Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].O.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][C:24]([CH2:33][CH2:34][OH:35])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:23][C:22]2=[O:36])[CH:16]=1.CC(C)=[O:39].OS(O)(=O)=O.[O:46]=[Cr:47](=[O:49])=[O:48]>CC(C)=O>[CH3:25][C:24]([CH3:27])=[O:23].[OH:4][S:2]([OH:5])(=[O:3])=[O:1].[O:46]=[Cr:47](=[O:49])=[O:48].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][C:24]([CH2:33][C:34]([OH:39])=[O:35])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:23][C:22]2=[O:36])[CH:16]=1
Reactant: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reaction time: 8 h
Yield: 19 %

Procedure:
Jones reagent was prepared by addition of CrO3 (1 g) to H2SO4 (1 mL) and addition of water to bring the total volume to 4 mL. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.24 mmol) was dissolved in acetone (2 mL), and cooled in an ice bath. Jones reagent (0.2 mL) was slowly added to the mixture and the reaction mixture was stirred overnight. Solvent was removed in vacuo and the obtained residue was purified by preparative HPLC to afford 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (20 mg, yield 19%). 1H NMR (400 MHz, CDCl3): δ=2.7-2.9 (m, 4H), 3.55 (m, 2H), 6.86 (m, 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.33 (m, 5H), 7.44 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](/[CH:39]=[CH:40]/[C:41]([O:43]CC)=[O:42])[CH:34]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[C:41](/[CH:40]=[CH:39]/[C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:11]1=[O:31])([OH:43])=[O:42]
Reactant: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)N(Cc2cccc(/C=C/C(=O)O)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 4-(4-cyanophenyl)-3-{3-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 37) (50 mg, 0.08 mmol) in tetrahydrofuran (2 ml) is added a solution of sodium hydroxide (32.4 mg, 0.8 mmol) in water (0.5 ml). After stirring at room temperature for 1 hour, ethanol (2 ml) is added. After 16 hours stirring, the pH of the solution is adjusted to 2 with 1 N hydrochloric acid, and the product is extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The title compound is obtained as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH3:17]>O.C(O)(=O)C.C(O)C>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH3:17])([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: CC=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 91.2 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are dissolved in a mixture of 250 ml of water, 400 ml of acetic acid and 175 ml of ethanol, then 10 ml (about 0.1 mole) of acetaldehyde in 10 ml of ethanol are added. Yellow crystals separate, immediately. Thus, 21.0 g (92%) of 1-nitro-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 173°-175° C.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:8][CH2:7][CH2:6][S:5][C:4]1=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:24][C:25]([OH:27])=[O:26].Cl>O>[C:25]([CH2:24][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9](=[C:4]2[S:5][CH2:6][CH2:7][CH2:8][S:3]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)CCl
Reactant: Oc1ccc(C(=C2SCCCS2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(C(=C2SCCCS2)c2ccccc2)cc1

Procedure:
To a solution of sodium hydroxide (1.3 g) in water (30 ml), (1,3-dithian-2-ylidene)-(4-hydroxyphenyl)-phenylmethane (3.0 g) and chloroacetic acid (1.4 g) are added. The mixture is refluxed for 3 hours. The water is slowly acidified with concentrated hydrochloric acid to pH 3. The aqueous phase is extracted with water (3×20 ml). The combined organic phases are washed with water (2×10 ml) and dried over magnesium sulphate. The solvent is evaporated in vacuo. The residue is purified by column chromatography on silicagel using dichloromethane/formic acid (99:1) as eluant. The fractions containing the pure product are washed with water to neutrality, dried over magnesium sulphate and evaporated. The residue is dried in vacuo to constant weight to give (4-carboxymethoxyphenyl)-(1,3-dithian-2-ylidene)-phenylmethane, m.p. 176°-177°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:14])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C([BH3-])#N.[Na+].[CH3:19][C:20]([CH3:22])=O>CO>[OH:14][CH:4]([CH2:3][NH:2][CH:20]([CH3:22])[CH3:19])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Cc1cccnc1OCC(O)CN
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1OCC(O)CNC(C)C

Procedure:
4 ml of a 2 N solution of hydrogen chloride in methanol are added to a solution of 3.6 g of 2-(3'-amino-2'-hydroxy-propoxy)-3-methyl-pyridine and 1.5 g of sodium cyanoborohydride in 70 ml of methanol and 12 ml of acetone are added dropwise over the course of approx. 30 minutes, whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo and the residue is acidified with 2 N hydrochloric acid. The aqueous solution is extracted once by shaking with 30 ml of ether. The hydrochloric acid phase is separated off and rendered alkaline with concentrated sodium hydroxide solution. 2-(2'-Hydroxy-3'-isopropylamino-propoxy)-3-methyl-pyridine is isolated by extraction with ethyl acetate and is identical with the material described in Example 21.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:11].[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c([N+](=O)[O-])cc(C)[n+]([O-])c1Br
Temperature: 60 °C

Procedure:
A solution of 124C (7.0 g, 32.4 mmol) in concentrate H2SO4 (9.5 mL) was added to a solution of concentrate H2SO4 (9.5 mL) and fuming HNO3 (13 mL) and the mixture was heated at 60° C. for 30 min. After cooling to room temperature, the reaction mixture was added to iced 6M solution of NaOH (150 mL) and neutralized to pH 6 with 1N NaOH solution. The reaction mixture was extracted with dichloromethane (4×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 124D as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:15])[CH2:12][C:13]#[N:14])[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.N1CCCCC1.O>[CH2:8]([O:10][C:11](=[O:15])[C:12]([C:13]#[N:14])=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:9]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCOCC1
Reaction time: 72 h

Procedure:
A stirred solution of tetrahydro-pyran-4-one (5 g) in toluene (50 mL) was treated sequentially with cyano-acetic acid ethyl ester (5.3 mL), ammonium acetate (0.7 g), acetic acid (2.2 mL) and piperidine (3 drops) then stirred at reflux temperature for 3.5 hours and then stood at room temperature for 3 days. The reaction mixture was evaporated to give a red oil, which solidified on standing at room temperature. This solid was treated with water (30 mL) and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated aqueous sodium bicarbonate solution (30 mL), then with water (30 mL), then dried over magnesium sulfate and then evaporated. The residual pale yellow waxy solid (8.92 g) was refluxed with petroleum ether (b.p. 80–100° C.) when partial solution was achieved. This mixture was treated with cyclohexane (20 mL) and then decanted to remove a small amount of brown gum. The decanted solution was stood at room temperature overnight and the resulting crystalline pale yellow solid was filtered then washed with pentane and then dried at 40° C. under vacuum to give the title compound (5.10 g) as a pale yellow crystalline solid. LC-MS: RT=2.85 minutes, MS(ES+): 169(M+H)+, MS(ES−): 194(M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([C:7]2[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH2:27]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(C)=O)C1
Temperature: 65 °C
Yield: 66.1 %

Procedure:
A stirred mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.120 g, 0.301 mmol), N-[(3S)-pyrrolidin-3-yl]acetamide (0.0464 g, 0.362 mmol, Lancaster), palladium acetate (1 mg, 0.006 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.274 g, 0.843 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane, and filtered. The filtrate was washed with brine, dried over sodium sulfate, and evaporated to dryness. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (75 mg, 66%). LCMS calculated for C18H22ClN4O3(M+H)+: m/z=377.1; found: 377.1.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH2:20][CH2:21][CH3:22])/[C:17]([OH:19])=[O:18].C1(=O)C2C(=CC=CC=2)C(=O)C=C1/C=C(\C)/C(O)=O>CCOCC>[C:3]1(=[O:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[C:4]1/[CH:15]=[C:16](\[CH2:20][CH2:21][CH3:22])/[C:17]([OH:19])=[O:18]
Reactant: CCC/C(=C\c1cc(OC)c2ccccc2c1OC)C(=O)O
Agent: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Solvent: CCOCC
Product: CCC/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 30b was prepared from 29b (0.193 g, 0.643 mmol) as described above for 30a to give 0.064 g (0.24 mmol, 37%) of the product as a yellow solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes. (0.064 g E; 0.006 g Z methyl ester)
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][Br:3])[N:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(CO)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(CBr)COc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.34 g of 3-bromo-2,2-dimethyl-1-propanol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.56 g of 4-chloro-6-(3-bromo-2,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[C:13]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.CI.[C:28]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:18][C:15]1[N:14]=[C:13]([NH:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]([C:10](=[O:11])[CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([S:1][CH3:28])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)CCc2ccc(S)nc2)c(Nc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccc(CCC(=O)c2ccc(C)nc2Nc2ccccc2)cn1
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
3-(6-Mercaptopyridin-3-yl)-1-(6-methyl-2-phenylaminopyridin-3-yl)-propan-1-one (0.4 g) was dissolved in DMF (5 mL), and methyl iodide (0.05 mL) added, followed by K2CO3 (0.138 g). The reaction mixture was allowed to stand at RT for 2.5 h, then worked up in EtOAc/H2O. The organic layer was washed with LiCl (2×, 0.3 wt % aq), dried over MgSO4, filtered, concentrated, and chromatographed over silica (12 g, 1:2 EtOAc/hexane) to provide 1-(6-methyl-2-phenylamino-pyridin-3-yl)-3-(6-methylsulfanyl-pyridin-3-yl)-propan-1-one (0.23 g). M+H=264.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: CN1CCC(N)CC1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)C2(C(=O)Nc3ccc(Oc4ccnc(NC(=O)N(C)C5CCN(C)CC5)c4)cc3F)CC2)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 4-amino-1-methylpiperidine (18.8 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 8 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (20.0 mg, 42%).
Reaction SMILES: [NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH2:6][O:5][C@H:4]([CH3:7])[C@H:3]1[CH2:8][OH:9].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C@@:2]1([NH:1][C:27]([NH:26][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[S:28])[C@H:3]([CH2:8][OH:9])[C@@H:4]([CH3:7])[O:5][CH2:6]1
Reactant: C[C@H]1OC[C@@](N)(c2ccc(F)cc2F)[C@@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccc(F)cc2F)[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
((2R*,3R*,4S*)-4-Amino-4-(2,4-difluorophenyl)-2-methyltetrahydrofuran-3-yl)methanol (120 mg, 0.49 mmol) was dissolved in DCM (2 mL). Benzoyl isothiocyanate (66 μl, 0.49 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and purified by column chromatography, eluting with 0-30% EtOAc in n-hexane to leave the title compound as a yellow oil (165 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 11.81 (s, 1H), 8.89 (s, 1H), 7.84-7.91 (m, 2H), 7.62-7.75 (m, 2H), 7.49-7.58 (m, 2H), 6.91 (dt, J=1.71, 8.38 Hz, 1H), 6.80 (ddd, J=2.63, 8.80, 11.80 Hz, 1H), 4.69 (d, J=10.15 Hz, 1H), 4.39 (dd, J=1.71, 10.15 Hz, 1H), 3.91-4.08 (m, 3H), 2.85 (dd, J=4.58, 6.79 Hz, 1H), 2.59 (dt, J=3.73, 8.10 Hz, 1H), 1.37 (d, J=5.99 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C(F)F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75.1 %

Procedure:
To a cooled solution of ethyl 4,4-difluoro-3-oxobutanoate (5.0 g, 30.1 mmol) in toluene (150 mL) was added NaBH4 (1.26 g, 33.1 mmol) at 0° C. The mixture was then stirred at RT for 4.5 hours. The reaction was quenched with aqueous HCl (10%) carefully. The separated aqueous phase was extracted with EtOAc (20 mL×2). The combined organic phases were dried over Na2SO4, and then filtered and then concentrated in vacuo to give the crude ethyl 4,4-difluoro-3-hydroxybutanoate as colorless oil (3.8 g, yield: 76%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCCO3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:18][C:8]1([C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][CH:6]=2)[CH2:9][CH2:10][CH:11]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:16][CH2:17]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CSc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Product: CSc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 8-(2-methylsulfanyl-thiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=C[C:9]=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([OH:49])=O)=[N:45][CH:46]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(N)C>CN(C)C=O>[CH2:10]([NH:6][C:47]([C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:46][N:45]=1)=[O:49])[CH3:9]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1 mL) at room temperature. The resulting solution was stirred for 25 min, before ethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid. Yield: 25 mg (24% of theory). Mass spectrum (ESI+): m/z=502 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>>[C:12]([NH:11][S:8]([C:6]1[CH:5]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:3]=[C:2]([NH:1][C:35]2[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)[CH:7]=1)(=[O:10])=[O:9])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)(C)NS(=O)(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Cl)c1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 2,4,5-trichloropyrimidine as the starting materials in 35% yield. LCMS for C27H33Cl2N5O4SNa (M+Na)+: m/z=616.2, 618.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:20])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[O:15])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)[CH3:17]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C=O)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.