Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH2:15])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)cc2ccccc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of 1-methylindole-2-carboxylic acid (5.0 g, 28.5 mmole) in THF (100 mL) at 0° C. was added N-methylmorpholine (3.5 mL, 31.8 mmole) followed by isobutyl chloroformate (4.0 mL, 30.8 mmole) dropwise over 5 minutes. A thick slurry formed quickly. The mixture was stirred for 30 min, then conc. NH4OH (4.0 mL. 58 mmole) was added in one portion with vigorous stirring, and the cooling bath was removed. The reaction was stirred at RT for 4 hr then was concentrated to dryness. The residue was triturated with 1.0 N Na2CO3 (50 mL), filtered, washed with a small volume of cold water, and dried under vacuum to give the title compound (2.46 g, 50%) as a white solid: Silica gel TLC (5% MeOH/CHCl3) Rf0.50.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[NH:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:29]([C:42](ON1C(=O)CCC1=O)=[O:43])[CH2:30][CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl>CN(C=O)C>[NH:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:29]([C:42]([NH:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:43])[CH2:30][CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O

Procedure:
A suspension of H-Lys(Z)-OH (0.89 g, 3.18 mmol) in DMF (25 ml) was stirred with Et3N (0.5 ml) and Boc-Glu(OBzl)-OSu (1.58 g, 3.5 mmol) at 0° C for 1 hr and 25° C for 24 hr. The reaction mixture was worked up as described above in Example 2 to produce a clear oil which was crystallized from EtOAc and petroleum ether to yield 1.47 g (77.4%); mp 110°-112° C.; [α]D25 +6.0° (c 1, CHCl3). Anal. Calcd for C31H41N3O9 (599.69): C, 62.08; H, 6.89; N, 7.00. Found: C, 62.04; H, 6.96; N, 7.10.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.COCCOC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc3ccccc3n2)cc1
Yield: 68.6 %

Procedure:
2-Chloroquinoline (5.0 g, 31 mmol) and 4-methoxyphenylboronic acid (5.5 g, 36 mmol) were dissolved in a solvent mixture containing 40 mL ethylene glycol dimethyl ether and 60 mL water containing 12.0 g K2CO3. To the stirred solution was added 1.6 g tetrakis(triphenylphosphine)palladium(O) and the mixture refluxed under N2 overnight. The cooled reaction mixture was then removed of water, extracted with methylene chloride three times. The combined organic phase was washed with portions of brine and then dried with anhydrous sodium sulfate, filtered, and evaporated of solvent to give 2-(p-methoxyphenyl)quinoline (5.0 g) after column chromatography (20% ethyl acetate in hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][CH:19]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.Cl[C:27]1[CH:32]=[C:31]([CH2:33][N:34]2[C:38]([C:39]3[O:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[N:37][C:36]([CH3:50])=[N:35]2)[CH:30]=[CH:29][N:28]=1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CCN(C(C)C)C(C)C>[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[C:13]([CH3:14])=[N:12][C:11]([C:15]4[O:16][C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)=[N:10]3)[CH:5]=[CH:4][N:3]=2)[CH2:54][CH2:53]1.[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([C:27]2[CH:32]=[C:31]([CH2:33][N:34]3[C:38]([C:39]4[O:40][C:41]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:42][CH:43]=4)=[N:37][C:36]([CH3:50])=[N:35]3)[CH:30]=[CH:29][N:28]=2)[CH2:54][CH2:53]1
Reactant: Cc1nc(-c2ccc(-c3ccccc3)o2)nn1Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ccc(-c3ccccc3)o2)n(Cc2ccnc(Cl)c2)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccc(-c3ccccc3)o2)n(Cc2ccnc(N3CCN(C)CC3)c2)n1
Product: Cc1nc(-c2ccc(-c3ccccc3)o2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Reaction time: 0.3 h
Yield: 53 %
Yield: 34 %

Procedure:
A mixture of 2-chloro-4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl) methyl)pyridine and 2-chloro-4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridine (100 mg, 0.3 mmol) was treated with 1-methylpiperazine (280 mg, 3 mmol) in DIEA (10 ml), and refluxed overnight. The mixture was cooled, concentrated, treated with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by prep-HPLC (Mobile phase: A=0.1% NH4OH/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm×150 mm) to give 1-methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine as a yellow solid (66 mg, 53%) and 1-methyl-4-(4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine as a yellow solid (42 mg, 34%). For 1-methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl) pyridin-2-yl)piperazine: MS (ES+) C24H26N6O requires: 414. found: 415 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=5.1 Hz, 1H), 7.89-7.72 (m, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.28 (td, J=7.4, 1.3 Hz, 1H), 7.04 (d, J=3.5 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 6.44-6.26 (m, 2H), 5.26 (s, 2H), 3.53 (t, J=5.0 Hz, 4H), 2.48 (t, J=5.1 Hz, 4H), 2.44 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]O)[C:5]=12.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccn2ccnc12
Reactant: O=S(Cl)Cl
Product: ClCc1cccn2ccnc12
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of imidazo[1,2-a]pyridin-8-ylmethanol (800 mg) and excess thionyl chloride was stirred at 70-80° C. for 8 h. Excess thionyl chloride was removed under vacuum. The residue was then diluted with toluene and evaporated. This procedure was repeated 3 times.
Reaction SMILES: C[NH:2][C:3]1[C:4]([I:17])=[C:5]([C:14]([Cl:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([Cl:10])=[O:9].[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19].[CH3:26]C(N(C)C)=O>>[CH3:26][CH2:19][C:18]([O:21][CH2:22][C:23]([NH:2][C:3]1[C:11]([I:12])=[C:7]([C:8]([Cl:10])=[O:9])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([Cl:16])=[O:15])=[O:24])=[O:20]
Reactant: CC(=O)N(C)C
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Product: CCC(=O)OCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 0 °C
Yield: 98.8 %

Procedure:
A solution of 32 g of 5-methylamino-2,4,6-triiodoisophthalic acid dichloride (0.0525 moles in 80 ml of DMAC is treated dropwise at 0° to 5° C. with stirring with 10.7 g of acetoxyacetylchloride. Subsequently, stirring is continued over night and at room temperature. The reaction solution is stirred into ice water. A total of 36.7 g of 5-(N-methylacetoxyacetylamino)-2,4,6-triiodo-isophthalic acid dichloride, melting at 198°-200° C., are obtained, corresponding to a theoretical yield of 98.8%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].BrN1C(C)(C)C(=O)N(Br)C1=[O:16].[C:24](#[N:26])C>>[OH:16][CH:11]1[CH:10]([NH:26][CH3:24])[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:12]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Product: CNC1CN(C(=O)OC(C)(C)C)CC1O

Procedure:
N-Boc-3-pyrroline (1) (16 kg) was treated with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (15.2 kg) in aqueous ACN to form the bromohydrin (2). After the reaction was complete, the excess brominating agent was quenched with aqueous sodium thiosulfate solution and the crude reaction mixture was treated with aqueous NaOH. The resulting epoxide was extracted with MTBE and the organic layer was concentrated to give the crude epoxide (3). This epoxide was added to 40% aqueous methylamine and, after the reaction was complete, the excess methylamine and water were removed by distillation and the product, (4), (18.5 kg) was isolated from diisopropyl ether.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH2:13][CH3:14])[CH2:11][OH:12])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[CH:19][CH:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH2:13][CH3:14])([CH3:15])[CH2:11][O:12][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:20]3[CH:30]=[CH:31][C:17]([Br:16])=[CH:18][CH:19]=3)[CH:23]=2)=[CH:8][CH:9]=1
Reactant: BrCc1cccc(Oc2ccc(Br)cc2)c1
Reactant: CCC(C)(CO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(COCc1cccc(Oc2ccc(Br)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To 20 ml of toluene was added 0.60 g of sodium hydride (60% in oil) and the mixture was refluxed, and a solution of 2.0 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol in 10 ml of 40% DMF/toluene was added dropwise to the mixture over a period of 20 minutes. The mixture was stirred for 10 minutes and a solution of 4.0 g of 3-(4-bromophenoxy)benzyl bromide in 10 ml of toluene was added dropwise to the mixture over a period of 10 minutes. The mixture was further heated and refluxed for 1 hour and cooled to room temperature, and poured into water. The toluene layer was separated, washed with water, dried over Na2SO4, and evaporated under reduced pressure and the obtained crude ether was purified by column chromatography on 100 g of silica gel (1:1 mixed solvent of toluene and hexane was used as eluent) to give 3.7 g of the desired ether (the yield was 76% of the theoretical yield).
Reaction SMILES: C(O[C@@H]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H](C(Br)[C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])C1)(=O)C.[OH-:34].[K+].Cl.[OH2:37]>CO>[OH:34][C@@H:9]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:11]([C@H:12]([OH:37])[C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C(Br)[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of methyl 3α-acetoxy-6-bromo-7-keto-5β-cholanoate (10.0 g, 19.025 mmoles) in methanol (600 ml) was added to a solution of potassium hydroxide (24 g) in water (100 ml), dropwise, in 1 hour. The resulting mixture was left to react for 48 hours under argon atmosphere, with magnetic stirring. The reaction mixture was diluted with water (100 ml), acidified with 10% hydrochloric acid and extracted with chloroform (3×200 ml). The combined organic phases were washed with brine (1×50 ml) and dried over sodium sulfate. After evaporation of the solvent, the residue (7.7 g) was reacted with p-toluenesulfonic acid (0.5 g) in methanol (250 ml) under magnetic stirring for one night. The reaction mixture was concentrated under vacuum, taken up into chloroform (150 ml) and washed first water (3 x 30 ml), then with brine (1×50 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue (8.0 g) was subjected to flash chromatography on silica, eluting with chloroform/methanol 98:2, to obtain 4.5 g of a pure product (56%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16](Cl)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CCO.CCOC(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:10](=[O:19])[C:11]3[CH:17]=[C:16]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3]1
Reactant: C1CCNC1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(Cl)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2cnc(N3CCCC3)cc2c1=O
Yield: 41.9 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1yl)-6-chloro-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzonitrile (Example 18) (120 mg, 0.3 mmol), pyrrolidine (75 μL, 0.91 mmol) and sodium bicarbonate (76 mg, 0.91 mmol) were stirred in EtOH in a sealed tube at 150° C. for 16 h. After cooling, the reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by preparative HPLC yielded 54 mg (32%) of the title compound as a bright orange solid. 1H NMR (400 MHz, MeOD-d4): δ 8.40 (s, 1H), 7.64 (dd, 1H, J=7.6, 1.2 Hz), 7.48 (dt, 1H, J=7.6, 1.2 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.07 (d, 1H, J=7.6 Hz), 6.67 (s, 1H), 5.43 (s, 2H), 3.20-3.32 (m, 5H), 3.02-3.10 (m, 1H), 2.81-2.90 (m, 1H), 2.69-2.78 (m, 1H), 2.59-2.67 (m, 1H), 1.87-1.99 (m, 5H), 1.51-1.73 (m, 2H), 1.18-1.28 (m, 1H). MS (ES) [m+H] calc'd for C24H27N7O 430; found 430.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:13][C:14]2[N:15]=[N:16][NH:17][N:18]=2)=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.4 %

Procedure:
To a solution of 4-carboxybenzaldehyde (40.2 g, 0.27 mol) in DMF (400 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (65.5 g, 0.33 mol) followed by 5-aminotetrazol monohydrate (36.6 g, 0.35 mol). The mixture was stirred for 24 hours at ambient temperature. The reaction volume was then reduced to one half by rotary evaporation, and water (800 mL) was added. The precipitate was collected by filtration, washed with cold acetonitrile and dried overnight in a vacuum oven to afford 46.0 g (80%) of 4-formyl-N-(2H-tetrazol-5-yl)benzamide.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.ClC1N=C(C(N[C@H]2CCN(C(OC(C)(C)C)=O)C[C@H]2OC)=O)NC=1CC.C1(C)C=CC(S(O[CH2:55][CH:56]([F:58])[F:57])(=O)=O)=CC=1>CN(C=O)C>[F:57][CH:56]([F:58])[CH2:55][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (4.6 g, 17.6 mmol), sodium hydride (55% content, 1g, 22.9 mmol), 2,2-difluoroethyl p-toluenesulfonate (5 g, 21.6 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (85%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].C[O:19][B:20](C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([B:20]([OH:21])[OH:19])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: COB(C)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 9.2 ml (1.5 g, 23.0 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 5.0 g (20.9 mmol) of 4-methyl-3-(trifluoromethyl)bromobenzene were dissolved in 15 ml of THF and slowly added dropwise. 3.3 g (31.4 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 2.6 g (60% of theory)
Reaction SMILES: C1(C)C=CC(S(N2C3=NC=CC=C3C(C3C=C(N)SC=3)=C2)(=O)=O)=CC=1.COC1C=C(CC(O)=O)C=CC=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([NH:49][C:50]2[S:51][CH:52]=[C:53]([C:55]3[C:63]4[C:58](=[N:59][CH:60]=[CH:61][CH:62]=4)[N:57](S(C4C=CC(C)=CC=4)(=O)=O)[CH:56]=3)[CH:54]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1.O[Li].O>C1COCC1.O.CCOC(C)=O>[NH:57]1[C:58]2=[N:59][CH:60]=[CH:61][CH:62]=[C:63]2[C:55]([C:53]2[CH:54]=[C:50]([NH:49][C:47](=[O:48])[CH2:46][C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=3)[S:51][CH:52]=2)=[CH:56]1
Reactant: COc1cccc(CC(=O)Nc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncccc34)cs2)c1
Agent: COc1cccc(CC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3csc(N)c3)c3cccnc32)cc1
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CC(=O)Nc2cc(-c3c[nH]c4ncccc34)cs2)c1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
4-[1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-thiophen-2-ylamine was coupled to 3-methoxyphenylacetic acid according to General Method B and the product 2-(3-methoxyphenyl)-N-(4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl)acetamide (70 mg, 0.14 mmol) was dissolved in 6 mL THF and LiOH hydrate (63 mg, 1.5 mmol) was added in 1 mL of water. The reaction mixture was heated to 150° C. by microwave irradiation for 15 minutes and then diluted with EtOAc and water and the organic layer dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (40 to 100% EtOAc/hexanes to give 20 mg of a light brown solid, 0.055 mmol, 39%. 1H NMR 500 MHz (DMSO-d6) 11.80 (1H, s), 11.37 (1H, s) 8.28 (2H, m), 7.78 (1H, s), 7.25 (1H, t), 7.16 (2H, m), 7.07 (1H, s) 6.88 (2H, m), 6.82 (1H, m), 3.78 (3H, s), 3.69 (2H, s). MH+ 364.20.
Reaction SMILES: C[C:2]1[C:3](=O)N[C:5]2[C:10]([CH:11]=1)=[C:9](O)[CH:8]=[CH:7][C:6]=2C.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][N:22](C)[CH:23]=[O:24]>O>[CH3:3][C:2]1[C:23](=[O:24])[NH:22][C:21]2[C:10]([CH:11]=1)=[C:5]([O:18][CH2:15]/[CH:3]=[CH:2]\[CH2:11][CH3:10])[CH:6]=[CH:7][C:8]=2[CH3:9]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Agent: [K+]
Solvent: O
Product: CC/C=C\COc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 77.3 %

Procedure:
Z-2-Penten-1-ol (5.0 g, 58.1 mmol), trimethylamine (6.45 g, 63.9 mmol), methanesulfonylchloride (7.0 g, 61.1 mmol) and ether (30 ml) were allowed to react at ambient temperature for 1 hour. After the completion of the reaction, the insoluble matter was removed and washed with water. The washed substance was dried over sodium sulfate. The solvent was distilled off to obtain 7.95 g of Z-1-mesyloxy-2-pentene as pale yellow oily material (83.4%). This material was added to a mixture of 3,8-dimethyl-5-hydroxycarbostyril (7.0 g, 37.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and dimethylformamide (210 ml), and allowed to react at 70° C. for 1 hour. The reaction mixture was condensed under reduced pressure, and the residue was poured into water to obtain 7.36 g of the title compound as a brown solid (77.3%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11])[CH3:23]
Reactant: CCO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Br)cc1C
Temperature: 25 °C

Procedure:
25.3 g of 4-bromo-2-methyl benzoic acid and 5 mL of concentrated sulfuric acid were added to 425 mL of ethanol. The mixture was heated at reflux temperature for 3 days. The solution was cooled to room temperature, adjusted to neutral pH with the addition of sodium bicarbonate, and concentrated to ca. 100 mL volume under reduced pressure. The reduced mixture was partitioned between ethyl acetate and water, and the organic phase was successively washed with saturated bicarbonate and brine solutions. The organic fraction was dried over anhydrous sodium sulfate, and concentrated to 28.2 g of a clear liquid product; 1H NMR (200 MHz, CDCl3) δ 7.78-7.73 (d, J=8.2 Hz, 1H), 7.38-7.32 (m, 2H), 4.40-4.28 (q, J=7 Hz, 2H), 2.57 (s, 3H), 1.42-1.35 (t, J=7 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][N:26]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][N:26]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCc2ccccc2C(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
Batch size: 2.8 g (18.8 mmol) 3-(3-Pyridyl)-acrylic acid, 2.2 ml (25.5 mmol) oxalyl chloride and 5.0 g (17.0 mmol) 4-(1-phenyl-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-butylamine.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:11])[N:9]=1)(=[O:3])[CH3:2].C[O-].[Na+].[Cl-:15].[NH4+:16]>CO>[ClH:15].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH2:16])=[NH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: CC(=O)Nc1nc(C#N)cs1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1nc(C(=N)N)cs1
Product: Cl

Procedure:
10 mmol 2-Acetylamino-4-cyanothiazole was dissolved in 10 ml anhydrous methanol, and 10 mmol sodium methoxide was added. Upon complete reaction of the starting materials, 20 mmol ammonium chloride was added, to carry out reaction in closed state for 12 hr. The reaction product was filtered to remove inorganic salt, and then the resultant filtrate was concentrated to obtain 2-acetylamino-4-thiazolformamidine hydrochloride.