Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:22][CH3:23])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1Br
Temperature: 85 °C
Yield: 95.9 %

Procedure:
Ethyl 2,4-dibromo-3-hydroxybenzoate (50 g) was added to a stirred suspension of potassium carbonate (106.4 g) in dry N,N-dimethylformamide (DMF). A solution of iodoethane (25.7 g) in DMF was added over 18 minutes, and the resulting mixture was heated at 85° C. for 1.3 hours. The cooled mixture was poured onto water and extracted with ether. The extract was washed (brine solution), dried (anhydrous magnesium sulphate) and the solvent evaporated in vacuo to give ethyl 2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H), 4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5](I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>CC#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:17]2[CH2:19][CH2:18]2)=[CH:4][N:3]=1
Reactant: CNc1cc(Cl)ncc1I
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1cc(Cl)ncc1C1CC1
Temperature: 130 °C
Yield: 49.1 %

Procedure:
2-Chloro-5-iodo-N-methylpyridin-4-amine (Intermediate I-8) (30 mg, 0.112 mmol), tetrakis(triphenylphosphine) palladium (0) (6.5 mg, 5.59 μmol) and 0.5 M aqueous sodium carbonate solution (290 μL, 0.145 mmol) were added to 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 μL, 0.335 mmol) in MeCN. The mixture was heated at 130° C. in a microwave reactor for 1 hour. The mixture was concentrated in vacuo. Preparative thin layer chromatography, eluting with 1% NH3, 6% MeOH in CH2Cl2, gave 2-chloro-5-cyclopropyl-N-methylpyridin-4-amine (10 mg, 0.055 mmol, 49% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]1=2)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.9 %

Procedure:
6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (215 mg, 1.213 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (805 mg, 1.820 mmol) were dissolved in N,N-dimethylformamide (6 ml). Cesium carbonate (553 mg, 1.698 mmol) was added to the solution and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 399 mg (67%) of the title compound in the form of a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.Cl.[O:28]([NH2:30])[CH3:29].C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C.C1C=CC=CC=1>[CH3:29][O:28][NH:30][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1)=[O:22]
Reactant: CON
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CONC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (0.00128 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy)-2-pyridine carboxylic acid was mixed with 0.3 g (0.00128×2.0 mol) of thionyl chloride and then with about 10 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and mixed with methylene chloride and then with 0.21 g (0.00128×2.0 mol) of methoxylamine hydrochloride and 0.33 g (0.00128×2.5 mol) of triethyl amine, followed by stirring at room temperature for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)ccc1[N+](=O)[O-]

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (382 mg, 1 mmol) was treated as described in general procedure B using 5-fluoro-2-nitrotoluene (310 mg, 2 mmol) to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(3-methyl-4-nitro-phenyl)-1H-imidazole.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as in EXAMPLE 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.72 min. MS (ESI−): mass calcd. for C22H15BrClFN4O5S2, 613.87; m/z found, 611/613 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 8.34 (d, J=6.9, 1H), 8.16(d, J=8.7, 1H), 7.74-7.67 (m, 1H), 7.66-7.63 (m, 1H), 7.38-7.32 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.05 (m, 1H), 7.05-6.98 (m, 1H), 6.91-6.84 (m, 1H), 6.68 (d, J=6.7, 1H), 6.09 (s, 2H), 5.04-4.94 (m, 1H), 3.35-3.15 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[C:18]([C:35](O)=[O:36])=[CH:17]2)#[N:13].OCC1(CNC(C2N(CC3C=CC=C(OC(F)(F)F)C=3)C3C(C=2)=CC(C#N)=CC=3)=O)CCCC1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH:11][C:35]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=3)[C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]#[N:13])=[CH:22][CH:21]=3)=[O:36])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CN)CCC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Agent: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)C1(CNC(=O)c2cc3cc(C#N)ccc3n2Cc2cccc(OC(F)(F)F)c2)CCC1
Yield: 52.2 %

Procedure:
1-({[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}methyl)-cyclobutanecarboxylic acid ethyl ester was prepared from 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester (262 mg, 1.65 mmol) and 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (400 mg, 1.10 mmol) in the same manner as 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)amide giving 1-({[5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}methyl)cyclobutanecarboxylic acid ethyl ester as a colourless gum (287 mg, 50%).
Reaction SMILES: [C:1]([C:3]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([CH3:18])[N:4]=1)#[N:2].OO.C(=O)([O-])[O-:22].[K+].[K+].[OH-].[K+]>CS(C)=O.O.CO>[NH2:2][C:1]([C:3]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:18])[N:4]=1)=[O:22]
Reactant: CCC(CC)Nc1cc(C(=O)[O-])c(C)nc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)O)c(C)nc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 348.5 %

Procedure:
To a solution of 6-cyano-2-methyl-5-(pentan-3-ylamino)nicotinate (0.543 g, 1.97 mmol) in DMSO (10 ml) were added 50% aqueous hydrogen peroxide (0.2441 g, 3.55 mmol) and potassium carbonate (0.068 g, 0.49 mmol) at 10° C. The reaction mixture was stirred at room temperature for two hours then a solution of potassium hydroxide (0.22 g, 3.94 mmol) in water (2 ml) and methanol (10 ml) were added to above reaction mixture. After being stirred for another two hours at 45° C., the reaction mixture was cooled to room temperature and neutralized to PH 7. 6-(Aminocarbonyl)-2-methyl-5-(pentan-3-ylamino)nicotinic acid (0.453 g, 87%) was obtained by filtration and drying. 1HNMR (400 MHz, MeOH-D4): 7.62 (s, 1H), 3.35 (m, 1H), 2.60 (s, 3H), 1.65 (m, 2H), 1.52 (m, 2H), 0.95 (t, J=7.20 Hz, 6H). MS (EI) for C13H20N3O3: 267.2 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[CH3:41][NH2:42]>>[CH3:41][NH:42][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: CN
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Product: CNCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and methylamine (8 M solution in ethanol) in the manner of Example 42, m.p. 149-150° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[NH:14]C(OC(C)(C)C)=O)=O)[CH2:3][CH2:2]1.[CH2:22](Cl)Cl>FC(F)(F)C(O)=O>[CH:3]1([C:1]2[NH:14][C:7]3[C:6]([CH:4]=2)=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=3)[CH2:2][CH2:22]1
Reactant: ClCCl
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C2CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(C3CC3)cc2c1
Yield: 49 %

Procedure:
[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl] cyclopropyl ketone (13 g, 43 mmol) in 250 mL of CH2Cl2 and 25 mL of trifluoroacetic acid was stirred for 4 hours, washed with water, NaHCO3 solution, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with a gradient, toluene→20% EtOAc/hexane) to give 4.15 g (49% yield) of 2-cyclopropyl-5-methoxy-1H-indole as an oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][O:4]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C1C=CC=CC=1>[F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8][N:26]=[N+:27]=[N-:28])[CH2:5][O:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C(F)(F)F)(C(F)(F)F)O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: [N-]=[N+]=NCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 3.5 h

Procedure:
A sample of 14.00 grams of 2,2-bis(trifluoromethyl)-4-tosyloxymethyl-1,3-dioxolane (m.p. 58°-60° C.) is dissolved in 40 ml of dimethylformamide and 4.85 grams NaN3 is added. The mixture is stirred magnetically at 140°-149° C. for 3.5 hours. The product is diluted with benzene and filtered. The filtrate is washed thoroughly with water, vacuum-stripped and distilled. The product, 2,2-bis(trifluoromethyl)-4-azidomethyl-1,3-dioxolane, has a boiling point of 78° C./20 mm Hg and a refractive index of 1.37447 at 20° C. Analysis Found: (In Percent) C, 26.95; H, 1.73; N, 16.06. Calculated for C6H5F6N3O2 (M.W. 265.1): C, 27.18; H, 1.90; N, 15.84.
Reaction SMILES: C1O[CH:4]([CH:5]([CH3:17])[CH2:6][C:7](=O)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)OC1.[C:19]([NH:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH3:20].Cl>O1CCCC1>[C:19]([NH:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([N:30]2[CH:4]=[C:5]([CH3:17])[CH:6]=[C:7]2[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH3:20]
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)CC(C)C2OCCO2)cc1C
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C)cc2-c2ccc(C)c(C)c2)cc1
Temperature: 70 °C
Yield: 25.3 %

Procedure:
3.26 g (13.1 mmol) of 3-(3,4-dimethylbenzoyl)-2-methylpropionaldehyde ethylene acetal [prepared as described in step (ii) above] and 2.81 g (13.1 mmol) of 4-acetylaminosulfonylaniline were dissolved in a mixture of 52 ml (52 mmol) of 1N aqueous hydrochloric acid and 16 ml of tetrahydrofuran, and the mixture was heated at 70° C. for 1 hour. At the end of this time, the mixture was left to stand to allow it to cool. The mixture was then extracted three times with ethyl acetate. The organic extracts were combined and washed with a saturated aqueous solution of sodium chloride. The resulting solution was then dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate and crystallised from diisopropyl ether, to give 1.27 g (yield 25%) of the title compound as a white powder, melting at 192-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6](O)=[O:7].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6]([Cl:24])=[O:7]
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Temperature: 75 °C

Procedure:
A stirred mixture of (R)-2-(2,4-dichlorophenoxy)propionic acid (588 g, 2.5 mol), 588 g of toluene and 0.6 g of dimethyl formamide (DMF) is heated to 75° C., treated with thionyl chloride (304 g, 2.55 mol) over a 1.5 hour period, heated at 75° C. for 1 hour and cooled to 20-25° C. The resultant reaction mixture may be distilled to obtain the title product in quantitative yield, as an amber oil, or used as is in the next process step. The isolated product is characterized by NMR analysis. The product toluene solution is assayed by HPLC analysis.
Reaction SMILES: [C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH2:18][CH2:19][Cl:20])=[CH:11][C:10]=1[N+:21]([O-])=O)/[C:4]([O:6][CH3:7])=[O:5])#[N:2]>C(O)(=O)C.[Fe]>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH2:19][Cl:20])=[C:13]([O:15][CH3:16])[CH:14]=2)[N:21]=1
Reactant: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Yield: 83 %

Procedure:
To methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate (19.3 g, 56.6 mmol) in 250 mL of acetic acid is added portionwise 12.0 g (215.0 mmol) of iron. The mixture is heated at reflux for 20 minutes, cooled slightly and filtered washing with ethyl acetate. The filtrate is concentrated in vacuo and water is added to the residue. The resulting yellow solid is collected by filtration washing with water to provide 14.6 g of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate. An analytical sample is obtained by stirring a portion of the product with a mixture of methanol and aqueous ammonium hydroxide. The undissolved solids are removed by filtration. Upon standing solids appeared in the filtrate and are collected to provide methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate as light yellow crystals, mp 145-157° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].O>C1COCC1>[C:18]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-phenyloxazolidin-2-one (65.00 g, 398.3 mmol) in dry THF (612.8 mL) at −78° C. was quickly added n-BuLi (167.3 mL, 418.3 mmol) dropwise, and the mixture was stirred at −78° C. for 0.5 hours. To this cold stirring solution was quickly added dropwise a solution of methacryloyl chloride (40.86 mL, 418.3 mmol) in THF (60 mL), and the mixture was allowed to warm to ambient temperature and stirred for 0.5 hours. Water (300 mL) was added and the suspension was stirred for 1 hour and then filtered to give desired product as a hard solid cake (66 g). The filtrate was concentrated under reduced pressure to a yellow solid residue, which was taken up in Et2O (400 mL) and filtered to give additional pure desired product (9 g). The products were combined to give (R)-3-methacryloyl-4-phenyloxazolidin-2-one (75 g, 81% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[CH3:15][NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH3:15])=[O:11])=[CH:12][CH:13]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)N(C)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
0.995 g of terphthalic acid monomethyl ester chloride and 0.756 g of methyl 4-(methylamino)-benzoate were dissolved in 25 ml of acetone and treated with 0.691 g of anhydrous potassium carbonate. The reaction mixture was stirred at room temperature for 30 hours and was evaporated. The residue was treated with water and the crystals were filtered off yielding N-(4-methoxycarbonyl-phenyl)-N-methyl-terephthalamic acid methyl ester in the form of colourless crystals, MS: m/z 327 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.[CH:30]1([C:36](=[S:38])[NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:38][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:37][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)C1CCCCC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCCCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 66 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.45 g, 1.019 mmol) and cyclohexanecarbothioamide (0.18 mg, 1.23 mmol) the title compound of Step B was obtained (0.38 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.61-7.75 (m, 1H), 7.39-7.50 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.86 (d, J=5.3 Hz, 1H), 2.96-3.12 (m, 1H), 2.09 (d, J=10.6 Hz, 2H), 1.78 (dd, J=9.7, 3.2 Hz, 2H), 1.68 (d, J=12.5 Hz, 1H), 1.47-1.61 (m, 2H), 1.33-1.45 (m, 2H), 1.21-1.32 (m, 1H). m/z (ES+): 566 [M+H]+.
Reaction SMILES: ClC1C(OC2CCC(=O)CC2)=CC(F)=C(C=1)C(O)=O.[CH:20]1([C:23]2[C:24]([O:33][CH:34]3[CH2:41][CH2:40][C:37]4([CH2:39][CH2:38]4)[CH2:36][CH2:35]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=2)[C:28]([OH:30])=O)[CH2:22][CH2:21]1.[N:42]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43]1>CO>[N:42]1([S:46]([NH:49][C:28](=[O:30])[C:27]2[CH:31]=[C:23]([CH:20]3[CH2:21][CH2:22]3)[C:24]([O:33][CH:34]3[CH2:35][CH2:36][C:37]4([CH2:38][CH2:39]4)[CH2:40][CH2:41]3)=[CH:25][C:26]=2[F:32])(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Solvent: CO
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 357 Step 4 and making non-critical variations to replace 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid and methanol with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.029 g, 12% yield): 1H NMR (300 MHz, DMSO-d6) δ11.57 (br s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.01 (d, J=13.2 Hz, 1H), 4.67-4.61 (m, 1H), 4.00 (t, J=7.7 Hz, 4H), 2.17-1.98 (m, 3H), 1.90-1.83 (m, 2H), 1.72-1.61 (m, 2H), 1.49-1.29 (m, 4H), 0.90-0.84 (m, 2H), 0.68-0.63 (m, 2H), 0.30-0.19 (m, 4H); MS (ES−) m/z 421.15 (M−1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][O:45][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1
Yield: 58.9 %

Procedure:
To a solution of triphenylphosphine (1.24 g, 4.74 mmol) in 20 mL of tetrahydrofuran at room temperature was added diethyl azodicarboxylate (0.746 mL, 4.74 mmol) dropwise with stirring. After stirring at room temperature for 30 minutes, (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (350 mg, 3.16 mmol) and 3-hydroxypyridine (450 mg, 4.74 mmol) were added to the reaction mixture. The resultant solution was then stirred at room temperature overnight. After all of the starting material was consumed, the organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography. Elution with chloroform:methanol (10:1) provided 518 mg of the title compound along with substantial amount of reduced DEAD reagent. MS (DCI/NH3) m/e 279 (M+H)+.