Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5]1)([OH:3])=[O:2].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:14]([N:5]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
188 g (1.05 moles) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline are added to 1,050 ml of 1N NaOH at 0°, and 160 ml of benzyl chlorocarbonate and a further 1,050 ml of 1N NaOH are then simultaneously added dropwise at this temperature, while stirring. The mixture is then stirred for 2 hours at room temperature and extracted three times with ether, and the alkaline/aqueous phase is acidified to pH 1 with concentrated HCl. The oil which separates out is extracted with ethyl acetate. The ethyl acetate solution is washed with water until the water phase has a pH of 3.0. After the ethyl acetate solution has been dried over sodium sulfate, the product crystallizes from this solution after concentration and trituration. 1.5 liters of diisopropyl ether are added to the suspension of crystals, and the latter is stirred for one hour at room temperature, and filtered under suction. The product is dried over phosphorus pentoxide in a high vacuum.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=2)=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(Cl)c2)n(C)n1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=470.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[C:4]([C:26](=O)[CH3:27])[CH:3]=1.C([O-])(=O)C.[NH4+:33]>CO.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=2)=[C:4]([CH:26]([NH2:33])[CH3:27])[CH:3]=1
Reactant: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC#N
Product: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Yield: 31.5 %

Procedure:
A solution of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanone (190 mg, 0.47 mmol), ammonium acetate (360 mg, 4.7 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65° C. for 3 hours. The reaction mixture was quenched with acetic acid (˜100 uL) and poured into sodium bicarbonate (50 mL). This mixture was extracted with dichloromethane (3×60 mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (60 mg, 32%). LCMS for C21H23ClF2N3O (M+H)+: m/z=406.1. Found: 406.1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[Cl-].[Li+].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30](S(C(F)(F)F)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>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.CCOC(C)=O.C(Cl)Cl.COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH3:7])[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(S(=O)(=O)C(F)(F)F)CC1
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: [Cl-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A three necked flask purged with nitrogen is charged with aqueous 2N Na2CO3 (1.4 mL), 1,2-dimethoxyethane (3.7 mL), 2-methoxyphenyl boronic acid (206 mg, 1.35 mmol), anhydrous lithium chloride (123 mg, 2.9 mmol), 4-trifluoromethanesulfonyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (321 mg, 0.96 mmol) and tetrakis(triphenylphosphine)palladium (56 mg, 0.048 mmol). The mixture is stirred at reflux for 2 h under nitrogen, cooled and concentrated under reduced pressure. The residue is partitioned between CH2Cl2 (10 mL), aqueous 2N Na2CO3 (10 mL), and concentrated NH4OH (1 mL). The aqueous layer is extracted twice with CH2Cl2. The combined organic layers are dried (MgSO4), filtered and concentrated to provide a crude oil. Flash chromatography (Hex/AcOEt/CH2Cl2: 5/1/1) provides the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[N:28]=1>C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:29](=[O:36])(=[O:37])[N:28]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCOn1cc(CN2CCCCC2)cn1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NCCCCOn2cc(CN3CCCCC3)cn2)c2ccccc21
Reaction time: 3 h
Yield: 29.4 %

Procedure:
3.5 g of 4-(4-piperidinomethylpyrazol-1-yloxy)butylamine and 1.4 g of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 2.8 g of 3-chlorobenzoisothiazole 1,1-dioxide in 15 ml of methylene chloride is then added dropwise. After standing for 3 hours at room temperature, the reaction mixture is washed with water, the organic phase is evaporated down and the residue is chromatographed over neutral Al2O3 (activity level III), using methylene chloride as the mobile phase. 1.7 g of the title compound are obtained, the product being crystallized from ether.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>CC(N(C)C)=O.CO>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Cc1ccc(Oc2ccc(Br)cc2)cn1

Procedure:
2.84 g of a potassium salt of 5-hydroxy-2-methylpyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous oxide were suspended in 10 ml of dimethylacetamide, and the mixture was allowed to react in a nitrogen gas stream at 150° C. for 15 hours. The reaction mixture was diluted with 30 ml of methanol and then filtered. The filtrate was immediately dried, and the residue was taken into 100 ml of chloroform and washed successively with a 3% aqueous sodium carbonate solution and 50 ml of water. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 2.1 g of oily 5-(p-bromophenoxy)-2-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)cc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-morpholinobenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 570.1 [M]+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([O:12]CC)=[O:11])[S:7][CH:8]=1>>[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[S:7][CH:8]=1
Reactant: CCOC(=O)Cc1cc(Br)cs1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc(Br)cs1
Reaction time: 5 h
Yield: 96.5 %

Procedure:
12 ml of 10% aqueous sodium hydroxide solution was added to the 4.94 g (19.8 mmol) of ethyl 4-bromo-2-thiopheneacetate and stirring carried out for 5 hours at 90° C. The reaction liquid was then cooled and extracted with ether. The aqueous layer was neutralized with hydrochloric acid, extracted with ether, then dried and concentrated. 4.24 g (19.1 mmol, 96%) of 4-bromo-2-thiopheneacetic acid was obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8].[OH-].[Na+]>CO>[CH2:12]([S:11][CH:4]([C:3]([OH:16])=[O:2])[NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSC(NC(=O)C(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCSC(NC(=O)C(C)C)C(=O)O
Yield: 60 %

Procedure:
To a solution of Compound (25) (7.7 g; 30 mmol) in methanol (70 ml), 1N sodium hydroxide solution (33 ml; 33mmol)) was added under cooling, and the resultant mixture was stirred at the same temperature for 1 hour and at room temperature for 4 hours, followed by concentration. The residue was washed with ether. The aqueous layer was adjusted to pH 3 with citric acid under cooling and saturated with sodium chloride, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give Compound (26) as an oil (4.2 g; yield, 59%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([NH2:33])=[CH:31][C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[C:32]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[F:19])[C:3]=3[CH3:20])=[CH:31][C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][N:28]=2)[CH2:23][CH2:22][O:21][CH2:26][CH2:25]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (100 mg, 0.34 mmol), 2,5-dimorpholinopyridin-3-amine (91 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.017 mL, 0.069 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm δ ppm 7.85 (1H, br. s.), 7.81 (1H, dd, J=9.9, 2.6 Hz), 7.58-7.65 (2H, m), 7.44-7.51 (1H, m), 7.30-7.37 (2H, m), 7.20 (1H, t, J=9.2 Hz), 6.85 (1H, br. s.), 6.27 (1H, br. s.), 3.94 (4H, t, J=4.6 Hz), 3.71-3.80 (4H, m), 3.22 (4H, br. s.), 2.98 (4H, br. s.), 2.18 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:17]([N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1F)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1F)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A mixture of diethyl trans-4-fluoropiperidin-3-ylphosphoramidate (0.35 g, 1.38 mmol), benzaldehyde (0.21 mL, 2.07 mmol) and acetic acid (0.16 mL, 2.75 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.13 g, 2.07 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-fluoropiperidin-3-ylphosphoramidate (0.47 g, 99%), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1

Procedure:
76 mg of solid yellow 3-[4-(3-p-tolylureido)phenyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and p-tolyl isocyanate.
Reaction SMILES: O.[NH:2]([CH2:7][C:8]([O-:10])=[O:9])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])CNCC(=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Disodium iminodiacetate monohydrate (11.7 g, 0.060 m) was dissolved in water (40 ml) and cooled to 0°. Benzyl chloroformate (13.3 g, 0.078 m) was added in portions as the pH of the solution was kept at 9-12 by addition of 2N sodium hydroxide solution as needed. When addition was complete the mixture was stirred an additional 3 hours at 0°-10° C., then extracted with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 13.0 g (81%) of N-benzyloxycarbonyliminodiacetic acid (V-C).
Reaction SMILES: [OH:1][C@:2]([C@H:9]1[CH2:13][N:12]([C@H](C2C=CC(OC)=CC=2)C)[C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]>C(O)(C(F)(F)F)=O.CC(O)C>[OH:1][C@:2]([C@H:9]1[CH2:13][NH:12][C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@@](C)(O)c3nccs3)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C[C@](O)(c1nccs1)[C@H]1CNC(=O)C1
Temperature: 25 °C

Procedure:
A solution of (4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL), and stirred until the color dissipated. The reaction mixture was then absorbed on silica gel and purified by silica gel chromatography to afford (4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one. MS ESI calc'd. for C9H13N2O2S [M+H]+ 213. found 213. 1H NMR (600 MHz, DMSO-d6) δ 7.69 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 6.12 (s, 1H), 3.08 (dd, J=9.1, 7.3 Hz, 1H), 2.96-2.86 (m, 1H), 2.82 (t, J=9.0 Hz, 1H), 2.22 (dd, J=16.8, 8.7 Hz, 1H), 2.14 (dd, J=16.8, 9.6 Hz, 1H), 1.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27]O)=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[N:22]=2)[CH2:20][CH2:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:27][C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=3)=[CH:24][C:25]=2[C:29]([F:30])([F:32])[F:31])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Ic1cc(I)ncn1
Reactant: Nc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(Nc2ccc3cccnc3c2)ncn1

Procedure:
This compound could be prepared from 4,6-diiodo-pyrimidine and 7-aminoquinoline in the presence of K2CO3 and DMF.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl-].[F:11][C:12]([F:40])([F:39])[C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:39])[F:40])=[CH:38][CH:37]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(C=Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
8.9 g of (72 mmol) of 4-fluorobenzaldehyde and 32 g (72 mmol) of (4-trifluromethylbenzyl)triphenylphosphonium chloride were dissolved in 300 ml of methylene chloride. While vigorously stirring the solution, 280 ml (0.84 mol) of 3N sodium hydroxide was dropwise added at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was subjected to liquid separation. The organic layer was washed twice with water and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: n-hexane) to obtain 12.4 g of 4-fluoro-4'-trifluoromethylstilbene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:33])[CH2:18][N:19]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:14]([O:16][C:17](=[O:33])[C@H:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[N:19]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:15]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N=C(c1ccccc1)c1ccccc1

Procedure:
5-(4-bromomethylphenyl)-isoxazole (700 mg) and N-diphenylmethylene-glycine ethyl ester (890 mg) are dissolved in dichloromethane (20 ml) and stirred vigorously with a solution of tetrabutylammonium hydrogensulfate in 2.5 molar aqueous sodium hydroxide, at room temperature, over night. The organic layer is then separated off and concentrated. The residue is partitioned between ether and water, the etherphase washed with water and brine, dried over magnesium sulfate and evaporated to give crude N-diphenylmethylene-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester, which is used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].ClC1N=C(C[O:19][C:20](=[O:22])[CH3:21])C=CC=1>>[C:20]([O:22][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:19])[CH3:21]
Reactant: CC(=O)OCc1cccc(Cl)n1
Reactant: COc1cc[n+]([O-])c(C)c1
Product: COc1ccnc(COC(C)=O)c1

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H--NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:26])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH2:19]([C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:26])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1c(Cc2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n2c(c1Cc1ccccc1)SCCC2
Reaction time: 0.5 h

Procedure:
To a solution of 9.11 g (25 mmol) of 7,9-dibenzyl-3,4-dihydro-2H,6H-pyrimido-[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 4.88 g (71.1%, light white crystal) of the desired product.