Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)=[O:4].Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: COC(=O)c1ccccc1B(O)O
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1ccccc1-c1cc(F)ccc1[N+](=O)[O-]
Yield: 56.9 %

Procedure:
To a microwave vessel was added 2-(methoxycarbonyl)phenylboronic acid (63.4 mg, 0.352 mmol), 2-bromo-4-fluoro-1-nitrobenzene (77 mg, 0.35 mmol), diacetoxypalladium (0.93 mg, 4.1 μmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.47 mg, 8.45 μmol). Ethanol (1760 μl) and sodium carbonate (176 μl, 0.352 mmol) were added and the mixture was reacted in a microwave reactor at 100° C. for 30 min. The reaction mixture was diluted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluant: 9:1 hexane/ethyl acetate) to provide methyl 5′-fluoro-2′-nitrobiphenyl-2-carboxylate (37a, 54.8 mg, 0.199 mmol, 56.6% yield).
Reaction SMILES: [CH:1](O)=O.[Cl:4][C:5]1[CH:6]=[N+:7]([O-:54])[CH:8]=[C:9]([Cl:53])[C:10]=1[CH2:11][C@H:12]([O:23][C:24](=[O:52])[C:25]1[CH:30]=[C:29]([CH2:31][N:32]([C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:28]=[C:27](Br)[CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.CB1OBOBO1.Cl.ClC1C=[N+]([O-])C=C(Cl)C=1C[C@@H](C1C=CC(OC)=C(OC)C=1)O.Cl.CN(C)CCCN=C=NCC>O1CCOCC1.O.CN(C=O)C.CN(C)C1C=CN=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:4][C:5]1[CH:6]=[N+:7]([O-:54])[CH:8]=[C:9]([Cl:53])[C:10]=1[CH2:11][C@H:12]([O:23][C:24](=[O:52])[C:25]1[CH:26]=[C:27]([CH3:1])[CH:28]=[C:29]([CH2:31][N:32]([C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cc(Br)cc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)c2)cc1OC
Reactant: O=CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OBOBO1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cc(C)cc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)c2)cc1OC
Temperature: 160 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
A mixture of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt (98 mg, 0.20 mmol), methylboroxine (0.03 mL, 0.20 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in 10% dioxane in water (2.5 mL) was heated to 160° C. under microwave irradiation for 5 minutes. After cooling to room temperature, the reaction mixture was neutralized with 0.30 mL of 2 N HCl and filtered through celite, washed with EtOAc (50 mL) The solvent was removed in vacuo and the residue was azeotroped with toluene to yield a white foam that was redissolved in DMF (2 mL). (S)-3,5-dichloro-4-(2-(3,4-dimethoxylphenyl)-2-hydroxyethyl)pyridine 1-oxide (76 mg, 0.22 mmol) followed by 4-(dimethylamino)-pyridine (12 mg, 0.10 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) were then added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate (19 mg) as white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[CH2:1]([O:8][C@@H:9]([C@@H:10]([O:12][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:11])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)[C@@H](C)OCc1ccccc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCO[C@@H](C)[C@@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
1.90 g of (2S,3R)-3-benzyloxy-2-butanol was dissolved in 50 ml of dry N,N-dimethylformamide. Thereto was added in small portions 2.53 g of about 60% oily sodium hydride. The mixture was stirred for 1 hour at room temperature. 11.63 g of butyl iodide was dropped with ice cooling. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water. The resulting mixture was extracted with ether three times. The extract was washed with water three times, dried and concentrated. The residue was subjected to Kugel-rohr distillation (1 mmHg) to obtain 2.05 g of (2R,3S)-2-benzyloxy-3butoxybutane.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]=1[C:4](N(OC)C)=[O:5].[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:3]=1[C:4](=[O:5])[CH3:24]
Reactant: COc1ccc(COc2cccc(F)c2C(=O)N(C)OC)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(F)c2C(C)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-N-methoxy-6-[(4-methoxybenzyl)oxy]-N-methylbenzamide (6.926 g, 21.70 mmol) in tetrahydrofuran (10 mL) was added 1N methyl magnesium bromide in tetrahydrofuran (43.40 mL, 43.40 mmol). The reaction mixture was stirred at reflux for 4 hrs. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3/1) to give 1-{2-fluoro-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a pale yellow solid (1.21 g, yield; 20%). [Starting Compound 1J]
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)C(C)C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[O:32][CH2:31][CH2:30][CH:29]2[C:46]([O:48][CH2:49][CH3:50])=[O:47].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](=[O:42])[NH:15][CH:12]3[CH2:13][CH2:14][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)[CH2:11]3)=[CH:39][CH:38]=1)[O:32][CH2:31][CH2:30][CH:29]2[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CCN(c2cccc(Cl)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCN(c5cccc(Cl)c5)C4)cc3)c(Cl)cc21
Reaction time: 5 h
Yield: 94.7 %

Procedure:
Crude 1-(3-chlorophenyl)pyrrolidin-3-amine dihydrochloride (53.7 mg, 0.199 mmol) in dichloromethane was treated sequentially with N-ethyl-N-isopropylpropan-2-amine (78.6 μl, 0.451 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 5 hours, the reaction was applied directly to a silica gel column. Elution with a gradient of 20-70% ethyl acetate-hexanes provided the title compound (70 mg, 0.126 mmol, 95.0% yield) as a solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[N:10]([C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:24])=[CH2:23])[CH:17]=1)([CH3:15])[CH3:14])=[C:11]=[O:12]>C(Cl)(Cl)Cl>[CH2:23]=[C:22]([C:18]1[CH:17]=[C:16]([C:13]([NH:10][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[O:12])([CH3:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1)[CH3:24]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: C1CN2CCC(CC2)N1
Solvent: ClC(Cl)Cl
Product: C=C(C)c1cccc(C(C)(C)NC(=O)N2CCN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (350 mg, 2.77 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (1.09 mL, 5.55 mmol) in chloroform (2 mL) was added 3-4 pieces of molecular sieves. The reaction mixture was stirred at room temperature for 18 h and then concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea as an off-white solid (650 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.31-7.26 (m, 3H), 5.34(s, 1H), 5.07 (s, 1H), 4.73 (br s, 1H), 4.03 (BR s, 1H), 3.64 (m, 2H), 3.14-3.03 (m, 6H), 2.15 (s, 3H) 2.06 (m, 2H), 1.72 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.7, 148.3, 143.8, 141.3, 128.5, 124.1, 123.9, 122.0, 112.5, 57.8, 55.8, 48.1, 46.4 (2×), 41.2, 30.2 (2×), 27.3 (2×), 22.1 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.71 min; (M+1) 328
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3](OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)(=[O:5])=[O:4].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([OH:46])=[C:37]([CH3:45])[CH:38]=[C:39]3[C:44]=2[N:43]=[CH:42][CH:41]=[CH:40]3)=[CH:31][CH:30]=1>>[F:1][C:2]([F:27])([F:26])[S:3]([O:46][C:36]1[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=2)=[C:44]2[C:39]([CH:40]=[CH:41][CH:42]=[N:43]2)=[CH:38][C:37]=1[CH3:45])(=[O:5])=[O:4]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1O
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 4D was prepared following the procedure used to prepare compound 1F of example 1, except that 8-(4-chloro-phenyl)-6-methylquinolin-7-ol (4C) was used instead of compound 1E. LCMS-ESI+ (m/z): 402.0, 403.9 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=4)[N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C(Cl)(=O)C(C)(C)C.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O>[C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:27])[CH:20]=4)[N:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(2-benzenesulfonylmethyl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid (Example 8733 step (h), 0.1 g, 0.2 mmol) and 5 mL of anhydrous CH2Cl2 was added TEA (0.2 mL, 1.4 mmol) and pivaloyl chloride (0.1 mL, 0.8 mmol). The solution was stirred overnight at RT. The reaction was now homogenous and piperidine (0.5 mL, 5.1 mmol) was added. After 6 h, the reaction was diluted with H2O. The aqueous solution was extracted with EtOAc (6×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was suspended in a minimum of EtOAc and filtered to give a solid. MS m/z: 494.1 (M+1). Anal. Calc'd for C25H23N3O4S2.0.5H2O: C, 59.74; H, 4.81; N, 8.36. Found: C, 59.64; H, 4.82; N, 8.30.
Reaction SMILES: COC(=O)C(O)=C[C:6](=O)[N:7](CC1C=CC(Cl)=C(Cl)C=1)[CH3:8].C=O.CC(N)CN.[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37][N:38]([CH3:43])[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37][N:38]([CH2:43][CH2:6][NH:7][CH3:8])[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CC(N)CN
Product: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 4 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and methyl-ethane-1,2-diamine as described in the preparation of Compound 12. The title compound was triturated with EtOAc to give a white solid (7.8 mg, 4% yield). 1H NMR (300 MHz, CDCl3) δ: 9.14, (bs, 1H), 7.40, (d, 1H, J=8.05), 7.34 (s, 1H), 7.11 (dd, 1H, J=8.05, J=1.10), 4.58, (s, 2H), 4.34, (s, 2H), 3.94 (m, 2H), 3.25 (m, 2H), 3.03 (s, 3H), 2.78 (s, 3H). HRMS (M+H) calcd for C16H19N3Cl2O3: 372.0881. found: 372.0886.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]3[O:25][CH2:24][CH2:23][O:21]3)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: OCCO
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC2OCCO2)ccc1OCCNc1ncnc(C)c1Cl
Yield: 69.4 %

Procedure:
10.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine and 3.0 g of ethylene glycol were dissolved in 300 ml of toluene. A small amount of p-toluenesulfonic acid was added to the solution, and the reaction vessel was equipped with a device for quantitatively determining water. The mixture was then heated under reflux for 8 hours. At the end of this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure and the oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product and give 7.9 g of the title compound as a colorless oily liquid, n23.4 =1.5730.
Reaction SMILES: [K].[CH2:2]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(N(C)C)=O>O>[CH2:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Brc1ccccc1
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccccc2)c1
Temperature: 150 °C

Procedure:
Into the round bottom flask containing potassium salt of 3-pentadecyl phenol is added bromobenzene followed by Cu powder and in a solvent, DMAc (dimethyl acetamide). The reaction mixture is heated at 150° C. for 6 h. After completion of the reaction, the obtained dark colored reaction mixture is poured into water and the Cu salts are removed by filtration. The filtrate is extracted in a solvent, washed with water and dried, purified to obtain arylated product, 1-pentadecyl-3-phenoxybenzene.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=1[N+:14]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[S:9]1[C:5]2[CH:4]=[CH:3][NH:14][C:6]=2[CH:7]=[C:8]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C=CN(C)C)s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc2[nH]ccc2s1
Yield: 15.8 %

Procedure:
To a solution of methyl 5-(2-dimethylaminovinyl)-4-nitro-thiophene-2-carboxylate (0.698 g, 2.73 mmol) in MeOH (15.0 mL) were added ammonium formate (0.332 g, 5.26 mmol) and Pd/C (33.2 mg, 10% by weight). The mixture was refluxed for 6 h. Additional ammonium formate (0.664 g, 10.53 mmol) was added to the reaction and the mixture was refluxed for 20 h. Additional ammonium formate (0.664 g, 10.53 mmol) and Pd/C (0.1 g, 30% by weight) were added and the reaction mixture was refluxed for another 8 h. Additional Pd/C (0.1 g, 30% by weight) was added and the mixture was refluxed for another 16 h. The reaction was cooled and filtered through a Celite® plug. The filtrate was concentrated in vacuo, taken up in EtOAc (0.2 L) and washed with water, saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC to obtain methyl 4H-thieno[3,2-b]pyrrole-2-carboxylate as a yellow solid (0.078 g, 16%). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (s, 1H) 7.71 (s, 1H) 7.20 (t, J=2.7 Hz, 1H) 6.50 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:9](=[O:11])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g, 6.18 mmol) was taken in dry DCM (20 mL) and cooled to 0° C. To this cold mixture was added N-boc piperazine (1.15 g, 6.18 mmol) followed by addition of T3P (8 g, 12.4 mmol, 50% solution in EtOAc). The reaction was left overnight at rt. The mixture was diluted with CH2Cl2, washed with NaHCO3 soln, brine, dried (Na2SO4) and concentrated to afford the crude product that was washed thoroughly with ether-pet ether to afford 4-[2-(4-Chloro-5 methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 2.9 mmol). This was dissolved in methanol (25 mL) cooled to 0° C. and HCl saturated ether (3 mL) was added to it. The mixture was stirred at room temperature for 4 h and concentrated. Crystallization from MeOH/Petroleum ether yielded product.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=2)=[CH:5][C:4]=1[C@:17]12[CH2:25][O:24][CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH:26]C(=O)C1C=CC=CC=1)=[N:18]2>CO>[ClH:1].[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=2)=[CH:5][C:4]=1[C@:17]12[CH2:25][O:24][CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH2:26])=[N:18]2
Reactant: O=C(NC1=N[C@@]2(c3cc(-c4cncc(F)c4)c(F)cc3F)COC[C@H]2CS1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NC1=N[C@@]2(c3cc(-c4cncc(F)c4)c(F)cc3F)COC[C@H]2CS1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
N Aqueous hydrochloric acid (8.70 mL) is added to N-((4aS,7aS)-7a-(2,4-difluoro-5-(5-fluoropyridin-3-yl)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (0.252 g, 0.435 mmol) in methanol (4 mL) and the mixture is heated to 90° C. After 18 hours, the heat is removed and the pH of the reaction mixture is adjusted to basic with 5 N aqueous sodium hydroxide. The mixture is extracted three times with 10% isopropyl alcohol in dichloromethane. The organic layer is concentrated under reduced pressure and the resulting residue is purified by radial chromatography eluting with 3% 2 M ammonia in methanol:dichloromethane to give the title compound as the freebase. The free base is dissolved in minimal dichloromethane and 1 M hydrogen chloride in ether is added in excess. Hexane (1 mL) is added and the solvent is removed under reduced pressure to give the title compound (0.129 g, 67%). ES/MS m/e: 366 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-cyclopropyl-4-methoxybenzoic acid (200 mg), toluene (2 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.10 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained resiue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Sc2cccc(/C=C/C(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(Sc2cccc(CCC(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Reaction time: 8 h

Procedure:
(E)-3-[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acrylic acid (0.2912 g, 0.67 mmol) was dissolved in EtOAc:MeOH (7:3, 10 mL) then palladium on carbon (0.214 g, 10% by weight, wet 50% H2O) was added and H2 (g) was bubbled through the mixture for 5 minutes. The reaction was stirred overnight under H2 atmosphere and then the palladium on carbon was filtered off. Standard workup procedure followed by preparatory HPLC (10-100% ACN in H2O) provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)=[O:4].[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.CC(O)C.N(C(OCC1C=CC(Cl)=CC=1)=O)=NC(OCC1C=CC(Cl)=CC=1)=O>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]1[C:8]([O:10][CH:18]([CH3:23])[CH3:19])=[CH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Agent: O=C(N=NC(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)c1cc(OC(C)C)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
150 mg (0.635 mmol) of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester, 166.6 mg (0.635 mmol) of triphenylphosphine and 38.16 mg (0.635 mmol) of 2-propanol were dissolved in 1.5 ml of DCM, and then a solution of 0.635 mmol of di(4-chlorobenzyl) azodicarboxylate in 1.5 ml of DCM was added. After stirring at room temperature for 4 h, the mixture was filtered and the solvent removed in vacuo. The obtained crude title compound was used in the hydrolysis step without further purification.