Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH:20](I)([CH3:22])[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: CC(C)I
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 18 mg of 60% sodium hydride was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.05 ml of isopropyl iodide was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 17 mg of the above compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[C:8]([Cl:13])[S:7][C:6]=1[Cl:14])=[O:4].[H][H]>C(O)C.[Ni]>[CH3:1][NH:2][C:3]([C:5]1[C:9]([NH2:10])=[C:8]([Cl:13])[S:7][C:6]=1[Cl:14])=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)c1c(Cl)sc(Cl)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CNC(=O)c1c(Cl)sc(Cl)c1N
Yield: 102.3 %

Procedure:
A mixture of 2,5-dichloro-4-nitro-thiophene-3-carboxylic acid methylamide (565 mg) and Raney Ni (50 mg) in ethanol was stirred under 1 atm hydrogen for 5 hours. The reaction mixture was filtered and concentrated to afford 510 mg of 4-amino-2,5-dichloro-thiophene-3-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 3.8-3.6 (bs, 3H), 3.0 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[S:3]1)[S:11][C:10]([CH3:15])([CH3:14])[S:9]3.[Li]CCCC.[CH3:22][S:23]SC>C(OCC)C>[CH3:22][S:23][C:13]1[C:4]2[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[S:11][C:12]=12
Reactant: CSSC
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1c2c(cc3c1SC(C)(C)S3)SC(C)(C)S2

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole is lithiated with n-BuLi in diethyl ether and then reacted with dimethyl disulfide to give 4-methylthio-2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole. This compound can then be reacted with n-butyl glyoxalate (0.5 eq.) in a solvent consisting of a mixture of concentrated sulfuric acid and glacial acetic acid (1:10) (analogously to: G. Werber, Ann. Chim. 49, 1898 (1959)). After work-up, including neutralization and extraction the product is purified by preparative HPLC. The n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate formed can be hydrolyzed with a 10% solution of sodium hydroxide and transferred into other esters, amides, thioesters and anhydrides etc. by standard procedures. If n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate is treated with n-BuLi (3 eq.) in tetrahydrofurane at ambient temperature and exposed to oxygen, the initially formed enolate anion is oxidized to the stable title radical (analogously to P. O'Neill and A. F. Hegarty, J. Org. Chem. 52, 2113 (1987)).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].C(O)C.ClC(OCC)=O>O.ClCCl.C(N(CC)CC)C>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C(O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(C)O
Yield: 146.4 %

Procedure:
9 g of a lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 7,500 (lactic acid/glycolic acid=75/25 (mol %)) (Wako Pure Chemical Industries, Ltd.) was dissolved in a mixed solvent consisting of 20 ml of dichloromethane and 20 ml of ethanol. While thus obtained solution was cooled and stirred, 0.45 ml of triethyl amine, 0.29 ml of ethyl chloroformate and 0.36 g of N,N-dimethylaminopyridine were added. After the resulting mixture was stirred for another 2 hours, 50 ml of dichloromethane and 50 ml of water were added and then dichloromethane phase was separated. The dichloromethane phase was washed 2 times with 50 ml of 10% ethanol-water, and then dried with magnesium sulfate. After magnesium sulfate was separated by filtration, the mixture was concentrated to dryness under reduced pressure to yield 7.7 g of the ethyl ester of lactic acid/glycolic acid copolymer.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:26].[K+].II.[N+]([O-])(OC(C)(C)C)=O>C(#N)C.[Cu](I)I>[I:26][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(N)c3c2CNC3=O)c1
Agent: I[Cu]I
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: II
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(I)c3c2CNC3=O)c1
Yield: 52.1 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-(3-tert-butyldimethylsilyloxyphenyl)isoindolinone (115 mg, 0.324 mmol) was dissolved in acetonitrile (8.0 mL), and the solution was treated with potassium iodide (73.8 mg, 0.441 mmol), copper iodide (84.8 mg, 0.441 mmol), iodine (113 mg, 0.441 mmol) and tert-butyl nitrate (0.071 mL, 0.551 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-iodo-4-(3-tert-butyldimethylsilyloxyphenyl)isoindolinone (78.6 mg, yield 52%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15]/[CH:16]=[C:17]3\[C:18](=[O:29])[NH:19][C:20](=[O:28])[C:21]4[C:26]\3=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15]/[CH:16]=[C:17]3\[C:18](=[O:29])[NH:19][C:20](=[O:28])[C:21]4[C:26]\3=[CH:25][C:24]([C:32]3[CH:33]=[CH:34][O:30][CH:31]=3)=[CH:23][CH:22]=4)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-c5ccoc5)cc43)cn2)CC1
Yield: 67.6 %

Procedure:
(4Z)-4-({[6-(4-Ethylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione (50.3 mg, 0.1 mmol) is mixed with 3-furanboronic acid (22 mg, 0.2 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), and cesium carbonate (65 mg, 0.2 mmol). After the solids were degassed, N,N-dimethylformamide (0.7 mL) and P(t-Bu)3 (6 mg, 0.03 mmol) were added. The mixture is heated at 100 C for 10 min, diluted with methylene chloride, and filtered. The filtrate is evaporated to dryness and purified by column chromatography to yield 30 mg (67%) of the title compound as an orange solid. MS (ESI) m/z 444 (M+H)+1
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCCC(O)CCCCl
Product: C=CCCCC(CCCCl)OC(C)=O

Procedure:
A mixture of 1-chloro-8-nonen-4-ol (22.10 g.; 0.125 mole) and acetic anhydride (25.52 g.; 0.0250 mole) is heated on a steam bath for 1 1/2 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C1(C)C(C)=CC=CC=1>[OH:16][CH2:15][CH2:14][CH2:13][NH:12][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: NCCCO
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCCO)c2[nH]ncc2n1
Yield: 64.3 %

Procedure:
7-Chloro-5-methyl-H-pyrazolo[4,3-b]pyridine (D4) (0.5 g, 0.003 mole) and 3-aminopropanol (0.75 g, 0.01 mole) in dry xylene (5 ml) were heated under reflux for 4 h. The solvent was removed under reduced pressure and the resulting oil recrystallised from methanol/ethyl acetate to give the hydrochloride salt of the title compound as a white crystalline solid (398 mg, 55%), m.p. 194°-196° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH2:30]([N:37]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:19](=[C:6]2\[C:5](=[O:29])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=3)/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:45][CH:46]=1)[CH3:38])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: CN(Cc1ccccc1)Cc1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:33]=[N:32][C:16]2[N:17]=[C:18]([NH:21][C:22]3[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:31])[N:19]=[CH:20][C:15]=2[CH:14]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:33]=[N:32][C:16]2[N:17]=[C:18]([NH:21][C:22]3[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:31])[N:19]=[CH:20][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(-c2cnc3nc(Nc4c(C)cccc4N)ncc3c2)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.168 mmol) in ethanol (4 mL) and water (4 mL) was added iron powder (75 mg, 1.344 mmol) and ammonium chloride (74 mg, 1.344 mmol). The mixture was stirred at 100° C. for 2 hrs, cooled to RT, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to afford N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-6-methylbenzene-1,2-diamine (40 mg, 53%) as a yellow solid. MS (ES+) C22H19Cl2N5O2 requires: 455, 457. found: 456, 458 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.33 (br. s., 1H), 9.01 (s, 1H), 9.65 (br. s., 1H), 8.23 (s, 1H), 7.05 (s, 1H), 6.93 (br. s., 1H), 6.64-6.63 (m, 1H), 6.50-6.49 (m, 1H), 4.80 (s, 2H), 3.99 (s, 6H), 2.09 (s, 3H).
Reaction SMILES: O.Cl.Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH3:10].C(#N)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[OH2:11].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH:18][C:23](=[O:25])[CH3:24])[CH:15]=[CH:16][CH:17]=1)[CH3:10].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[CH:9]([O:11][C:12]1[C:13]([CH3:19])=[C:14]([NH:18][C:23](=[O:25])[CH3:24])[CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: Cc1c(N)cccc1OC(C)C1=NCCN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(OC(C)C2=NCCN2)c1C

Procedure:
The title compound of Example 4 (1.5 g, 4.8 mmole) was stirred in 60 ml of acetonitrile containing 2.3 ml (ca. 24 mmole) of acetic anhydride. After 18 hours the reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in water. The solution was then made alkaline with aqueous sodium bicarbonate and extracted with dichloromethane. After the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo, the residue was recrystallized from diethyl ether to give 398 mg of the title compound. Structure assignment was supported by nmr spectrum and by elemental analysis.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][CH2:12][C:11](=[O:16])[C:10]=2[CH:17]=1)([O-:5])=[O:4]>CO>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][CH2:12][CH:11]([OH:16])[C:10]=2[CH:17]=1)([O-:5])=[O:4]
Reactant: O=C1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
10.2 g of sodium borohydride were added in portions at 0° C. with vigorous stirring to a suspension of 50 g of 3,4-dihydro-7-nitro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) in 345 ml of methanol. After 30 min, the reaction mixture was added to ice water, the solid was filtered off with suction and 43 g of 7-nitro-2,3,4,5-tetrahydro-1-benzoxepin-5-ol was obtained. This was heated on a water separator for 2 h with 1 g of p-toluenesulfonic acid in 520 ml of toluene. After cooling, the organic phase was washed with sodium bicarbonate solution and sodium chloride solution. After drying over sodium sulfate and concentrating, 38.8 g of 2,3-dihydro-7-nitro-1-benzoxepine were obtained, m.p. 98-100° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.Cl[Pd]Cl.O.C(#N)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ncc(C)nc2C)cc1
Yield: 99 %

Procedure:
First, to a recovery flask equipped with a reflux pipe were placed 1.03 g of 2-chloro-3,5-dimethylpyrazine, 1.09 g of 4-methoxyphenylboronic acid, 0.76 g of sodium carbonate, 0.032 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the atmosphere in the flask was replaced with argon. This reaction container was subjected to irradiation with a microwave (2.45 GHz, 100 W) for 10 minutes to be heated. Then, water was added to this solution, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After drying, the solution was filtrated. The solvent of this solution was distilled off, whereby a pyrazine derivative Hdmmoppr (dark yellow liquid, yield: 99%), which was a target substance, was obtained. For the irradiation with a microwave, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme of Step 1 is shown by the following (A-1).
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[C:5]([C:7]1[CH:8]=[C:9]([N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][C:20]=3[CH3:34])[S:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1F)#[N:6].[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:5]([C:7]1[CH:8]=[C:9]([N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[CH:21][C:20]=3[CH3:34])[S:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[O:3][CH2:2][C:1]#[N:4])#[N:6]
Reactant: N#CCO
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(F)c(C#N)c2)CS1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(OCC#N)c(C#N)c2)CS1
Temperature: 75 °C

Procedure:
Glycolonitrile (0.013 mmol, 0.1 mL) was added to a solution of tert-butyl 3-(4-(3-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-5-yl)-3-methylphenyl)propanoate (0.012 mmol, 0.005 g, from Step B) in THF (1 mL). Sodium hydride (95%, 5 mg) was added to the reaction mixture which was heated at 75° C. for 16 h. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 25% EtOAc/hexanes yielded the title compound: ESI-MS (m/z) 461.2; HPLC A: 3.94 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][C:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[O:11])[CH:13]=2)(=[O:19])=[O:20])[CH2:22]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(=O)O)C2)c1
Product: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(=O)NCc3ccccc3)C2)c1

Procedure:
The entitled compound was produced according to the method of Example 57 but using the compound obtained in Example 56 and benzylamine as the starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)N3CCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)N2CCCC2)c1
Yield: 59.7 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(pyrrolidine-1-carbonyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.31 mmol) in methanol (4.8 mL) and 1N sodium hydroxide aqueous solution (4.58 mL, 4.58 mmol) was heated to reflux for 2 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residual was acidified with 1N hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with dichloromethane to afford 70 mg of 3,3-dimethyl-2-(3-(pyrrolidine-1-carbonyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white powder. Yield: 60.5%. LC-MS (M+1)=379.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O[CH:23](OCC)[C:24]1C=CC(CCCNC2C=CC(F)=CC=2)=C[CH:25]=1)C.BrC(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:24]([CH3:25])[CH3:23])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[O:17])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(CCCNc2ccc(F)cc2)cc1
Reactant: CCOC(OCC)c1ccc(CCCNc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: CC(C)N(CCCc1ccc(C=O)cc1)c1ccc(F)cc1
Yield: 83 %

Procedure:
A mixture of 4-(3-(4-fluorophenylamino)propyl)benzaldehyde (0.09 g, 0.35 mmol) [prepared form the product of Step B by stirring in acidifies CHCl3] and 2-bromopropane (0.2 ml) and K2CO3 (0.1 g; 0.73 mmol) was stirred at reflux in anhydrous DMF (5 ml) for 6 h. The solvent was evaporated under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC(SiO2, hexane/EtOAc), to give the title compound (0.078 g, 83%) as creamy paste. 1H-NMR (CDCl3) 10 (s, 1H); 7.78 (d, 2H, J=8.13 Hz); 7.32 (d, 2H, J=8.07 Hz); 6.93-6.86 (m, 2H); 6.82-6.66 (m, 2H); 3.07 (t, 2H, J=7.5 Hz); 2.71 (t, 2H, J=7.5 Hz); 2.71 (t, 2H, 7.62 Hz); 2.27-2.21 (m, 1H); 1.86-1.83 (m, 1H); 1.08 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[NH2:27][CH2:28][CH:29]([CH:31]1[CH2:33][CH2:32]1)[OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:31]1([CH:29]([OH:30])[CH2:28][NH:27][C:18]([C:15]2[N:16]=[N:17][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([O:5][C:4]4[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=4[C:2]([F:26])([F:1])[F:25])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[O:19])[CH2:33][CH2:32]1
Reactant: NCC(O)C1CC1
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)C1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid (120 mg, 0.3 mmol), 2-amino-1-cyclopropylethanol (57 mg, 0.56 mmol) and HATU (249 mg, 0.65 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (285 μL, 3.4 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, diluted twice with brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 90-100% EtOAc in hexanes in 20 min, 20 mL/min, 18 mL/fraction) gave the title compound as a light brown foam. 1H NMR (400 MHz, acetone-d6): δ 0.30-0.52 (m, 4H), 0.93-1.01 (m, 1H), 1.92-2.00 (m, 2H), 2.14-2.24 (m, 2H), 3.22-3.28 (m, 1H), 3.43-3.49 (m, 1H), 3.71-3.77 (m, 1H), 3.94-4.08 (m, 4H), 4.24 (d, 1H), 5.04 (m, 1H), 7.13 (t, 1H), 7.38 (m, 2H), 7.62-7.68 (m, 2H), 7.94 (d, 1H), 8.35 (s, 1H). MS (+ESI) m/z 451 (MH+).
Reaction SMILES: [Br:1]Br.[F:3][CH:4]1[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:1][C:4]1([F:3])[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13]
Reactant: O=C1c2ccsc2CCC1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1c2ccsc2CCC1(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Add a solution of bromine (10.08 g, 63.1 mmol, 1.1 equiv.) in dry carbon tetrachloride (60 mL) dropwise via addition funnel over 1 h20 min to a cold (0° C.) solution of 5-fluoro-6,7-dihydro-5H-benzo[b]thiophen-4-one (9.72 g, 57.1 mmol, 1 equiv.) in dry diethyl ether (300 mL). Once all the bromine is added warm to room temperature for 2 hours and add more bromine (0.7 M in CCl4, 7 mL, 4.9 mmol, 0.09 equiv.) and stir the reaction mixture at room temperature for 1 hr before adding saturated aqueous sodium thiosulfate. The layers are separated and the aqueous layer is extracted with diethyl ether (three times). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purify the resultant crude material by medium pressure liquid chromatography eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (6.976 g, 49%). δH (400 MHz, CDCl3) 2.67-2.78 (m, 1H), 2.93 (dddd, 1H, J=14, 4, 4, 4 Hz), 3.24-3.31 (m, 2H), 7.21 (d, 1H, J=6 Hz), 7.45 (d, 1H, J=6 Hz).