Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)#[CH:18]>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 63.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynyltoluene (0.08 mL, 0.65 mmol) to provide 258 (85 mg, 64% yield) as a brown solid. LC-MS (M+H=311 obsd.=311).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11]C(=O)C(F)(F)F)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CC[C@H](NC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](N)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of (S)—N-(1-(4-bromophenyl)propyl)-2,2,2-trifluoroacetamide (45.24 g, 0.1464 mol) in methanol (317 mL) was added a solution of NaOH (188 mL, 13%) at 0° C. The mixture was stirred for 2 h. The mixture was concentrated and extracted with methylene chloride. The solvent was removed to give (S)-1-(4-bromophenyl)propan-1-amine (29.65 g, 95%). 1H NMR (CDCl3): 084 (t, 3H), 1.63 (m, 2H), 3.79 (m, 1H), 7.19 (m, 2H), 7.45 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].Cl.[H][H].[OH-].[Na+].S(=O)(=O)(O)O>CO.C(O)C>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)CC(=O)OC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCC[C@@H](O)CC(=O)O
Reaction time: 4 h

Procedure:
Typically, hydrogenation of β-ketoester XVI, e.g., methyl 3-oxotetradecanoate, is conducted in a conventional hydrogenation solvent including an alkyl alcohol, such as ethanol or preferably in methanol, at a reaction temperature of about 80° C. The concentration of the substrate (i.e., β-ketoester XVI) in hydrogenation reaction is generally at about 40 wt %, and the ratio of HCl to Ru(OAc)2((R)-MeOBIPHEP) in the hydrogenation catalyst is about 20:1. A typical ratio of methyl 3-oxotetradecanoate to the hydrogenation catalyst is about 50,000:1. To this reaction mixture, typically about 40 bar of technical grade hydrogen gas is added, and the reaction is allowed to proceed for about 4 hours (h). The resulting methyl (R)-3-hydroxy tetradecanoate is then saponified by diluting the crude hydrogenation solution in methanol and 28% aqueous sodium hydroxide solution at room temperature. The saponified product is then acidified with an acid, such as sulfuric acid, to isolate (R)-3-hydroxy tetradecanoic acid. In this manner, the β-hydroxy acid IIA, such as(R)-3-hydroxy tetradecanoic acid, can be produced in at least about 90% isolated yield from the corresponding β-ketoester XVI, more preferably in at least about 93% isolated yield and most preferably in at least about 95% isolated yield. The enantiomeric excess of the product is at least about 90%ee, preferably at least about 95%ee, and more preferably at least about 99%ee. The enantiomeric excess can be increased to at least about 95%ee after a single recrystallization, preferably at least about 99%ee, and most preferably at least about 99.5%ee.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCc3ccccc3)cc2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (D1) (1.06 g, 3 mmol) was dissolved in dichloromethane (15 ml) and treated with trifluoroacetic acid (15 ml). The solution was stirred at room temperature for 2 hours, concentrated in vacuo and then twice co-evaporating with dichloromethane. The residue was dissolved in methanol and applied to a SCX ion exchange column (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were reduced in vacuo and the residue purified by column chromatography, eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D2) (702 mg, 93%), MS (ES+) m/e 254 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14]COC=O>C(N(CC)CC)C>[Br:8][C:7]1[C:2]2[N:1]=[CH:14][NH:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CCOC=O
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Solvent: CCN(CC)CC
Product: O=S1(=O)NC=Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using ethylformiat and a catalytic amount of triethylamine). M.p. 289-292° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20]3[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Product: COc1cc(OC)nc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
6-Chloro-N-(4,6-dimethoxypyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4,6-dimethoxy-2-methylsulfonylpyrimidine in a similar manner as described above to give 8 mg (10% yield) of a pale yellow solid. 1H-NMR (CDCl3): δ 8.79 (s, 1H), 7.45 (s, 1H), 7.18 (dd, 1H), 7.08 (dd, 1H), 5.50 (s, 1H), 5.24 (m, 1H), 5.18 (m, 1H), 3.88 (2 s, 6H), 2.70 (m, 2H), 2.28 (m, 1H), 2.04-1.83 (m, 3H); MS m/z 359 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([Br:14])[C:3]=1[C:4]#[N:5].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)#[CH:16].CCN(C(C)C)C(C)C>>[Br:14][C:6]1[C:3]([C:4]#[N:5])=[C:2]([C:16]#[C:15][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=2)[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1
Reactant: C#Cc1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
step 2—A mixture of 92 (0.750 g, 1.90 mmol), Cu(I) (0.027 g, 0.09 mmol), Pd(II)(PPh3)2Cl2 (0.203 g, 0.19 mmol), 80 (0.748 g, 2.85 mmol) and DIPEA (5 mL mL) under an argon atmosphere was heated overnight at 80° C. The reaction was cooled to RT then concentrated. The crude residue was purified by SiO2 chromatography eluting with 40% EtOAc/hexanes to afford 0.293 g (24%) of N-[4-(3-bromo-5-tert-butyl-2-cyano-phenylethynyl)-phenyl]-methanesulfonamide (94) as a light brown solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].CCCCCO.C(O)CC.[CH3:23][N:24](C)C=O>O>[CH3:23][NH:24][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN(C)C=O
Solvent: O
Solvent: CCCO
Solvent: CCCCCO
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
20 g of polifungin and 6 g of glucose were dissolved in 100 ml of dimethyl formamide and then the procedure was carried out as in the Example V, but instead of n-amyl alcohol there was used n-propyl alcohol in the same quantity as n-amyl one. 16.0 g of N-methylglucamine salt of N-glycosyl polifungin, soluble in water, of biological activity of 2010 U/mg, E1 cm1% =558 at 304 nm were obtained. Original antibiotic: E1 cm1% =720 at 304 nm.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[N:12]1([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=2)[C:21]#[N:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:12]1([C:18]2[CH:19]=[C:20]([C:21]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:22]=3)[CH:23]=[CH:24][N:25]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccnc(N3CCOCC3)c2)sc2ccccc12
Yield: 24.6 %

Procedure:
Methyl thiosalicylate (0.49 g, 2.9 mmol) and 2-morpholinylisonicotinonitrile (0.38 g, 2.0 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.48 ml, 3.4 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol. The obtained crystals were recrystallized from ethyl acetate again to give the titled compound (0.16 g, 25%) as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:19])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([OH:20])=[N:6][CH:5]=1.[OH-].[Na+]>CO>[CH2:12]([NH:11][C:10]([C:8]1[C:7]([OH:20])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a suspension of 5-Benzylcarbamoyl-6-hydroxy-nicotinic acid methyl ester in methanol (20 ml) was added 5.2 ml (5.2 mmol) 1N NaOH. The mixture was heated to 50° C. and stirred overnight. Additional 1N NaOH was added (8.0 ml, 8.0 mmol). The mixture was heated to reflux for 6 hours. The mixture was allowed to cool and was stirred overnight. Methanol was removed by concentrating at reduced pressure. The resulting residue was dissolved in H2O and extracted with diethyl ether. The aqueous layer was acidified with 1M HCl and filtered. The solid product was washed with water and dried at reduced pressure overnight at 55° C. 1.2 g (85% yield). MS: m/z (APCI, AP+) 373.0 [M.]+. CHN Analysis: Calcd: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.41; H, 4.42; N, 9.98.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][N:18]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>CCOCC>[CH3:2][NH:3][C:4]1([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][N:18]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CNC1(c2ncnn2C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOCC
Product: CNC1(c2ncnn2C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
5% hydrochloric acid (330 ml) was added at room temperature to methyl-[8-(2-methyl-2H-[1,2,4]triazol-3-yl)-1,4-dioxaspiro[4.5]dec-8-yl]-amine (4.2 g, 16.646 mmole) and the mixture was stirred for 3 days at room temperature. Ether (120 ml) was added to the reaction mixture. The phases were separated. The aqueous phase was made alkaline with 5N NaOH and extracted with dichloromethane (4×50 ml). The organic phase was dried over sodium sulfate and concentrated by evaporation to dryness in vacuo. The product was obtained as a colourless crystalline solid in a yield of 83% (2.89 g, 13.862 mmole).
Reaction SMILES: [F:1][C:2]([F:17])([CH:14]([F:16])[F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22]([NH:24][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:17])([F:1])[CH:14]([F:16])[F:15])=[CH:6][CH:7]=1)[CH3:12])=[O:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)C(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)C(F)F)nc1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (6.0 g, pale brown oil) from 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (5.6 g, 22.2 mmol) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH:6]([N+:8]([O-:10])=[O:9])[CH3:7].[N:11]([O-:13])=[O:12].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C(Cl)Cl>[CH3:3][O:4][CH2:5][C:6]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[CH3:7]
Reactant: COCC(C)[N+](=O)[O-]
Reactant: O=N[O-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COCC(C)([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
A solution of 1.0 g (25 mmoles) of sodium hydroxide in 10 mL of water was treated with 2.0 g (16.8 mmoles) of 2-nitropropyl methyl ether. After 10 minutes, 10 mL of methylene chloride was added, followed by a solution of 5.0 g (72 mmoles) of sodium nitrite in 10 mL of water. Next, a solution of 1.0 g (3 mmoles) of potassium ferricyanide in 5 mL of water was added, followed by 4.4 g (18 mmoles) of solid sodium persulfate. A cold water bath was used to moderate exothermic reaction. After 30 minutes, the reaction mixture was extracted with two 15 mL portions of methylene chloride. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. The solution was distilled in a short-path distillation apparatus to give 2.43 g (88% yield) of 2,2-dinitropropyl methyl ether, a colorless liquid, b.p. 100° (16 mm). 'H NMR (CDCl3): & 2.18 (s. 3H, --CH3), 3.35 (s, 3H, --OCH3), 4.15 (s, 2H, --CH2O).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[S:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[S:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=S)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 84.0 mg (0.184 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)thiocarbonyl]amino]-benzoate (Compound 42) in 2.0 ml EtOH and 2.0 ml of THF was added 60.0 mg NaOH (1.50 mmol, 1.5 ml of a 1M aqueous solution). After stirring at room temperature overnight, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a yellow solid. 1H NMR (d6-acetone): δ 10.96 (1H, s), 8.05 (4H, m), 7.72 (1H, dd, J=2.0, 8.0 Hz), 7.54 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.20 (4H, m), 6.04 (1H, t, J=4.7 Hz), 2.38 (2H, d, J=4.7 Hz), 2.33 (3H, s), 1.35 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:12])[CH:4]=1.N1C=CC=CC=1.CC(C)=O.[C:23](Cl)(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH3:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:9]([O:10][CH3:11])=[CH:8][C:6]=1[NH:7][C:23](=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cc(C)c(N)cc1OC
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C)c(NC(=O)C=Cc2ccccc2)cc1OC
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
To a solution of 4,5-dimethoxy-2-methylaniline (40.1 g), pyridine (48.5 ml), and acetone (350 ml), cinnamoyl chloride (44.0 g) was added dropwise at room temperature over 15 minutes. After allowing to react at room temperature for 2 hours, water (15 ml) was added and the mixture was stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, followed by washing with 1N HCl, 1N caustic soda and water in this order, and drying. Chloroform was evaporated. Precipitated crystals were collected by filtration with ether. 69.8 g of the title compound was obtained as yellow crystals (97.8%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([O:19]CC)=[O:18])[N:6]=1)=[O:4].O.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=[O:18])[N:6]=1)=[O:4]
Reactant: CCOC(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.30 g ethyl [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetate from the Step D above in 20 mL MeOH and 2 mL water was added 0.50 mL of 5 N NaOH solution. After the solution was stirred at room temperature for 16 hours, the solvents were removed under reduced pressure. The residue was partitioned between cold water and EtOAc with 3 mL 1 N HCl. Separate the layers. Extract the aqueous layer with EtOAc (4×). The combined EtOAc extract was washed with saturated brine (2×), dried over anhydrous Na2SO4, and evaporated to give the title compound as yellowish solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=8.9 Hz, 1H), 7.00 (dd, =2.1 & 8.9 Hz, 1H), 6.68 (d, =2.1 Hz, 1H), 5.21 (s, 2H), 3.90 (s, 3H), 1.50 (s, 9H). LC-MS: 3.40 min. (m/Z=245.1, 291.1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH2:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([NH:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])=[O:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(=O)O)c(O)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Reaction time: 1.5 h
Yield: 51.9 %

Procedure:
To a suspension of 2-amino-4-hydroxypyrimidine-5-carboxylic acid (311 mg), (2,4-dichlorophenyl)methanamine (353 mg), and triethylamine (2.8 mL) in N,N-dimethylformamide (8 mL), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (839 mg) was added at room temperature, and the mixture was stirred for 90 minutes. 2,4-Dichlorobenzylamine (353 mg) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (839 mg) were added thereto, and the mixture was stirred for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 1 hour and then filtered. The product collected by filtration was washed with water, dried under reduced pressure, and then suspended in ethyl acetate. This suspension was shaken for 1 hour in an ultrasonic bath and then filtered. The obtained product collected by filtration was dried under reduced pressure to obtain the title compound (326 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 3 product (i.e., N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in absolute ethanol (100 ml), acetic acid (1.25 mole eq.) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40° C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2×200 ml). The toluene was then completely recovered under vacuum at 50° C. to 55° C. to get an oil. Yield=18 gm.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCCCN
Product: CCCCNCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, while maintinaing the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional 1 hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.0 g (90.0 percent) of N-butylglycine tert-butyl ester, B.P. 76° C/4 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]=[C:38]=[S:39])=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:37][C:35](=[O:36])[C:32]2[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=2)=[S:39])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 94%).