Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[CH:28]C=N2)[CH:22]=[CH:23][CH:24]=1>>[ClH:16].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:29][CH2:28][N:7]([CH2:10][CH:2]=[CH:1][C:4]3[CH:5]=[N:6][N:7]([C:10]4[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])[CH2:8][CH2:4]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Reactant: Clc1cccc(-n2cccn2)c1
Agent: Cl
Product: Cc1c(C=CCN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccc1Cl
Yield: 68.7 %

Procedure:
4-Acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole (648 mg), 1-(3-chlorophenyl)pyrazole hydrochloride (641 mg), and p-formaldehyde (1.65 g) were reacted, and the product was worked up in the same manner as in Example 5-(4) to yield 439 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([I:29])[CH:24]=1)(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)C.Cl>O>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:12]([OH:14])=[O:13])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([I:29])[CH:24]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(Cc1cccc(I)c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Temperature: 25 °C

Procedure:
240 ml of a 1N sodium hydroxide solution are added to a suspension of 30.3 g (62 mmol) of diethyl[(tert-butoxycarbonyl)amino](3-iodobenzyl)malonate (Example 7D) in 440 ml of a mixture of ethanol and water (3:1). After 3 h under reflux and after cooling to RT, the pH of the reaction mixture is adjusted with concentrated hydrochloric acid to approx. pH 2. The reaction mixture is concentrated in vacuo. The residue is taken up in MTBE and water. The aqueous phase is extracted three times with MTBE. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by RP-HPLC (acetonitrile/water gradient).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CCOC(C)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH2:14][CH2:13]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 4-bromo-2-chloro-5-fluorobenzoic acid (50 g, 0.25 mol) in 200 mL of EtOAc at 0° C. (ice/water bath) was added triethyl amine (237 mL, 0.50 mol), pyrrolidine (41.2 mL, 0.5 mol), followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (CAS # 68957-94-8) (237 mL, 0.37 mol, 50 wt %, EtOAc). After 1 hr, the reaction was quenched with a saturated solution of NaHCO3, and extracted with EtOAc, and CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75L column, eluting with a gradient of 2%-50% EtOAc/hexanes. The product containing fractions were collected and concentrated to give the title compound (52 g, 68% yield) as a white solid: Rf=0.23 (40% EtOAc/hexanes): LRMS m/z Calcd for C11H10BrClFNO, 306.6, found, 306, 308, 310 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J=6.2 Hz, 1H), 7.02 (d J=7.9 Hz, 1H), 3.54 (apt t, J=6.6 Hz, 2H), 3.13 (apt t, J=6.6 Hz, 2H), 1.92-1.83 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 164.5, 158.1 (d, JC-F=249.5 Hz), 138.2, 134.3, 126.0, 115.5 (d, JC-F=25.5 Hz), 110.3 (d, JC-F=22.5 Hz), 47.0, 45.8, 26.0, 24.6.
Reaction SMILES: C[O-].[Na+].CO.C[O:7][C:8](=O)[CH2:9][C:10]([O:12]C)=O.[F:15][C:16]([F:25])([F:24])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22]C)=[O:20].C(O)(=O)C.[CH:30]([NH2:32])=[NH:31].Cl>>[OH:7][C:8]1[C:9]([CH:17]([C:16]([F:25])([F:24])[F:15])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:10]([OH:12])[N:32]=[CH:30][N:31]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC(c1c(O)ncnc1O)C(F)(F)F
Temperature: 62 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Heat a solution of 25% sodium methoxide in methanol (1.49 L, 0.86 eq) at 62° C. Add a mixture of propanedioic acid dimethyl ester (1.00 kg, 7.57 mol) and ethyl 4,4,4-trifluorocrotonate (1.27 kg, 1.0 eq) dropwise over two hours. Heat the mixture at 62° C. for two hours. Cool the mixture to 30° C. Add 25% sodium methoxide in methanol (2.34 L, 1.35 eq) and formamidine acetate (867.2 g, 1.1 eq). Stir at 30° C. overnight. Cool the mixture to 0° C. and add 5 M aqueous hydrochloric acid, adjusting the pH to 4.5. Filter and wash with water (2 L). To the wet solid, add methyl tert-butyl ether (5 L). Filter, wash with additional methyl tert-butyl ether (2 L), and dry at 50° C. to give methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate (1.05 kg, 52%).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[CH3:13][O:14][CH2:15]Cl.CO>O1CCCC1.O>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH3:15])([CH3:5])[CH3:4]
Reactant: COCCl
Reactant: CC(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCOc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Firstly, sodium hydride (275 mmol) was suspended in tetrahydrofuran (THF) (120 ml) and to this, 2-isopropylphenol (111 mmol, reference symbol A1 in FIG. 1) dissolved in THF (30 ml) was added dropwise at 0° C. After 30 minutes, chloromethyl methyl ether (221 mmol) was added to this solution and after heating to room temperature, the reaction was stopped by adding methanol and then water. The aqueous phase was extracted with ether. The organic phases were combined and washed with water and a saturated sodium chloride solution in that order and then dried using anhydrous sodium sulfate. After removing the drying agent by filtering, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 1-isopropyl-2-methoxy methoxybenzene (17.5 g, 87% yield, reference symbol A2 in FIG. 1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:21][CH:20]1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:21][CH:20]1[CH:22]=[O:23]
Reactant: OCC1CC1c1cc(F)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1CC1c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.2 mL, 13.5 mmol) in dichloromethane at −78° C. was added dimethyl sulfoxide (1.9 mL, 27 mmol) dropwise and it was stirred at −78° C. for 30 minutes. A solution of [2-(2,5-difluorophenyl)cyclopropyl]methanol (Intermediate 69) (830 mg, 4.5 mmol) in dichloromethane was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. Triethylamine (6.3 mL, 45 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (9:1) afforded the desired product, 546 mg (66%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>ClCCl>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCC#CCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1OCC#CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 64.7 %

Procedure:
Into 35 ml of dichloromethane were dissolved 2.67 g of 4-diphenylmethoxypiperidine, 2.93 g of 1-chloro-4-(2-nitrophenoxy)-2-butyne and 1.68 g of N,N-diisopropylethylamine, and the resultant solution was stirred at room temperature for 20 hours. The reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate by silica gel column chromatography to give 2.95 g of oily 4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2-butynyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7](=[CH:10][N:11]([CH3:13])C)[CH:8]=[O:9])=[CH:4][CH:3]=1.NC[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:13][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[O:9])=[CH:14][CH:15]=1
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenoxy)-3-dimethylaminoacrylaldehyde (11.3 g., 50 mmoles) was dissolved in 200 ml. of ethanol, mixed with a solution of ethyl glycinate (14 g., 100 mmoles) in 90 ml. of 1N sodium hydroxide and refluxed for 15 hours. Ethanol was evaporated in vacuo, the aqueous residue diluted with 150 ml. of water and product extracted into 200 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil. Trituration of the oil with 100 ml. of ether gave crystalline 2-(4-chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde in two crops (7.3 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant).
Reaction SMILES: [CH3:1]S[CH2:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([NH:17][C:18]([NH2:20])=[NH:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:22]1C=CC=C(C(OO)=O)C=1.[S:32]([O-:36])([O-:35])(=[O:34])=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[CH3:1][S:32]([OH:36])(=[O:35])=[O:34].[CH3:22][S:32]([CH2:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([NH:17][C:18]([NH2:20])=[NH:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:36])=[O:34]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)Cc1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of (2,3-dihydro-9-methylthiomethyl-1-benzoxepin-4-carbonyl)guanidine (0.4 g) and m-chloroperbenzoic acid (0.52 g) in chloroform (20 ml) and methanol (4 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was added to 10% aqueous sodium thiosulfate, adjusted to pH 9 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (5 ml), and methanesulfonic acid (0.11 ml) was added with stirring. To the mixture was added diisopropyl ether (5 ml) and isolated crystalline was collected by filtration. The crystalline was recrystallized from a mixture of methanol and diisopropyl ether to give (2,3-dihydro-9-methanesulfonylmethyl-1-benzoxepin-4-carbonyl)guanidine methanesulfonate (0.16 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:13]2)[CH:8]=[CH:7][CH:6]=1
Reactant: C=Cc1cccc(OC)c1
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1 mL, 37.0 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reaction was allowed to warm to RT and then 2M NaOH (50 mL) was added. The reaction was left to stir at RT overnight. The reaction mixture was then partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.60 g (100%) of the title compound as a slightly tinted oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:27])(=[O:26])[NH2:25])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:26])(=[O:27])[NH2:25])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1cccc(C(F)(F)F)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1cccc(C(F)(F)F)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 273°-274°C.
Reaction SMILES: [CH:1]1([CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])[C:20]=4[S:19](=[O:31])(=[O:32])[N:18]=3)[C:7]2=[O:33])[CH2:2][CH2:3]1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N=CC3CC3)c1=O)N2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
The product of Example 350F (78.9 mg, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.013 mL, 0.32 mmol) at 0° C. was treated dropwise with a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.131 mL, 0.24 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1N hydrochloric acid to approximately pH 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol/dichloromethane to give the title compound (41.6 mg, 52.5%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.41 Hz, 2 H), 0.42 (d, J=8.09 Hz, 2 H), 1.01 (m, 1 H), 2.84 (d, J=6.62 Hz, 2 H), 4.64 (s, 2 H), 4.71 (s, 2 H), 6.36 (br.s, 1 H), 7.41 (m, 2 H), 7.88 (t, J=7.35 Hz, 1 H), 8.07 (d, J=8.46 Hz, 1 H), 8.16 (d, J=8.09 Hz, 1 H). MS (ESI−) m/z 489 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:27][NH:28]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCCC3C(F)(F)F)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
4-{2-Amino-6-[2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (60 mg, 0.17 mmol) was disolved in ethanol (1.5 mL) with stirring in a 5 mL microwave vessel. Hydrazine monohydrate (0.207 mL, 4.27 mmol) was added, and the mixture was capped and heated at 100° C. in an oil bath overnight. HPLC showed complete conversion. The hot mixture was filtered through a 0.2 um filter disc, rinsing with ethanol (1 mL). Water (˜3 mL) was added to the filtrate with stirring, and the mixture was heated to evaporate most of the ethanol to a volume of ˜4 mL. The mixture was allowed to cool with stirring to room temperature, at which time some product had precipitated as a gum. Stirring was continued for approximately one hour and the precipitate became a free flowing white solid, which was filtered, washed with water and dried to afford the title compound (42 mg) as an off-white solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.98-2.08 (m, 2H), 2.08-2.23 (m, 2H), 3.49-3.60 (m, 1H), 3.60-3.72 (m, 1H), 5.06-5.17 (m, 1H), 5.39 (s, 2H), 6.22 (s, 2H), 6.52 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17]([OH:19])=O.CN(C)C=O.[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[NH:37][CH3:38])[CH3:26]>ClCCl.N1C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:39])[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[N:31][C:30]=1[N:37]([C:17](=[O:19])[CH2:16][C:9]1[C:10]([F:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[Cl:7])[CH3:38])[CH3:26]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1NC
Reactant: O=C(O)Cc1c(F)ccc(F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(Cl)cc(C)nc1N(C)C(=O)Cc1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
Oxalyl chloride (0.19 ml) was added dropwise to a solution of (2-chloro-3,6-difluoro-phenyl)-acetic acid (373 mg) in dichloromethane (5 ml) at ambient temperature. A drop of N,N-dimethylformamide (“DMF”) was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated to give a colourless oil which was dissolved in dichloromethane (5 ml). The mixture was added dropwise to a slurry of 4-chloro-6-methyl-2-methylamino-nicotinic acid ethyl ester (Example 4.1) (413 mg) and pyridine (0.16 ml) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:4) to give 4-chloro-2-{[2-(2-chloro-3,6-difluoro-phenyl)-acetyl]-methyl-amino}-6-methyl-nicotinic acid ethyl ester as a yellow solid (299 mg). 1H NMR (400 MHz, CDCl3): 7.32 (bs, 1H), 7.00-7.05 (m, 1H), 6.90-6.96 (m, 1H), 4.43-4.45 (m, 2H), 3.66 (s, 2H), 3.24 (m, 3H), 2.60 (s, 3H), 1.37-1.40 (t, 3H) ppm.
Reaction SMILES: N1CCOCC1.C([O:10][C:11]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC=C)=[O:44])=[C:38]([F:49])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C=C.O>O1CCCC1.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>[C:16]([O:15][C:13]([C:12]1[C:11]([OH:10])=[C:23]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:21][C:20]=1[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[C:38]([F:49])[CH:37]=2)=[CH:34][CH:35]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)c(F)c3)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Morpholine (0.27 ml, 3.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol) were successively added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (790 mg, 1.32 mmol) obtained in Example (11-6) in tetrahydrofuran (8 ml), and the mixture was stirred at room temperature for 1 hour. After water was poured into the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. After the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1-0/1), it was crystallized from a mixture solvent of methylene chloride-ethyl acetate to give the title compound as a colorless powder (323 mg, yield: 47%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[S:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 47.1 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.40 g, 25.84 mmol) and 4-methylbenzene-1-sulfonyl chloride (14.22 g, 74.6 mmol) were combined in pyridine (50 mL) at 0° C. and store in the refrigerator for 3 days. The reaction mixture was concentrated to half the volume under vacuo and some water (300 mL) was added slowly. The mixture was stirred 1 h until a white solid formed. The solid was filtered and dried on the pump on high-vacuum over night. The solid was recrystallized from MeOH (˜20 ml) and water (few drops) to afford title compound 204 (6.40 g, 49%). LRMS: (calc) 525.15 (found) 426.4 (MH-Boc)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][CH:4]=1.C[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[C:24]([O-:27])([O-])=O.[K+].[K+]>C(O)(C)C>[OH:13][C@@:12]([CH3:15])([CH2:14][O:23][C:20]1[CH:19]=[CH:18][C:17]([O:27][CH3:24])=[CH:22][CH:21]=1)[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(NC(=O)[C@]2(C)CO2)cc1
Reactant: Cc1ccc(O)cc1
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(NC(=O)[C@@](C)(O)COc2ccc(OC)cc2)cc1
Yield: 98.8 %

Procedure:
(S)—N-(4-Methoxyphenyl)-2-methyloxirane-2-carboxamide (0.50 g, 2.41 mmol), 4-methylphenol (0.39 g, 3.14 mmol) and K2CO3 (0.67 g, 4.82 mmol) were placed in a 250 mL round-bottomed flask fitted with a stirring bar. 100 mL of isopropanol was added at room temperature. The reaction solution was heated to reflux for 3 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=2/3 v/v) to give a white solid product, (S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide (6d), 0.79 g, 98.8% yield.