Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[N:4]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(CC)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 74.2 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 4-isopropoxyphenylboronic acid (0.5 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.51 g, 77%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:6]=1.C[O-].[Na+].[CH2:23]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:23]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: COc1cc(NCCCN)nc2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(NCCCNCc2cn(Cc3ccccc3)c3ccccc23)nc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
A solution of N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine dihydrochloride (200 mg, 0.66 mmol) [4a] in methanol (50 ml) was treated with glacial acetic acid (20 drops) and sodium methoxide (95%, 71 mg, 1.31 mmol) followed by a solution of 1-benzyl-3-indole carboxaldehyde (155 mg, 0.66 mmol) in methanol (5.0 ml). The reaction stirred at ambient temperature for 24 hours then was treated with a solution of sodium cyanoborohydride (83 mg, 1.31 mmol) in methanol (2.0 ml). The reaction stirred at ambient temperature for 24 hours. The solution was evaporated under reduced pressure to a residue that was taken into a mixture of saturated aqueous sodium chloride (20 ml) and 10% sodium hydroxide solution (20 ml). It was extracted in ethyl acetate and the extracts were dried (sodium sulfate) then concentrated to an oil. Column chromatography on silica (95/5 dichloromethane/methanolic ammonia) gave N-(1-benzyl-1H-indol-3-ylmethyl)-N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine (126 mg, 84%) as a white solid. [M+H]+ 451.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH2:34][CH2:35][C:36](OCC)=[O:37])[CH:11]=[C:12]([F:33])[C:13]=1[O:14][CH2:15][C:16]1[C:17]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:18][S:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:7][C:8]1[CH:9]=[C:10]([CH2:34][CH2:35][CH2:36][OH:37])[CH:11]=[C:12]([F:33])[C:13]=1[O:14][CH2:15][C:16]1[C:17]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:18][S:19][C:20]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(OC)nc3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCCO)cc2F)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 110 by LAH reduction of ethyl 3-(3,5-difluoro-4-((3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)phenyl)propanoate to afford the desired product as an off-white solid. 1HNMR (300 MHz, CD3OD) δ 8.57 (s, 1H), 8.13 (d, J=8.7 Hz, 1H), 6.84-6.93 (m, 3H), 5.23 (s, 2H), 3.99 (s, 3H), 3.56 (t, J=6.3 Hz, 2H), 2.65 (t, J=8.1 Hz, 2H), 1.80-1.85 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H17F5N2O3S, 461.1 (M+H). found 461.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C2C=C(C(O)=O)C(=CC=2)C(O)=O)=[CH:3][CH:2]=1.C(O[C:22](=[O:35])[C:23]1[CH:33]=[CH:32][C:31](Br)=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=1)C.N1C=CC(B(O)O)=CC=1.[Li]N1C(C)(C)CCCC1(C)C>C1COCC1>[O:35]=[C:22]1[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]=2[C:33]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][C:23]1=2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1C(=O)O
Reactant: CCOC(=O)c1ccc(Br)c(C(=O)OCC)c1
Agent: OB(O)c1ccncc1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1cnccc1-2

Procedure:
9-Oxo-9H-indeno[2,1-c]pyridine-7-carboxylic acid was obtained by allowing 4-pyridin-4-ylphthalic acid [FAB: 244 (M+H)+] which had been synthesized by carrying out the same operations of Reference Examples 27 and 28 using 4-bromoisophthalic acid diethyl ester and 4-pyridine boronic acid to undergo the reaction with lithium 2,2,6,6-tetramethylpiperidide at 0° C. in THF. By carrying out reaction of this compound by the same method of Reference Example 30, ethyl 9-oxo-9H-indeno[2,1-c]pyridine-7-carboxylate was obtained. FAB: 254 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:30][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)[N:7]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1C1=CCCO1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester and 4-trifluoromethylbenzylamine in DME. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: Cl.[CH2:2]([C:5]1[NH:9][CH:8]=[N:7][C:6]=1[C:10]([OH:12])=O)[CH2:3][CH3:4].C(Cl)(=O)C([Cl:16])=O>>[CH2:2]([C:5]1[NH:9][CH:8]=[N:7][C:6]=1[C:10]([Cl:16])=[O:12])[CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1[nH]cnc1C(=O)O
Agent: Cl
Product: CCCc1[nH]cnc1C(=O)Cl
Yield: 71.1 %

Procedure:
5-Propyl-1H-imidazole-4-carboxylic acid hydrochloride 3 (1.0 g; 5.3 mmol) was added to nitrogen-purged CH3CN (10 mL). Oxalyl chloride (2.5 ml; 29 mmol) was then added, and the mixture was heated to reflux under N2 for 1 h. The brown solution was then allowed to cool, and the product began to precipitate. Ice-cold dry Et2O (30 mL) was added to the reaction flask to complete the precipitation. The green-gold solid was collected by suction filtration, washed with Et2O, and dried under vacuum to afford 0.65 g (71%) of 4. 1H NMR (DMSO-d6): δ 0.90 (t, 3H), 1.70 (m, 2H), 2.90 (t, 2H), 8.70 (s, 1H); 13C NMR (DMSO-d6): δ 13.6, 21.3, 29.4, 118.1, 137.9, 150.46, 155.8.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH3:13].[N+:14]([C:17]1[CH:18]=[N:19][NH:20][CH:21]=1)([O-:16])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:13][C:5]1[N:4]([CH2:3][CH2:2][N:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:21]=[N:20]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: Cc1nc2ccccc2n1CCCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc2ccccc2n1CCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To 1-(2-chloroethyl)-2-methyl-1H-benzoimidazole) (4.42 g, 22.71 mmol), in MeCN (50 mL), 4-nitro-1H-pyrazole (2.57 g, 22.71 mmol) and Cs2CO3 (8.14 g, 24.98 mmol) was added. After stirring at 80° C. for 18 h the reaction mixture was allowed to reach rt and filtered. The filter cake was washed with DCM and the filtrate was concentrated in vacuo, then the residue was dissolved in DCM and washed with H2O. The combined aq. layers were reextracted with DCM, the combined org. layers were dried (MgSO4), filtered and the solvent removed under reduced pressure to yield 2-methyl-1-(2-(4-nitro-1H-pyrazol-1-yl)-ethyl)-1H-benzoimidazole, which is used in the next step without further purification. LC-MS conditions B: tR=0.42 min, [M+H]+=272.07.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.CCN(CC)CC.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[N:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (15 g, 92.5 mmole) was taken up in DCM (190 ml) under nitrogen and NEt3 (16 ml, 115.7 mmole) was added. The solution was cooled to −5° C., a solution of trimethyl acetyl chloride (12.5 ml, 101.8 mmole) in DCM (65 ml) was added dropwise, and the mixture was stirred for a further 15 minutes in an ice bath. The mixture was then stirred for 2 hours at RT. The suspension was washed with H2O (150 ml), then with dilute NaHCO3 solution, and the organic phase was dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator the residue was crystallised. N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide (20.8 g, 91) was obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH2:5][O:6][CH3:7].[H][H]>[Pd].C1COCC1>[F:1][C:2]([F:31])([F:32])[C@H:3]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH2:5][O:6][CH3:7]
Reactant: COCC[C@@H](OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COCC[C@@H](OC(=O)c1ccc(-c2ccc(O)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.93 g (6.60 mmol) of the 4'-benzyloxy-4-biphenylcarboxylic acid (R)-1-trifluoromethyl-3-methoxypropyl ester obtained in the second stage and 0.4 g of 5% palladium/carbon as catalyst was added to 50 ml of THF. The solution was placed in a hydrogen atmosphere, using a hydrogen baloon, and was stirred at room temperature overnight. After filtering out the catalyst and concentrating the filtrate, there was obtained approximately quantitatively 4'-hydroxy-4-biphenylcarboxylic acid (R)-1-trifluoromethyl-3-methoxypropyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([NH2:25])=O)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]([NH:28][NH2:29])=O.C(O)=O>O(Cl)Cl.[P].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[N:25]=[CH:26][NH:28][N:29]=4)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Reactant: NNC=O
Agent: ClOCl
Agent: [P]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Fc1ccc(-c2cc(N3CCC(c4nc[nH]n4)CC3)c3sccc3n2)cc1
Yield: 5.8 %

Procedure:
A suspension of 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide (100 mg, 0.32 mmole) in phosphorus oxochloride (5 mL) is refluxed for about 30 minutes. After the excess phosphorus oxychloride is removed under vacuum, the residue is treated with ethyl acetate (5 mL), and ice-water (10 mL). The mixture is extracted with ethyl acetate (3×10 mL). The combined organic layers are washed with brine, dried over sodium fate, filtered, and concentrated. The residue is dissolved in toluene (5 mL) and then formic hydrazide (100 mg, 1.7 mmole) and formic acid (0.05 mL) are added. The reaction mixture is refluxed for about 16 hours. It is then cooled, diluted with ethyl acetate (15 mL), and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by preparative tlc to give 5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine (7 mg, 6% yield) as a white solid. This material is dissolved in ethyl acetate (1 mL), saturated with HCl (2 mL), and then concentrated to afford 5-(4-Fluorophenyl)-7-[4-(4H-1,2,4-triazol-3-yl)piperidyl]thioheno[3,2-b]pyridine hydrochloride (compound 2) as greasy oil. Trituration with ether, filtration and drying in vacuo affords the desired product as a solid. m.p. >300° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[Br:20][C:3]1[C:2]([OH:1])=[C:11]([CH3:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ncccc2cc1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cc2ncccc2c(Br)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6-Hydroxy-7-methylquinoline (76 mg) was dissolved in chlorobenzene (7 ml) to prepare a solution. N-Bromosuccimide (180 mg) and 2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and the mixture was stirred at 80° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 5-bromo-6-hydroxy-7-methyl-quinoline (111 mg, yield 97%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][NH:5][CH3:6].C(OCC)(=O)C.C(=O)([O-])O.[Na+].[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([O:27][CH2:28][C:29]([N:5]([CH3:6])[CH2:4][C:3](=[O:7])[CH:2]([CH3:8])[CH3:1])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCC(=O)C(C)C
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A mixture of 6.1 g (52.9 mmol) of 3-methyl-1-methylamino-2-butanone, 70.0 ml of ethyl acetate and 41.0 ml of water was stirred at 0° C. Added was 7.1 g (84.6 mmol) of sodium hydrogen carbonate, and the mixture was stirred for 10 minutes. There was added 8.5 ml (54.0 mmol) of benzyloxyacetylchloride over 30 minutes. After stirring at room temperature for 10 hours, the ethyl acetate layer was seperated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to give 5.8 g of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)-acetamide (18a') (yield 42%).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH:2]1[C:20]([O:22]CC)=[O:21].[Li+].[OH-]>CO>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH:2]([C:20]([OH:22])=[O:21])[NH:3][CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=CNC(C(=O)OCC)Cc2c1[nH]c1ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a suspension of diethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylate (0.48 g, 1.46 mmol) in MeOH (6 mL) was added 4 N aqueous LiOH (1 mL) and the suspension was stirred for 2 hours at 20° C. Solvent was removed and the crude was dissolved in water (50 mL). The aqueous solution was then extracted with EtOAc (3×30 mL) and acidified with HOAc. Precipitate appeared and were collected by filtration and washed with water and EtOAc, then dried under high vacuum to give the title compound (300 mg); 1H-NMR (MeOH-d4): δ 8.06 (1H, s), 7.54 (1H, dd), 7.44 (1H, dd), 7.12 (2H, m), 4.43 (3H, m), 3.61 (1H, d), 3.41 (1H, m), 1.49 (3H, t); MS (ES): 301 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)[C:14](Cl)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:13][CH3:14])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C)ccc1C(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C)cc1OC

Procedure:
A stirred solution of 2-methoxy-4-methylbenzoic acid (35 g, 0.211 mol) in benzene (400 ml) was treated dropwise with oxalyl chloride (40 g, 0.317 mol). After 3 hours at room temperature the solvent and excess oxalyl chloride were evaporated under reduced pressure and the resulting crude acid chloride residue was treated with ethanol (200 ml) and heated under reflux for 1 hour. The solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, dichloromethane) to yield ethyl 2-methoxy-4-methylbenzoate as a pale yellow oil having the following structural characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]#[C:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.ClC1C=CC2OCCC3C=C(C4N(C5C=CC(F)=CC=5F)N=CN=4)SC=3C=2N=1.CC(O)(C#C)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([CH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC(C)(O)C#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: C#CC(C)(C)O
Agent: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Product: CC(C)(O)CCc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 37 %

Procedure:
Following the procedures for 246, 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2-methyl-but-3-yn-2-ol was prepared (Yield: 69%. 1H NMR (DMSO-d6, 400 MHz): δ8.30 (s, 1H), 7.93-7.877 (m, 1H), 7.74-7.68 (m, 1H), 7.43-7.37 (m, 2H), 7.29 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 5.60 (s, 1H), 4.30 (t, J=4.4 Hz, 2H), 3.12 (t, J=4.4 Hz, 2H), 1.21 (s, 6H). ESI-MS: (m/z)=465 [M+H]+) from 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene and 2-methylbut-3-yn-2-ol, and hydrogenated to give 272 Yield: 37%. 1H NMR (DMSO-d6, 400 MHz): δ8.26 (s, 1H), 7.90-7.84 (m, 1H), 7.69-7.63 (m, 1H), 7.39-7.34 (m, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06-7.03 (m, 2H), 4.22 (t, J=4.8 Hz, 2H), 3.08 (t, J=4.8 Hz, 2H), 2.68-2.63 (m, 2H), 1.69-1.64 (m, 2H), 1.10 (s, 6H). LC-MS (ESI): m/z=469[M+H]+
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: CC(C)(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)O
Temperature: -45 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
Dimethylformamide (DMF), 100 ml, was poured into a 4 l indented 3 neck round bottom flask equipped with a nitrogen bubbler and an overhead stirrer (glass shaft, teflon Paddle). The hot 2-bromo-2-methylpropionic acid was then added to the flask through a powder funnel. The flask and the funnel were rinsed with 4×100 ml portions of DMF and were added to the reaction flask. A thermometer was placed in the third neck and the stirred solution was cooled under an atmosphere of nitrogen to -45° C. by placing it in a methanol/water 50:50 dry ice bath. The thermometer was removed and potassium carbonate 250.21 g (1.810 mol, 100 M %) was added through a powder funnel over a 5 minute period. The reaction mixture warmed to -40° C. but there was no apparent reaction and the carbonate did not dissolve. The solution was diluted with 200 ml DMF and potassium thioacetate 407.10 g (3.564 mol, 196.9 M %) was added through a powder funnel over a 5 minute period. The powder funnel was rinsed with 300 ml DMF which was added to the reaction solution which had warmed to -30° C. The reaction was allowed to slowly warm up as the dry ice was consumed. When the reaction temperature reached -10° C. the reaction began to bubble. The reaction was allowed to warm slowly to room temperature and was stirred under nitrogen for 22 hours. Water, 2 1, and 500 ml concentrated hydrochloric acid were mixed and cooled to 9° C. in an ice bath. The tan colored reaction mixture was slowly poured into the stirred acid solution over a 25 minute period. The reaction flask was washed with 2×100 ml portions of deionized water which was added to the acid solution (10° C., pH 1.5). The acid solution was poured into a 4 l separatory funnel and was extracted sequentially with 3×500 ml and 1×250 ml ethyl acetate. Each organic extract was washed with a separate 100 ml portion of saturated sodium chloride solution. The organic extracts were combined and dried over 400 g of anhydrous sodium sulfate. The solution was filtered through a fluted filter paper into a 2,000 ml round bottom flask and the solvent was removed in two portions under reduced pressure on the rotary evaporator. The sodium sulfate was washed with 3×100 ml portions of ethyl acetate which were filtered into the 2,000 ml round bottom. After all the solvent was removed, the rotary evaporator was connected to the high-vacuum pump and the water bath was heated to 100° C. The product was removed after 1.5 hour to afford 241.07 g of the crude brown oily product which crystallized on cooling. The crystalline mass was placed under high vacuum at 22° C. for 16 hours to afford 240.51 g (82% yield) of the crude crystalline 2-acetylthio-2-methylpropanoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][NH:21][N:20]=1.O>CS(C)=O>[I:8][C:7]1[C:2]([N:21]2[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([C:18]([F:17])([F:29])[F:30])=[N:20]2)=[N:3][C:4]([S:13][CH:14]([CH3:16])[CH3:15])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CC(C)Sc1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2nc(SC(C)C)nc(C(F)(F)F)c2I)nc1C(F)(F)F
Temperature: 80 °C
Yield: 70.4 %

Procedure:
4-Chloro-5-iodo-2-isopropylthio-6-trifluoromethylpyrimidine (0.30 g) was dissolved in dimethylsulfoxide (3.0 ml) and ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.16 g) and 1,8-diazabicyclo-[5,4,0]-under-7-ene (0.12 g) was added at room temperature with stirring. The mixture was heated to 80° C. and stirred for 2 hr. After cooling to room temperature, the mixture was added water and extracted with benzene. The benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1-(5-iodo-2-isopropylthio-6-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.30 g) as colorless crystalline solid, mp 107-108° C.