Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:15][C:16]1[C:24](O)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CN(C=O)C.O>[CH:1]1([CH2:4][C:5]2[O:7][C:24]3[C:16](=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][CH:23]=3)[N:15]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc2oc(CC3CC3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To an ice-cold solution of 2-cyclopropyl acetic acid (321 mg, 3.21 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.29 mL, 3.21 mmol) dropwise and a few drops of DMF. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (750 mg, 3.21 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (735 mg, 3.87 mmol). The reaction mixture was then heated to reflux for 3 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water (5×50 mL) and brine, dried (Na2SO4), filtered, and concentrated. The crude was purified by recrystallization from diethyl ether and hexanes to afford 2-(cyclopropylmethyl)benzoxazole-4-carboxylic acid (441 mg, 63%) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) δ 13.04 (br s, 1H), 7.94 (dd, J=8.1, 0.9 Hz, 1H), 7.81 (dd, J=7.8, 0.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 2.92 (d, J=7.0 Hz, 2H), 1.27-1.16 (m, 1H), 0.60-0.54 (m, 2H), 0.36-0.30 (m, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH2:23]([O:22][C:15]1[CH:14]=[CH:13][C:12]([NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)(=[O:10])=[O:9])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(OCc2ccccc2)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(OCc2ccccc2)c2cccnc12)c1ccccc1
Yield: 5.5 %

Procedure:
In a similar fashion using route 20 general procedure 36, 2-amino-N-(5-benzyloxy-quinolin-8-yl)-benzenesulfonamide 567 (417 mg, 1.03 mmol), t-butyl nitrite (209 μl, 1.75 mmol), AcOH (4 ml) and THF (10 ml) gave the title compound (22 mg, 5%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([O:26][Si](C)(C)C)[CH2:15][N:16]([CH2:20][CH:21](OC)OC)[C:17]([NH2:19])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([OH:26])[CH2:15][N:16]3[CH:20]=[CH:21][NH:19][C:17]3=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(CN(CC(OC)OC)C(N)=O)O[Si](C)(C)C)cc1OCC1CC1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(O)Cn2cc[nH]c2=O)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
A mixture of (±)-N-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-2-[(trimethylsilyl)-oxy]ethyl]-N-(dimethoxyethyl)urea (39.6 g) and HCl (150 ml) in methanol (450 ml) was stirred for 48 hours at RT. The resulting mixture was concentrated and the concentrate (150 ml) was extracted three times with CH2Cl2. The combined organic layer were poured out into a NaOH solution. The mixture was stirred and the layers were separated. The aqueous phase was extracted twice with CH2Cl2. The separated organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ethylacetate/diisopropyl ether. The precipitate was filtered off and dried, yielding 10.36 g (37.9%) of 1-[2-[3-(cyclopropylmethyloxy)-4-methoxyphenyl]-2-hydroxy-ethyl]-1,3-dihydro-2H-imidazol-2-one (interm. 6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[C:13]1(=O)[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:6]=1[CH3:7])=[O:12])[CH3:2]
Reactant: CCOC(=O)C=C(C)NC1CC1
Reactant: O=C1C=CC(=O)C=C1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C2CC2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.1 %

Procedure:
Neat 3-cyclopropylamino-but-2-enoic acid ethyl ester (5.63 g, 33.2 mmol) is added to a mixture of p-benzoquinone (7.19 g, 66.5 mmol) and acetic acid (120 mL). The mixture is stirred at room temperature for 5 h and a dark solid is precipitated. The solid is washed with acetic acid and water, dried, adsorbed onto silica gel, and purified via flash chromatography eluting with dichloromethane. The product is triturated in dichloromethane-hexane to afford the title compound (440 mg, 21%). ES/MS m/e 260.0 (M+1)
Reaction SMILES: COC(C1C2C(=CC=CC=2)C=C(Br)C=1)=O.[C:16]([C:18]1[CH:19]=[C:20]([C:28]([O:30]C)=[O:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)#[N:17].[Li+].[OH-]>>[C:16]([C:18]1[CH:19]=[C:20]([C:28]([OH:30])=[O:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)#[N:17]
Reactant: COC(=O)c1cc(C#N)cc2ccccc12
Agent: COC(=O)c1cc(Br)cc2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: N#Cc1cc(C(=O)O)c2ccccc2c1

Procedure:
Using the procedure of Rule, HG and Thompson, S B; J. Chem. Soc. 1764-1767 (1937), 1,8-naphthalic anhydride was brominated and converted to 3-bromo-1-naphthoic acid. This was esterified to methyl 3-bromo-1-naphthoate according to the following procedure. 3-Bromo-1-naphthoic acid (103.0 g, 410 mmol) was dissolved in DCM (1250 mL) and the solution cooled to 0° C. Oxalyl chloride (67.5 g, 532 mmol) was added in one portion followed by a catalytic amount of DMF (1.5 mL), and the resulting solution allowed to warm to ambient temperature and stir for 4 hours. The mixture was evaporated in vacuo, and the residue concentrated a second time from toluene. The resultant acid chloride was dissolved in methanol (1250 mL) and stirred at ambient temperature for 18 h. The mixture was evaporated in vacuo, and the residue purified by chromatography (eluent: DCM:hexanes 1:3) to provide methyl 3-bromo-1-naphthoate as a white solid (106.9 g, 98%). 1H-NMR (CDCl3) δ4.01 (s, 3H, CO2CH3); 7.50-7.69 (m, 2H, aromatic); 7.78-7.87 (d, 1H, aromatic); 8.18 (s, 1H, aromatic); 8.25 (s, 1H, aromatic); 8.80-8.94 (d, 1H, aromatic). Using the procedure of Dewar, J S and Grisdale, P J; J. Amer. Chem. Soc., 84, 3541-3546 (1962), methyl-3-bromo-1-naphthoate was converted to methyl 3-cyano-1-naphthoate and then saponified (LiOH) to afford 3-cyano-1-naphthoic acid. 3-Cyano-1-naphthoic acid (15.9 g, 80.6 mmol) was suspended in DCM (450 mL). To the stirred mixture was added oxalyl chloride (12.8 g, 100 mmol) in one portion followed by a catalytic amount (5 drops) of DMF. The mixture was stirred for 5 hours at room temperature giving a clear solution. The mixture was concentrated in vacuo, and the residue concentrated twice from toluene to provide the acid chloride as a light yellow solid (17.4 g, quantitative). 1H-NMR (300 MHz, d6 acetone) δ7.86-7.91 (t, 1H, aromatic); 7.98-8.04 (t, 1H, aromatic); 8.28-8.32 (d, 1H, aromatic); 8.66-8.72 (d, 1H, aromatic); 8.80 (s, 1H, aromatic); 8.93 (s, 1H, aromatic).
Reaction SMILES: [C:1](/[CH:3]=[C:4]1/[N:5]([CH3:24])/[C:6](=[N:22]/[CH3:23])/[S:7][CH:8]/1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.C(OCC)(=O)C>[C:1]([CH2:3][C:4]1[N:5]([CH3:24])/[C:6](=[N:22]/[CH3:23])/[S:7][C:8]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]1)(=[O:26])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: C/N=C1\SC(C2CCN(C(=O)OC(C)(C)C)CC2)/C(=C\C#N)N1C
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)c(CC(N)=O)n1C
Yield: 120 %

Procedure:
To a solution of tert-butyl 4-((2Z,4E)-4-(cyanomethylene)-3-methyl-2-(methylimino)-1,3-thiazolidin-5-yl)piperidine-1-carboxylate (0.30 g) obtained in Example 74a) in DMSO (6.0 mL) were added potassium carbonate (0.1 g) and a 30% aqueous hydrogen peroxide solution (1 mL) at 0° C. and mixed for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from hexane to give the title compound (0.32 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:26])=[CH:20][C:21](OCC)=[O:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:21](=[O:22])[CH:20]=[C:19]([CH3:26])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methyl-vinyl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 134°-136° C.,
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH:15]3C)=[O:13])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.O>CN(C)C=O>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(S)cc1
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.0 g, 6.10 mmol) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (1.27 g, 9.14 mmol) and 4-aminothiophenol (0.92 g, 7.31 mmol), and the mixture was stirred at 80° C. for 4 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate to give the title compound (1.53 g, 77%) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.O>CS(C)=O>[NH2:1][C:2]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH:27][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: NCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])cc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.1 %

Procedure:
2-Amino-6-(2-amino-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (25 mg, 65 μmol) described in Preparation Example A+-12, 4-fluoronitrobenzene (7.6 μl, 71 μmol) and N,N-diisopropylethylamine (22.7 μl, 130 μmol) were dissolved in dimethylsulfoxide (0.5 mL), the solution was stirred for 3.5 hours at room temperature, and then, the solution was stirred for 15.5 hours at 70° C. The reaction solution was cooled to room temperature, water was added, the solution was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, residue was purified by reverse phase high performance liquid chromatography (mobile phase:acetonitrile-water (containing 0.1% trifluoroacetic acid) was used), and the title compound (23 mg) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O:24][C:25]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CCCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-butyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=433.69.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][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].O[CH2:28][CH:29]([OH:31])[CH3:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:28][CH:29]([OH:31])[CH3:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][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: CC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(C)O)cc1
Reaction time: 8 h

Procedure:
A solution of 7.2 g. of 4-n-hexadecylaminobenzoic acid, 15.2 g. of 1,2-dihydroxypropane, and 3.9 ml. of boron trifluoride etherate are stirred together, under nitrogen, at 115° C. for 19 hours. The solution is cooled, diluted with methylene chloride, and placed in a freezer overnight. The solid is collected, washed with hexane, and oven-dried to yield a white solid. The solid is recrystallized from hexane and chromatographed on alumina with chloroform. This process yields 2-hydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, m.p. 91°-93° C.
Reaction SMILES: [CH:1]1([CH:6]([O:19][CH3:20])[C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[CH2:17]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][CH2:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C@H:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[O:19][CH3:20]
Reactant: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol (enatiomer 2 from the chiral separation of the racemate in STEP C, 23.1 mg, 0.080 mmol) and carbon tetrabromide (34.5 mg, 0.10 mmol) in methylene chloride (0.5 mL) at room temperature was added triphenyl phosphine (27.3 mg, 0.10 mmol). The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20-30% ethyl acetate in heptane) to afford the title compound (23.1 mg, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 1.15-1.27 (m, 1H) 1.34-1.44 (m, 1H) 1.44-1.72 (m, 5H) 1.78-1.87 (m, 1H) 2.16-2.26 (m, 1H) 3.21 (s, 3H) 4.32 (d, J=7.88 Hz, 1H) 4.57 (d, J=10.37 Hz, 1H) 4.67 (d, J=10.37 Hz, 1H) 7.49-7.59 (m, 2H) 7.61 (s, 1H). The other enantiomer of the title compound was prepared in the same manner using enantiomer 1 from the chiral separation of the racemate in STEP C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:13]=[C:12]([S:14](=[O:26])(=[O:25])[NH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[F:24][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:16]=1[NH:15][S:14]([C:12]1[CH:13]=[C:4]([C:3]([OH:27])=[O:2])[CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8])(=[O:25])=[O:26]
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(C(=O)O)cc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6.05 g (15 mmol) of 5-[N-(2,4,6-trifluorophenyl)sulfamoyl]-isophthalic acid dimethyl ester is dissolved in 60 ml of dioxane, 15 ml (30 mmol) of 2N NaOH is added and it is stirred for 3 hours at 50° C. The solution is then concentrated by evaporation to about 15 ml at reduced pressure, acidified with 2N hydrochloric acid and the resulting solid precipitate is suctioned off. The filter residue is dissolved in ethyl acetate, the solution is shaken out twice with water, dried on sodium sulfate, filtered and evaporated to dryness. 4.8 g (12.78 mmol)=85.22% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1cccnc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[CH:6][C:5]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+]>CN(C)C=O.CCOC(C)=O>[CH2:20]([N:7]1[CH:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([N+:1]([O-:3])=[O:2])=[N:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of C1 (2.86 g, 15.4 mmol) in N,N-dimethylformamide (60 mL) was added anhydrous potassium carbonate (12.8 g, 92.6 mmol), benzyl bromide (2.20 mL, 18.5 mmol) and a catalytic amount of potassium iodide. The reaction was heated at 60° C. for 18 hours, then diluted with EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C2 as an oil. Yield: 1.35 g, 4.90 mmol, 32%. An NOE experiment revealed a strong interaction between the pyrazole CH and aromatic protons on the phenyl group, supporting the indicated regiochemistry for C2. LCMS m/z 276.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.1 Hz, 3H), 4.31 (q, J=7.1 Hz, 2H), 5.33 (s, 2H), 7.30-7.35 (m, 2H), 7.40-7.45 (m, 3H), 7.78 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]([OH:27])[CH3:30])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde, (Example 60b), (220 mg, 0.56 mmol) in anhydrous THF (10 mL) was magnetically stirred under N2 in a −78° C. bath while methylmagnesium bromide (0.22 mL, 0.66 mmol, 3.0 M in Et2O, Aldrich) was added quickly. The reaction mixture was stirred at −78° C. for 5 min, then treated with satd NH4Cl (5 mL). The bath was removed and the mixture was stirred for 5 min, then diluted with EtOAc (60 mL) and washed with satd NH4Cl (20 mL), water (20 mL), satd NaHCO3 (20 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient: 60A-85% EtOAc in hexanes) provided the title compound as an off-white solid. Mp: 156–157° C. MS (ESI, pos. ion.) m/z: 412 (M+1). Anal. Calcd for C22H16F3N3O2: C, 64.23; H, 3.92; N, 10.21; F, 13.85. Found: C, 63.99; H, 4.05; N, 10.01; F, 13.63.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[C:6](=O)[CH2:7][C:4]=2[CH:3]=1.C1(P(=[CH:31][C:32](=[O:34])[CH3:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:31](=[C:6]1[C:5]2=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[CH2:7]1)[C:32]([CH3:33])=[O:34]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c2c(c1)CC2=O
Product: CC(=O)C=C1Cc2cc(C)cc(C)c21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
4,6-Dimethylbenzocyclobut-en-1-one (5.5 g, 38 mmol) and triphenylphosphoranylidene-2-propanone (15.0 g, 47 mmol) were heated together with stirring at 180° C. for 0.5 hours. After cooling the mixture was triturated with ether, filtered and the filtrate evaporated to give 1-acetonylidene-4,6-dimethylbenzocyclobutene as a pale brown solid (5.7 g, 81%). Pmr spectrum (CDCl3, δ in ppm): 2.30 (6H, s); 2.35 (3H,s); 3.94 (2H, s); 6.25 (1H, s); 6.86 (2H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]4[CH2:29][OH:28])=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5]
Reactant: OCC1CCCCN1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Product: O=C(CCN1CCCCC1CO)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4CO)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 2-hydroxymethylpiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-11 (888 mg, 63%) as a pale yellow/green solid.