Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([OH:11])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([O:11][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)Cl
Reactant: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 0 °C
Yield: 68.3 %

Procedure:
To an ice-cold, stirring solution of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-hydroxy-cepham-4-carboxylate (2.72 g., 5.47 mMol) and Et3N (1.15 ml., 8.25 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise a solution of methanesulfonyl chloride (0.51 ml., 6.56 mMol) in anhydrous CH2Cl2 (15 ml.). After stirring 15 more mins. in the cold, the solution is washed with H2O, 5% HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil is crystallized from CH2Cl2 --MeOh to afford p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxycepham-4-carboxylate (2.15 g.) as yellow crystals: mp 147° C.; ir (CHCl3) 4.72, 5.59, 5.71, 6.58 and 7.42μ; nmr (CDCl3)δ 2.17 (s, 3, COCH3), 2.20 (s, 3, SCH3), 3.00 (s, 3, SO2CH3), 3.22, 4.28 (ABq, 2, J=14Hz, SCH2, 4.67, 4.95 (ABq, 2, J=13Hz, CH2OAc), 4.88 (s, 1, H7), 5.20 (s, 1, H4), 5.35 (s, 2, CH2Ar), and 7.63, 8.25 (ABq, 4, J=9, ArH).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:17][CH3:18])[C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:4]=1.C(N(CC)CC)C.Cl[C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>C(O)CCC>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[N:22]1[CH2:23][CH2:24][N:19]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[C:8]([O:17][CH3:18])[C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:20][CH2:21]1
Reactant: Clc1nc2ccccc2s1
Reactant: COc1cc2c(N)nc(N3CCNCC3)nc2c(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2c(N)nc(N3CCN(c4nc5ccccc5s4)CC3)nc2c(OC)c1OC
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
A mixture of 4-amino-2-(1-piperazinyl)-6,7,8-trimethoxyquinazoline hydrochloride (4.0 g) and triethylamine (4.1 g) in butanol (250 ml) was stirred for 15 min and 2-chlorobenzthiazole (1.7 g) was added. The resulting mixture was refluxed for 20 hr, concentrated to about 150 ml, cooled and filtered. The precipitate was washed with water, dried and crystallized from methanol to give the title compound (2.2 g): mp>250° C.; ir (nujol) 3370, 3300 and 3610 cm-1 ; uv max (MeOH) 225 (ε=45,900), 250 (ε=56,700), 277 (ε=45,200) and 353 nm (ε=5,100); nmr (DMSO-d6) δ3.7 (m, 8H), 3.8 (s, 6H), 3.95 (s, 3H) and 7.3 (m, 7H); and Anal. Calcd. for C22H24N6O3S: C, 58.40% H, 5.30% N, 18.58% and Found: C, 58.22% H, 5.50% N, 18.62%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:44]([CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:46])=[O:45])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 73 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (265 mg, 0.54 mmol), phenylmethanesulfonyl chloride (98 mg, 0.51 mmol) and triethylamine (185 mg, 1.83 mmol) in dry tetrahydrofuran (23 ml). This gave the title compound (240 mg) as a gum. MS: 645 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].O[CH2:19][CH:20]1[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCC1CC1
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAN 862111-61-3) (1.3 g, 3.6 mmol) was dissolved in THF (15 mL). To the solution were added hydroxymethylcyclopropane (0.35 mL, 4.3 mmol), triphenylphosphine (1.1 g, 4.3 mmol) and diethyl azodicarboxylate (0.69 mL, 4.3 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and for 16 h at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel with dichloromethane:methanol 4:1 to yield the product as yellowish oil, MS (ISP) 368.0, 370.0 (M+H)+.
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:14][CH:13]=1.Cl>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:28])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1 tetrahydrofuran:methanol (9.0 mL) solution of (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester (270 mg, 0.977 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified to pH=1 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (233mg, 91%). 1H NMR (400 MHz, CDCl3) δ8.01-7.39 (m, 11H), 3.72 (s, 2H)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@@H:12]([OH:20])[C:11]1=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22]([Zn]CC)C.ICI>CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[C:11]2([CH2:22][CH2:21]2)[C@H:12]([OH:20])[C@@H:13]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][C@H:14]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC[Zn]CC
Reactant: C=C1[C@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: ICI
Solvent: CCOCC
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)C1(CC1)[C@@H]2O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a solution of 12 (3 g, 9.5 mmol) in anhydrous ether (50 mL) was added diethyl zinc (1.0 M solution in hexane, 24.2 mL, 28.6 mmol) followed by diiodomethane (4.6 mL, 57.3 mmol) at 0° C. The reaction mixture was allowed to room temperature and was refluxed for 8 hr. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (20 mL) and extracted with ether (2×60 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (5% EtOAc/hexane) to afford 13 (3.0 g, 93%) as an oil. [α]24D −86.03° (c 2.01, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.55 (m, 1H), 4.49 (m, 1H), 4.08 (m, 1H), 3.59 (dd, J=3.0 & 9.5 Hz), 3.50 (dd, J=4.5 & 10.5 Hz, 1H), 2.22 (d, J=10.5 Hz, D2O exchange OH, 1H), 1.57 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H), 0.84 (m, 10H), 0.43 (m, 1H), 0.32 (m, 1H), 0.24 (1H), −0.06 (s, 6H). 13C NMR (125 MHz, CDCl3) 159.01, 115.9, 115.4, 86.85, 84.85, 79.48, 71.63, 57.21, 32.13, 31.54, 30.33, 29.24 23.83, 7.14, 0.015; HR-MS Calcd. For (C17H32O4Si)+ 328.2070, found 328.2195.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Oc1ccc(Br)nc1Br
Reactant: C=CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(Br)nc1Br

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 ml) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diethyl azodicarboxylate (41.77 g, 0.207 mol). The mixture was heated at reflux for 1 h and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 ml) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/EtOAc, 30/1) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:28]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.70 g of desired compound.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:32])([OH:31])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:32][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCC(OCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylbenzyloxy)piperidin-1-yl]propan-2-ol prepared in Example 254 (1.36 g, 2.8 mmol) was dissolved in DMF (15 ml). To the solution, sodium hydride (134 mg, 3.36 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethylbenzyloxy)piperidin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (431 mg, yield 44%) as a white powder.
Reaction SMILES: [CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Yield: 98 %

Procedure:
A solution of (S)-tert-butyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (150 mg, 0.359 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 2 h. The mixture was concentrated to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (112 mg, crude), which was used for the next without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccccn3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.55 g, 1.6 mmol) in acetonitrile (10 mL), was added picolinoyl chloride hydrogen chloride (0.32 g, 1.8 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give pyridine-2-carboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (67 mg, 10% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.85 min (99.4%); mp, 261-263° C.; 1HNMR (DMSO-d6)2.08-2.27 (m, 1H, CHH), 2.64-2.93 (m, 6H, CHCH2, CH3), 4.91-5.05 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.33-8.69 (m, 7H, Ar), 9.32 (t, J=6 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.31, 30.62, 42.12, 56.57, 117.72, 121.86, 125.18, 125.76, 126.60, 134.05, 137.82, 140.30, 148.55, 149.77, 154.87, 161.17, 163.79, 169.47, 172.65. LCMS MH=406; Anal Calcd For C21H19N5O4+0.5H2O: C, 60.86; H, 4.86; N, 16.90. Found: C, 60.72; H, 4.62; N, 16.69.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([OH:18])[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)[CH3:2].[CH2:20](I)[CH3:21]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:18][CH2:20][CH3:21])[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1nc(C)n(-c2ccccc2)n1
Reactant: CCI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OCC)c1nc(C)n(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a stirred solution of (RS)-hydroxy-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (1.12 g) at r.t. in toluene (30 ml) under an argon atmosphere were added silver (I) oxide (2.99 g) and ethyl iodide (1.74 ml). The mixture was heated to reflux and stirring was continued for 16 h. The solids were filtered off and washed with EtOAc. The filtrate was concentrated. The product was isolated by chromatography (silica gel, gradient cyclohexane=>EtOAc) to give (RS)-ethoxy-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (0.87 g) as orange oil. MS 290.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:18]=[O:19]
Reactant: CSc1cc(N)c(Br)cc1Cl
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CSc1cc(N=C=O)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-chloro-5-methylsulfanyl-phenylamine (0.10 g, 0.396 mmol) in toluene (3 ml) was added pyridine (0.042 ml, 0.515 mmol), DMAP (0.048 g, 0.396 mmol) and 20% phosgene in toluene (0.225 ml, 0.436 mmol). The mixture was stirred at room temperature for two hours, then filtered. The filtrate was concentrated to dryness to give 1-bromo-5-chloro-2-isocyanato-4-methylsulfanyl-benzene (0.095 g) as a white solid that was used directly in the next step.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:38])[CH2:9][C@@:10]1([C:26]([O:28]CC2C=CC(OC)=CC=2)=[O:27])[C@H:14]([CH3:15])[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>[Pd].O>[C:3]([O:7][C:8](=[O:38])[CH2:9][C@@:10]1([C:26]([OH:28])=[O:27])[C@H:14]([CH3:15])[CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 72 h
Yield: 71.3 %

Procedure:
Methanol (70 ml) and 10% Pd/C (600 mg) were added to 1-benzyl 3-(4-methoxyphenyl)methyl (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained by the method of Example 4e (3.3 g, 6.63 mmol), followed by stirring at mom temperature for three days under a hydrogen atmosphere. Water (70 ml) was added to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give the title compound (1.15 g, yield: 71.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1
Reactant: O=C(O)C1=Cc2cc(-c3cccnc3)ccc2OCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccnc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 7—(3-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetra-hydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7—(3-pyridyl)-N-(4—((N-tetrahydropyran-4-yl-N-methylamino)-methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 146) (0.06 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]([CH2:23][C@@H:24]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH2:25])([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1>>[CH2:29]([O:28][C:26](=[O:27])[C@H:24]([CH2:23][C:19]([CH3:21])([CH3:20])[CH3:22])[NH:25][C:15](=[O:17])[C@@H:9]([CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 97 %

Procedure:
N-(tert-Butoxycarbonyl)-3-tert-butyl-D-alanine (3.28 g, 13.4 mmol) and benzyl 3-tert-butyl-L-alaninate hydrochloride (4.0 g, 14.7 mmol; J. X. He, W. L. Cody, A. M. Doherty, J. Org. Chem. 1995, 60, 8262-8266) are reacted by general procedure 6 (in this case 5 equivalents of N-methylmorpholine). Aqueous workup results in 6.0 g of product (97% of theory). The product can be finally purified by preparative HPLC (method 16).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[O:9]([C:16]1[CH:17]=[C:18]([N:22]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34](OC)=[O:35])[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN([Al]CCl)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[C:31]([CH2:30][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:32]=1
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Reactant: CNC
Agent: CN(C)[Al]CCl
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at 40° C. was added dropwise a 2.0 M solution of trimethylaluminum in toluene (3.2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl )(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. was slowly added the (N,N-dimethylamino)chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3-ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl) amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C25H25F3N2O3.0.5 H2O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85.HRMS calcd. 459.1896 [M+H]+, found: 458.1887. 1H NMR (C6D6) δ7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H), 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 3H), 2.14 (bs, 3H). 19F NMR (C6D6) δ−78.69 (d, 3F).