Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[CH:2].[N:25]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1)=[N+:26]=[N-:27].[Na+].[Cl-]>CC(O)(C)C.O>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:25]2[CH:2]=[C:1]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]4[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[N:27]=[N:26]2)[CH2:29]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: C#Cc1ccc2c(c1)c(-c1ccncc1)nn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N=[N+]=[N-])C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(=O)OC(C)(C)C)nn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
Tert-butyl 5-ethynyl-3-(pyridin-4-yl)-1H-indazole-1-carboxylate (0.385 g, 1.2 mmol) and (R)-tert-butyl 3-azidopiperidine-1-carboxylate (0.273 g, 1.2 mmol) were suspended in t-BuOH:H2O (1:1, 15 mL:15 mL) and then CuSO4.5H2O (0.060 g, 0.24 mmol) and Na-Ascorbic acid (0.096 g, 0.48 mmol) were added sequentially. Reaction mixture was stirred vigorously at room temperature overnight. After the completion of reaction, added sat. NaCl (30 mL), extracted with EtOAc (3×50 mL), evaporated the organic solvent to give (R)-tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole-1-carboxylate (0.81 g) which was used for next step without purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
A solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 0.5 g, 2.36 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. Et3N (0.5 mL, 3.54 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.2 mL, 2.60 mmol). The reaction mixture was allowed to warm up to ambient temperature and stirred for 1 h and diluted with CH2Cl2. The mixture was washed with water, saturated aqueous NaHCO3, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 0.71 g of the crude 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate as a light brown solid, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.90 (septet, 1H, J=6.2 Hz), 4.25-4.15 (m, 2H), 4.06 (d, 2H, J=6.6 Hz), 3.01 (s, 3H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.80-1.65 (m, 2H), 1.30-1.15 (m, 8H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:32][C:33](O)=[O:34])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=12.Cl.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][CH2:41][N:42]=[C:43]=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Cl:10][C:11]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:32][C:33]([N:42]3[CH2:41][CH2:40][CH:39]([N:38]([CH3:47])[CH3:37])[CH2:43]3)=[O:34])[N:24]=[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:12]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and N,N-dimethylpyrrolidine (34 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h then N,N-dimethylpyrrolidine (10 mg, 0.09 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.15 mmol) were added. After a further 3.5 h the reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 67 as a white solid (27.3 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[N:12]=[CH:11][C:10]([C:13](=[C:19]([CH3:21])[CH3:20])[C:14]([O:16]CC)=[O:15])=[CH:9][N:8]=1)([CH3:6])[CH3:5]>C(O)(C)C.O>[CH3:6][C:4]([C:7]1[N:8]=[CH:9][C:10]([C:13](=[C:19]([CH3:21])[CH3:20])[C:14]([OH:16])=[O:15])=[CH:11][N:12]=1)([CH3:3])[CH3:5]
Reactant: CCOC(=O)C(=C(C)C)c1cnc(C(C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)=C(C(=O)O)c1cnc(C(C)(C)C)nc1
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide 0.24 g) and ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.4 g) in isopropanol (10 cm3) and water (2 cm3) was heated to the reflux temperature for a period of 3 hours. After cooling to the ambient temperature the crude reaction mixture was concentrated by evaporation of the solvent under reduced pressure, and the residue was dissolved in water, and extracted with ethyl acetate. The aqueous portion was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to give 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoic acid, containing a small amount of 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-3-enoic acid. The crude produce was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:25]2[S:26][CH:27]=[C:23]([S:22][CH3:21])[N:24]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: CSc1csc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1csc(NC(=O)c2cccc(OC(C)=O)c2)n1
Temperature: 25 °C
Yield: 121.4 %

Procedure:
Into a solution of 511 (0.815 g, 4.10 mmol) and dry THF (25.0 mL) was added triethylamine (0.572 mL, 4.10 mmol), followed by a solution of the 508 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL). The reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed once with water, three times with saturated aqueous. sodium bicarbonate solution, and once with brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 85 (1.28 g, >100%) as a red foam. The crude product was dissolved in dichloromethane. Silica gel was added to the dichloromethane solution and the suspension was concentrated in vacuo. The residue was loaded on top of a 90 g silica gel cartridge and eluted down the column using a solution of 20% ethyl acetate in hexane. Appropriate fractions of the major product were combined and concentrated in vacuo to give 85 (0.614 g, 58%) as a tan solid. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5](=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[I:18]I>C(O)(=O)C>[I:18][C:11]1[CH:12]=[C:6]([C:5]([NH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[CH3:1])=[O:13])[C:7]([OH:8])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1NC(=O)c1ccccc1O
Reactant: II
Solvent: CC(=O)O
Product: Cc1ccccc1NC(=O)c1cc(I)ccc1O

Procedure:
45.4 g. of 2'-methyl salicylanilide are dissolved in about 170.0 g. of glacial acetic acid. A solution 50.8 g. of iodine in 20 g. of glacial acetic acid is added, drop by drop, to said solution with agitation and moderately cooling. After said reaction is completed, 70.6 g. of 5-iodo-2'-methyl salicylanilide are obtained by filtration. Said compound is dissolved in 500 cc. of glacial acetic acid and 150 g. of ethyl acetate. 7.0 g. of chlorine are introduced into said solution under existence of a little amount of iron powder at about 40° C. to obtain 5-iodo-2'-methyl-4'-chloro salicylanilide. Resulting compound (compound No. 3) forms slightly yellowish powder having properties shown in Table 3 by recrystallizing from ethyl acetate.
Reaction SMILES: Cl.[F:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([F:31])[CH:24]=1.[BH4-].[Na+]>CO>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:14][C@H:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:7]=[N:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:10]2)=[C:25]([F:31])[CH:24]=1
Reactant: NC1CCN(c2ccc(F)nc2)C1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3F)C2)cn1

Procedure:
Dissolve 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.20 mmol) in methanol (1 mL). Add triethylamine (90 μL, 0.65 mmol) and 4-chloro-2-fluorobenzaldehyde (35 mg, 0.22 mmol), vortex and let sit overnight at room temperature. Add sodium borohydride (15 mg, 0.39 mmol) and let sit 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200 (1.5 g). Wash with methanol and discard the washing, then elute with 5% triethylamine in methanol. Concentrate to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in vacuum oven at 50° C. overnight to give the title compound as its hydrochloride salt (53 mg, 74%). 1H NMR (400 MHz, MeOH-d4) δ 7.63 (t, 1H, J=8.0 Hz), 7.58-7.57 (m, 1H), 7.45 (dd, 1H, J=9.6, 2.0 Hz), 7.40 (dd, 1H, J=8.0, 2.0 Hz), 7.36-7.32 (m, 1H), 7.00 (dd, 1H, J=8.8, 2.8 Hz), 4.44 (s, 2H), 4.21-4.15 (m, 1H), 3.74-3.61 (m, 3H), 3.42-3.36 (m, 1H), 2.68-2.60 (m, 1H), 2.38-2.29 (m, 1H), MS (ES): m/z=324 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+].O>CO>[C:14]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of methyl-indole-6-carboxylate in MeOH (1.7 M) was added cyclohexanone (3.0 eq.) followed by 30% NaOMe in MeOH (6.0 eq.) in 100 ml portions over 20 min. The resulting mixture was stirred at RT for 45 min and refluxed for 8 h. Water was added, and the mixture stirred at RT until all solids had dissolved. The organic solvent was removed under vacuum and the pH of the aqueous phase adjusted to 1, by slow addition of concentrated HCl at 0° C. The precipitate was isolated by filtration, and then washed with water, until the pH of the water reached 6-7. Drying under high, vacuum gave the title compound as a beige solid (100%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.49-1.98 (m, 8H), 6.22 (bs, 1H), 7.50 (s, 1H), 7.64 (d, J 7.6, 1H), 7.75 (d, J 7.6, 1H), 8.02 (s, 1H), 11.39 (s, 1H); MS (ES+) m/z 242 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([NH:34][C@H:35]([CH:57]=O)[CH2:36][S:37][C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:57][C@@H:35]([NH:34][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:36][S:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)cc1-c1ccccc1
Reaction time: 12 h
Yield: 67 %

Procedure:
To a mixture of 4-amino-2-phenylbenzoyl-(S)-methionine methyl ester hydrochloride (1.27 g, 3.22 mmol) in 20 mL of methanol was added N-Boc-S-trityl-(L)-cysteinal (1.0 eq, according to 1H NMR determination of aldehyde percentage) and sodium cyanoborohydride (400 mg, 2.0 eq). The mixture was stirred for 12 hr. After the evaporation of solvents, the residue was extracted with ethyl acetate and concentrated sodium bicarbonate. After removing solvents, the residue was purified through flash column chromatography (1:1=hexane:ethyl acetate, silica) to give the product 1.67 g (yield 67%). 1H NMR (CDCl3) δ 7.65 (d, 8.6 Hz, 1H), 7.34-7.42 (m, 11H), 7.18-7.29 (m, 9H), 6.52 (dd, 2.3 and 8.1 Hz, 1H), 6.34 (d, 2.3 Hz, 1H), 5.65 (d, 7.7 Hz, 1H), 4.64 (ddd, 1H), 4.55 (d, 8.1 Hz, 1H), 4.19 (br t, 1H), 3.78 (br m, 1H), 3.64 (s, 3H), 3.09 (t, 6.1 Hz, 2H), 2.44 (m, 2H), 2.04-2.10 (m, 2H), 2.00 (s, 3H), 1.81-1.90 (m, 1H), 1.60-1.70 (m, 1H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 172.0, 168.3, 155.7, 149.4, 144.3, 141.6, 141.1, 131.3, 129.5, 128.7, 128.5, 127.9, 127.7, 126.8, 122.6, 113.6, 111.3, 79.8, 67.1, 52.2, 51.7, 49.5, 47.2, 34.3, 31.6, 29.4, 28.2, 15.2.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[N:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](=[O:18])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[N:49]([CH:9]1[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[N:11]([CH2:13][C:14]([F:15])([F:17])[F:16])[C:10]1=[O:18])=[N+:50]=[N-:51]
Reactant: O=C1CN=C(c2ccccc2)c2cccc(Cl)c2N1CC(F)(F)F
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1N=C(c2ccccc2)c2cccc(Cl)c2N(CC(F)(F)F)C1=O
Reaction time: 0.25 h

Procedure:
A solution of 9-chloro-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.287 g, 0.813 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C., and potassium t-butoxide (0.905 mL, 1 M in tetrahydrofuran) was added. After 15 min, 2,4,6-triisopropylbenzenesulfonylazide (0.976 mL, 1M in tetrahydrofuran) was added. After 15 min, acetic acid (0.186 mL, 3.2 mmol) was added and the reaction warned to room temperature and stirred for 3.5 h. Workup with ethyl acetate and saturated sodium bicarbonate solution, followed by saturated brine and drying gave a solid. Tetrahydrofuran (30 mL) was added, the solid filtered, and the filtrate concentrated to obtain the title compound. MS 394 (M+1) 1H NMR (500 MHz, CDCl3) δ 7.77–7.20 (m, 8H), 6.40 (s, 1H), 5.20 (m, 1H), 4.30 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:20]=1[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1.COC(C)(C)C>[CH3:16][C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=[C:2]([O:1][CH2:21][C:20]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:19]=3[F:18])[N:7]2[N:8]=1
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: OCc1c(F)ccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
1.2 g (5.25 mmol) of ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 8A were dissolved in 48 ml of THF. 1.7 g (10.50 mmol) of 2,3,6-trifluorobenzyl alcohol and 2.9 g (11.03 mmol) of triphenylphosphine were added. Subsequently, 2.2 ml (11.03 mmol) of diisopropyl (E)-diazene-1,2-dicarboxylate were added to the solution, which was stirred at RT for 1 h. 120 ml of tert-butyl methyl ether were added, then the mixture was stirred briefly, and the solids formed were filtered off and dried under high vacuum. 1.2 g of the target compound were obtained (62% of theory).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:40])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1.[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][CH2:2][C:3]([OH:40])([CH3:41])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CF)CC2)c2ncnn12
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), Dess-Martin periodinane (0.24 g) and acetonitrile (2 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). Methylmagnesium bromide (0.58 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 62%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>Cl>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: CC(C)C(=O)NC1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 76.7 %

Procedure:
Combine p-bromophenylhydrazine hydrochloride (10.0 g, 44.7 mmol) and N-(4-oxo-cyclohexyl)isobutyramide (8.20g, 44.7 mmol) in saturated ethanolic HCl (180 mL) and heat at reflux under nitrogen for 18 h. Concentrate in vacuo to remove about ½ of the EtOH, then dilute with water (300 mL). Collect the resulting solid, slurry in EtOAc and recollect to give 11.5 g (77%) of a beige solid. MS (ES): 335 (M+1), 337 (M+H+2). 1H NMR(DMSO-d6): δ 10.93 (s, 1H, NH), 7.80 (d, 1H, J=7.9 Hz), 7.48 (s, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.07 (d, 1H, J=8.4 Hz), 4.00 (m, 1H), 2.86 (dd, 1H, J=15.2, 5.1 Hz), 2.77 (m, 2H), 2.46-2.32 (m, 2H), 1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, J=6.6 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21])(=[O:3])[CH3:2].[K+].[Br-]>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cccs2)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [Br-]
Agent: [K+]
Product: CC(=O)Nc1c(C(=O)c2cccs2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-(ethoxycarbonyl)-2-(thiophene-2-carbonyl)indole (step2). m.p.: 228-231° C. 1H-NMR (CDCl3) δ: 10.10 (1H, br s), 8.40 (1H, br s), 8.25 (1H, d, J=9.2 Hz), 7.86 (1H, dd, J=1.1, 3.7 Hz), 7.77 (1H, dd, J=1.1, 5.1 Hz), 7.34 (1H, d, J=1.8 Hz), 7.27 (1H, dd, 3.7, 5.1 Hz), 7.12 (1H, dd, J=1.8, 8.8 Hz), 2.29 (3H, m) IR (KBr) ν: 1660, 1560, 1440, 1325, 1250 cm−1
Reaction SMILES: [ClH:1].CC1CCOCCN1.C([N:17]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)C1C=CC=CC=1>>[ClH:1].[C:24]1([CH:23]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH:17]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCOCCC2c2ccccc2)cc1
Agent: CC1CCOCCN1
Agent: Cl
Product: c1ccc(C2CCOCCN2)cc1

Procedure:
5-Phenyl-[1,4]oxazepane hydrochloride was prepared by the same procedure as that of 5-methyl-[1,4]oxazepane hydrochloride except for utilizing 4-benzyl-5-phenyl-[1,4]oxazepane instead of 4-benzyl-5-methyl-[1,4]oxazepane. Then 5-phenyl-[1,4]oxazepane hydrochloride was obtained as white solid (0.14 g, 0.65 mmol, 73%).
Reaction SMILES: S(Cl)(Cl)=O.CC1OC(C)=CC=1C(O)=O.CC1OC(C)=CC=1C(Cl)=O.[CH3:25][C:26]1[O:27][C:28]([CH3:36])=[CH:29][C:30]=1[C:31]([N:33]=[C:34]=[S:35])=[O:32].[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[C:54]([F:59])[CH:53]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:34]([NH:33][C:31]([C:30]2[CH:29]=[C:28]([CH3:36])[O:27][C:26]=2[CH3:25])=[O:32])=[S:35])=[C:54]([F:59])[CH:53]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1cc(C(=O)N=C=S)c(C)o1
Agent: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cc1cc(C(=O)O)c(C)o1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)oc4C)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethyl-3-furoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-3-furancarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-3-furancarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-3-furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).