Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:1][N:2]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:28]([C:26]2[N:27]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:24][C:25]=2[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)CCN(C)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 7.6 %

Procedure:
Methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine (110 mg, 0.49 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (138 mg, 0.54 mmol), Et3N (352 uL, 2.5 mmol) and BOP (227 mg. 0.514 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl}-amide as a light purple solid (16 mg). ES-MS calcd for C22H23F3N4O2 (m/e) 432.51, obsd 433.2 M+H).
Reaction SMILES: N[C@H](C(O)=O)CCCCN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C[O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29].CN1CCOCC1>CN(C=O)C>[NH2:29][C@H:28]([C:27]([OH:34])=[O:26])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: NCCCC[C@H](N)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29 %

Procedure:
L-Lysine, N-e-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl)-butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-, (0.46 g. 6.46 mmol), HOBT (0.089 g, 6.78 mmol), and EDC (0.13 g, 6.78 mmol) were dissolved in 15 mL of DMF. The solution was stirred for 40 minutes at room temperature. L-Leucine methyl ester (0.13 g, 7.11 mmol) was dissolved in 5 mL of DMF containing N-methylmopholine (0.20g, 1.94 mol) and then added to this solution. The reaction mixture was stirred overnight at room temperature, and the DMF was removed in vacuo. The concentrated residue was brought up in 150 mL of dichloromethane, and the organic phase was washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered and concentrated. The concentrated residue was purified by silica gel flash column chromatography eluting with 5% methanol in methylene chloride to give 0.27g (49.8%) of L-leucine, N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-N-ε-(carbobenzoxy)-L-lysyl]-, methyl ester as a white solid. FAB-MS m/z=839 (M+H). HRMS: calcd for C47H63N6O8 (M+H) 839.4707, found: 839.4706.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]I>[I:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(I)ccn1
Reactant: N#Cc1ccccc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Ic1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 61 %

Procedure:
A mixture of 2-amino-4-iodopyridine (2.60 g, 11.8 mmol), copper (I) iodide (115 mg, 0.60 mmol), 1,10-phenanthroline monohydrate (120 mg, 0.60 mmol) and benzonitrile (33 mL) was heated in a 100 mL 4-necked flask to 130° C. During 23 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 7-iodo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (2.31 g, 61%) as a green solid with 100% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[C@H:10](N)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C1C=C(OC)C(OC)=C(OC)C=1)=C=[O:30].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:30])[C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCC(Cc3ccc(Cl)cc3)CC2)C1

Procedure:
Following General Procedure C, (±)-trans-3-amino-4-[4-(4-chlorobenzyl)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (394 mg, ˜0.9 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene (250 mg, 1.2 mmol) were coupled in CH2Cl2 (6.0 mL) at 0° C. for 1 h. Chromatography of the crude product with 1:1 hexanes:EtOAc to 100% EtOAc gave the product (445 mg, 77% from (±)-trans-3-[4-(4-chlorobenzyl)piperidin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester) as a white solid: mp 99.0-102.5° C.; IR 3371 (br), 2932, 1655, 1607, 1552, 1507 cm−1; 1H NMR δ 1.17-1.80 (m, 14H), 2.18 (m, 2H), 2.48 (d, J=7.0 Hz, 2H), 2.95-3.51 (m, 8H), 3.81 (m, 9H), 4.32 (br, 1H), 5.30 (br, 1H), 6.61 (s, 2H), 7.02 (m, 2H), 7.20 (m, 2H); MS m/z 603.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ncccn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ncccn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
1.0 g of 2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile was dissolved in 100 ml of ethanol, added to 10% palladium-on-charcoal and shaken under an atmosphere of hydrogen at room temperature. After 2 hours the catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:1) for the elution. The product was recrystallized from cyclohexane to give 0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile of melting point 109°-111° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])[S:10][CH:11]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of n-butyl lithium (2.71 M hexane solution, 3.9 ml) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise a solution of 4-methylthiazole (1.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for one hour and thereto was added dropwise a solution of tri-n-butyltin chloride (3.6 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for 30 minutes, warmed, and further stirred at room temperature overnight. Thereto was added water, and the mixture was extracted with diethyl ether. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (hexane) to give the title compound (1.76 g) as oil. APCI-Mass m/z 386/388 (M+H)
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:17][C:18]4[N:19]=[C:20]([C:24]([O:26]CC)=[O:25])[N:21]([CH3:23])[CH:22]=4)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:29])[NH:4][CH2:3]1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:30])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:17][C:18]4[N:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=4)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:29])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1nc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)nc1C(=O)O
Temperature: 60 °C
Yield: 70.6 %

Procedure:
A suspension of ethyl 4-{[(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)carbonyl]amino}-1-methyl-1H-imidazole-2-carboxylate (540 mg, 1.3 mmol) in 3N NaOH solution (2.2 mL, 6.6 mmol) and methanol (5 mL) is heated at 60° C. for 2 h. The mixture is acidified with 2N HCl solution until the pH is about 2. The solution is allowed to cool with stifling. After 2 h the resulting solid is collected by filtration, washed with water and dried to afford the title compound (350 mg, 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5](=[O:24])[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:9][CH:8]=2.O.Cl>CO>[CH3:3][C:4]1[C:5](=[O:24])[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCCCOc1ccc2[nH]c(=O)c(C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Reaction time: 8 h
Yield: 96.6 %

Procedure:
2N-NaOH solution 29.6 ml was added to the compound 1036 (8.99 g, 29.6 mM) suspended in methanol 29.6 ml and the mixture was stirred overnight. Water 88.8 ml was added to the reaction mixture, and the mixture was adjusted to pH 2 by adding 6N-HCl. Precipitated crystals were collected by filtration, washed completely with water and dried to obtain the compound 1037.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]([CH2:14][CH3:15])=[N:12][CH:13]=2)=[C:6]([NH:28][C@H:29]([C:31]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:43])[C:34]3=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]3[N:32]=2)[CH3:30])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[C:11]([CH2:14][CH3:15])=[N:12][CH:13]=2)=[C:6]([NH:28][C@H:29]([C:31]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:43])[C:34]3=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]3[N:32]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: CCc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 22 %

Procedure:
(S)—N-(5-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-2-ethylpyridin-3-yl)-4-methoxybenzenesulfonamide (146 mg, 0.22 mmol) was treated with boron tribromide (1M in dichloromethane, 700 μl, 0.70 mmol) in dichloromethane (1 ml) as a solvent according to the method described in Example 23. The residue was purified by reverse phase chromatography using SP1® Purification System to give 31 mg (22% yield) as a solid. Purity 100%.
Reaction SMILES: [CH3:1][O:2][C:3]([O:17][CH3:18])([C:13]([F:16])([F:15])[F:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27]Br>>[CH3:18][O:17][C:3]([O:2][CH3:1])([C:13]([F:15])([F:16])[F:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:26][Br:25])=[CH:8][CH:7]=1
Reactant: COC(CCc1ccc(O)cc1)(OC)C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(CCc1ccc(OCCBr)cc1)(OC)C(F)(F)F
Temperature: 130 °C
Yield: 86.9 %

Procedure:
A mixture of 4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenol (1.64 g, 6.2 mmol), potassium carbonate (1.3 g, 9.3 mmol) and 1,2-dibromoethane (5 ml, 58 mmol) was stirred and heated under reflux (130° C.) for 26 h. After cooling to room temperature, the mixture was filtered and washed with ethyl actate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate 20:1 to 4:1) to give the title compound (2.0 g, 85%) as a colorless liquid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:34]=[CH:35]/[C:36]([OH:38])=O)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.Cl.[NH2:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)=[O:43]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:34]=[CH:35]/[C:36]([NH:40][CH2:41][C:42]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[O:43])=[O:38])[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: COc1ccc(C(=O)CN)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CNC(=O)/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)cc1

Procedure:
EDC (223 mg), HOBT (157 mg) and IPEA (0.337 mL) were sequentially added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (100 mg) and 2-amino-1-(4-methoxyphenyl)ethanone hydrochloride (CAS No. 3883-94-1, 117 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 104.7 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:32][S:29]([N:26]1[CH2:25][CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH3:15])=[CH:18][CH:19]=2)[CH2:28][CH2:27]1)(=[O:30])=[O:31]
Reactant: CC(Oc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 4-{1-[4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (1.16 g, 2.50 mmol) in dichloromethane (25 mL) is added trifluoroacetic acid (1.32 mL, 17.48 mmol). The reaction is stirred at room temperature for 18 h. The mixture is concentrated in vacuo and diluted with 3 mL of ethyl acetate. 2 M aqueous sodium hydroxide is added to produce a white solid. The solid is filtered and dried to afford 0.86 g of the title compound. MS (m/z) 365 (M+1). The title compound (0.320 g, 0.88 mmol) is separated into its enantiomers using an eluent of 0.2% dimethylethylamine in 2:3 acetonitrile:methanol on a 4.6×150 mm Chiralcel AD-H column at 1 mL/min to afford 0.115 g of isomer 1 (100% ee, RT=5.27 min) MS (m/z) 365 (M+1) and 0.112 g of isomer 2 (100% ee, RT=8.59 min). MS (m/z) 365 (M+1).
Reaction SMILES: C[C:2]1(C)[CH2:10][C:9]2[NH:8][C:7]([CH:11]=[O:12])=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.C1(=O)CCCC(=O)C1.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.Cl.C(=O)([O-])[O-].[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>O>[O:13]=[C:4]1[CH2:3][CH2:2][CH2:10][C:9]2[NH:8][C:7]([CH:11]=[O:12])=[CH:6][C:5]1=2
Reactant: CC1(C)CC(=O)c2cc(C=O)[nH]c2C1
Agent: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])O
Solvent: O
Product: O=Cc1cc2c([nH]1)CCCC2=O
Reaction time: 0.33 h

Procedure:
By using a procedure analogous to preparation of 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxaldehyde, 1,3-cyclohexane dione 4.55 g (39.36 mmol) was condensed with D-glucosamine.HCl 6.84 g (31.72 mmol) in water 40 mL in the presence of sodium carbonate 1.683 g, at ambient temperature for 11 days. (The polyol intermediate did not crystallize). The reaction mixture was extracted twice with chloroform (2×100 mL) and the aqueous phase was retained. The organic phases were back-extracted with water 150 mL. The combined aqueous phases were cooled in a 1 L flask on ice, solid sodium periodate 35.0 g (160 mmol) was gradually added over 10 minutes and the reaction was continued for additional 20 minutes on ice. The mixture was them made basic by gradual addition of saturated sodium bicarbonate solution 80 mL (foaming) and the stirring was continued for 30 minutes. The reaction mixture was filtered, the solids were washed with chloroform 0.5 L. The biphasic filtrates were shaken and separated, the aqueous phase was re-extracted with additional chloroform 0.5 L. The combined organic extracts were dried (MgSO4) and evaporated. The obtained crystalline residue was suspended in benzene (10 mL), collected by filtration, washed with benzene and dried. Y=534 mg (10% overall) of a pale yellow solid. 1H-NMR (d6-DMSO, 400 MHz): 12.50 (br s, 1H), 9.51 (s, 1H), 7.23 (d, 2.0 Hz, 1H), 2.81 (t, 6.3 Hz, 2H), 2.39 (dd, 6.8 Hz, 5.8 Hz, 2H), 2.03 (quint, 6.2 Hz, 2H)
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24](O)=[O:25])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:25])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCO
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Product: O=C(NCCCO)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 496) and 3-amino-propan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2].[OH-:25].[Na+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:25])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 37 %

Procedure:
A mixture of 70 mg of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 800 mg of sodium hydroxide, 5 ml of water and 5 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with 10% hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining 26 mg (yield: 37%) of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo-[b,f]thiepin-2-yl)-propionic acid as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]([OH:9])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:9])[C:6]([O:8][CH3:19])=[O:7])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(O)c(O)c1

Procedure:
3,4-Dihydroxymandelic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,4-dihydroxyphenyl)-2-hydroxyacetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][P:11]([O-:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]([C:24]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[C:28]([CH:35]([CH3:37])[CH3:36])[C:25]=1[CH2:26]Br)([CH3:23])[CH3:22].P([O-])([O-])[O-]>O1CCCC1>[CH2:13]([O:12][P:11]([CH2:26][C:25]1[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:31][C:30]([CH:32]([CH3:34])[CH3:33])=[CH:29][C:28]=1[CH:35]([CH3:37])[CH3:36])(=[O:20])[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Agent: [O-]P([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CP(=O)(OCc2ccccc2)OCc2ccccc2)c(C(C)C)c1
Temperature: 25 °C

Procedure:
Sodium hydride (2.0 g, 50 mmol), was added in portions to dibenzylphosphite (13.0 g, 50 mmol) in tetrahydrofuran (250 mL) at room temperature. When no further reaction was apparent, added 2,4,6-triisopropylbenzyl bromide (14.47 g, 49 mmol) and stirred at room temperature. Stirred overnight at room temperature, added more phosphite anion (11.94 g phosphite, 1.30 g NaH), and stirred over 2 days at room temperature. The reaction mixture was concentrated, the residue was taken up in ethyl acetate, washed with 10% aqueous citric acid solution, brine, dried (magnesium sulfate), filtered, and concentrated to an oil. The oil was chromatographed on silica gel using 4:1 hexanes/ethyl acetate as eluant. The product was obtained as a solid in two portions, 17.47 g, (73%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:6]=1[NH2:7].[CH2:18]([N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=[C:21]1SC)[CH3:19].Cl>C(OCC)(=O)C.CN(C=O)C>[F:3][C:4]([F:16])([F:17])[C:5]1[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=[CH:8][C:6]=1[NH:7][C:21]1[N:20]([CH2:18][CH3:19])[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[N:22]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCn1c(SC)nc(C(F)(F)F)cc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Nc2ccc(C(F)(F)F)cc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Sodium hydride (60% in oil, 0.45 g, 11.4 mmol) was added to DMF (5 ml) solution of 2,4-bis(trifluoromethyl)aniline (2.00 g, 8.73 mmol), followed by stirring for 30 minutes. Then, 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (2.08 g, 8 .73 mmol) was added, followed by stirring at 60° C. for 2 hours. After completion of the reaction, 1 N hydrochloric acid (30 ml) and ethyl acetate (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with water (30 ml×2) and saturated brine (70 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=9:1˜7:3), white solid of 2-{2,4-bis(trifluoromethyl)phenyl}amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 33] was obtained.