Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH3:27])[CH2:4][N:5]1[C:14]2[C:9](=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[CH:12][CH:13]=2)[C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1OB(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.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>[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:23])[N:7]([CH3:24])[C:6](=[O:25])[N:5]2[CH2:4][CH:3]([CH2:26][CH3:27])[CH2:1][CH3:2]
Reactant: Cc1ccc(OB(O)O)c(C)c1
Reactant: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(OS(=O)(=O)C(F)(F)F)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
To a mixture of [1-(2-ethylbutyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl]-trifluoromethanesulfonate (29 mg, 0.071 mmol), 2,4-dimethylphenylboroic acid (21 mg, 0.14 mmol) and potassium carbonate (20 mg, 0.14 mmol) and toluene (2 ml) was added of tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.036 mmol). The mixture was stirred at 90° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution in water, 10% citric acid solution in water and brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 11 mg (41%) the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[N:3]=1.[CH2:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)[CH3:11].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:20]2[CH:21]=[CH:22][C:15]3[CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:18][CH2:17][C:16]=3[CH:19]=2)[C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3nc(Cl)ncc3Cl)cc2CC1
Temperature: 80 °C
Yield: 539.7 %

Procedure:
2,5,6-trichloropyrimidine (200 mg, 0.15 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (209 mg, 1.10 mmol) were mixed with N,N-diisopropylethylamine (211 mg, 1.63 mmol) in 8 mL isopropyl alcohol and heated at 80° C. for 24 hours. The reaction was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, was dried (sodium sulfate), and was concentrated. Chromatography on silica (1% to 20% methanol:dichloromethane gradient elution) afforded 273 mg (74%) of (2,5-dichloro-pyrimidin-4-yl)-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amine as a tan foam. MS: 338.55 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl-].C[Al+]C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:19](OC)=[O:20])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:19](=[O:20])[CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension N-methoxy-N-methylamine hydrochloride (2.0 g, 21 mmol) in 50 mL CH2Cl2 at 0° C. was added dimethylaluminum chloride (1 M in hexane, 21 mL, 21 mmol). After stirring at room temperature for 1 h, a solution of methyl 3-(4-chlorophenyl)-2-(3-flurophenyl)propionate (Step A, 2.0 g, 10 mmol) in CH2Cl2 (10 mL) was added, and the resulting mixture was stirred overnight. The reaction mixture was quenched by addition of MeOH (5 mL), and the resulting mixture was concentrated with silica gel (50 g). The material was loaded onto a silica gel column, which was eluted with 10% EtOAc in hexane to 2% ammonia in MeOH (2 M) in 10% EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.35-6.90 (m, 8H), 4.39 (br, 1H), 3.41 (s, 3), 3.38-3.30 (m, 1H), 3.08 (s, 3H), 2.92 (dd, 1H). LC-MS: m/e 322 (M+H)+ (3.6 min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([OH:16])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc2cc(O)ccc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2cc1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 3,7-dihydroxynaphthalene-2-carboxylic acid methyl ester (3.32 g, 15.5 mmol), bromoacetic acid tert-butyl ester (2.29 mL, 15.5 mmol) and potassium carbonate (4.28 g, 31.0 mmol) in DMF (20 mL) is stirred at 60° C. for 18 h. The reaction mixture is poured to EtOAc, wash with water and brine. It is then dried with MgSO4 and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:17]O.O>C(O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=CC=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#CC=Cc1ccc(F)cc1
Yield: 70.4 %

Procedure:
p-Fluorocinnamaldehyde (9.0 g.) was refluxed for 1 hr. in 98% formic acid containing sodium formate (10 g.) and hydroxylamine hydrochloride (7 g.). The solution was cooled and poured into water (275 ml.), giving a solid. This was washed well with water, leaving p-fluorocinnamonitrile (6.21 g., 70%), m.p. 64°-65°, λmax. (EtOH) 271 nm ε 22500.
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[CH:5]1([CH2:11][CH2:12][NH2:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]1([CH2:11][CH2:12][NH:13][CH2:4][C:3]#[CH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C#CCBr
Reactant: NCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCNCCC1CCCCC1
Temperature: 80 °C

Procedure:
20 ml of 80% 3-bromopropyne are added dropwise to 30.3 ml of cyclohexylethylamine and 29.7 g of potassium carbonate in 300 ml of acetonitrile. The reaction mixture is heated at 50° C. for 12 hours and at 80° C. for 6 hours. The resulting mixture is filtered and the solvents are evaporated off under reduced pressure. Compound V.1 is purified by distillation.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1.[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2ccc(-c3cccc(N4CCNCC4)n3)cc21
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS401 starting from 142 mg (0.46 mmol) of 1-[6-(3,3-dimethylindan-5-yl)pyridin-2-yl]piperazine and 90 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:13]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Yield: 322.7 %

Procedure:
2.77 g (8.0 mM) of xanthine and 2.13 g (9.6 mM) of phosphorus pentasulfide were heated under reflux in 50 ml of pyridine for 7 days. At 0° C., 10.6 ml of 2N NaOH were added within 15 minutes. The solvents were evaporated in vacuo and the residue suspended (slow crystallization) in water. The solid was collected and washed, redissolved in 50 ml of 1N NaOH and 50 ml of isopropanol, treated twice with 0.3 g of charcoal, filtered neutralized with 5N HCl to pH 7. The isopropanol was distilled off with addition of water and the solid collected, washed and dried to give 2.60 g (89.7%) of crude thioxanthine, which was dissolved in 40 ml of dichloromethane and filtered through 30 g of silica gel: 1.91 g (65.9%) of 6-thioxanthine were recovered, mp 153-4° C.
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:16]([CH2:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:25]=O.[ClH:27]>C(O)C>[ClH:27].[CH2:16]([CH2:23][NH:24][CH2:25][CH:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:14]=2[C:1]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: C=O
Reactant: O=C1CCCc2c1ccc1ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1c2ccc3ccccc3c2CCC1CNCCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3,4-dihydro-2H-phenanthren-1-one (3.09 g), benzylmethylamine (2.51 g), paraformaldehyde (0.8 g), hydrochloric acid (5 M, 4.76 cm3) and ethyl alcohol (60 cm3) was heated to reflux for 48 h. It was then allowed to cool to room temperature and the alcohol was removed under reduced pressure. Water (100 cm3) was added and the remaining phenanthren-1-one was extracted into diethyl ether (2×100 cm3). The aqueous layer was further extracted with dichloromethane (2×100 cm3) and the combined dichloromethane extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a pink solid (3.5 g).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH2:38][CH:9]3[C:8](=[O:13])[O:7][C:6]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5([C:25]#[N:26])[CH2:23][CH2:24]5)=[C:18]([F:27])[CH:17]=4)([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:11][C:10]3=[O:12])[N:37]=2)[CH:34]=1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Solvent: CO
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2F)CC1
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with 6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (365 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour and then was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5% hexanes). The resultant oil was further purified by flash 509 SiO2, 1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (48.6 mg, 6%). 1H NMR (400 MHz, CDCl3) δ: 1.19–1.24 (m, 2 H), 1.39–1.61 (m, 10 H), 1.83–1.87 (m, 2 H), 2.25 (t, J=8.59 Hz, 1 H), 2.38 (d, J=17.94 Hz, 1 H), 2.54 (t, J=7.71 Hz, 2 H), 2.64 (d, J=17.94 Hz, 1 H), 3.98 (d, J=5.56 Hz, 2 H), 6.71–6.77 (m, 2 H), 7.06 (t, J=7.83 Hz, 1 H), 8.66 (s, 1 H), 8.73 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].[N:21]([CH2:24][CH3:25])=[C:22]=[S:23]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:22]([NH:21][CH2:24][CH3:25])=[S:23]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2N)C1
Reactant: CCN=C=S
Solvent: CC#N
Product: CCNC(=S)Nc1ccccc1C1CN(C)Cc2c(Cl)cc(Cl)cc21
Product: Cl
Reaction time: 15 h
Yield: 54 %

Procedure:
2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (95 mg, example 36) was dissolved in acetonitrile (4 ml) and isothiocyanato-ethane (27 mg) was added to the stirred solution. After standing for 15 h at room temperature the solvent was removed and the residue purified by preparative HPLC. The product containing fractions were combined and the acetonitrile was removed in vaccuo. After addition of potassium carbonate the aqueous phase was extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulphate), filtered and concentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 36 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13].[OH-].[K+]>C(O)C>[NH:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
5.0 g (31.7 mmol) 6-chloronicotinic acid and 30.9 ml (31.8 g, 634.7 mmol) hydrazine hydrate are initially introduced into 10 ml ethanol and the mixture is stirred at the boiling point at a bath temperature of 100° C. for 16 h. The solvent and excess hydrazine hydrate are distilled off on a rotary evaporator, the residue is taken up in water, 1.8 g (31.7 mmol) potassium hydroxide are then added and the mixture is stirred for 15 min. The solvent is removed completely on a rotary evaporator, the residue is dried in vacuo and 7.5 g of crude product, which is reacted further as such, are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.CS(Cl)(=O)=O.[CH2:34]([N:36](CC)[CH2:37][CH3:38])[CH3:35].N1CCCC1>C(Cl)Cl>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[N:25][C:24]([CH2:27][N:36]4[CH2:37][CH2:38][CH2:35][CH2:34]4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CCN(CC)CC
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CN4CCCC4)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-yl]methanol (Intermediate 125, 50 mg, 132 μmol) in DCM (10 mL) was added methanesulfonyl chloride (11 μL, 139 μmol) and triethylamine (20 μL, 145 μmol). The reaction mixture was stirred for 90 min at room temperature under an inert atmosphere and then evaporated to dryness. The resulting solid was dissolved in DCM (10 mL), pyrrolidine (24 μL, 333 μmol) and triethylamine (46 μL, 333 μmol) and stirred for a further 3 h at room temperature. Incomplete reaction was observed so the reaction was heated at 35 C for a further 16 h. The reaction mixture was then washed with water (3×25 mL) and combined organics were dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (5% MeOH in DCM) to afford the title compound as a beige solid (25 mg, 45%).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1([F:16])[CH2:3][CH2:4][CH:5]([C:8]([CH3:14])([CH3:15])[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)(C)C1CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)C1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate 232B (0.15 g, 0.640 mmol) in ethanol (2 mL) and water (1 mL) was added NaOH (0.256 g, 6.40 mmol) and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was acidified with an aqueous solution of 1.5N HCl and extracted with EtOAc (2×20 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 232C as a yellow solid (90 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.20 (br. s., 1H), 2.11-1.94 (m, 2H), 1.91-1.55 (m, 5H), 1.34-1.14 (m, 2H), 1.09-0.96 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N+:9]=1[O-:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
20.37 g (92.2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine was dissolved in 100 mL of chloroform, and the resulting solution was cooled with ice water. 25 g (101.4 mmol) of a 70% by weight product of meta-chloroperbenzoic acid was added thereto. After confirming that there is no large heat generation, the temperature was raised to room temperature. After 2 hours had elapsed, 20 mL of water was added thereto. Then, the pH was adjusted to 14 by adding an aqueous solution of caustic soda having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with chloroform. The chloroform layer was washed with a 28% aqueous solution of caustic soda and then with water, and then dried with magnesium sulfate. Chloroform was removed by distillation under reduced pressure to obtain 21.30 g of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide (yield: 99.6%) in a light orange oily form.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 1-methylimidazole
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1)=[O:68]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 56.1 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL). HOBT (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (140 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 96 mg (53.3% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.77%. 1H NMR (CDCl3): δ 8.42 (d, 2H), 8.04 (s, 1H), 7.8-7.64 (m, 3H), 7.52-7.42 (t, 2H), 7.4-7.3 (t, 1H), 7.1 (d, 1H), 7.0-6.9 (bs, 1H), 4.34-4.18 (m, 2H), 4.04-3.84 (m, 1H), 3.8-3.5 (m, 4H), δ 3.44 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][Cl:11])=[O:6].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.O>[Si:15]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][Cl:11])=[O:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCCCl)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCCl)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 3-chloropropyl 3-hydroxybenzoate (12.0 g, 0.055 mol) and tert-butyldimethylsilyl chloride (TBDMS-Cl, 10.00 g, 0.067 mol) in anhydrous DMF (10 mL) was added imidazole (7.61 g, 0.11 mol). The reaction mixture was stirred for 1 hour after which it was diluted with water (50 mL) and extracted with hexane (4×20 mL). The hexane layer was washed with water (2×10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound (16.64 g, 0.0506 mol, 90%): 1H NMR (CDCl3) δ0.216 (s, 6H), 0.994 (s, 9H), 2.19-2.27 (m, 2H), 3.69 (t, 2H, J=6.3 Hz), 4.46 (t, 2H, J=6.3 Hz), 7.01-7.64 (m, 4H); MS exact mass; calcd. 328.1264, found 328.1257.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]2[N:8]([CH3:24])[CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[C:11](=[O:12])[C:6]=2[S:5][C:4]=1[CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27].C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:10]2[C:11](=[O:12])[C:6]3[S:5][C:4]([CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH3:27])=[C:3]([CH2:2][NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:7]=3[N:8]([CH3:24])[CH:9]=2)=[O:14])=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN)C[C@@H](O)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CNS(C)(=O)=O)C[C@@H](O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.), stirred solution of 96 mg of 3-(aminomethyl)-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 40 μL of diisopropylethylamine in 2 mL of CH2Cl2 is added 15 μL of methanesulfonyl chloride. The solution is stirred at 0° C. for 20 min, then quenched with dil. HCl and aqueous NaHCO3 to pH 7.0. The mixture is extracted three times with CHCl3, and the combined extracts dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-4% MeOH in CH2Cl2 furnishes 114 mg of the title compound as a white foam. Recrystallization from EtOAc provides white crystals.