Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O.C(OCC)(=O)C.O>[O:58]=[C:57]([N:9]1[CH2:8][CH:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])[CH2:10]1)/[CH:56]=[CH:55]/[C:50]1[CH:49]=[C:48]2[C:53](=[N:52][CH:51]=1)[NH:54][C:45](=[O:44])[CH2:46][CH2:47]2
Reactant: FC(F)(F)CCCOC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCCCC(F)(F)F)C3)cnc2N1
Reaction time: 8 h
Yield: 351.1 %

Procedure:
3-(4,4,4-Trifluorobutoxy)-azetidine (129 mg, 0.59 mmol), EDCI (113 mg, 0.59 mmol), HOBt (80 mg, 0.59 mmol) and diisopropylethylamine (170 μL, 0.97 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100 mg, 0.039 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (95:5 to 9:1) as eluent. The residue was finally triturated in diethylether to give the title product as a pale yellow solid (52.5 mg, 35%).
Reaction SMILES: COP([CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)(=O)OC.[H-].[Na+].[N:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1>[N+:21]([C:17]1[CH:16]=[C:15]([C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:32][C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=Cc1ccncc1
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C(=Cc2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
[(3-Nitro-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-phosphonic acid dimethyl ester (40.7 g, 0.105 mol) was dissolved in dry THF (1 L) under nitrogen. Sodium hydride (60% suspension in mineral oil) (6.3 g, 0.158 mol, 1.5 eq) was added and the mixture was stirred for 10 minutes at room temperature. Neat 4-picolinaldehyde (10 mL, 0.105 mol, 1 eq) was then added dropwise and the mixture was heated to 60° C. and stirred at this temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure to ⅓ of the original volume and then diluted with water (500 mL). pH was adjusted to 7-8 by adding a saturated solution of NaHCO3 and the mixture was extracted with ethyl acetate (4×300 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. An oil (37.7 g) was obtained, which was used without further purification in the following step.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[F:22][C:21]([F:23])([F:24])[C:19]1[CH:20]=[C:15]([NH:14][C:12](=[O:13])[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=2)[C:29]2[CH:30]=[CH:31][C:32]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:33][CH:34]=2)[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: COC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester (4.2 g, 7.36 mmol) was suspended in ethanol (80 mL) and added sodium hydroxide (4 N, 11 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo, and the residue was added water (50 mL) and acidified with hydrochloric acid (4 N, 12 mL). The aqueous phase was extracted twice with ethyl acetate (75 mL and 25 mL) and the combined organic phases were washed with water (3×15 mL), dried (magnesium sulphate) and concentrated in vacuo to afford 4-[3-(3,5-bis(trifluoromethyl)-phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[N:4][CH:3]=1
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (2.152 g, 13.122 mmol) was suspended in dry DMF (40 ml) under argon at 0° C., and the stirred suspension was treated with sodium hydride (1.155 g of a 60% w:w dispersion in oil, 2.2 eq.) added in portions. The suspension was allowed to warm to rt. After stirring for 30 mins at rt, the mixture was treated with allyl iodide (2.67 ml, 2.2 eq) and then stirred for a further 30 min before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give a residue which was purified by column chromatography on silica with a 0-10% methanol in DCM gradient to give the desired product as a light brown solid (1.683 g, 63%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:23][C:24]1[C:28]([CH:29]=O)=[C:27]([CH3:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.CO.[C].[Pd]>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([CH2:29][C:28]2[C:24](=[O:23])[NH:25][N:26]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:27]=2[CH3:31])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(CCO)cc2)c(=O)[nH]n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of 4-bromophenethyl alcohol (0.21 g) in tetrahydrofuran (20 mL) was added tert-butyllithium (1.6 mol/L pentane solution, 1.5 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole (0.10 g) in tetrahydrofuran (3 mL), and the mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1-1/2) to give an oily substance. The obtained oily substance was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (0.044 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitates were collected by filtration and dried under reduced pressure to give the title compound (0.032 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH2:11][S:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(CSCCNCc2ccc(Cl)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: COc1ccc(CSCCN(Cc2ccc(Cl)nc2)CC(C)C)cc1

Procedure:
This compound was made in a manner analogous to that set forth in Step A of Example 3, using 2.0 grams (0.0062 mole) of [(6-chloro(3-pyridyl))methyl]{2-[(4-methoxyphenyl)methylthio]ethyl}-amine, 0.45 gram (0.0062 mole) of isobutyraldehyde, 2.0 gram (0.0093 mole) of sodium triacetoxyborohydride and 1.5 grams (0.0124 mole) of magnesium sulfate in 40 mL of 1,2-dichloroethane. The yield of the subject compound after one column chromatography purification on silica gel, eluting with a mixture of ethyl acetate and hexanes, was 2.05 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]([F:20])([F:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[F:19][C:12]([F:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCC(F)(F)c2ccccc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reaction time: 6 h
Yield: 105.7 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine (0.19 g, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [190 mg, 0.94 mmol, see Example 49(b), step 2], and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) at room temperature. After 6 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×20 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 70% EtOAc in heptane to afford 2-{3-[6-(2,2-difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acid [0.28 g Example 67]. LCMS: RT=2.82 minutes; MS: 428 (M+H); 1H NMR (300 MHz, CDCl3) 9.6 (1H, s), 8 (1H, s), 7.81 (1H, d, J=7.5 Hz), 7.5-7.4 (7H, m), 6.4 (1H, s), 4.2-4 (2H, m), 3.96 (3H, s), 1.65 (6H, s). IC50=38 nM
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:30][N:29]([CH2:26][CH2:27][CH3:28])[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:13][S:12][CH2:11][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)CSCC1=Cc1ccc(Cl)c(Cl)c1
Reactant: CCCNN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN1NC(c2ccc(Cl)c(Cl)c2)C2=C1C(=Cc1ccc(Cl)c(Cl)c1)CSC2
Yield: 68.5 %

Procedure:
A suspension of tetrahydro-3,5-bis-(3,4-dichlorophenylmethylene)-4H-thiopyran-4-one (6.5 g, 15 mmole) and n-propylhydrazine (1.1 g, 15 mmole) in methanol/chloroform (1:1, 250 ml) is heated at reflux temperature overnight. When the reaction mixture is slightly cooled, unreacted starting material precipitates out and is removed (about 2.2 g) by filtration. The filtrate is concentrated in vacuo and dissolved in CHCl3 and washed with dilute HCl and water. The organic layer is dried (anhydrous MgSO4) and concentrated in vacuo to give 5 g of a semi-solid material. This is applied to a wet-packed (hexane) Al2O3 column (neutral, activity I), and eluted with 0-100% ether/hexane. The major product is obtained eluting with 10-40% ether/hexane. The later fractions, eluted with 50-80% ether/hexane, are combined, concentrated and the residue crystallized from MeOH/CHCl3 to give 0.4 g of the product in crystalline form (99% pure), m.p. 161°-162.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:36])([CH3:37])[CH2:27][C:28]([C:31]([F:33])([F:34])[F:32])([OH:35])[CH:29]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:7]3)[CH:25]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2nc(CN3CCOCC3)ccc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 180 mg (0.74 mmol) of 5-amino-2-(morpholin-4-ylmethyl)quinoline is reacted with 274 mg (0.89 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.8 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 220 mg (56% of theory) of the product is obtained.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[CH3:16][O:17][C:18]([CH:20]1[O:24][CH:23]([C:25]([CH2:27][S:28][C@H:29]2[NH:32][C:31](=[O:33])[C@H:30]2[NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:26])[CH2:22][CH2:21]1)=[O:19].C(N(CC)CC)C>ClC(Cl)C>[OH:4][CH:3]([N:32]1[CH:29]([S:28][CH2:27][C:25]([CH:23]2[CH2:22][CH2:21][CH:20]([C:18]([O:17][CH3:16])=[O:19])[O:24]2)=[O:26])[CH:30]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]1=[O:33])[C:2]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: COC(=O)C1CCC(C(=O)CS[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Reactant: COc1ccc(COC(=O)C=O)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)C1CCC(C(=O)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C(O)C(=O)OCc2ccc(OC)cc2)O1
Temperature: 25 °C

Procedure:
4-Methoxybenzyl glyoxylate hydrate (1.50g) in dichloroethane (30ml) was heated at reflux for 1h using a Dean and Stark apparatus for heavy entrainers. The mixture was cooled to room temperature and then a solution of (3R,4R)-4-[(2RS,5SR)-5-methoxycarbonyltetrahydrofuran-2-ylcarbonylmethylthio]-3-phenylacetamidoazetidin-2-one (2.208g) in dichloroethane (20ml) was added followed by triethylamine (0.1ml). The mixture was stirred at room temperature for 1h and then the solvents were evaporated. The title compound was obtained as a mixture of isomers (2.66g) by column chromatography of the residue using gradient elution (silica gel, 1:1 hexane:ethyl acetate going to neat ethyl acetate); vmax (CHCl3) 3412, 1776, 1741 and 1681cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18](S(C)(=O)=O)[N:17]=1.[Cl-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11][C:18]2[N:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:16]([O:15][CH3:14])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(S)cccc1Cl
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Reaction time: 0.5 h

Procedure:
A solution of 1.4 grams (0.007 mole) of 6-chloro-2-mercaptobenzoic acid in 50 mL of dimethylformamide was stirred, and 0.6 gram (0.01 mole) of 60% sodium hydride in mineral oil was added in two portions during a 3 minute period. After this time the reaction mixture was stirred for 30 minutes, and 1.6 grams (0.007 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared as in Example 1, Steps A-C) was added. Upon completion of addition, the reaction mixture was stirred for about 60 hours. After this time the reaction mixture was poured into 150 mL of an aqueous solution saturated with sodium chloride. Water, 50 mL, was added, and the mixture was extracted with three 70 mL portions of ethyl acetate. The combined extracts were evaporated under reduced pressure, leaving no residue. The aqueous layer was cooled and acidified to pH 2 with aqueous 3N hydrochloric acid. The mixture was reextracted with three 70 mL portions of ethyl acetate. The combined extracts were washed with four 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to two purifications by column chromatography on silica gel. Elution for the first purification was accomplished using 10% methanol in methylene chloride, and with 33% acetone in methylene chloride for the second purification. The yield of 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoic acid was 0.3 gram. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:31])[C@@:11]([NH2:30])([CH3:29])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]=1.CCOC(C)=O.C([O-])(O)=O.[Na+].C(Cl)Cl.CO>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10](=[O:31])[C@@:11]([NH2:30])([CH3:29])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]2[O:28][C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:21][C:16]=2[CH:15]=1
Reactant: CCCCCC(=O)Nc1cc(CC[C@@](C)(N)C(=O)OC)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCCCCc1nc2cc(CC[C@@](C)(N)C(=O)OC)ccc2o1
Temperature: 200 °C

Procedure:
A suspension of (R)-2-Amino-4-(3-hexanoylamino-4-hydroxy-phenyl)-2-methyl-butyric acid methyl ester trifluoro acetic acid salt (460 mg, 1.02 mmol) in dry toluene was heated under pressure (microwave Emrys optimizer) to 200° C. for 10 minutes. After cooling to RT the reaction mixture was distributed between AcOEt and a saturated aqueous NaHCO3 solution. Silica gel chromatography (eluent CH2Cl2/MeOH 10/1) provided the title compound as an amorphous colorless solid. 1H-NMR (DMSO-d6): 7.51 (d, J=8.3 Hz; 1H), 7.42 (d, J=1.2 Hz; 1H), 7.12 (dd, J=8.3, 1.2 Hz; 1H), 3.60 (s; 3H), 2.88 (t, J=7.4 Hz; 2H), 2.71-2.63/2.58-2.50 (m; 2H), 1.92 (bs; 2H), 1.90-1.82/1.80-1.73 (m; 2H), 1.43-1.28 (m; 4H), 1.22 (s; 3H), 0.85 (m; 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:35]([CH2:6][CH2:7][C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 70 °C
Yield: 49 %

Procedure:
To a solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.47 mmol) in anhydrous DMF (5 mL) was added NaN3 (92 mg, 1.42 mmol). The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (30 mL), and water (20 ml). The organic phase was washed with water (3×20 mL), dried over Na2SO4 and evaporated to give 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 49%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:13][N:14]([C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:13][N:14]([C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:17]2[CH:22]=[C:23]([C:27]([F:28])([F:29])[F:30])[C:24]([CH3:26])=[CH:25][C:16]1=2)[C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
Add pyridine-4-carboxaldehyde (0.065 mL, 0.69 mmol) to a solution of (S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine (0.12 g, 0.23 mmol) in 1,2-dichloroethane (10 mL) and acetic acid (0.02 mL) at room temperature under nitrogen and stir for 5 min. Add sodium triacetoxy borohydride (0.29 g, 1.38 mmol) and stir for 12 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brine (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify by silica gel column (gradient eluent, 0-5% MeOH in ethyl acetate) to give the title compound (0.12 g, 87%). MS (ES+): 594 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][CH2:35][CH:34]([C:29]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=2)[CH3:37])=[O:8])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.78 min. MS (ESI+): mass calcd. for C24H19Cl3N4O3S, 548.02; m/z found, 551/553 [M+H]+, m/z found, 571/575 [M+Na]+. 1H NMR (400 MHz, CDCl3): 11.21 (s, 1H), 9.04 (d, J=1.7, 1H), 8.96 (d, J=1.7, 1H), 8.57 (dd, J=7.3, 1.3, 1H), 8.33 (dd, J=8.5, 1.2, 1H), 7.91-7.87 (m, 1H), 7.71 (d, J=1.9, 1H), 7.39 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.99 (d, J=8.4, 1H), 6.88 (dd, J=8.4, 2.0, 1H), 5.82 (s, 1H), 3.70-3.63 (m, 1H), 3.33-3.26 (m, 1H), 3.02-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).