Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[CH:15]=[C:16]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:17]=[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:35]([O:37][CH3:38])=[O:36])[NH:4][C:3]1=[O:39].C(N(CC)CC)C.[Cl:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Si:28]([O:27][C:16]1[CH:17]=[C:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[C:9]2[CH2:8][S:7][CH2:6][C@@H:5]([C:35]([O:37][CH3:38])=[O:36])[NH:4][C:3](=[O:39])[C@@H:2]([NH:1][C:49](=[O:50])[CH2:48][Cl:47])[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH:15]=1)([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](N)C(=O)N1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](NC(=O)CCl)C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 1.30 g of methyl (4R, 7S)-7-amino-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4 -carboxylate and 0.23 g of triethylamine in 50 ml of methylene chloride, was added at 0° C. within 2 minutes a solution of 0.25 g of chloro-acetyl chloride in 3 ml of methylene chloride. The mixture was stirred at 0° C. for 30 minutes, then diluted with methylene chloride and washed successively with 0.03N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 1.20 g of methyl (4R, 7S)-12,14-bis (tert-butyldimethylsilyloxy)-7-(2-chloroacetamido)-1,3,4,5,6,7,8,10-octahydro-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate as a white solid. A sample of 287 mg of this material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate, 115 mg of methyl (4R, 7S)-7-(2chloroacetamido)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4 -carboxylate as a white solid, m.p. 182° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].[OH:11]C1C=CC=C(O)C=1C#N.P(S)(OCC)(OCC)=S>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:11])[C:3]=1[C:8](=[S:10])[NH2:9]
Reactant: N#Cc1c(O)cccc1O
Reactant: NC(=S)c1ccccc1O
Agent: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)c1c(O)cccc1O
Yield: 43 %

Procedure:
The procedure used for the preparation of 3a was repeated with 2,6-dihydroxybenzonitrile (8.75 g, 64.8 mmol), (EtO)2P(S)SH (32.6 mL, 194 mmol) and water (26 mL) at 60° C. for 36 hr to give 3b (4.76 g, 43%) as a light yellow solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-5%) and crystallization from EtOAc/hexane. mp 180° C. (dec); IR (KBr) 3411, 3295, 3177, 2380, 1612, 1577, 1464, 1267, 1010 cm-1 ; 1H NMR (DMSO-d6) δ 6.31 (2H, d, J=8.1 Hz, Ar), 7.00 (1H, t, J=8.1Hz, Ar), 9.60 (1H, br s, NH), 9.96 (1H, br s, NH), 10.93 (2H, s, OH); FABMS m/z 169 (M+), 170 (M+ +1); Anal. Calcd for C7H7NO2S: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.89; H, 403; N, 8.36.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].CO.C([O-])=O.[NH4+].[BH3-]C#[N:22].[Na+]>Cl.C(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH2:1][CH2:2][NH2:22])[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: [BH3-]C#N
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(CCN)C(=O)OC
Yield: 59.8 %

Procedure:
Dimethyl acetylsuccinate (10 g, 53 mmol) was added to methanol (200 ml) followed by ammonium formate (34 g, 530 mmol) and NaBH3CN (3.4 g, 53 mmol) at 25° C. After 24 h the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride, dried over Na2SO4, and evaporated to give dimethyl-2-(aminoethyl)succinate (6 g) . 1H NMR (d6-DMSO) δ 0.97 (d, 3H, J=7.1 Hz), 2.66 (m, 2H), 3.05 (m, 1H), 3.56 (s, 3H), 3.60 (s, 3H), 4.15 (m, 1H); MS (FAB) m/z 190.2 (MH+), 158.2, 141.2.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:31])[CH:27]=3)[N:22]=1)[CH2:17][CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:31][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:27]=3)[N:22]=1)[CH2:17][CH2:16][CH2:15]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoyl chloride and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=427.3 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH:10]([OH:12])[CH2:9][C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OC)=O.[NH2:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](=[O:39])[C:31]([C:36]([OH:38])=[O:37])=[CH:32][NH:33]2)=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[C:1]([N:4]1[CH2:11][CH:10]([OH:12])[CH2:9][CH:5]1[C:6]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](=[O:39])[C:31]([C:36]([OH:38])=[O:37])=[CH:32][NH:33]2)=[CH:28][CH:27]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(O)CC1C(=O)Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A mixture of 6.41 g (37 mmol) of N-acetyl-4-hydroxy-L-proline, 4.07 ml (37 mmol) of N-methyl morpholine, 2.87 ml (37 mmol) of methyl chloroformate, and 90 ml of dichloromethane is stirred at -10° to -20° for 30 minutes. A mixture of 4.08 g (20 mmol) of 7-amino-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 100 ml of dichloromethane is stirred at room temperature for 30 minutes and then is cooled to -30°. The cold mixed anhydride is added to the cold silylated quinoline and is stirred with cooling for 4 hours and overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is treated with water and 1 N hydrochloric acid. The solid is filtered to give 5.30 g of 7-[[(1-acetyl-4-hydroxy-2-pyrrolidinyl)carbonyl]amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])=O.C(OCCOCCO)C.CO.C[O-].[Na+]>COCCOCCOC.CCCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])=[O:15])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: COC(=O)c1c(C)c(C)nn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: COCCOCCOC
Solvent: CCOCCOCCO
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 95.2 %

Procedure:
In a 10 L-reaction flask equipped with a rectification column and a separating tank, 314 g (1.81 mol) of 4-tert-butylphenylacetonitrile, 274 g (1.65 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid methyl ester, 3000 g of heptane, 225 g of diethylene-glycol dimethyl ether, and 99 g of diethylene glycol monoethyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 381 g (1.98 mol) of 28% sodium methoxide methanol solution was added dropwise over 13 hours, and the resulting mixture was further reacted for 10 hours. During this reaction, it is continued to remove alcohol separated in the phase under the heptane phase in the separating tank. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was further washed with 600 g of heptane to separate out heptane phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 486 g (yield 95.5%) of 2-(4-tert-butylphenyl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. To the aqueous phase, 206 g (1.98 mol) of 35% hydrochloric acid was gradually added dropwise to be neutralized. After stirring for 1 hour, separated crystal was filtered, washed with 300 g of water, and then dried to obtain 475 g (yield 93.4%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:43]NC1CCCC1>CS(C)=O.C1COCC1>[CH:1]1([N:6]([CH3:43])[C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNC1CCCC1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1)C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.033 mmol), prepared as described in Procedure 3, 4, 5, 6 and 2, in DMSO/THF (0.1 mL/0.1 mL) was added N-methylcyclopentanamine (32 mg, 0.33 mmol). The resulting solution was stirred at 120° C. under microwave irradiation for 1800 sec. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was then washed with H2O, sat. NaCl and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylurea (Example 246) as white lyophillate (13 mg, 65% yield). LCMS: [M+H] 619.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3].S(=O)(=O)(O)[OH:13]>>[O:13]=[CH:10][C@H:8]([C@@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:11])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: O=S(=O)(O)O
Reactant: O[C@H]1[C@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
0.16 g (1.00 mmol) of the compound (3) was dissolved in 5 ml of 1N sulfuric acid, and the resultant solution was kept stirred for 5 hours at 100° C. The reaction mixture was passed through an anion exchange resin (hydroxyl ion type amberlight IRA-410) for neutralizing purposes, followed by removing the solvent by means of distillation under reduced pressure. Formation of the desired compound of the present invention, i.e., D-altrose (compound 4), was confirmed by thin layer chromatography. It was also confirmed that the raw material compound (3) was mixed with the product compound (4). The mixing ratio of these compounds (3) and (4) was about 1:1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[O:7]1[CH2:8][CH2:9][O:10][C:5]2[CH:4]=[C:3]([CH2:2][C:13]#[N:14])[CH:12]=[CH:11][C:6]1=2
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)OCCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at 25° C. for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL×4). The combined organic layers were washed with water (50 mL×2), brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50:1) to yield 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile as a yellow oil (10.2 g, 86%). 1H-NMR (300 MHz, CDCl3) δ 6.78-6.86 (m, 3H), 4.25 (s, 4H), 3.63 (s, 2H).
Reaction SMILES: O1CCOCC1.I[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10](C(OC(C)(C)C)=O)[C:9]=1[CH3:24].[CH:25]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[C:29]=2[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH3:24][C:9]1[NH:10][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]=1[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[CH:28]=[CH:27][N:26]=[CH:25]2
Reactant: Cc1c(I)c2cccnc2n1C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc2cnccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1[nH]c2ncccc2c1-c1cccc2cnccc12
Temperature: 100 °C
Reaction time: 26 h

Procedure:
5 ml of dioxane and 0.5 ml of water are added to a mixture, kept under argon, of 179 g (0.5 mmol) of tert-butyl 3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 87 mg (0.5 mmol) of isoquinoline-5-boronic acid, 159 mg (1.5 mmol) of sodium carbonate and 57 mg (0.05 mmol) of [1,1′bis(diphenylphosphino)ferrocene]palladium(II) dichloride/dichloromethane adduct. The mixture is stirred at 100° C. in a sealed vessel for 26 hours. The reaction mixture is cooled to room temperature, evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline as colourless solid.
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[C:5](=[O:22])[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH-:26].[Na+]>C1(C)C=CC=CC=1>[OH:26][C:19]1[CH:20]=[CH:21][C:16]([CH3:7])=[CH:17][C:18]=1[CH:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH:23]([CH3:24])[CH3:25])=[O:22]
Reactant: [OH-]
Reactant: Cc1ccc(OC(CC(=O)N(C(C)C)C(C)C)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A three-necked round-bottom flask equipped with condenser, mechanical stirrer, thermometer, is loaded with N,N-diisopropyl-3-phenyl-3-p-tolyloxy-propionamide (1.0 g; 0.0029 mol) and polyphosphoric acid (16.5 g). After four hours under stirring at room temperature the reaction is completed. The reaction mixture is poured in ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30 minutes, then diluted with toluene (30 ml). The phases are separated and the aqueous phase is extracted with toluene (2×30 ml). The combined organic phases are dried over sodium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography (hexane/ethyl acetate 7:3). 0.59 g of product, as a pale yellow oil, are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[CH2:15][C:14](=[O:16])[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:20][CH:21](OCC)OCC)(=O)[CH3:18]>>[CH2:17]([O:20][CH:21]=[C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:13][C:14]1=[O:16])[CH3:18]
Reactant: O=C1Cc2cc(-c3ccccc3)cnc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2ncc(-c3ccccc3)cc21

Procedure:
This compound was synthesized from 5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 10.93 (s, 1H); 8.24 (s, 1H); 7.86–7.82 (m, 2H); 7.62–7.56 (m, 2H); 7.44 (m, 2H); 7.34 (m, 1H); 4.40 (m, 2H); 1.35 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:27]1([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[N:4]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(=Nc1ccccc1)n1nnc2ccccc21
Yield: 58.1 %

Procedure:
A solution of 4-Oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.153 g, 0.426 mmol), 1H-benzo[d][1,2,3]triazole (0.201 g, 1.69 mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in methylene chloride (2 mL) was heated under microwave heating conditions at 80 watts of power for 10 min. After that time, the reaction was concentrated and the crude product purified by flash column chromatography (silica gel, hexanes to ethyl acetate) to give 0.114 g (58%) of 3-[1H-benzotriazol-1-yl(phenylimino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale red solid that was used without further characterization.
Reaction SMILES: C([C:3]1[N:41]=[C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1)#C.[CH3:42][O-:43].[Na+]>CO.O.ClCCl>[CH3:42][O:43][C:3]1[N:41]=[C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1
Reactant: C[O-]
Reactant: C#Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 55 °C

Procedure:
To 110 mg 2-bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described under example 53) in 5 ml methanol are added 1.11 ml of a sodium methoxide solution (25% in methanol). The reaction mixture is heated to 55° C. for 3.5 hours and diluted with water and dichloromethane. The phases are separated and the water layer is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvent are removed by evaporation. The residue is purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3cccc(Cl)c3)nc2n1
Temperature: 120 °C
Yield: 75.9 %

Procedure:
2-Amino-7-chloro-1,8-naphthyridine (17.95 g) is added to a mixture, preheated to 60° C., of 3-chlorophenol (51.4 g) and potassium hydroxide pellets (85% pure; 13.2 g). The reaction mixture is heated to 120° C. for 3 hours. The product is separated by filtration, washed with water to a pH of approximately 7 and then dried in the air. 2-Amino-7-(3-chlorophenoxy)-1,8-naphthyridine (20.6 g), m.p. 166° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[N:12]=1.ClC1C=CC=C(C(OO)=[O:57])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:42]=1)[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:17])(=[O:57])=[O:16])[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfinyl-ethyl)-2H-tetrazol-5-yl]-amine (129 mg) is dissolved in chloroform (2 ml), and thereto is added m-chloroperbenzoic acid (50 mg) and the mixture is stirred at room temperature overnight. To the reaction solution is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfonyl-ethyl)-2H-tetrazol-5-yl]-amine (81 mg). MS (m/z): 724 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:32])[CH:14]([N:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[C:29]#[N:30])=[CH:18][C:17]2=[O:31])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:32])[CH:14]([N:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[C:29]#[N:30])=[CH:18][C:17]2=[O:31])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)Nc1ccc(C(=O)O)c(Cl)c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (purity 94%, 0.20 mmol) of methyl 2-chloro-4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 2.5A) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 8 mg (purity 93%, 10% of theory)