Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CC2)COc2ccccc2C3)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC1(CCNCC1)CO2
Yield: 91.1 %

Procedure:
1′-benzyl-4H-spiro[chromene-3,4′-piperidine] (800 mg, 2.7 mmol) was dissolved in methanol (100 mL). Acetic acid (5 mL) and palladium on activated charcoal (cat amount, 10%) was added. Reaction in a Parr apparatus at 35 psi for 18 hrs, followed by filtration, evaporation and HPLC purification on C18 (acetonitrile/water) yielded 500 mg (92%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CCOCC>C1COCC1>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([I:1])=[CH:3][C:4]=2[C:10]1=[O:11])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCC(=O)c2cc(I)ccc2N1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 70 °C

Procedure:
To a solution of 7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-a) (1.67 g, 5.54 mmol) in THF (15 mL) was added dimethylformamide dimethylacetal (4.0 mL, 27.7 mmol) and the reaction mixture heated to 70° C. for 1 h. The reaction mixture was cooled to 22° C., treated with Et2O (50 mL), and the resulting precipitate filtered and dried in vacuo to give v-a (1.64 g, 83%) as a brown powder: MS m/z═357 (M+H).
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[C:3]([C:5]([O-:7])=[O:6])=O.[Na+].[Na+].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][N:21]=[C:3]([C:5]([OH:7])=[O:6])[C:2]([OH:9])=[O:8]
Reactant: O=C([O-])C(=O)C(=O)[O-]
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(=NNc1ccccc1F)C(=O)O
Reaction time: 8 h

Procedure:
Sodium mesoxalate monohydrate (2.21 g, 12.3 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give a colourless cloudy solution. 2-Fluoro-phenylhydrazine hydrochloride (2.00 g, 12.3 mmol) was added portionwise at room temperature to the stirred mixture. A yellow precipitate formed, the mixture was diluted with water (50 ml) and stirring continued overnight. Ethyl acetate (150 ml) was added, the phases were mixed vigorously until the solids had dissolved. The phases were separated and the aqueous phase was washed with ethyl acetate (50 ml). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed under vacuum. The title compound was isolated as a yellow powder (2.55 g, 11.7 mmol, 92%). LCMS: m/z 227 [M−H]+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1O
Solvent: CC(=O)O
Product: CC(=O)c1cccc(O)c1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of catechol in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and diethylene glycol dibutyl ether was distilled under vacuum. 1 Liter of toluene was added to the reaction mixture and cooled to 0° C. and then the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired mono acetyl catechol was obtained by evaporating the residue in vacuum. (Yield: 149.0 g(98%). mp: oil. 1H-NMR(200 MHz, CDCl3, ppm) 2.33(s, 3H), 5.81 (br, 1H), 6.83-7.18 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[C:2]([C:11]([O:13][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:12])[N:1]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:28]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1
Reactant: N#Cc1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3-chloro-4-(3,4-dichlorobenzyl)benzonitrile (0.93 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.64 g of desired compound (melting point: 179.0°-185.0° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:6]2[NH:5][C:4](=[O:7])[NH:3][C:2]=2[CH3:1])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of 98.1 g (1 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 moles) of anhydrous aluminum chloride and 500 ml of nitrobenzene there is added dropwise over 10 minutes, 158.6 g (1 mole) of p-fluorobenzoyl chloride. The mixture is stirred at 60°-65° C. for 6 hours, then poured onto 2 kg of ice. The precipitate which forms is separated by filtration, washed with diethyl ether and water and recrystallized from dimethylformamide to give 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one melting at about 289°-292° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccccn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine and pyridine-2-carboxylic acid as starting materials, MS (LC/MS): 408.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH3:27])[N:26]=2)=[N:11][CH:12]=[C:13](/[CH:15]=[CH:16]/[CH2:17][N:18]([CH3:20])[CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(NN)(=O)=O)=CC=1.[ClH:40]>>[ClH:40].[ClH:40].[CH2:1]([O:8][C:9]1[C:10]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH3:27])[N:26]=2)=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(/C=C/CN(C)C)cc2OCc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Product: Cc1csc(Nc2ncc(CCCN(C)C)cc2OCc2ccccc2)n1
Yield: 31 %

Procedure:
(E)-3-(benzyloxy)-5-(3-(dimethylamino)prop-1-enyl)-N-(4-methylthiazol-2-yl)pyridin-2-amine (140 mg, 0.368 mmol) and 4-methylbenzenesulfonohydrazide (343 mg, 1.84 mmol) were reacted according to the method of Example 93 to afford the title compound (52 mg, 31.0% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 11.05 (bs, 1H), 10.66 (bs, 1H), 7.87 (s, 1H), 7.62 (m, 3H), 7.45-7.32 (m, 3H), 6.83 (s, 1H), 5.34 (s, 2H), 2.98 (m, 2H), 2.71 (d, 6H), 2.66 (t, 2H), 2.31 (s, 3H), 2.01 (m, 2H). Mass spectrum (apci) m/z=383.2 (M+H-2HCl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH2:26](OC(OCC(C)(C)C)N(C)C)C(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Yield: 75.4 %

Procedure:
In 4 ml of toluene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 200 mg of N,N-dimethylformamide dineopentylacetal was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 4 hours. The crystals thus deposited were collected by filtration, and to the crystals were added 5 ml of ethanol and 5 ml of water, after which the pH thereof was adjusted to 1.0 with 2N hydrochloric acid. Thereafter, the crystals thus deposited were collected by filtration to obtain 155 mg (yield 75.4%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 244°-248° C. The physical properties of this compound were identical with those of the compound obtained in Example 40.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([CH:35](I)[C:36]([NH2:38])=[O:37])(C)(C)C.Cl>O1CCCC1.CS(C)=O>[C:6]([NH:38][C:36](=[O:37])[CH2:35][N:4]1[C:5]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=2[CH:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:8][CH:2]([Br:1])[C:3]1=[O:20])([CH3:15])([CH3:7])[CH3:5]
Reactant: Cc1ccc2c(c1)NC(=O)C(Br)CC2C1CCCCC1
Reactant: CC(C)(C)C(I)C(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)NC(C)(C)C)C(=O)C(Br)CC2C1CCCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a 125 mL round-bottomed flask equipped with nitrogen inlet were added 4.7 grams (13.97 mmol) 3-bromo-5-cyclohexyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one and 70 mL dry tetrahydrofuran. The solution was cooled to -78° C., and 16.8 mL (16.76 mmol) of a 1N solution of sodium bistrimethylsilylamide in tetrahydrofuran was added, followed by a solution of 4.04 grams (16.76 mmol) of t-butyl iodoacetamide in 35 mL dry tetrahydrofuran dropwise over 15 minutes. The reaction was stirred for 10 minutes, then warmed, 35 mL dry dimethylsulfoxide added, and the reaction stirred at room temperature for 14 hours. It was then poured into 1N hydrochloric acid, extracted into ethyl acetate, and the organic layer washed with water, saturated aqueous sodium bisulfite solution, brine, dried, and evaporated. The residue was chromatographed on silica gel with hexane/ethyl acetate to afford the two diastereomeric products, the less polar isomer, M.P. 183°-186° C., 2.16 g, 34% yield, and the more polar isomer, M.P. 206.5°-207.5° C., 3.16 g. 50% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
To a solution of 5-hydroxy indole (4.56 gm, 0.034 moles) in DMF (20 ml), potassium carbonate (9.43 gm, 0.068 moles), ethyl bromoacetate (6.29 gm, 0.0377 moles) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 6.2 gm (82%) of product as solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1
Reactant: CC1(O)CCNC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CCCc2ccccc2)C1
Reaction time: 12 h
Yield: 70.4 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 3-bromopropylbenzene (1.29 g, 6.48 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=10:1 (volumetric ratio)) to produce 3-methyl-1-(3-phenylpropyl)pyrrolidin-3-ol (1 g) in a yield of 70.4%.
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[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.Cl.[F:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][C@H:33]([F:32])[CH2:34]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: F[C@H]1CCNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Agent: Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CC[C@H](F)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and (3S)-3-fluoropyrrolidine hydrochloride. LCMS (M+H)+=519.1/521.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:11][P:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])(=[O:15])[O:13][CH3:14]
Reactant: COP(OC)OC
Reactant: Cc1ccc(I)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COP(=O)(OC)c1ccc(C)cc1C
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Iodo-m-xylene (8.62 mmol), trimethyl phosphite (12.07 mmol) and palladium acetate (0.86 mmol) were mixed together in acetonitrile (12 ml), in a microwave tube. The vessel was sealed and placed in a microwave to react at 160° C., for 45 minutes. After cooling to room temperature, acetonitrile was removed. The crude material was purified by silica gel chromatography to yield Intermediate I.4 as an oil (95%). Intermediate 1.4 was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.35 (s, 3H), 2.51 (s, 3H), 3.74 (d, J=12.0 Hz, 6H), 7.08-7.09 (m, 2H), 7.75-7.81 (m, 1H); 31P NMR (CDCl3, 162 MHz) δ (ppm) 23.18 (s, 1P); and MS (ESI, EI+) m/z=215 (MH+)
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(O)(=O)/C=C\CC=CCC=CCCCCC(O)=O.C(O)(=O)CC/C=C\CC=CCC=CCCC(O)=O.C(O)(=O)/C=C\CC=CCC=CCCC(O)=O.C(O)(=O)C/C=C\CC=CCCCCC(O)=O.C(O)(=O)/C=C\CC=CCC=CC(O)=O.C(O)(=O)C/C=C\CC=CCCC(O)=O.C(O)(=O)CC/C=C\CCCCC(O)=O.C(O)(=O)/C=C\CC=CCC(O)=O.C(O)(=O)CC/C=C\CCC(O)=O.C(O)(=O)/C=C\CCCCC(O)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCC=CCC=CC/C=C\CCCCC(=O)O
Agent: O=C(O)/C=C\CC=CCC(=O)O
Agent: O=C(O)/C=C\CC=CCC=CCCC(=O)O
Agent: O=C(O)/C=C\CC=CCC=CCCCCC(=O)O
Product: O=C(O)CC/C=C\CC=CCC=CCCCCC(=O)O

Procedure:
cis-6, 9, 12-hexadecatriene dioic acid; cis-2, 5, 8-tetradecatriene dioic acid; cis-4, 7, 10-tetradecatriene dioic acid; cis-2, 5, 8-dodecatriene dioic acid; cis-3, 6-dodecadiene dioic acid; cis-2, 5, 8-decatriene dioic acid; cis-3, 6-decadiene dioic acid; cis-4-decene dioic acid; cis-2, 5-octadiene dioic acid; cis-4-octene dioic acid and cis-2-octene dioic acid.
Reaction SMILES: [CH2:1]([NH2:5])[C:2](=[CH2:4])[CH3:3].Cl[CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]1([S:9]([CH2:8][CH2:7][NH:5][CH2:1][C:2](=[CH2:3])[CH3:4])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: C=C(C)CN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)CNCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of methallylamine (8.0 g; 1.12 mol), in toluene (20 ml) was added dropwise to a solution of 1-chloro-2-phenylsulphonylethane (11.54 g; 56.4 mmol) in toluene (100 ml) at 0° C. When the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Thin layer chromatography indicated that all of the starting material had been consumed. Ether (150 ml) was added and the precipitate filtered off. Removal of the solvent from the filtrate produced a colourless oil which was subjected to silica gel column chromatography using ethyl acetate as eluent. Fractions containing the component Rf=0.37 (ethyl acetate) were combined and evaporated to give the title amine as a colourless oil, in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[NH:21][C:20]([C:22]([F:25])([F:24])[F:23])=[N:19][N:18]=1)=[N:5]2.[CH2:26](N(CC)CC)C.IC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[N:21]([CH3:26])[C:20]([C:22]([F:23])([F:24])[F:25])=[N:19][N:18]=1)=[N:5]2
Reactant: CCN(CC)CC
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)[nH]1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the above 6,7-dichloro-2-isopropyl-3-(5-trifluoromethyl-4H-1,2,4-triazol-3-ylsulfanyl)quinoxaline (78 mg, 0.19 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.05 ml, 0.38 mmol) followed by addition of iodomethane (0.02 ml, 0.29 mmol). The reaction was stirred under nitrogen overnight at room temperature. Purification by flash column chromatography using ethyl acetate:hexanes 1:10 afforded the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2[CH:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(NS(C)(=O)=O)C1

Procedure:
To a tetrahydrofuran solution (2.0 mL) of tert-butyl 5-amino-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.342 mmol) synthesized in Reference Synthesis Example 202, triethylamine (52.0 μL, 0.374 mmol), and N,N-dimethyl-4-aminopyridine (2.00 mg, 0.0170 mmol) were added, and then methanesulfonyl chloride (29.0 μL, 0.374 mmol) was added at 0° C. with stirring, followed by stirring the resultant reaction solution for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:37](=[O:38])[CH2:36][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and tert-butylacetyl chloride as a pale yellow oil (97%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (dd, J=6.0, 1.9 Hz, 1H), 7.44 (m, 4H), 7.16 (m, 4H), 7.08 (m, 1H), 6.99 (m, 1H), 4.88 (s, 2H), 3.94 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 2.00 (s, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.99 (s, 9H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 514.0, HPLC, Rt: 5.92 min (Purity: 100.0%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH2:9][C:10]2[N:11]=[C:12]([Br:16])[S:13][C:14]=2[N:15]=1)=[O:7])C>C1COCC1.O>[Br:16][C:12]1[S:13][C:14]2[N:15]=[C:8]([C:6]([OH:7])=[O:5])[CH2:9][C:10]=2[N:11]=1
Reactant: CCOC(=O)C1=Nc2sc(Br)nc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=Nc2sc(Br)nc2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Add KOH (1.07 gm, 2 eq) to a mixture of 2-bromo-6H-pyrrolo[3,2-d]thiazole-5-carboxylic acid ethyl ester (2.6 gm, 9.38 mmol) in THF (15 ml) and water (20 ml), and then heat at 100° C. for 1 hr. Allow to stand overnight at room temperature and collect the crystalline solids by filtration (weight 1.7 gm). Concentrate the aqueous solution in vacuo, and combine the residue with the previously isolated crystalline solid. Acidify with acetic acid in methanol to provide the title compound (2.31 g).