Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.FC(C1C=CC(F)=CC=1)C[NH2:16]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:16])=[O:12]
Reactant: NCC(F)c1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Product: NC(=O)Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Preparation of 2,4-difluorophenylethylamine 2,4-Difluorophenylacetic acid (5 g, 29 mmol) in thionyl chloride (50 mL) was heated at reflux for 10 min and the excess thionyl chloride removed by distillation. The acid chloride in dichloromethane (10 mL) was added to a cooled (−78° C.) solution of NH3 (20 mL) in dichloromethane (250 mL). Triethylamine (40 mL) was added and the reaction stirred at ambient temperature for 60 min. The solvents were then evaporated and the remaining solid dissolved in diethyl ether (500 mL). The organic solution was washed with 10% HCl (4×100 mL), 1 N NaOH (4×100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 630 mg (13%) of 2,4-difluorophenylacetamide.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42](OC)=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42]([N:3]([O:4][CH3:5])[CH3:2])=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54 mmol) and iPr2NEt (9.41 mL, 54 mmol) in CH2Cl2 (50 mL) was added AlMe3 (1.8 M solution in toluene, 30 mL, 54 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.07 g, 21 mmol) in CH2Cl2 (50 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (7.79 g, 90% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.70 (3H, s), 3.89 (3H, s), 5.11 (2H, s), 6.82-6.91 (2H, m), 7.33-7.45 (5H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=1.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[Cl:12][O-].[Na+]>Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cnc(Cl)c(O)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a flask containing methyl-5-hydroxynicotinate (4.5 g, 29 mmol) was added sodium hypochlorite aqueous solution (6.15%, 26.7 mL, 22 mmol) dropwise under ice bath cooling. After 30 min of stirring, 2 M HCl (20 mL) was added and the resulting white crystals collected by filtration to give 2.31 g of 6-chloro-5-hydroxynicotinic acid methyl ester in 42% yield. 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 8.48 (d, 1H), 7.84 (d, 1H), 7.40 (s, 1H), 3.93 (s. 3H); LC-MS (ELSD): mass calcd for C7H6ClNO3 [M]+ 187. Found 187.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:21](#[N:25])[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:22]([CH3:24])([CH3:23])[C:21]#[N:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(C)C#N
Reactant: CCOc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cccc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
2-(3-Ethoxy-phenyl)-2-methyl-propionitrile was prepared using a procedure adapted from literature (Organic Syntheses, Vol. 79, pp. 209-215). To a solution of 1-ethoxy-3-fluoro benzene (3.0 g, 19.4 mmol) in 25 mL of toluene was added solid potassium bis(trimethylsilyl)amide (5.84 g, 29.2 mmol, 1.5 eq) followed by isobutyronitrile (7.08 mL, 77.8 mmol, 4 eq). The reaction mixture was stirred at 100° C. for 12 hr. It was diluted with 75 mL of ethyl acetate and 75 mL of 1N aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of methylene chloride and applied to a 40 g silica gel cartridge. The product was eluted using a gradient of ethyl acetate in hexanes to yield 2.96 g (15.6 mmol, 80%) of pure 2-(3-ethoxy-phenyl)-2-methyl-propionitrile. LR-MS: 190.12 [(M+H)+]
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:27]([O-])=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:36][CH2:37][CH2:38][CH3:39])(=O)CCCC.[OH-].[NH4+:41]>C(Cl)Cl>[NH2:41][C:26]1[C:25]2[N:24]=[C:23]([CH2:36][CH2:37][CH2:38][CH3:39])[N:22]([CH2:21][CH2:20][CH2:19][OH:18])[C:34]=2[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]=1
Reactant: CCCCC(=O)OCCCn1c(CCCC)nc2c[n+]([O-])c3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Reaction time: 3 h

Procedure:
p-Toluenesulphonyl chloride (0.93 g) was added portionwise to a vigourously stirred mixture of the product from step (iv) (1.77 g) in DCM (50 mL) and ammonium hydroxide solution (35%, 5 mL) at rt. The reaction mixture was stirred for 3 h then partitioned between water/DCM. The organics were washed with saturated NaHCO3 solution, water, dried, and the solvent evaporated under reduced pressure. The residue was dissolved in MeOH (40 mL), water (20 mL) then 6M NaOH solution (2 mL) added and the mixture stirred at rt for 18 h. The solid formed was filtered off washed with water and dried, yield 965 mg.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([O-])(=O)C.[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)C=C(O)[CH:18]=[CH:17]2>C1(C)C=CC=CC=1>[C:5]([O:4][C:1]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=2)[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc2cc(Br)ccc2c1

Procedure:
6-bromo-2-naphthol is obtained according to the procedure of Example 1. A solution of acetic anhydride, sodium acetate, and the 6-bromo-2-naphthol in toluene is then refluxed for about 2 1/2 hours. Crude 2-acetoxy-6-bromonaphthalene is isolated therefrom by stripping the solvent from the organic layer after washing with water. The acetoxy compound is then purified by recrystallization from n-butanol.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].ClC[CH2:21][O:22][CH2:23][CH3:24]>C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:7][CH2:24][CH2:23][O:22][CH3:21])=[CH:8][C:9]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Reactant: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(C(C)(C)C)c(OCCOC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2,5-Di-tert-butylhydroquinone (0.2 mmol) was dissolved in anhydrous THF (20 ml). Sodium hydride (0.6 mmol) and 2-chloroethylethylether (0.4 mmol) was then added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane and aqueous NaHCO3 (0.1M). The organic portion was separated and dried over Na2SO4. After solvent removal in vacuo, the crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to afford 1,4-bis(2-methoxyethoxy)-2,5-di-tert-butyl-benzene in an 81% yield. The product was characterized by 1H NMR (300 MHz, CDCl3, δ/ppm): 7.14 (s, 2H), 4.11 (t, J=4.5 Hz, 4H), 3.80 (t, J=4.5 Hz, 4H), 3.45 (s, 6H), 1.37 (s, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]SC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (R)-methyl 2-(tert-butoxycarbonylamino)-2-phenylacetate (E4) in DMF at −40° C. was added NaH and the solution was warmed to 0° C. for 20 minutes. DMS was added and solution was stirred at room temperature for 3 hours. The mixture was poured into NH4Cl(sat)/HCl (1N) 3:1 and extracted with EtOAc. The organics were dried (Na2SO4), filtered and evaporated to give crude E5. Column chromatography Hexanes/EtOAc gave pure (R)-methyl 2-(tert-butoxycarbonyl (methyl)amino)-2-phenylacetate (E5).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([O:6]/[N:7]=[C:8](/[C:14](=O)[CH2:15]Cl)\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:18].[C:19]([NH:22][C:23]([NH2:25])=[S:24])(=[O:21])[CH3:20].CN(C)C1C=CC=CC=1>C(O)C>[C:19]([NH:22][C:23]1[S:24][CH:15]=[C:14](/[C:8](=[N:7]/[O:6][CH:3]2[CH2:4][CH2:5][NH:1][C:2]2=[O:18])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:25]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)C(=O)CCl
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(C)=O)n1
Reaction time: 4 h
Yield: 49.9 %

Procedure:
2.77 g of ethyl (Z)-2-[(2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate and 1.2 g of acetylthiourea are added to 20 ml of ethanol, and 2.0 g of N,N-dimethylaniline are added thereto. The mixture is stirred at 20° to 30° C. for 4 hours. Then, the mixture is concentrated under reduced pressure to drynss. The residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropanol, and the crystals are collected by filtration. 1.7 g of ethyl (Z)-2-(2-acetamidothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: OS(O)(=O)=O.[C:6]([NH:9][C@@H:10]([CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:34])=[O:17])[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].O.[CH3:46]O>>[C:6]([NH:9][C@H:10]([C:11]([O:13][CH3:46])=[O:12])[CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)=[O:34])=[O:17])(=[O:8])[CH3:7]
Reactant: COc1ccc(COC(=O)c2cc(-c3ccc(F)cc3F)ccc2OC(=O)SC[C@H](NC(C)=O)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccc(OC)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
H2SO4 (0.04 mL, 0.750 mmol) was added to a solution of (R)-2-acetamido-3-((2′,4′-difluoro-3-((4-methoxybenzyloxy)carbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid (160 mg, 0.286 mmol) in MeOH (25 mL). The reaction mixture was stirred at r.t. for 2 days, poured into H2O (100 mL) and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→80% EtOAc/hexanes) to furnish (R)-4-methoxybenzyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (white solid, yield: 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>ClCCl>[C:21]1([O:20][C:18](=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Amino pyridine (500 mg, 5.3 mmol) and N,N-diisopropylethylamine (685 mg, 5.3 mmol) are dissolved in dichloromethane (5 ml). Phenyl chloroformate (830 mg, 5.3 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 72 hours. The reaction mixture is partitioned between dichloromethane and saturated NaHCO3 (aq). The aqueous is washed with dichloromethane (×2). The organics are combined, dried (MgSO4), filtered and reduced in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:3])[NH2:2].C(OCC)(=O)C.Cl>C(O)C>[ClH:19].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][CH:6]2[CH2:5][NH:4][C:1]([NH2:2])=[O:3])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNC(N)=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-[(carbamoylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (160 mg) in ethanol (0.5 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3.0 mL), and the mixture was stirred at room temperature for 2 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (102 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>>[C:25]([O:21][C:17]1[CH:16]=[C:15]([CH3:22])[C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11])=[C:19]([CH3:20])[CH:18]=1)(=[O:27])[CH3:26]
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cc(C)c(CC(NC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Reaction time: 2 h

Procedure:
To a solution of 0.77 g (2.5 mmol) of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid and 3 mL of 3N sodium hydroxide solution, cooled in an ice bath, was added 0.89 mL (9.4 mmol) of acetic anhydride dropwise over about 30 seconds. After stirring for 2 hours, the mixture was acidified with addition of 4.5 mL of 2N hydrochloric acid. The mixture was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate and concentrate to a clear oil. The title product was used for the next reaction without further purification.
Reaction SMILES: O[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1
Reactant: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The ethyl 2-(4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (9 g, 0.03078 mol) and phosphorous oxy-chloride (45 ml) was refluxed for 4 h. After completion of the reaction, it was concentrated under reduced pressure. The resulting residue was cooled to 0° C. To this, ice water (200 ml) was added and stirred for 30 min. Then it was basified with 25% aq. NH4OH solution slowly to pH=8. It was extracted with DCM (250 ml×3). Organic extracts were washed with water followed by brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to get crude product. It was purified by column chromatography by using 100-200 mesh silica gel and DCM as eluent to give ethyl 2-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate as yellow liquid. Yield—(7 g, 73.16%); 1H-NMR: (400 MHz, CDCl3); δ=4.22-4.16 (q, 2H), 4.02 (s, 2H), 3.06 (m, 2H), 2.85-2.84 (m, 2H), 1.93-1.83 (m, 4H), 1.26-1.23 (t, 3H); LC-MS [M+H]=310.9.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O>[C:27]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([OH:29])=[O:28]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Solvent: O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-tyrosine in H2O to provide the title compound in good yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: Cc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl>[N:28]([CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a stirred solution of Part A N-Boc-3-hydroxymethylpiperidine (27.0 g, 126 mmol) in 150 mL of dry dichloromethane under argon at 0° C. was added in order triethylamine (22.7 mL, 163 mmol) and methanesulfonyl chloride (11.7 mL, 151 mmol). The reaction was stirred at room temperature for 1.5 h and diluted with 450 mL of dichloromethane. The reaction was washed with 0° C. 1N HCl solution (2×100 mL) and brine (1×100 mL). The dichloromethane layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 200 mL of DMF and combined with sodium azide (24.5 g, 377 mmol). The mixture was stirred at room temperature for 33 h and the solid was filtered off. The filtrate was concentrated under pump vacuum at 45° C. The residue was partitioned between 400 mL of EtOAc and 10% sodium thiosulfate solution (2×100 mL) and brine (1×100 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. Purification was effected by a flash column chromatography on silica gel to give 19.5 g (65%) of title azide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14](O)[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:25].CCN(C(C)C)C(C)C>C(Cl)CCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14]([Cl:25])[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOc1ccc(C2(C)CC(O)=C(C#N)C(=O)N2)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(C2(C)CC(Cl)=C(C#N)C(=O)N2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a stirred solution of Intermediate 107E (130 mg, 0.433 mmol) in ClCH2CH2Cl (3 mL) was added POCl3 (0.056 mL, 0.606 mmol) and Hunig's base (0.113 mL, 0.649 mmol). The reaction was stirred at rt for 30 min and then heated to 85° C. for 3 h. The reaction mixture was concentrated and the residue was diluted with EtOAc. The organic layer was washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (102 mg, 74%) as a white solid. LCMS Anal. Calc'd for C17H19ClN2O2 318.11, found [M+H] 319.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.80 Hz, 2H), 6.90 (d, J=8.80 Hz, 2H), 3.97 (t, J=6.60 Hz, 2H), 2.05 (s, 2H), 1.74-1.82 (m, 2H), 1.69 (s, 3H), 1.46-1.55 (m, 2H), 0.99 (t, J=7.43 Hz, 3H).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH:14]=[CH:13]1.FC(F)(F)C(O)=O>[OH-].[Na+]>[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)Cn1ccc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21
Reaction time: 1 h

Procedure:
Triethylsilane (0.13 mL, 0.77 mmol) was added to a solution of {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (82 mg, 0.16 mmol) and trifluoroacetic acid (4 mL) at rt. After 1 h, more triethylsilane (0.2 mL, 1.2 mmol) was added. After an additional 4 h, the reaction was poured into 1.2 M NaOH (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried, filtered, concentrated and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid methyl ester: MS (ESI): 500.1 (M+H). {6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid methyl ester was hydrolyzed following the procedure outlined in Example 1 Step 2 to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid: 1H NMR (400 MHz, DMSO-d6): 7.24 (d, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 6.93 (d, 1H), 6.68 (s, 1H), 4.05 (s, 2H), 3.57 (t, 2H), 3.24-3.17 (m, 4H), 3.03 (t, 2H), 3.00-2.94 (m, 4H); MS (ESI): 486.1 (M+H).