Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[C:16](OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(C)=O
Reactant: O=C(O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(O)CC1
Temperature: 25 °C

Procedure:
5.00 g (34.68 mmol) of 4-hydroxycyclohexanecarboxylic acid are dissolved in 80 ml of methanol, and 2 ml of conc. sulfuric acid are added slowly. The mixture is stirred under reflux for 20 h. After cooling to RT, the mixture is carefully poured into a mixture of 100 ml of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate solution. The phases are separated, and the organic phase is washed once with 20 ml of saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is directly used in the next reaction without further purification.
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:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])=[CH:18][CH:17]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>CN(C)C=O.O1CCCC1.O>[NH:30]1[C:25]2[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:31]1=[O:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2nccc(Oc3ccc(NCc4ccccc4N)cc3)c2cc1OC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N4Cc5ccccc5NC4=O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
6,7-Dimethoxy-4-(4-(2-aminophenyl)methylaminophenyloxy)quinoline (40 mg, 0.0996 mmol) was dissolved in dimethylformamide (0.5 ml), 1,1′-carbonyldiimidazole (19 mg, 0.1196 mmol) was added, and the mixture was stirred at 70° C. for 8 hours. After cooling to room temperature, the reaction solution was diluted with tetrahydrofuran, water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified with a silica gel column (ethyl acetate-methanol system) and recrystallized with hexane-diethyl ether to obtain the title compound (3 mg, 0.0070 mmol, 7.05%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]12[CH2:12][C:6]3(CO)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Br:1][C:2]12[CH2:12][C:6]3([N:16]4[CH:20]=[CH:19][CH:18]=[N:17]4)[CH2:5][C:4]([CH3:15])([CH2:10][C:8]([CH3:11])([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: c1cn[nH]c1
Reactant: CC12CC3(C)CC(Br)(C1)CC(CO)(C2)C3
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC12CC3(C)CC(Br)(C1)CC(n1cccn1)(C2)C3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of the 5-bromo-3,7-dimethyltricyclo[3.3.1.13,7]dec-1-ylmethanol (8.0 g, 29.3 mmol) in toluene (60 mL) was added 1H-pyrazole (1.55 g, 22.7 mmol) and cyanomethylenetributylphosphorane (2.0 g, 29.3 mmol) under nitrogen. After the addition, the mixture was stirred at 90° C. overnight. The reaction mixture was then concentrated, and the residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=3[CH:9]=2)[CH:2]=1>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1cccnc1)=C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)CCC(Cc1cccnc1)C2
Yield: 99.3 %

Procedure:
1.8 g of ethyl 6-(3-pyridylmethyl)-7,8-dihydro-2-naphthalenecarboxylate was dissolved in 100 ml of ethanol and 1 g of 10% palladium carbon was added thereto. The mixture was catalytically reduced. After absorption of hydrogen gas was completed, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.8 g of ethyl 6-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:27])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([OH:7])=O.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:49]([O:53][C:54](=[O:59])[NH:55][CH2:56][CH2:57][NH2:58])([CH3:52])([CH3:51])[CH3:50].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:27])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:22]([CH:24]3[CH2:25][CH2:26]3)=[O:23])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([NH:58][CH2:57][CH2:56][NH:55][C:54](=[O:59])[O:53][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To the stirred mixture of 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (50 mg, 0.119 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (26.8 mg, 0.14 mmol) and 1-hydroxybenzotriazole (19 mg, 0.14 mmol) in N,N-dimethylformamide, was added tert-butyl(2-aminoethyl)carbamate (19 mg, 0.119 mmol). The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was poured drop wise into cold saturated solution of sodium bicarbonate. The precipitated solid was filtered, washed with water and dried. Purification by preparative thin layer chromatography (2% methanol and dichloromethane as eluent) afforded tert-butyl {2-[(3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoyl)amino]ethyl}carbamate (23 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH3:14][CH:15]([CH3:18])[CH:16]=O>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][C:15]([S:13][CH:10]([CH3:11])[CH3:9])([CH3:18])[CH3:16]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: CC(C)C=O
Product: CC(C)SC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 28 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.515 g, 2.65×10-3 mol) and 0.786 g (5.31×10-3 mol, 200 M%) 2-(1-methylethylthio)-2-methylethylthio)-2-methypropanal were reacted by the method of Example 2 to give 2-(2-mercapto-2-methylpropylamino)-1-[2-(1-methylethylthio)-2-methylpropylamino]benzene 0.244 g (28% yield) as a colorless oil after purification by radial chromatography on a 2 mm silica gel plate eluting with 100 ml 100% petroleum ether and 200 ml 5% diethyl ether/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:33][N:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCOCC2)cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cn3)ncc12
Temperature: 25 °C
Yield: 26.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL). The solid obtained was refluxed in ethyl acetate (15 mL), cooled and filtered to give 6-bromo-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a dark brown-gray solid (0.350 g, 26.7%). 1H NMR δ (400 MHz, CDCl3) 8.78 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.97 (s, 1H), 7.32 (dd, J=2.9, 9.0 Hz, 1H), 5.99 (m, 1H), 3.89 (m, 4H), 3.16 (m, 4H), 2.61 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:12][CH3:13])[O:4][CH2:3]2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1cccc2c1CC(N)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Temperature: 60 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
In a round bottomed flask, 2.2 mmol of 3-amino-5-methoxychroman (described in Patent EP 279,150) are dissolved in 6 ml of dimethylformamide in the presence of 2.4 mmol of N-(4-bromobutyl)phthalimide, 6.6 mmol of potassium carbonate and a catalytic amount of potassium iodide. The mixture is left stirring at 60° C. for 6 hours. After cooling, the solvent is evaporated off and, after aqueous hydrolysis, the crude reaction mixture is extracted with dichloromethane. After washing, drying and evaporation of the organic phase, the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 5:95).
Reaction SMILES: [Na+].[Br:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.[CH3:16]I.O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([Br:2])=[CH:4][CH:5]=1
Reactant: CI
Reactant: O=C([O-])C(=O)C=Cc1ccc(Br)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=O)C=Cc1ccc(Br)nc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of the 4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid sodium salt (900.0 mg, 3.2 mmol) in the form of a pale yellow solid, methyl iodide (400.0 mL, 6.47 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at 75° C. for 3 hours. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 615.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN(C)C)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 591.27 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([C:24]([CH3:27])([CH3:26])[NH2:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:29])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:24]([CH3:27])([CH3:26])[NH2:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(C)(C)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(N)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80.1 %

Procedure:
In a solution of 1.35 g of methyl 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-(dimethyl-aminomethyl)benzoate in 30 mL of ethanol, a solution of 0.48 g of potassium hydroxide in 15 mL of water was added, and stirred under reflux with heating for 30 minutes. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and 10 mL of 2N hydrochloric acid was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate, insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.05 g of the crude aimed product as white crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F.[F-].[K+]>>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[Br:14]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: [F-]
Agent: [K+]
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1

Procedure:
According to other embodiments, the present invention provides methods of preparing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfoneamide-dibenzo[b,d]furan-1-carboxamide comprising the steps of: (a) reacting 4-difluoromethoxy-3-hydroxybenzaldehyde with 2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising potassium fluoride to produce 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde; (b) cyclizing 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde in a second solvent comprising a catalyst to produce 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran; (c) oxidizing 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran in a third solvent comprising an oxidizing agent to produce 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid; (d) reacting 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid in a fourth solvent comprising an inorganic acid halide, 4-amino-3,5-dichloropyridine and a first base, wherein N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide is produced; (e) reducing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide in the presence of a reducing agent to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide; and (f) reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide in a fifth solvent comprising methanesulfonyl chloride and a second base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:31])(O)=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:55][C@@H:56]([CH3:59])[CH2:57][OH:58].C(=O)([O-])O.[Na+]>O1CCCC1>[F:31][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:4]=1[C:1](=[O:2])[NH:55][C@H:56]([CH3:59])[CH2:57][OH:58])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)=[CH:12][N:11]=1
Reactant: C[C@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C(=O)O)c(F)c3)nc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO)NC(=O)c1ccc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl 4-[2-(4-carboxy-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 10) (21 mg, 0.049 mmol), 1-hydroxybenzotriazole monohydrate (9.3 mg, 0.061 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol) in dry tetrahydrofuran (0.5 mL) was stirred at room temperature for 1 hour followed by the addition of a solution of (S)-(−)-2-amino-1-propanol (7.6 μL, 0.098 mmol) in dry tetrahydrofuran (0.05 mL). The mixture was stirred at room temperature overnight, to which was added saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound as a white crystal (21 mg, yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)=[CH:31][CH:32]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1O
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)NC(=O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Yield: 13.5 %

Procedure:
(S)-2-[2-(biphenyl4-ylmethoxy)-benzoylamino]-3-[4-(biphenyl-4-ylmethoxy)-phenyl]-propionic acid methyl ester (48 mg) was prepared from (S)-2-(2-hydroxy-benzoylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester (175 mg, 0.55 mmol) and 4-biphenylmethyl chloride (240 mg, 1.2 mmol) with K2CO3 (306 mg, 2.2 mmol) as described in Procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([NH:14][CH2:15][CH2:16][S:17][CH2:18][C@@:19]([CH3:24])([C:21]([OH:23])=[O:22])[NH2:20])=O)C.[ClH:26]>>[ClH:26].[NH2:14][CH2:15][CH2:16][S:17][CH2:18][C@@:19]([CH3:24])([C:21]([OH:23])=[O:22])[NH2:20]
Reactant: CC(C)(C)OC(=O)NCCSC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@](N)(CSCCN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example-I-4, S-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]-2-methyl-L-cysteine trifluoroacetate, (5.5 g, 14.0 mmol) was dissolved in 1 N HCl (100 mL) and stirred at room temperature under nitrogen overnight. The solution was removed by freeze-drying to give the title S-(2-aminoethyl)-2-methyl-L-cysteine hydrochloride, 1H NMR?(DMSO-d6/D2O)? 1.43 (s, 3H), 2.72 (m, 2H), 2.85 (d, 1H), 2.95 (t, 2H), 3.07 (d, 1H). m/z [M+H+] 179.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27]#[N:28])[N:5]([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[S:22][CH2:23][CH3:24])=[CH:9][CH:8]=2)[CH:6]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCN(C)C1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:27]2[NH:31][N:30]=[N:29][N:28]=2)[N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[S:22][CH2:23][CH3:24])=[CH:25][CH:26]=2)[CH:6]=1
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
To a mixture of 3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (846 mg) in 1,3-dimethyl-2-imidazolidinone (10 ml) was added sodium azide (539 mg) and triethylamine hydrochloride (1.425 g) and stirred at 135° C. for 24 hours. The reaction mixture was poured into ice-water and the pH value was adjusted to 4 with 7% hydrochloric acid, extracted with ethyl acetate (twice) and the organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from methyl cyanide and washed hot methyl cyanide to give 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]-benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine(766 mg) as a brown solid. mp: 88°-90° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])[N:5]=[N:6][C:7]=1[NH2:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH2:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])=[N:3][C:2]=1[NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])=[CH:24][CH:25]=1
Reactant: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(-c2nnc(N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1[N+](=O)[O-]
Yield: 33.9 %

Procedure:
A mixture of 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (1.05 g, 3.95 mmol), (4-aminophenyl)(morpholino)methanone (1.630 g, 7.90 mmol), and N,N-diisopropylethylamine (1.243 mL, 7.11 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 2 days. The volatiles were removed under vacuum. To the residue was added water (60 mL). The precipitating material was collected by suction filtration. The filter cake was purified by ISCO (120 g silica gel, solid loading, 3-8% MeOH/CH2Cl2) to provide the desired product, (4-(6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5-ylamino)phenyl)(morpholino)methanone (0.595 g, 1.339 mmol, 33.9% yield), as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([OH:8])[C@H:3]1[OH:9]>C1C=CC=CC=1.C([O-])([O-])=O.[Ag+].[Ag+]>[CH:6]1[O:7][C@@H:2]([CH3:1])[C@H:3]([OH:9])[C:4](=[O:8])[CH:5]=1
Reactant: C[C@@H]1OC=C[C@H](O)[C@H]1O
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: C[C@@H]1OC=CC(=O)[C@H]1O

Procedure:
When Fetizon's reagent is used, L-rhamnal is dissolved in benzene and then the Fetizon's reagent is added to the mixture (20 g reagent: 1 g L-rhamnal). The mixture is refluxed for 1 hour, the spent reagent removed by filtration, and the solvent removed by evaporation to yield nearly pure enone. When the oxidant is chromium trioxide:pyridine complex, L-rhamnal is added to a solution of the oxidant in dichloromethane followed by addition of 4 equivalents of acetic anhydride. After 20 minutes the reaction mixture is poured onto a column of silica gel (ethyl acetate eluent) containing excess ethyl acetate at the top to precipitate insoluble chromium compounds. The product is eluted with ethyl acetate. If manganese dioxide is used, L-rhamnal is dissolved in tetrahydrofuran and treated with active manganese dioxide (15 g MnO2 : 1 g L-rhamnal) and stirred at room temperature for 2-3 days. The oxidant is then removed by filtration and the product purified by chromatography on a silica gel column (ethyl acetate eluent).