Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:9]2=[O:10])=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][C:5]([N:8]2[C:9](=[O:10])[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: -3 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(4-chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide (24.4 g, 86.7 mmol) in sulfuric acid (150 mL) is cooled to -3° C., treated dropwise with nitric acid (70% real, 6.70 mL, 104 retool) while maintaining the temperature at 0°-2° C., stirred at room temperature for 90 minutes, and poured onto ice. The aqueous mixture is stirred for several minutes, and filtered to obtain a solid which is washed with water and dried to give the title product as a white powder (28.6 g, mp 152°-155° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH:19]([S:20]([NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])(=[O:22])=[O:21])=[CH2:18]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cold (−10° C.) stirred solution of glycine tert-butyl ester (3.0 g, 22.9 mmol) and triethylamine (7.1 mL, 50.9 mmol) in dichloromethane (150 mL), 2-chloro-ethanesulfonyl chloride (2.4 m/L, 23 mmol) in dichloromethane (10 mL) was added over a period of 15 minutes. The resulting mixture was stirred at 0° C. for 8 hours, and at room temperature overnight. The product mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 40-50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided tert-butyl N-(ethenesulfonyl)glycinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>C([O-])(O)=O.[Na+]>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:32]4[CH2:33][O:30][CH2:31]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2COC2)C3)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (ca) (1.0 g, 2.5 mmol), 3-oxetanone (0.91 mL, 13 mmol) and sodium triacetoxyborohydride (1.7 g, 8.1 mmol) in 1,2-dichloroethane (25 mL, 320 mmol) was stirred at 70° C. under N2 for 3 h. The mixture was then cooled down and poured in diluted NaHCO3. The organic and aqueous phases were separated. The aqueous phase was extracted with 2×50 mL of DCM. The combined organic phases were dried with Magnesium sulfate, filtered and concentrated. The crude solid was purified by flash chromatography (100% DCM to 5% MeOH/DCM) to provide product ih as a pale yellow solid: 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.15 (s, 1H), 4.64 (t, J=6.5 Hz, 2H), 4.55 (d, J=5.9 Hz, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.87 (d, J=11.4 Hz, 1H), 3.62 (dd, J=34.1, 22.2 Hz, 6H), 3.43 (d, J=16.1 Hz, 2H), 3.20-3.04 (m, 2H), 2.69 (d, J=4.6 Hz, 3H), 1.24 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS: m/z=+453 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:7][CH2:6][C:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:4][O:3]1.C(C1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2)#CCCCCCC>>[CH3:35][C:2]1([CH3:1])[O:3][CH2:4][C:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:6][O:7]1
Reactant: CCCCCCC#Cc1ccc2c(c1)CCCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: CCCCCCC#Cc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CCCCCCCCc1ccc2c(c1)CCCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Yield: 90 %

Procedure:
When the product of Step C is substituted for 5-(oct-1-ynyl)-2-tritylisoindoline in Example 2, Step E, the identical process afforded the title compound in 90% yield, as a colourless foam. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.24 (m, 10H); 1.42 (m, 15H); 1.91 (m, 2H); 2.43 (tr, 2H, J=8 Hz); 2.75 (tr, 2H, J=6.5 Hz); 3.25 (tr, 1H, J=5.5 Hz); 3.64 (s, 2H); 3.8-3.99 (m, 4H); 4.7 (s, 1H); 6.7 (d, 1H, J=8.4 Hz); 6.76 (s, 1H); 6.82 (d, 1H, J=8.4 Hz).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]I>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: Clc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: 140 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A 50 mL of flask was charged with 2.87 g of 4-chlorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2×50 mL) and brine (2×50 mL). The organics were dried over MgSO4 and concentrated under reduced pressure. The residued was purified via flash column chromatography on silica gel (0-25% EtOAc in hexanes) to get the desired product (1.25 g, 50%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:8][CH:7]=1.C(O)C.[ClH:21]>O>[ClH:21].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:10][CH:11]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: CN(C)C(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)Cc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An ice cold solution of sodium nitrite (1.088 g) in water (6 ml) was added to a stirred solution of 2-(4-aminophenyl)-N,N-dimethylacetamide (2.67 g) in concentrated hydrochloric acid (10 ml) at -5° C. After stirring the yellow solid for 15 min, it was added to a stirred solution of stannous chloride (16.88 g) in concentrated hydrochloric acid (10 ml) at -10° C. When the addition was complete, the mixture was stirred at room temperature for a further 30 min and poured into ethanol (100 ml). The mixture was evaporated to dryness under reduced pressure, basified using 2N sodium hydroxide (350 ml) and extracted with ethyl acetate (3×200 ml). Evaporation of the dried (Na2SO4) solvent gave a pale yellow gum which was dried under high vacuum. This was dissolved in ethyl acetate (50 ml) and ethereal hydrogen chloride was added until no more solid deposited. Collection of the solid by filtration and washing with ether gave the title compound as a white powder (1.45 g) which was 82.6% pure and was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](CC#N)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].OS(O)(=O)=O.O.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:21]([OH:24])=[O:23])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CC#N)cc(Br)c1O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(CC(=O)O)cc(Br)c1O
Temperature: 25 °C
Yield: 47 %

Procedure:
(3-acetyl-5-bromo-4-hydroxy-phenyl)-acetonitrile 213 (6 g, 23.6, mmol) is refluxed in a mixture of 50 mL acetic acid, 5 mL conc. H2SO4 and 5 mL water for about 2-3 h. This refluxed mixture is cooled to ambient temperature and poured onto ice forming a solid. The solid is isolated and recrystallized from a ethanol-water mixture to yield (3-acetyl-5-bromo-4-hydroxy-phenyl)-acetic acid 214 in a 47% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC(C)=O>O>[F:18][CH:17]([F:19])[C:9]1[N:8]([C:6]2[N:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:3]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:7]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(C)=O
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
For example, a mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), piperazine (3.45 g, 40 mmol), and acetone (50 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and precipitated crystals were filtered, and washed with methanol to afford 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine (3.87 g, 9.3 mmol) in a yield of 93% as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20])=[O:18].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:19]([C:17]([O:16][CH3:15])=[O:18])([CH3:21])[CH3:20])=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
0.780 g (3.78 mMol) of 4-amino-piperidine-carboxylic acid tert-butyl ester was suspended in 10 mL of MeCl2 at rt under argon; then, 0.80 g (3.60 mmol) of 4-(1-methoxycarbonyl-1-methyl-ethyl)-benzoic acid, 0.845 g (1.20 eq.) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and 0.583 g (1.30 eq.) of N,N-dimethyl-4-aminopyridine were added. The reaction mixture became a clear solution after stirring for 1 h at rt. After 5 hours, the solution was evaporated i.V. and the residue was purified by chromatography (silicagel, eluent:MeCl2) to yield 1.28 g of the title compound as colorless foam. MS: 405.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a 100 mL autoclave with a stirrer bar, acetophenone (1.2 g, 10 mmol) and {RuCl[(S)-daipena][(S)-xylbinap]}PF6 (the complex described in the Patent Literature 4) (13.3 mg, 0.01 mmol, 1/1000 molar fold of acetophenone) were added. After purging with a nitrogen gas, toluene (5 mL) and 1,8-diazabicyclo[5,4,0]undeca-7-ene (15.2 mg, 0.1 mmol) were added thereto. Subsequently, purging with a hydrogen gas, the mixture was stirred at 30° C. for 3 hours under hydrogen pressure 1 MPa. As a result of analysis of the reaction mixture by gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 1.4%.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[O:13]=[C:12]1[C:6]2[C:5]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[N:4][C:3]([NH:40][C@@H:41]3[CH2:42][CH2:43][NH:44][CH2:45]3)=[N:8][C:7]=2[CH:9]=[CH:10][NH:11]1
Reactant: CSc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(Nc2nc(N[C@@H]3CCNC3)nc3cc[nH]c(=O)c23)c1)N1CCCC1

Procedure:
The compound was prepared from N-(3-{[2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl]amino}phenyl)-1-pyrrolidinecarboxamide using m-CPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar to that described for Example 1 (Scheme 2).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine)palladium (II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid. 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the expected imine (2.72 g, 97%), which was used in next step without further purification. To a solution of the above imine (2.7 g, 9.23 mmol) in anhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol). The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark-colored solid. Purification by column chromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl)[1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl)[1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The compound was purified by column chromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP 219-221° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OCC)=O)CCC1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:21][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CCOC(=O)C1CCC1
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclobutyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using ethyl cyclobutanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 298.3 [(M+H)+; calcd for C16H28NO4: 298.2].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc23)CC1
Yield: 81.9 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.6 mg (0.0458 mMol) 3,4-dichlorobenzoyl chloride, 14.4 mg (82%) of the title compound were recovered.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5]([N:8]([CH3:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6].[NH2:25][OH:26]>>[OH:26][NH:25][C:3](=[O:2])[CH2:4][S:5]([N:8]([CH3:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NO
Product: CN(Cc1ccc(-c2ccc(Cl)cc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl-2-({methyl[(4'-chlorobiphenyl-4-yl)methyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CCO)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 2-(4-methoxyphenyl)ethanol (0.065 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 16 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0362 g, 0.060 mmol, 70.4% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.09-7.04 (m, 1H), 7.00-6.95 (m, 2H), 6.92-6.88 (m, 2H), 6.08 (s, 1H), 4.29-4.12 (m, 4H), 3.83 (s, 3H), 3.18 (br. s., 1H), 3.11 (t, J=7.1 Hz, 2H), 2.88 (br. s., 1H), 2.61 (s, 3H), 2.28 (br.s., 1H), 2.20 (s, 3H), 2.12-2.00 (m, 1H), 1.71-1.81 (m, 1H), 1.60-1.49 (m, 1H), 1.41-1.32 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.08-1.12 (m, 1H), 0.90 (br.s., 2H), 0.67 (br. s., 2H). LCMS (M+H)=603.5.
Reaction SMILES: [P:1]([O-:35])([O:31][CH2:32][CH2:33]Br)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[CH3:36][N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[P:1]([O-:35])([O:31][CH2:32][CH2:33][N+:37]([CH3:39])([CH3:38])[CH3:36])([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)OC
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)OC
Reaction time: 72 h

Procedure:
In 60 ml of toluene containing 10 g of trimethylamine is dissolved 2.0 g of the phosphate ester obtained in Example 10, and the solution is allowed to stand at room temperature for 3 days. The reaction mixture is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of methanol, and 2 g of silver carbonate is added. The mixture is refluxed for 1 hour and, then, filtered. The filtrate is evaporated to dryness, and the residue is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone. By this procedure is obtained 640 mg of the contemplated product as colorless powders.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][O:23][C:24]2([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:17]1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][O:23][C:24]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:17]1
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC4(C(=O)OC(C)(C)C)CCCC4)C3)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC4(C(=O)O)CCCC4)C3)c(C)o2)cc1
Yield: 42.4 %

Procedure:
20 mg of impure tert-butyl 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexylmethoxy]cyclopentanecarboxylate is stirred in 1 ml of trifluoroacetic acid at room temperature overnight. The solution is concentrated completely and the residue is chromatographed on silica gel (heptane/ethyl acetate 10/1->1/1->methyl tert-butyl ether), giving 7.5 mg of 1-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]cyclo-pentanecarboxylic acid. C25H33NO5 (427.55); LCMS 428.2 (MH+).