Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[NH:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].C(N(CC)CC)C.S(Cl)(Cl)=O.Cl>O1CCCC1.O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:12])=[N:2][O:11][C:5]=2[CH:6]=1
Reactant: Cc1ccc(C(=O)NO)c(O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(O)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
44.0 g of N,2-dihydroxy-4-methylbenzamide was suspended in 880 mL of tetrahydrofuran, to which 147 mL of triethylamine was added dropwise at room temperature and then 28.7 mL of thionyl chloride was added dropwise at 5 to 10° C. successively, and this mixture was stirred for one hour at room temperature. The reaction mixture was added to water, and adjusted to pH 1 with 12M hydrochloric acid, and then resultant precipitate was filtered out thereof. The resultant solid was washed with water to yield 35.2 g of 6-methyl-1,2-benzisoxazol-3-ol as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH2:14]([NH:21][CH2:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)c1ccc(Br)cc1
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)c1ccc(Br)cc1
Reaction time: 48 h
Yield: 60.3 %

Procedure:
To a solution of methyl 2-(4-bromophenyl)acrylate (8.2 g, 34 mmol) in methanol (100 mL) at room temperature was added benzylamine (3.7 mL, 34 mmol). The resulting mixture was stirred for 2 days and concentrated. The residue was purified by flash column chromatography on silica gel (chloroform/methanol=90/10 as an eluant) to yield methyl 3-benzylamino-2-(4-bromophenyl)propionate (7.1 g, 20.5 mmol, 60%) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH:9]([OH:11])[CH3:10])=[CH:7][C:6]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])=[N:5]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:18][C:13]1[N:12]([C:6]2[CH:7]=[C:8]3[CH:9]([CH3:10])[O:11][CH2:2][CH2:3][N:4]3[N:5]=2)[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C)n1-c1cc(C(C)O)n(CCBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C)n1-c1cc2n(n1)CCOC2C
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 150f (2.0 g, 1.0 eq., 6.4 mmol), K2CO3 (1.77 g, 2.0 eq., 12.8 mmol), acetonitrile (50 mL). The reaction mixture was reflux overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 150g (550 mg, 37%, over two steps) as a colorless oil. MS-ESI: [M+H]+ 232.3
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:17][C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC1=NCCC1
Reactant: NC(Cc1cccnc1)c1cccc(Cl)c1Cl
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(C(Cc2cccnc2)NC2=NCCC2)c1Cl
Temperature: 70 °C
Yield: 49.7 %

Procedure:
To 1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethanamine (258 mg, 0.97 mmol) in methanol (5 mL) was added 5-methoxy-3,4-dihydro-2H-pyrrole (96 mg, 0.97 mmol) followed by acetic acid (2 drops). The mixture was heated at 70° C. for 16 hours. The mixture was cooled to room temperature and methanol was removed. Purification by chromatography on silica gel (5% 7N NH3 in MeOH/CH2Cl2) gave N-(1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethyl)-3,4-dihydro-2H-pyrrol-5-amine (161 mg, 50%) as an off white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22](=[O:45])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:22]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])=[O:45]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Yield: 98.1 %

Procedure:
To 0.59 g of (1S,4S)-(1-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid tert-butyl ester in 5 mL of dichloromethane under stirring were added 5 mL of trifluoroacetic acid. The reaction was followed by TLC and upon disappearance of the starting material the mixture was evaporated in vacuo. The residue was taken up in ethyl acetate and the organic layer washed with aqueous 1.0N sodium hydroxide, with brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and then placed under mechanical vacuum overnight to provide 0.49 g (94%) of title compound as a light brown foam. The product was used without further purification to give a series of diphenyl-propionamide derived tests compounds.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.[N:29]([CH2:32][C:33]1[N:42]=[C:41](Cl)[C:40]2[CH2:39][C:38]([CH3:45])([CH3:44])[CH2:37][CH2:36][C:35]=2[N:34]=1)=[N+]=[N-].[N-]=[N+]=[N-]>>[CH3:44][C:38]1([CH3:45])[CH2:37][CH2:36][C:35]2[N:34]=[C:33]([CH2:32][NH2:29])[N:42]=[C:41]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:40]=2[CH2:39]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CC1(C)CCc2nc(CN=[N+]=[N-])nc(Cl)c2C1
Agent: [N-]=[N+]=[N-]
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CN)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared as an acetate salt by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 2-(azidomethyl)-4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 45) in step 3 followed by reduction of the azide to the amine (LaRock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations 1989, VCH Publishers, Inc., New York). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.54 (dd, 1H), 7.04 (d, 1H), 4.68 (s, 2H), 4.34-4.28 (m, 2H), 3.92-3.87 (m, 2H), 3.63-3.59 (m, 2H), 2.69 (t, 2H), 2.54 (s, 3H), 2.46 (s, 2H), 1.86 (s, 5H), 1.59 (t, 2H), 0.86 (s, 6H); MS (EI) for C27H31N7O: 470 (MH+).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Br[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1.CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc2c(cc1Nc1ccc3c(c1)OCO3)OCO2
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 3,4-(methylenedioxy) aniline (5.34 grams, 38.9 mmoles), 4-bromo-1,2-(methylenedioxy) benzene (6.41 grams, 31.9 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.71 grams, 0.8 mmoles), 1,1′-bis(diphenylphosphino)-ferrocene (1.29 grams, 2.3 mmoles), sodium tert-butoxide (4.20 grams, 43.7 mmoles) and anhydrous toluene (40 mL). The contents of the flask were heated to 80° C. for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (240 mL). The combined organic layers were concentrated in vacuo to yield a dark yellow oil. The oil was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 6 grams of yellow solid. The solid was triturated with hexane and filtered to afford 3.9 grams of the desired product as a white solid. 1H NMR (CDCl3) δ 6.7 (d, 2H), 6.55 (s, 2H), 6.35 (d, 2H), 5.85 (s, 4H), 5.35 (bs, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[F:16])[CH3:6])=[O:4].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[C:12]2[C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2]2
Reactant: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 80 °C

Procedure:
Following the method described by Hennessy and Buchwald in J. Am. Chem. Soc., 2003, 125, 12084-12085, 2-chloro-N-(2-fluoro-4-nitro-phenyl)-N-methyl-acetamide (15, 1.00 g, 4.05 mol), palladium acetate (27.3 mg, 0.122 mmol) and 2-(di-tert-butylphosphino)biphenyl (72.5 mg, 0.243 mmol) are placed under a nitrogen atmosphere, and toluene (20 ml) and triethylamine (0.85 ml, 6.08 mmol) are added via syringe. The reaction is heated at 80° C. for 4 hours and then evaporated to dryness. The dark residue is purified by PTLC (dichloromethane) to give the title compound as a light brownish-orange solid. HPLC r.t. 4.4 min.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:10]([NH:17][C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:19][C:18](=[O:21])[NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: O=C(CCl)NCc1ccccc1
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCc1ccccc1
Yield: 52.5 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.85 mmol) dissolved in NMP was reacted at ca. 55° C. with N-benzyl chloroacetamide (0.84 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.56 g (53% yield) of the title compound (2) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 7.36-7.26 (m, 5H), 6.94-6.88 (m, 2H), 6.19 (br s, 1H), 4.73 (s, 2H), 4.51 (d, J=5.6 Hz, 2H), 3.81 (s, 3H). MS (ESI): m/z 278.04 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:35][S-:36].[Na+].[I-].[K+].CN(C)C=O>O1CCCC1.O>[F:24][C:15]1[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:13][N:12]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][S:36][CH3:35])[CH:4]=2)(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CCl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CSCc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Reaction time: 21 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl {[1-{[3-(chloromethyl)phenyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (386 mg) in tetrahydrofuran (3 mL) were added sodium thiomethoxide (58 mg) and potassium iodide (125 mg) and the mixture was stirred for 21 hr. Dimethylformamide (3 mL) was added and the mixture was stirred at 100° C. for 76 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a yellow oil (yield 291 mg, 74%).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([N:15]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(OC(C)(C)C)=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[ClH:1].[NH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:16]([N:15]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
A 4N-hydrochloric acid/1,4-dioxane solution (4.5 ml) was added to a solution of tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate (0.749 g, 1.773 mmol) in tetrahydrofuran (4.5 ml) and stirred overnight. The solvent was distilled off under reduced pressure, followed by replacement with toluene (twice), whereby 3-amino-N,N-dibenzylcyclohexanecarboxamide monohydrochloride (0.848 g, >99%) was obtained.
Reaction SMILES: [Si:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cu]I>[C:15]([O:14][C:13](=[O:19])[N:12]([CH3:20])[CH2:11][C:10]1[CH:9]=[CH:8][CH:23]=[C:22]([C:6]#[C:5][Si:1]([CH3:4])([CH3:3])[CH3:2])[CH:21]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
TMS-Acetylene (2.2 mL, 15.0 mmol) was added dropwise to commercially available tert-butyl 3-bromobenzyl(methyl)carbamate (3.0 g, 10 mmol), CuI (100 mg, 0.5 mmol) and palladium dichlorobistriphenylphosphine (210 mg, 0.3 mmol) in triethylamine (30 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 12 hrs before cooling to room temperature and evaporating in vacuo. The residue was triturated with diethyl ether (30 mL), filtered and the filtrate evaporated in vacuo and purified by column chromatography (5% ethyl acetate in hexane) to yield A314.1 (3.2 g, 100%) as a brown oil. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.34 min, M+Na+=340.34
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2].Br[CH2:36][CH2:37][O:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:36][CH2:37][O:38][CH3:39])=[CH:31][CH:32]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2]
Reactant: COCCBr
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(OCCOC)cc4)nn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution (S)-3-{4-[2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.250 g, 0.585 mmol) and 1-bromo-2-methoxy-ethane (0.22 mL, 2.34 mmol) in acetonitrile (10 mL) is added cesium carbonate (0.381 g, 1.17 mmol) at room temperature and the reaction mixture is stirred at room temperature overnight. The reaction mixture is filtered through diatomaceous earth and washed with EtOAc (20 mL), and the filtrate is concentrated to dryness. The residue is dissolved in EtOAc (30 mL), washed with water (2×30 mL), brine solution (30 mL), dried over sodium sulphate, and evaporated under reduced pressure. The crude compound is purified by silica gel (combiflash purifier) and is eluted with 17-19% EtOAc in hexane to give the title compound as a white semi solid (0.190 g, 64%). LCMS m/z 514 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:23][CH2:24][CH2:25][O:26]C2CCCCO2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)(=O)C.C1COCC1.O>[OH:26][CH2:25][CH2:24][CH2:23][N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)c1ccc(N(CCCOC2CCCCO2)C(=O)C2CCCc3ccccc32)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(N(CCCO)C(=O)C2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
N-(4-Isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.24 g) was dissolved in a mixed solvent (7 mL) of acetic acid: THF: water (4:2:1) and stirred at room temperature for 2 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-(3-hydroxypropyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([S:4][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:3])[CH3:2]
Reactant: Fc1cccnc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1ncccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
181.2 g of isopropylmercaptan are added dropwise at a temperature of 0° to +2° C. in the course of 25 minutes to a suspension of 324 g of anhydrous potassium carbonate and 335.6 g of 2,3-difluoropyridine in 4500 ml of dimethylformamide. After the reaction mixture has been stirred for 18 hours at room temperature, it is poured into a mixture of 8000 ml of ice-water and 4000 ml of ethyl acetate. The organic phase is subsequently separated off and washed with ice-water and then with ethyl acetate. The combined organic phases are dried with sodium sulfate and subsequently concentrated. Purification by column chromatography over silica gel with ethyl acetate/n-hexane (1:9) gives 362.9 g of 2-isopropylthio-3-fluoropyridine in the form of an oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][O:25][CH3:26])[CH:18]=1.[C:27](=[O:29])=[O:28]>C1COCC1.O.C(OCC)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][O:25][CH3:26])[C:18]=1[C:27]([OH:29])=[O:28]
Reactant: O=C=O
Reactant: COCOc1cccc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorophenol (8 ml, 77 mmol, ABCR) in DCM (120 ml) was added dimethoxymethane (32 ml, 362 mmol, Aldrich) and then p-toluenesulphonic acid (0.164 g, 0.952 mmol, Alfa Aesar). The solution was heated to reflux under nitrogen using a Soxhlet apparatus containing 3A activated molecular sieves (approximately 20 g)* for 24 h. *The 3A molecular sieves were replaced after 6 h. Approximately a quarter of the reaction mixture was applied to a 70 g aminopropyl cartridge (prewashed with methanol). The cartridge was eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to give 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (1.66 g). The remaining reaction mixture was applied evenly to 3×70 g aminopropyl cartridges (pre-washed with methanol). The cartridges were eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to leave a colourless mobile oil (first batch). The mixed fractions were combined and the solvent removed in vacuo to leave a colourless mobile oil. The residue from the mixed fractions was applied to a 70 g aminopropyl cartridge (pre-washed with methanol) and eluted with methanol. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and added to the first batch. The solvent was removed in vacuo to give another batch of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (5.27 g). To THF (20 ml) under nitrogen at 0° C. was added 1.6 M n-butyllithium in hexanes (18.1 ml, 29.0 mmol, Aldrich). To the solution at −60° C. was added a solution of 2,2,6,6-tetramethylpiperidine (4.90 ml, 29.0 mmol, Alfa Aesar) in THF (5 ml) and then a solution of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene (5.01 g, 29.0 mmol) in THF (10 ml). The temperature was maintained below −50° C. during the addition. The solution was stirred at −60° C. to −70° C. for 1 h. To the solution was added a large excess of freshly ground solid carbon dioxide and the mixture allowed to warm to ambient temperature. The reaction mixture was diluted with water (100 ml) and diethyl ether (130 ml). The phases were separated and aqueous phase carefully acidified to pH1 using concentrated HCl. The suspension was extracted with dichloromethane (3×40 ml). The solvent was removed in vacuo to give the title compound as a white solid (4.36 g);
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH2:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:22]1([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:21][CH2:20][C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]3=[N:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=C(c4ccccc4)c4ccccc4)cnc32)cc1
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (2.00 g, 6.61 mmol, Example #5 Step C) in DCM (30 mL) was added diphenylmethanimine (1.16 mL, 6.61 mmol). After about 2 d, the reaction mixture was concd in vacuo to provide N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (2.75 g, 89%) as a foam and used without further purification. LC/MS (Table 1, Method a) Rt=3.02 min; MS m/z: 467 (M+H)+.