Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1
Reactant: CO
Reactant: O=C(O)Cc1ccc(SC2CC2)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC2CC2)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of [3-bromo-4-(cyclopropylsulfanyl)phenyl]acetic acid (13.5 g), concentrated sulfuric acid (0.135 mL), and methanol (40 mL) was stirred under heating and reflux for 4 hours. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and then a 1 M aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL×3). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain methyl [3-bromo-4-(cyclopropylsulfanyl)phenyl]acetate (13.8 g) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].I[CH2:26][CH:27]([OH:30])[CH2:28][OH:29].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 7.34 g. of 4-(11-hydroxyundecylamino)benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(11-hydroxyundecylamino)benzoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1.ClC1C=CC=CC=1[C@](O)([C@H](N1N=CC=N1)C)CN1C=NC=N1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]([OH:14])([C@H:15]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:16])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1Cl
Reactant: c1c[nH]nn1
Agent: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccccc1Cl
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccccc1Cl

Procedure:
Using 1H-1,2,3-triazole and (2R,3S)-2-(2-chlorophenyl)-3-methyl-2-[(1H-1,2, 4-triazol-1-yl)methyl]oxirane, Compound 42 and Compound 43 were obtained by the same way as in Example 30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH:30](O)[CH3:31])=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:30]([CH3:31])[CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:33])[F:34])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CC(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OC(C)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with [rac]-6-(4-trifluoromethoxy-phenyl)-hex-5-yn-2-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:26][O:27][CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.9 %

Procedure:
Conc.hydrochloric acid (1.6 ml.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.) in methanol (30 ml.), and stirred at room temperature for 3.5 hours. After evaporating the solvent in vacuo, methanol was added to the residue and the mixture was evaporated in vacuo again. The residue was dissolved in water (30 ml.) and adjusted to pH 3.5 with a sodium bicarbonate saturated aqueous solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).
Reaction SMILES: Cl[C:2]([F:12])([C:9]([OH:11])=[O:10])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5]>O1CCOCC1.[Zn]>[F:7][C:3]([F:8])([CH:2]([F:12])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(F)(F)C(F)(Cl)C(=O)O
Agent: [Zn]
Solvent: C1COCCO1
Product: O=C(O)C(F)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.7 %

Procedure:
To a stirring solution of the chlorotrifluorosuccinic acid (part b) (24.5 g) in 200 ml dioxane was added portionwise zinc metal (85 g) and the mixture was stirred at ambient temperature for 10 hours to yield a viscous liquid which was decanted from the unreacted zinc. Most of the dioxane was evaporated in vacua. The residue was dissolved in 100 ml H2O and a solution of 7.7 ml of concentrated H2SO4 in 25 ml of water was added. The solution was extracted with ether (3×100 ml) and dried over anhydrous MgSO4. The organic layer was stripped to yield 8.3 g (32%) of the product as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C1CCNCC1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
To a cooled (0° C.) solution of 1.75 g (10.0 mmol) of 4-chloro-2-fluoronitrobenzene in 15 mL of EtOH was added 2.97 mL (30.0 mmol) of piperidine dropwise over 5 min. The solution stirred at 0° C. for 10 min and then at 23° C. for 30 min. The mixture was poured into water (225 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with saturated aq NaHCO3 and brine (30 mL each) and then dried (Na2SO4). Concentration afforded 2.33 g (97%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C11H13ClN2O2, 241.1 (M+H), found 241.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:22]/[C:23]2[NH:24][CH:25]=[CH:26][C:27]=2[O:28][CH3:29])/[C:15](=[O:21])[NH:16]3)=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1

Procedure:
Using general Method D above, 4-methoxyphenyl acetylene (0.49 g, 3.68 mmol) (from Step A above) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (0.47 g, 1.47 mmol) using DPPFPdCl2 (0.12 g) (Aldrich) and CuI (28 mg) (Aldrich) as catalyst in DMF (10 mL) and Et3N (15 mL) as solvent and was heated at reflux for 1 day, yielding (Z)-1,3-dihydro-4-[(4-methoxyphenyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 0.31 g, 57%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:34])[CH:16]([C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26](Cl)[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:13].C(OC(C)(C)C)(=O)CC(OCC)=O>CCO.CCOC(C)=O>[CH2:12]([O:14][C:15](=[O:34])[CH:16]([C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26]([NH:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]2)[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:13]
Reactant: COCCN1CCC(N)CC1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: CCOC(=O)CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1[N+](=O)[O-]
Yield: 29 %

Procedure:
To 1-(2-methoxy-ethyl)-piperidin-4-ylamine (4, 1.7 g, 11 mmol) in EtOH (20 mls) was added a solution of the 1:1 mixture of 2-(2-chloro-5-nitro-pyrimidin-4-yl)-malonic acid tert-butyl ester ethyl ester (3) and tert-butyl ethyl malonate (2) (˜5.3 mmol of 3) in EtOH (20 mls) dropwise with stirring. The resulting mixture was stirred at room temperature overnight and then diluted with EtOAc, washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by flash chromatography (eluting solvents=CH2Cl2, followed by 2% MeOH in CH2Cl2, followed by 4% MeOH in CH2Cl2) to give 2-{2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-5-nitro-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (5, 733 mgs, 29%). LC/MS Calcd for [M+H]+ 468, found 468.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([CH2:15][C:16]2[N:20]([CH3:21])[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1COCC1>[Br:8][C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])[N:20]([CH3:21])[C:16]=1[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cn1c(CC2CCCCC2)ccc1S(N)(=O)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(S(N)(=O)=O)cc(Br)c1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of NBS (68.7 mg, 386 μmol) was added a solution of compound 25e (104 mg, 410 μmol) in THF at −78° C. and stirred for 2 h at −78° C. Water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 25f (134 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:21])[C:8]([F:19])([F:20])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of compound 2-Chloro-9-cyclohexyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (6.0 g, 18.98 mmol) in 30 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 1.138 g, 28.47 mmol) at 0° C., followed by the dropwise addition of methyl iodide (1.42 mL, 22.78 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether/EtOA to afford the desired compound (3.0 g, 47.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.85 (m, 10 H) 3.33 (s, 3 H) 4.15 (t, J=12.88 Hz, 2 H) 4.44 (m, 1 H) 8.31 (s, 1 H). [M+H] calc'd for C14H17ClF2N4O, 331; found 331.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([NH2:8])[CH2:5][CH2:4][O:3]1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:9])([CH3:1])[CH2:7]1)=[O:15]
Reactant: O=C=NCCCl
Reactant: CC1(C)CC(N)CCO1
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)NCCCl)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A 0° C. suspension of 2,2-dimethyltetrahydro-2H-pyran-4-amine (0.806 g, 6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was treated with additional 2-chloroethyl isocyanate (160 μL) and stirred at RT for an additional 24 hours, then concentrated to dryness, the residue dissolved in EtOAc and washed with saturated NH4Cl (1×), NaHCO3 (1×) and brine (1×), dried over MgSO4 and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg, 48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OC)(OC)[CH2:9]Br)[CH:3]=1.[NH2:15][C:16]1[CH:28]=[C:27]([CH3:29])[C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([Cl:30])[N:17]=1>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:15]=[C:16]3[CH:28]=[C:27]([CH3:29])[C:19]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[C:18]([Cl:30])[N:17]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CBr)(OC)c1cccc(Br)c1
Reactant: Cc1cc(N)nc(Cl)c1C(=O)OC(C)(C)C
Solvent: Clc1ccccc1
Product: Cc1cc2nc(-c3cccc(Br)c3)cn2c(Cl)c1C(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A flask charged with chlorobenzene (300 ml) was heated to reflux (140° C. oil bath) and to this was added sequentially 1-bromo-3-(2-bromo-1,1-dimethoxyethyl)benzene (56.05 g, 173 mmol) as an oil, and tert-butyl 6-amino-2-chloro-4-methylnicotinate (33.91 g, 140 mmol) as a powder, rinsing both with additional chlorobenzene (70 mL total) to facilitate transfer. The reaction was returned to reflux and heated for 90 min, then cooled and poured slowly into vigorously stirred Et2O (1500 mL). The resulting suspension was stirred for 15 min, then solids were collected by vacuum filtration to afford the product (47 g, 111 mmol, 64.4% yield) as a tan powdery solid. A 3 g sample of product was first purified by biotage (80 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes), then recrystallized from hot acetonitrile to afford a high purity sample for spectra. 1H NMR (500 MHz, CDCl3) δ 8.14 (t, J=1.7 Hz, 1H), 8.02 (d, J=0.5 Hz, 1H), 7.89 (dq, J=7.7, 0.9 Hz, 1H), 7.48 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 2.45 (d, J=0.9 Hz, 3H), 1.65 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 164.3, 145.6, 145.2, 135.3, 133.6, 131.3, 130.3, 129.2, 124.7, 123.9, 123.0, 121.7, 115.4, 107.6, 83.9, 28.1, 19.9. LCMS (M+H)=421.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:14]([OH:16])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:56][N:57]1[C:61]([NH2:62])=[CH:60][C:59]([CH3:63])=[N:58]1>CN(C=O)C>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:14]([NH:62][C:61]2[N:57]([CH3:56])[N:58]=[C:59]([CH3:63])[CH:60]=2)=[O:16])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)n(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)c(Cl)c2)n(C)n1
Reaction time: 8 h
Yield: 9 %

Procedure:
4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.030 g, 0.07 mmol), HBTU (0.080 g, 0.21 mmol), N-methyl morpholine (0.023 mL, 0.21 mmol) and DMF (1 mL) were added to a sealed reaction tube containing 1,3-dimethyl-1H-pyrazol-5-amine (0.023 g, 0.21 mmol). The reaction mixture was allowed to shake overnight and was concentrated. The residue was dissolved up in THF/chloroform (1:3) (4 mL) and washed with sat NaHCO3 (2 mL). The organic solution was separated and concentrated. The crude product was dissolved in DMSO (1.5 mL) and was purified by reverse phase chromatography to give 4-cyano-3-(3,4-dichlorophenyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-morpholin-4-ylthiophene-2-carboxamide (85) (0.003 g, 10%). LCMS: (FA) ES+ 476.4.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:8]2[C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:15])=[O:14])=[O:29])[N:22]=1
Reactant: CCCS(=O)(=O)c1cccnc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCS(=O)(=O)c1cccnc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred suspension of 0.4 g (0.0015 mol) of the product from Example 4 and 0.63 g (0.0023 mol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate in 4 mls acetonitrile was added 0.35 g (0.0023 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and stirred for 30 minutes. The solution was diluted with water and acidified with 1 normal hydrochloric acid. The resulting precipitate was collected and washed with water and ether to afford 0.45 g (67%) white solid: m.p. 168°-170°; NMR (CDCl3, 200 MHz), 1.07 (3H, t, J=7 Hz), 1.85 (2H, m), 3.7 (2H, m), 3.97 (6H, s), 5.8 (1H, s), 7.26 (NH), 7.8 (1H, m), 8.6 (1H, m), 8.9 (1H, m), 12.9 (NH); IR (nujol) 3320, 1740, 1610, 1580, 1375, 1195, 1170 cm-1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CC(C)(C)[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.[CH3:43][C:44](C)(C)[CH2:45]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:32][CH2:31][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:11]5[CH2:10][CH2:45][CH2:44][CH2:43]5)[O:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:35][CH2:34]1)(=[O:38])=[O:37])[CH3:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Reactant: CC(C)(C)CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CN5CCCC5)c4)cc23)CC1
Yield: 7.2 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (99.6 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 6 mg of the title compound (7.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: OCC1CCNCC1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCC1CCN(c2ncc(F)cn2)CC1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (1.1 g, 8.05 mmol) and 4-piperidinemethanol (1.14 g, 9.66 mmol) in DMSO (20 mL) was treated with K2CO3 (2.23 g, 16.10 mmol). The reaction mixture was heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with CH2Cl2 (60 mL×3). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a brown oil. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 40% EtOAc/hexanes to give 1.62 g (95%) of [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methanol as a white solid upon standing. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 4.75-4.65 (m, 2H), 3.51 (d, 2H, J=6.1 Hz), 2.95-2.80 (m, 2H), 1.85-1.70 (m, 3H), 1.30-1.15 (m, 2H); LRMS (ESI), m/z 212 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:5]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Reaction time: 24 h
Yield: 93 %

Procedure:
A mixture of 1.0 g (2.45 mmol) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester, 0.6 ml (2.69 mmol) of 1-bromodecane and 0.7 g (4.9 mmol) of potassium carbonate in 20 ml of DMF was stirred at 80° for 24 hours. The usual workup followed by recrystallization from ether-hexane gave 1.25 g (93% yield, mp 68°-70°) of 3-(decyloxy)-5-[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOC(=O)Nc1cc(OC(=O)OC)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Nc1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 97.2 %

Procedure:
The resulting ethyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate (45.2 g, 155 mmol) was reacted with potassium carbonate (21.4 g, 155 mmol) and water (100 ml) for 2 hours while heating under refluxing. After completion of the reaction, the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was made acidic by adding 1N hydrochloric acid (300 ml), and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the precipitated solid was isolated by filtration. The solid was recrystallized from chloroform-hexane to obtain ethyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate as white crystals (35.2 g, 97% yield).