Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH:41]([CH3:43])[CH3:42].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33]/[C:34](=[N:39]\[O:40][CH:41]([CH3:43])[CH3:42])/[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Reactant: CC(C)ON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N\OC(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.059 g, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14].NCC([O-])=O.NCC([O-])=O.[Fe+2:26]>O>[Fe:26].[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [Fe+2]
Agent: NCC(=O)[O-]
Agent: O=C(O)CNCCc1ccc(O)cc1O
Solvent: O
Product: [Fe]

Procedure:
Ingredients. (1) Water 96.50 (2) N-[(2,4-dihydroxyphenyl)ethyl]glycine 1.5 (3) Iron Bis-glycinate 2.0. Procedure. The mixture of all ingredients is heated at 90 to 95 C for 2 hours. The green color of iron glycinate changes to a dark red-brown color. Water is then evaporated off to ½ of its original volume. Ethanol (50 mL) is then added and the mixture cooled. A reddish brown material is formed. The precipitate is filtered and washed with water to remove any unreacted iron glycinate. A reddish brown N-[(2,4-dihydroxyphenyl)ethyl]glycine Iron is obtained.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([N:18]=[C:10]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Product: O=C1C(=Nc2ccc(Cl)nc2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 59 %

Procedure:
1-Phenylisatin (23.0 mg, 0.10 mmol) and 5-amino-2-chloropyridine (12.8 mg, 0.10 mmol) were mixed and heated at 140° C. for 7 h. The resulting crude product was purified by preparative TLC using hexane/ethyl acetate (8:2) as the eluent, giving the desired product as a yellow solid (19.7 mg, 59%). 1H NMR (400 MHz) δ 8.15 (d, J=8, 1H), 7.6-7.2 (m, 9H), 6.85-6.75 (m, 2H); ESI-MS m/z found 334 (MH+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[CH2:28]([O:36][CH2:37][CH:38]([CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1(S(Cl)(=O)=O)C=CC=CC=1.S(=O)(=O)(O)O>N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[CH:16]([C:20]([O:22][CH:38]([CH2:37][O:36][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:21])[CH:17]=[CH:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCCCCCOCC(O)COCCCCCCCC
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Yield: 30 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.0 g) and molecular sieves (20 g) in dry pyridine (60 ml) was stirred at 0° to 5° C. for an hour, and 2-n-octyloxy-1-n-octyloxymethylethanol [4.6 g] was added thereto. Benzenesulfonyl chloride (2.6 g) was dropwise added to the stirred solution at -5° to -3° C. over 30 minutes, and then stirred at 0° C. for an hour. The resultant mixture was poured into the crushed ice (300 g), adjusted to pH 1 to 2 with 20% sulfuric acid, and then extracted with ethyl acetate (300 ml). The extract was washed with a saturated aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel (200 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [3.1 g] of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4.C([O-])([O-])=O.[K+].[K+].[N:28]#CBr>C(Cl)(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]3)#[N:28]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1CCC(=O)C3
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
An 8.4 g sample of 3-methoxy-17-methylmorphinan-6-one (prepared as in Part 6A) in 85 ml of chloroform containing 6.09 g of dry K2CO3 was reacted with 3.8 g of cyanogen bromide and the product isolated as described in Example 1B. The product was crystallized from ethanol; yield 6.96 g (80%), mp 211°-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1C[CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([Li])CCC.CCCCCC.[C:35]1([CH2:41][CH:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:42]([OH:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: O=CCc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.50 g, 1.0 mmol) in dried tetrahydrofuran (15 mL) under nitrogen at −78° C. was added dropwise a 1.6 M solution of butyl lithium in hexane (1.1 mL, 1.7 mmol). After stirring for 20 minutes, to the reaction mixture was added phenylacetaldehyde (0.228 g, 1.9 mmol). The reaction mixture was stirred additional 1 hour at −78° C. and the temperature was gradually raised to room temperature. It was quenched with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.246 g, 44% yield): 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.80 (d, 1H), 7.09-7.47 (m, 9H), 6.98 (dd, 1H), 5.70 (dd, 1H), 5.07 (t, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.06 (d, 1H), 2.67 (m, 2H), 2.11 (m, 2H), 1.75 (m, 3H); ES-MS (m/z) 417 [M+1]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:36]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)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: [K+]
Solvent: COCCOC
Product: COc1cc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Temperature: 90 °C
Yield: 98.2 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) and 3,4,5-trimethoxyphenylboronic acid (78 mg, 0.37 mmol) were dissolved in DME (2.0 mL). Aqueous K2CO3 (2.0 M, 0.37 mL, 0.74 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) were added and the mixture degassed with a gentle stream of N2 for 15 min. The reaction mixture was heated at 90° C. for 1.5 h then cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/heptane) to afford 146 mg (>100%) of 2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH2:8][OH:9])[NH:5][C:4]1=[O:10])[CH3:2].[Mn]([O-])(=O)(=O)=[O:12].[K+].P([O-])(O)(O)=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[CH2:1]([C@@H:3]1[C:4](=[O:10])[NH:5][C@H:6]1[CH2:7][C:8]([OH:12])=[O:9])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCC1C(=O)NC1CCO
Agent: O=P([O-])(O)O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Product: CC[C@@H]1C(=O)N[C@H]1CC(=O)O
Temperature: 15 °C
Reaction time: 22 h
Yield: 6 %

Procedure:
The crude 3-ethyl-4-[2-(hydroxy)ethyl]-2-azetidinone (34 g; 0.237 mol) obtained according to step (c) is added to 63 g (0.394 mol) of potassium permanganate and 79 g (0.59 mol) of potassium dihydrogen phosphate in 870 ml of water. The mixture is maintained under stirring at 15° C. for 22 hours, then 220 ml of a saturated solution of sodium metabisulfite are added thereto maintaining the value of the pH at about 3 by the gradual addition of 220 ml of 10% sulfuric acid. The mixture is stirred under cooling at 5° C. until a clear solution is obtained (about 30 minutes), then, after saturation with ammonium sulfate, it is extracted with four 250-ml portions of ethyl acetate. The organic extracts are pooled together and dried over MgSO4. Concentration of the ethyl acetate solution to 100 ml and cooling overnight in a refrigerator gives a crystalline precipitate which is recovered by filtration. Yield 16.43 g of the product of the title. Concentration of the mother liquors yields 2.23 g of the product. Elemental analysis, I.R. and N.M.R. data are in agreement with the assigned structure.
Reaction SMILES: FC(F)(F)C1C=CC(C2C=CC(CO)=CC=2)=NC=1.C([O:21][C:22](=[O:52])[CH2:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=4)=[CH:38][CH:37]=3)[CH:30]=2)[O:25]1)C>>[F:51][C:48]([F:49])([F:50])[C:45]1[CH:46]=[CH:47][C:42]([C:39]2[CH:38]=[CH:37][C:36]([CH2:35][S:34][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[O:25][CH:24]([CH2:23][C:22]([OH:52])=[O:21])[CH2:33][CH2:32]4)=[CH:41][CH:40]=2)=[N:43][CH:44]=1
Reactant: CCOC(=O)CC1CCc2cc(SCc3ccc(-c4ccc(C(F)(F)F)cn4)cc3)ccc2O1
Agent: OCc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Product: O=C(O)CC1CCc2cc(SCc3ccc(-c4ccc(C(F)(F)F)cn4)cc3)ccc2O1

Procedure:
The title compound was prepared in the manner analogous to example 5E using 10D. MS m/z 272 (M+1). Step 6. Preparation of {6-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-chroman-2-yl}-acetic acid ethyl ester (Compound 10F)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].CN1C(=O)CCC1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH2:53][C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([NH:43][C:44]4[CH:52]=[CH:51][CH:50]=[C:49]5[C:45]=4[CH:46]=[N:47][N:48]5[CH2:53][C:54]4[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=4)[C:57]([O:59][CH3:60])=[O:58])=[O:22])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.09578 g, 0.2933 mmol) and NMP (1.5 mL) were warmed to provide a homogeneous solution and then cooled to ambient temperature. 2,4,6-Trichlorobenzoyl chloride (0.04277 mL, 0.2737 mmol) was added and the mixture stirred at ambient temperature for 0.5 hours. Methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.055 g, 0.1955 mmol) was added as a NMP solution (1.5 mL) and the mixture was heated to 80° C. and stirred for 4 hours. The mixture was dissolved in MeOH and concentrated. The residue was dissolved in saturated aqueous NaHCO3 and EtOAc and the organic layer was washed with brine and dried over Na2SO4. The crude material was purified by column chromatography (15% MeOH/CH2Cl2 adding 1% 7N NH3/MeOH) to provide methyl 3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate as the free base. This material was dissolved in MeOH (3.0 mL) and CHCl3 (1.0 mL), and HCl (1.955 mL, 3.910 mmol, 2.0M Et2O) was added and the mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and then with hexanes, and dried under vacuum to afford 0.085 g (64%) of the title compound. MS (ES+APCI) m/z=568 (M+H-2HCl).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)=[CH:4][CH:3]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:21][S:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])=[CH:3][CH:4]=3)[CH:8]=2)=[CH:15][CH:16]=1
Reactant: CSc1ccc(Nc2cc(Oc3ccc(N)cc3)ncn2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)ncn2)cc1
Yield: 94 %

Procedure:
N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (194 mg, 0.600 mmol) and phenyl isocyanate (78.6 mg, 0.660 mmol) were stirred in dimethylformamide (2 ml) at room temperature for 18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (250 mg, 0.564 mmol, 94%) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.C([O:35][C:36]1[C:37]([S:48]([CH3:50])=[O:49])=[C:38]([CH:45]=[CH:46][CH:47]=1)[O:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])C1C=CC=CC=1>>[OH:35][C:36]1[C:37]([S:48]([CH3:50])=[O:49])=[C:38]([CH:45]=[CH:46][CH:47]=1)[O:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:25](=[O:27])[CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=1
Reactant: CS(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Product: CS(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 4-(3-benzyloxy-2-methanesulfinylphenoxy)-butylamine analogous to Example 100 steps C and D: (M−1)−=524. HPLC retention time: 0.89 min. (Method A).
Reaction SMILES: [CH2:1]([C@@H:8]1CO[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH:37]1C2CCCC(N)C=2C=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:8]3[CH2:1][CH2:2][CH2:7][C:6]4[NH:38][N:37]=[CH:4][C:5]3=4)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCCc2[nH]ncc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Reaction time: 1 h

Procedure:
To a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (2 g, 3.81 mmol) in DCE (75 mL) at room temperature, add 4,5,6,7-tetrahydro-1H-indazol-4-ylamine (0.66 g, 4.77 mmol) and sodium triacetoxy borohydride (2.42 g, 11.45 mmol). Stir the reaction at room temperature for 12 h and at 50° C. for 1 hour. Cool the reaction, dilute with dichloromethane and wash with water. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate in hexane to 100% ethyl acetate to afford 1.32 g of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH:14](=[O:17])[CH2:15][CH3:16].CC(O)C>CCCCCC>[CH3:16][C@@H:15]([C@@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17]
Reactant: CCC=O
Reactant: O=[N+]([O-])/C=C/CCc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H](C=O)[C@H](CCc1ccccc1)C[N+](=O)[O-]

Procedure:
The title compound was prepared from (E)-(4-nitrobut-3-enyl)benzene and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=2:98), 1 mL/min, tmajor=15.4 min, tminor=14.4 min, the diastereomeric ratio was determined by
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:38]([O:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3][C@H:2]1[F:1])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1F)c1ccccc1
Temperature: 0 °C
Reaction time: 168 h
Yield: 89 %

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.306 g, 1.21 mmol) was treated with triphenylphosphine (0.475 g, 1.81 mmol) and benzoic acid (0.221 g, 1.81 mmol) and the solids were dissolved in THF (5 mL), then cooled to 0° C. The solution was treated dropwise with diisopropyl azodicarboxylate (0.357 mL, 1.81 mmol) dissolved in THF (1 mL). The solution was warmed to ambient temperature with a bath and stirred for 7 days, then concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated NH4Cl, water, 50% saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to a colorless oil. The oil was chromatographed on SiO2 eluting with 1:12 acetone/hexanes. The desired fraction was isolated to provide the desired product as a colorless oil (385 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]1=[S:27]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][N:23]3[CH:24]=[CH:25][CH:26]=[N:21][C:22]3=[S:27])=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: S=c1nccc[nH]1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2cccnc2=S)cc1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and pyrimidine-2(1H)-thione. m/e+ 367 for C20H19N4S [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.54 (d, J=4.8 Hz, 2H), 7.94 (d, J=4.8 Hz, 1H), 7.74 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.27 (dd, J=4.2, 7.8 Hz, 2H), 7.05 (m, 2H), 4.94 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13][CH2:14]1)(=[O:27])[CH3:26]
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To an ice-cold solution of 2-amino-4-(4-piperidyl)quinazoline (500 mg, 2.19 mmol) and triethylamine (233 mg, 2.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise acetic anhydride (0.22 ml, 2.30 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for about 3 hours and was evaporated. The residue was partitioned between dichloromethane and saturated sodium hydrogencarbonate aqueous solution. The organic layer was washed with water and then dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethanol. Recrystallization from methanol gave the titled compound(452 mg).