Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:40])=[O:39]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.063 g) in CH2Cl2 (6 mL) was added DIEA (0.05 mL) and methanesulfonyl chloride (0.015 mL). After 1 hour, the mixture was concentrated and purified by chromatography (Silica gel: 4% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.069 g). MS (m/z) 546 (MH+). mp 229° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1F
Reactant: COC(=O)c1cccc(N)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2F)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of methyl 3-amino-2-hydroxybenzoate (1.42 g, 8.50 mmol) and pyridine (1.0 mL, 8.5 mmol) in toluene (20 ml) was added 2-fluoro-4-(pyridine-2-yl)benzoyl chloride (2.0 g, 8.50 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (4×100 mL). The organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 3-(2-fluoro-4-(pyridin-2-yl)benzamido)-2-hydroxybenzoate as a yellow solid (1.40 g, yield 45%). LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: [C:1]([C:3]1C=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].OC1C=CC2C(=O)C3C4C=CC(C#N)=NC=4[NH:39]C=3C(C)(C)C=2C=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])=[CH:18][C:10]=4[C:11]([CH3:16])([CH3:17])[C:12]=3[NH:13][C:14]=2[N:39]=1)#[N:2]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B1, 8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile was subjected to trifluoromethanesulfone esterification to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[Ni]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(N)c1SCc1ccccc1

Procedure:
The 2-benzylthio-3,5-dinitrobenzoic acid methyl ester obtained in the previous stage (see Example 1.14), which is still damp, is dissolved in 2 l of tetrahydrofuran and hydrogenated at from 30° to 35° C. with the addition of 3×40 g of Raney nickel. The catalyst is then removed by filtration, the filtrate is concentrated and the residue is taken up in ethyl acetate. After drying over magnesium sulfate and treating with activated carbon and fuller's earth, the filtrate is concentrated and the product is caused to crystallise by the addition of diethyl ether. Yield: 253 g (77% of the theoretical yield over three stages); m.p. 84°-86° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:8][CH:7]1[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][N:3]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C@H:2]1[CH3:1]
Reactant: C=CCOC(=O)N1CCC(C(=O)OCC)C(=O)[C@@H]1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CCC(C(=O)OCC)C(O)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 1-allyl 4-ethyl (2S)-2-methyl-3-oxo-1,4-piperidinedicarboxylate (1.40 g, 5.2 mmol) in methanol (27 ml) were added acetic acid (0.36 ml, 6.3 mmol) and sodium cyanoborohydride (0.39 g, 6.3 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give 1-allyl 4-ethyl (2S)-3-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.36 g). A solution of this compound in dichloromethane (24 ml) was cooled at −30° C. and to the solution were added methanesulfonyl chloride (0.58 ml, 7.5 mmol), triethylamine (1.4 ml, 10.0 ml) and dimethylaminopyridine (61 mg, 0.50 mmol). The mixture was stirred at 0° C. for 20 minutes and poured into 1N hydrochloric acid and the solution was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was dissolved in toluene (10 ml) and dichloromethane (5 ml). To the solution was added DBU (2.3 ml, 15.4 mmol) and the solution was stirred at room temperature for 5 hours. To the reaction solution was added water and after separating the mixture with a separating funnel the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 1-allyl 4-ethyl (6S)-6-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (825 mg) with an intermediate, a methanesulfonylated compound (409 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH:13]=[CH2:14])=[O:8])=[O:5].[OH:15]O>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12]([CH:13]=[CH2:14])=[O:15])=[O:8])=[O:5]
Reactant: C=CSCCNC(=O)NC(=O)CCCl
Reactant: OO
Solvent: CC(=O)O
Product: C=CS(=O)CCNC(=O)NC(=O)CCCl
Reaction time: 2 h

Procedure:
4.05 g Intermediate 6 in 20 ml acetic acid was oxidised with 30 % hydrogen peroxide in the usual way. After 2 hours, the solution was evaporated and the residue stirred with ether. The solidified product was filtered off and recrystallised from ethanolpetrolether. Yield 3.1 g; Mp. 113° to 135° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)butanoic acid (2.00 g) in N,N-dimethylformamide (28.0 mL) were added potassium carbonate (1.61 g) and benzyl bromide (1.46 mL), followed by stirring at room temperature overnight. The reaction suspension was concentrated under reduced pressure, and then to the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl 4-(4-hydroxyphenyl)butanoate (2.64 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10]C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)[CH3:10]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CCC(=O)c1ccc(O)cc1O
Product: CC(=Nc1ccc(C2=NNC(=O)CC2C)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A mixture of 0.167 g (0.0011 mol) of 2',4'-dihydroxypropiophenone and 0.203 g (0,001 mol) of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazin-3(2H)one was heated for 1 h at 140° C. The product was triturated with ethanol and filtered. Yield 0.15 g (45%), m.p. 185°-190° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O=S(Cl)Cl.[CH3:18][CH2:19]O>>[CH2:18]([O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH3:19]
Reactant: CCO
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(N)Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 2-amino-3-(4-bromophenyl)propanoic acid (40 g, 164 mmol) in EtOH (100 mL) was added SOCl2 (30 ml, 422 mmol) dropwise at 80° C. The mixture was stirred at 80° C. for 2 hrs. After the solvent was evaporated, the residue was extracted by EA. The combined organic layers were washed with aqueous NaCl, dried by anhydrous Na2SO4, and concentrated in vacuo to afford ethyl-2-amino-3-(4-bromophenyl)propanoate as a yellow liquid (32 g, yield: 72%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (1.74 g, 5.11 mmol) and 3,4-dichloroaniline (870 mg, 5.37 mmol) to yield 820 mg (44%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.C1COCC1.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.39 g, 0.73 mmol) in 2.0 M dimethylamine in THF (10 mL, 20 mmol) was stirred for 16.5 hours at 80° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 35 minutes to give dimethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a light brown-orange semi-solid (0.257 g, 86.2%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a buff-colored foam (0.254 g). Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ10.25 (s, 1H), 8.74-8.76 (m, 1H), 8.51 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.03-8.05 (m, 1H), 7.71-7.74 (m, 2H), 7.56-7.66 (m, 2H), 7.39 (d, 1H, J=2.08 Hz), 7.22 (dd, 1H, J=9.28 Hz and 2.32 Hz), 4.39-4.42 (m, 2H), 4.05 (s, 3H), 3.50-3.52 (m, 2H), 2.83 ppm (s, 6H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[C:29](=O)[CH2:28][CH2:27][CH2:26]2>CCOCC.C1COCC1>[CH3:34][O:33][C:32]1[CH:31]=[C:30]2[C:25](=[CH:24][C:23]=1[O:22][CH3:21])[C:26]([C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1)=[CH:27][CH2:28][CH2:29]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(c1ccc(OCCN3CCCC3)cc1)=CCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 6.75 g (0.025 moles) of 1-(2-(4-bromophenoxy)ethyl)pyrrolidine in 250 ml of ether was cooled to −78° C. under N2. Several ml of THF were added to maintain a clear solution. 16.7 ml of 1.6 M n-butyllithium was added dropwise keeping the temperature below −70° C. After stirring at −78° C. for 1 hour, a solution of 5 g (0.024 moles) of 6,7-dimethoxy-1-tetralone in 25 ml of THF was added dropwise during 1 hour keeping the temperature below −70° C. After stirring for 2.5 hours at −78° C., the reaction was quenched by addition of 100 ml of 2N HCl. The reaction was allowed to warm to room temperature and the pH was adjusted to 7 by addition of 5N NaOH. The Et2O layer was separated and the aqueous layer was extracted 2 times with EtOAc. The combined Et2O/EtOAc layers were dried over Na2SO4 and evaporated to give 9 g of crude product, which was purified on 400 g of silica gel eluting with 95/5 CH2Cl2/MeOH to remove starting tetralone then with 85/15 CH2Cl2/MeOH to give 3.3 g of product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1.CN(C)C=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+:25]>CO>[N:18]1([CH2:2][C:3]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[O:5][N:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Na+:25]
Reactant: O=C(O)CCc1nc(CCl)no1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C([O-])CCc1nc(CN2CCOCC2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A 25 mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with 3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)propionic acid (1.48 g, 7.77 mmol), dimethylformamide (4 mL) and morpholine (2.0 g, 22.9 mmol). The reaction mixture was then stirred for 4 h at ambient temperature. The resulting suspension was filtered, and the filter cake was washed with ether and dried to afford 2.52 g of the crude product. A portion (1.49 g) of this material was dissolved in methanol (6 mL) and treated with sodium hydroxide (399 mg, 9.98 mmol). After 1 h, the reaction mixture was concentrated to dryness under vacuum, and then triturated with ethyl acetate. The precipitate was filtered and dried under reduced pressure affording a 68% yield of sodium 3-[3-(morpholin-4-ylmethyl)-1,2,4-oxadiazol-5yl]propionate, contaminated with a small amount of sodium acetate, as a white solid. This material was used directly. m.p. 155-161° C. (dec.); 1H NMR (DMSO-d6) δ (ppm) 3.56 (m, 6H), 2.98 (t, 2H,J=7.2 Hz), 2.46 (t, 4H,J=4.3 Hz), 2.36 (t, 2H,J=7.2 Hz): m/z=263 (M−Na).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:4]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([OH:48])=[O:47]>>[CH2:38]([O:37][C:35]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:22]=[C:23]([C:31]([F:32])([F:34])[F:33])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=2)[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([OH:48])=[O:47])=[O:36])[CH3:39]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58 %

Procedure:
Ethyl 6-(bromomethyl)-4-(5-fluoro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.37 g, 5.3 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.69 g, 5.3 mmol) according to the procedure described in Example 1, Step C to give the title compound as a yellow solid (2.11 g, 58%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C@@H:11]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([N:29]=[N+:30]=[N-:31])[C@@H:18]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:17][C@H:12]1[O:13]C(=O)C)(=O)C>CO.O>[N:29]([C@H:19]1[C@@H:18]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:17][CH:12]([OH:13])[C@H:11]([OH:10])[C@H:20]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:30]=[N-:31]
Reactant: CC(=O)O[C@@H]1O[C@H](COCc2ccccc2)[C@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)[C@@H](O)C(O)O[C@@H]1COCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Potassium carbonate (0.600 g, 4.34 mmol, 3.99 equiv) was added to a solution of diacetate 222 (0.511 g, 1.09 mmol, 1.00 equiv) in methanol (50 mL) and water (5 mL). After 1.5 h, the yellow solution was decanted from the undissolved potassium carbonate and concentrated to about 4 mL and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried with magnesium sulfate and purified by silica gel chromatography (ethyl acetate) to afford 223 (0.353 g, 0.917 mmol, 84% yield) as a yellow oil (1:1 α:β). Rf=0.17, 014 (hexane/ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 7.43-7.27 (m, 20H), 5.28 (d, J=3.8, 1H), 4.78 (d, J=11.5, 1H), 4.78 (d, J=11.5, 1H), 4.67 (d, J=11.5, 1H), 4.68 (d, J=11.5, 1H), 4.58 (d, J=11.9, 1H), 4.56 (d, J=11.9, 1H), 4.52 (d, J=11.9, 1H), 4.51 (d, J=11.9, 1H), 4.51 (d, J=7.7, 1H), 4.21 (td, J=6.5, 1.1, 1H), 4.02 (dd, J=3.4, 1.3, 1H), 3.99 (dd, J=9.9, 3.8, 2H), 3.85 (dd, J=9.7, 3.5, 1H), 3.73 (dd, J=9.5, 7.7, 1H), 3.69-3.51 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 137.62, 137.50, 137.48, 128.67, 128.59, 128.16, 128.13, 128.10, 128.09, 128.07, 128.02, 128.00, 97.08, 92.50, 80.85, 78.06, 73.64, 73.61, 72.63, 72.51, 72.14, 71.82, 69.25, 68.76, 68.68, 67.38, 60.27, 59.49; FTIR (neat film) 3401.3, 3032.4, 2921.6, 2105.6, 1454.4, 1367.2, 1279.3, 1095.8, 1028.3, 738.1, 698.0 cm−1; HRMS (ESI) m/z: Calcd for C20H23N3O5Na (M+Na+) 408.1535, found 408.1535.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](N)C>>[CH2:9]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])[CH3:11]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: CCN
Product: CCn1ccc(=O)c(O)c1C

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed, starting with 70% ethylamine (4.6 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (4.2 g). Proton NMR (D20): 7.85 (d, 1H), 6.88 (d, 1H), 4.12 (q, 2H), 2.36 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.O[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][O:1][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OCCc1ccccn1
Product: O=C(O)c1cccc(OCCc2ccccn2)c1

Procedure:
Prepared from 2-(2-hydroxyethyl)pyridine and ethyl 3-hydroxybenzoate. LC-MS (m/z): 245 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:26]([OH:29])(=[S:28])[CH3:27].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:28][C:26](=[O:29])[CH3:27])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(C#N)c1
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1cnc(C#N)c1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(4-cyanoimidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (13.4 g) was reacted with thioacetic acid (5.46 ml) and potassium t-butoxide (8.17 g) in substantially the same manner as Preparation 4-12) to give (2R,4S)-1-allyloxycarbonyl-4-acetylthio-2-[2-(4-cyanoimidazol-1-yl)ethyl]pyrrolidine (12.5 g) as a yellow paste.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][C:11](OC)=[O:12])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[Li+].[BH4-]>C1COCC1>[OH:12][CH2:11][CH2:10][N:9]([CH2:15][C:16]([F:17])([F:18])[F:19])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:5]=1
Reactant: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 79.6 %

Procedure:
To a solution of methyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycinate (1.67 g, 4.91 mmol) in THF (17 mL) at 0° C. was added a solution of LiBH4 in THF (4.91 mL of a 2 M solution, 9.82 mmol), dropwise over 5 min. The cooling bath was removed, and the mixture was stirred 19 h at rt. The mixture was cooled to 0° C., quenched by dropwise addition of sat'd NH4Cl and poured into water. The whole was extracted with EtOAc (×3). Combined organic portions were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.22 g of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=9.1 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.96 (dd, J=8.8, 2.5 Hz, 1H), 4.16 (q, J=8.5 Hz, 2H), 3.95 (app. q, J=5.1 Hz, 2H), 3.76 (t, J=5.4 Hz, 2H), 1.68 (t, J=4.6 Hz, 1H); MS (APCI) m/z 313 (M+1).