precipitate was filtered of, rinsed with water and dried to give the title compound (41 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=N.O[N:45]=[C:46]([NH2:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([S:54][CH3:55])=[CH:50][CH:49]=1>ClCCl.O1CCOCC1>[CH3:55][S:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C:46]2[N:45]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:56]=2)=[CH:53][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CSc1ccc(CC(N)=NO)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CSc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 92 h
Yield: 54.2 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (1.00 g, 4.36 mmol), 1-hydroxybenzotriazole (589 mg, 4.36 mmol) and N-methylmorpholine (0.97 mL, 8.72 mmol) were dissolved in dicloromethane (50 mL), under argon, and (3-dimethylaminopropyl)carbodiimide hydrochloride (921 mg, 8.72 mmol) and N′-hydroxy-2-[4-(methylthio)phenyl]ethanimidamide (855 mg, 4.36 mmol) were added. The mixture was stirred at room temperature for 92 hours. The organics were washed with sodium hydroxide (0.1N) and citric acid (0.5M), dried (phase separating filter) and the solvent evaporated to give a yellow oil which was redissolved in 1,4-dioxane (100 mL) and heated to reflux for 5 hours, cooled and the solvent evaporated and chromatographed (50 g Silica Isolute, eluent 20% ethyl acetate/isohexane) to give a yellow oil, tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (920 mg, 54%); NMR (CDCl3): 1.46 (9H, s), 1.71-1.87 (2H, m), 2.03 (2H, m), 2.48 (3H, m), 2.92 (2H, t), 3.05 (1H, m), 4.00 (2H, s), 4.07 (2H, m), 7.24 (4H, m).
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[C:34]#[N:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Fe].O>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:18]2[C:17]3[C:22](=[CH:23][C:14]([O:13][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:15]([C:34]#[N:35])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Iron powder (0.6 g), ammoniumchloride (1.4 g), ethanol (100 ml) and water (30 ml) were added to the 7-benzyloxy-6-cyano-4-(4-nitrophenoxy)quinoline obtained in Production Example 5, and the mixture was stirred at 90° C. for 2.5 hours. The reaction system was returned to room temperature and then filtered with celite, the filtrate was subjected to liquid separation, and the organic layer was washed with water and saturated brine in that order, dried over sodium sulfate and then concentrated to dryness under reduced pressure to obtain 1.31 g of a crude product containing the target substance. The crude product was used directly for the following reaction. (Production Example 7).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)([OH:3])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43](=[N:45]O)[NH2:44])[CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:1]3[O:3][N:45]=[C:43]([C:39]4[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=4)[N:44]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3nc(-c4cccnc4)no3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(nn) In an analogous manner to that described in Example 38, by condensing tert-butyl (3RS,4RS)-4-(4-carboxymethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 86(mm)] with 3-pyridinamidoxime in the presence of HBTU and subsequent cyclization there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-pyridin-3-yl-[1,2,4]oxadiazol-5ylmethoxy)-phenyl]-piperidine-1-carboxylate as a yellowish solid; MS: 593 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28](=[S:30])[NH2:29])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:31]([O:36][CH2:37][CH3:38])(=[O:35])[C:32]#[C:33][CH3:34].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:37]([O:36][C:31](=[O:35])[CH2:32][CH:33]1[S:30][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:29][CH2:34]1)[CH3:38]
Reactant: CC#CC(=O)OCC
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 90 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carbothioamide (1.4 g) in tetrahydrofuran (10 mL) and toluene (15 mL) were added ethyl 2-butynoate (0.88 g) and tri-n-butylphosphine (0.63 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.05 g, yield 60%) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][O:31]C3CCCCO3)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11](=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][OH:31])[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11](=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(CN2CC(CCCO)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 11.5 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-2-one (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:12]2[C:13]([C:21]([OH:23])=O)=[N:14][N:15]([CH:18]3[CH2:20][CH2:19]3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:12]3[C:13](=[N:14][N:15]([CH:18]4[CH2:19][CH2:20]4)[C:16]=3[CH3:17])[C:21]2=[O:23])[CH:3]=1
Reactant: Cc1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)nn1C1CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1c2c(nn1C1CC1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylic acid (Step 17.7). tR: 4.28 min (HPLC 1); tR: 0.96 min (LC-MS 2); ESI-MS: 429/431 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.19 (m, 4H) 2.14 (s, 3H) 3.43 (s, 3H) 3.57-3.68 (m, 1H) 6.13 (s, 1H) 7.27 (d, J=8.6 Hz, 2H) 7.36 (d, J=8.6 Hz, 2H) 7.89 (d, J=2.3 Hz, 1H) 7.92 (d, J=2.3 Hz, 1H).
Reaction SMILES: [H][H].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:22]([OH:23])[CH2:21][C:20]3[C:19]([OH:24])=[CH:18][C:17]([OH:25])=[CH:16][C:15]=3[O:14]2)=[CH:9][C:8]=1[OH:26])[CH:4]=[CH2:5]>[Pd].C(O)C>[OH:26][C:8]1[CH:9]=[C:10]([CH:13]2[CH:22]([OH:23])[CH2:21][C:20]3[C:19]([OH:24])=[CH:18][C:17]([OH:25])=[CH:16][C:15]=3[O:14]2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: C=CCOc1ccc(C2Oc3cc(O)cc(O)c3CC2O)cc1O
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(C2Oc3cc(O)cc(O)c3CC2O)cc1O
Reaction time: 3 h

Procedure:
To a suspension of 10% palladium on carbon (5 mg, 10 mol %) in 5 mL ethanol which had been stirred vigorously under 1 atmosphere of hydrogen for 10 minutes then cooled with an ice/methanol bath was added a solution of 2-(4-Allyloxy-3-hydroxy-phenyl)-chroman-3,5,7-triol (50 mg) in 2 mL ethanol. The ice bath was removed and the reaction was stirred for 3 h under 1 atmosphere of hydrogen. The mixture was passed through a 0.22 micron nylon syringe filter and concentrated to a foam which was dissolved in acetonitrile/water, frozen, and lyophilized give 2-(3-Hydroxy-4-propoxy-phenyl)-chroman-3,5,7-triol as a white powder.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(O)O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccccc1-c1ccccn1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
A mixture of 2-boronobenzoic acid (400 mg, 2.4 mmol), 2-bromopyridine (416 mg, 2.6 mmol), K2CO3 (994 mg, 7.2 mmol) and Pd(dppf)Cl2 (20 mg) in dioxane (8 mL) and H2O (2 mL) was stirred at 125° C. for 30 min. under microwave heating under N2. The catalyst was filtered, and the filtrate was acidified with 2N HCl to pH 5˜6. The solution was concentrated, and the residue was dissolved in MeOH and filtered. The filtrate was concentrated, and the residue was purified by prep-TLC to give the title compound (205 mg, Yield 42.9%). LCMS (m/z): 200.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1

Procedure:
Compound 165A was prepared from racemate 1G and benzaldehyde by procedures analogous to those described in Example 22A.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:21][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:22][CH3:23])=[CH:11][CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OC)cc1
Solvent: CO
Solvent: c1ccncc1
Product: CCN(CC)C(=O)c1ccc(C(OC(C)=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(4-Diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl alcohol (14.14 g) was dissolved in pyridine (280 ml), added with acetic anhydride (140 ml) with ice cooling and stirred at room temperature for 15 hours. After the reaction mixture was added with methanol (140 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH3:32][NH2:33].C1COCC1>C1COCC1>[CH3:32][NH:33][C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1
Reactant: CN
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Solvent: C1CCOC1
Product: CNc1nc(SC)nc2c1C(=O)N(c1cccc(-c3nn(C)c(=O)o3)c1)C[C@@H]1CCCN21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 71.2 %

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (50.0 mg, 0.109 mmol) obtained in Step 8 was dissolved in THF (5 mL), and the mixture was stirred at room temperature for 75 minutes after adding a 2.0 mol/L methylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-methylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (35.2 mg, 71%).