Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].[CH:7]([OH:11])(O)[CH2:8][CH3:9].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:14]2[CH:13]=[C:8]([CH:9]=[CH:16][C:15]=2[O:4][CH3:1])[CH:7]=[O:11])[CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: CCC(O)O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)cc1-c1cccnc1
Reaction time: 2 h
Yield: 87 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.2 g) was added to a solution of 3-bromo-4-methoxybenzldehyde (1.25 g) in toluene (10 ml) and ethanol (10 ml), followed by addition of 2M aqueous sodium carbonate (11 ml). To this mixture was added pyridine-3-boronic acid propane diol (1 g), and the mixture was heated to reflux. After 2 hours, the reaction was added to water (75 ml) and extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, 20-50% ethyl acetate/hexanes) afforded 1.08 g (87%) of 3-(3-pyridyl)-4-methoxybenzaldehyde as a white solid.
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH:8]=[CH:9][C:10]([CH3:14])=[CH:11][CH2:12]Br.BrCC=C(C)C=CCC(C)CCC=C(C)C.C1C=CC=CC=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>C(Cl)Cl>[CH2:40]([N:42]([CH2:12][CH:11]=[C:10]([CH3:14])[CH:9]=[CH:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:17])[CH3:16])[CH2:43][CH3:44])[CH3:41]
Reactant: CCNCC
Reactant: CC(C=CCC(C)CCCC(C)(C)Cl)=CCBr
Agent: CC(C)=CCCC(C)CC=CC(C)=CCBr
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCN(CC)CC=C(C)C=CCC(C)CCC=C(C)C

Procedure:
Five grams of 1 bromo-3,7,11-trimethyldodeca-2,4,10-triene in 25 ml. of benzene is mixed with 4 g. of diethylamine and the mixture stirred for about three hours. Methylene chloride (50 ml.) is added and the mixture washed with dilute sodium hydroxide and then water and evaporated to yield N,N-diethyl 3,7,11-trimethyldodeca-2,4,10-trienylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[H-].[Na+].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].O>CN(C)C=O>[S:19](=[O:22])(=[O:21])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:20]
Reactant: NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
108 mg of 2′-nitrobiphenyl-4-ol was dissolved in 1.5 ml of N,N-dimethyformamide, and a suspension of 120 mg of sodium hydride in 1.5 ml of N,N-dimethyformamide was added thereto under cooling with ice, followed by stirring for 10 minutes under cooling with ice. 367 mg of sulfamoyl chloride was added to this mixture, followed by stirring at room temperature for 3 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium. sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 106 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.C(OCC)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:27]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine 4-chlorophenylacetonitrile (50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate.(84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound. Elemental Analysis calculated for C16H18ClNO4: C 59.35; H 5.60; N 4.33; Found: C 59.27; H 5.54; N 4.33.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[Cl:6][C:7]1[N:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccc(Cl)cc23)cc1

Procedure:
A mixture of sodium acetate (0.56 g), 2,4,6-trichloroquinazoline (0.40 g) and 4'-aminomethyl (1,1'-biphenyl)-2-carboxylic acid (0.43 g) was stirred at room temperature in 10 mL of THF for 5 days. All solvents were removed by evaporation and the resulting residue was partitioned between ethyl acetate and brine. The ethyl acetate fraction was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude material was purified using silica gel chromatography to yield 0.15 g (21%) of an off white solid (m.p.=210°-240° C.): 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (t, J=6.2 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 7.83 (dd, J=2.3, 8.9 Hz, 1H), 7.66 (m, 2H), 7.49 (m, 1H), 7.35 (m, 7H), 4.77 (d, J=5.2 Hz); negative FAB MS m/e 422(M-H). Anal. calcd for C22H15Cl2N3O2 : C, 62.28; H,3.56; N, 9.90. Found: C, 62.44; H, 3.52; N, 9.95.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[C:2]1C=CC=CC=1.[O:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[Li].[CH3:28][N:29]([CH:31]=[O:32])[CH3:30]>>[C:24]([O:22][C:31]([N:29]1[CH2:30][CH2:30][N:29]([CH2:31][C@H:1]2[O:8][C:9](=[O:21])[N:10]([C:11]3[CH:20]=[CH:19][C:14]4[O:15][CH2:16][CH2:17][O:18][C:13]=4[CH:12]=3)[CH2:2]2)[CH2:28][CH2:28]1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C)C=O
Reactant: [Li]OC(C)(C)C
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CN(c3ccc4c(c3)OCCO4)C(=O)O2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (commercial; 1.40 g, 7.6 mmol) in dry MeOH (25 mL) was treated with MgSO4 (1.9 g). (R)-Epichlorohydrin (1.47 mL, 18.9 mmol) was added dropwise and the mixture was heated at 35° C. for 2 h and was then stirred at rt overnight. The mixture was filtered over Celite and concentrated under reduced pressure. The residue was taken up in DCM and washed with water. The org. phase was dried over MgSO4 and concentrated under reduced pressure to afford the crude 4-((R)-3-chloro-2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester. To a solution of the above intermediate chlorohydrin (2.10 g, 7.53 mmol) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (2.15 g, 1 eq, prepared according to WO2007107965) in DMF (30 mL) was added LiOtBu (10.3 mL, 2.2M in THF) at rt. The mixture was stirred at rt over night and subsequently at 50° C. for 5 h. The mixture was partitioned between EA and 0.5M HCl. The aq. phase was basified (NH4OH) and extracted with EA. The org. layer was dried over MgSO4 and concentrated under reduced pressure to afford the title compound as a colorless solid (1.15 g, 36%).
Reaction SMILES: [C:1]1([P:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:8]2[CH2:12][NH:11][C@H:10]([CH2:13][P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:40]1([P:46](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[C:1]1([P:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:8]2[CH2:12][N:11]([P:46]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:47])[C@H:10]([CH2:13][P:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: c1ccc(P(C[C@@H]2C[C@H](P(c3ccccc3)c3ccccc3)CN2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: O=P(c1ccccc1)(c1ccccc1)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 76.8 %

Procedure:
1.01 g (2.23 mmol) of (2S,4S)-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine, 1.46 ml (13.38 mmol) of N-methylmorpholine and 30 ml of toluene were placed in a 500 ml sulphonation flask which was provided with a stirrer, thermometer, dropping funnel and argon gasification. While stirring there was then added dropwise thereto at room temperature within 10 minutes a solution of 0.79 g (3.35 mmol) of diphenylphosphinyl chloride in 10 ml of toluene. The reaction was finished after 7 hours. The mixture was then filtered through a sintered glass suction filter and the filtrate was evaporated on a rotary evaporator at 60° C./17 mbar. The residue (2.2 g) was taken up in 30 ml of diethyl ether and treated with 30 ml of 3N hydrochloric acid. The ether phase was then separated and the aqueous phase was extracted a further twice with 30 ml of diethyl ether each time. The extracts were dried over sodium sulphate, filtered off and concentrated on a rotary evaporator at 60° C./17 mbar. For purification the residue (1.57 g) was chromatographed over 140 g of Kieselgel 60 (0.063 to 0.20 mm granular size). A mixture of benzene/ethyl acetate/ethanol (8:2:1) was used as the eluant. After evaporation of the solvent and drying for 16 hours/1 mbar, there was obtained 1.12 g (76.8%) of pure (2S,4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-1-(diphenylphosphinyl)-pyrrolidine. Melting point: sintering from 65° C., clear melting at 130° C. [α]D20 =-21.4° (c=0.5 in benzene).
Reaction SMILES: [Cl:1][C:2]1[C:6](C(O)=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>[Cu-]=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2cccnc2)nc1Cl
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 125 °C

Procedure:
In another embodiment, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) and copper(I) oxide are mixed with N,N-dimethylacetamide and heated to about 125° C. The 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) can be isolated and purified by standard techniques.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([CH3:10])[N:3]=1.C(O)=[O:12].[H][H]>[Ni].O>[NH2:1][C:2]1[C:7]([CH:8]=[O:12])=[CH:6][N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: [H][H]
Reactant: O=CO
Reactant: Cc1ncc(C#N)c(N)n1
Agent: [Ni]
Solvent: O
Product: Cc1ncc(C=O)c(N)n1

Procedure:
A mixture of 76.5 g of 4-amino-2-methylpyrimidine-5-carbonitrile, 380 ml of 97% formic acid, 380 ml of water, and 8 g of Raney nickel catalyst is treated in a Parr pressure apparatus with hydrogen gas at an initial pressure of 51 psi at room temperature for 2.75 hours. The catalyst is removed by filtration and the filtrate is treated with 47.5 ml of concentrated hydrochloric acid and evaporated at reduced pressure. The residue is dissolved in hot water, treated with charcoal and filtered. Neutralization of the filtrate with concentrated ammonium hydroxide precipitates the product which is then collected by filtration and washed with water. Recrystallization from ethanol gives 37.9 g of 4-amino-2-methylpyrimidine-5-carboxaldehyde, mp 191°-192.5° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Yield: 99.5 %

Procedure:
A solution of 12.5 g (40 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 8.9 g (48 mmol) of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 8.1 g (80 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for 18 hours. The reaction mixture was cooled to 5° and the solid was removed by filtration, washed with acetonitrile, ether and dried in vacuo to give 19.0 g of the title compounds, mp 148°-151°.
Reaction SMILES: BrC[C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13].C([O-])(=O)C.[K+].O.[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21]>CN(C)C=O>[C:20]([O:23][CH2:24][C:8]1[S:7][C:6]2[CH:10]=[C:11]([F:12])[CH:3]=[C:4]([F:13])[C:5]=2[CH:9]=1)(=[O:22])[CH3:21]
Reactant: Fc1cc2sccc2c(F)c1CBr
Reactant: CCOC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc2c(F)cc(F)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo[b]thiophene in 5 ml of N,N-dimethyl-formamide is added 0.23 g of potassium acetate, and the resulting mixture is stirred at 60° C. for one hour. The temperature of the thus stirred mixture is lowered to room temperature, and 10 ml of water and 10 ml of ethyl acetate are added thereto. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under educed pressure, to obtain 0.14 g of colorless, oily acetoxymethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=[O:15].[K+].[K+]>CC(C)=O.O>[CH2:10]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[C:5]=1[OH:15])[CH:11]=[CH2:12]
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Reactant: Oc1cc(F)cc(F)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1cc(F)cc(F)c1O
Temperature: 25 °C
Yield: 101.9 %

Procedure:
3,5-difluorophenol (3.9 grams, 30 mmol), allyl bromide (3.4 mL, 39 mmol) and K2CO3 (12.4 grams, 90 mmol) were suspended in 75 mL acetone and the mixture was refluxed overnight. The mixture was diluted with water and extracted with EtOAc. The organic was dried over sodium sulfate and concentrated. 5.5 grams of crude allyl-3,5-difluorophenylether. The oil was heated to reflux for 6 h then cooled to room temperature. Flash chromatography (150 g silica, 1011 Hexane/EtOAc) afforded 5.2 grams (100%) of product. 1H NMR (400 MHz, CDCl3). δ 3.4 (d, 2H), 5.1-5.2 (m, 2H), 5.6 (s, 1H), 5.9-6.0 (m, 1H), 6.46.5 (m, 2H).
Reaction SMILES: C1(C2N=C(C(C(N[C:15]([CH:17]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:18][S:19]([CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[O:16])CC)=O)ON=2)CC1.FC(F)(F)C(O)=O.[NH2:42][CH:43]([CH2:55][CH3:56])[C@@H:44]([C:46]1[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[O:48][N:47]=1)[OH:45].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:23]1([CH2:22][S:19]([CH2:18][C@H:17]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[C:15](=[O:16])[NH:42][C@H:43]([CH:44]([OH:45])[C:46]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[O:48][N:47]=2)[CH2:55][CH3:56])(=[O:20])=[O:21])[CH2:24][CH2:25]1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(C2CC2)no1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid (266 mg, 0.83 mmol, Reference Example 4) in dimethylformamide (10 mL) was treated successively with (S)-2-amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol trifluoroacetate (282 mg, 0.83 mmol, Reference Example 13), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (316 mg, 0.83 mmol) and diisopropylethylamine (0.289 mL, 1.66 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give morpholine-4-carboxylic acid ((R)-2-cyclopropylmethanesulfonyl-1-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propylcarbamoyl}-ethyl)-amide as a brown oil (370 mg). MS: 528 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])=[O:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Temperature: 23 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
A solution of crude ethyl 4-hydroxy-1,1-dimethyl-2-oxo-6-(trifluoromethyl)-naphthalene-3-carboxylate (562 mg, 1712 μmol), glycine tert-butyl ester hydrochloride (316 mg, 1883 μmol) and DIPEA (447 μL, 2568 μmol) in 1,4-dioxane (20 mL) was heated to 120° C. in a sealed vessel. After 14 hours, the reaction was cooled to 23° C., and the solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL), washed with water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4-8% EtOAc/hexane) affording 435 mg of the title compound. MS m/e=358.1 (M-C4H8+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:20]I.C(=O)([O-])O.[Na+].[C:27](=[S:29])=[S:28]>O1CCCC1>[CH3:20][S:28][C:27]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[S:29]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: S=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(=S)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of t-butyl 3-aminopropylcarbamate (6 g) and triethylamine (5.03 ml) in tetrahydrofuran (10 ml) was added dropwise carbon disulfide (2.07 ml), and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added dropwise methyl iodide (2.14 ml), and the mixture was stirred at room temperature for 0.5 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (11 g) as crude oil.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[S:26])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: S=C=Nc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=S)Nc2ccccc2)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isothiocyanate (0.49 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.83 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(2-(3-phenylthioureido)ethyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]2=[O:10])=[CH:4][CH:3]=1.C(O)=O.N([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([NH2:37])=O>>[CH2:17]([N:11]1[C:12](=[O:13])[C:14]2[NH:37][CH:35]=[N:16][C:15]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:10])[CH2:18][CH3:19]
Reactant: CCCn1c(=O)cc(N)n(-c2ccc(Cl)cc2)c1=O
Reactant: NC=O
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCn1c(=O)c2[nH]cnc2n(-c2ccc(Cl)cc2)c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-n-propyl-6-aminouracil (28.0 g; 0.1 mole), formic acid (15.1 ml; 0.4 moles) and sodium nitrite (7 g; 0.1 mole) in formamide (600 ml) was heated to 60° C. for 10 minutes. The temperature was then increased to 100° C. and sodium dithionite (2.3 g; 0.013 moles) was added over a period of 10 minutes. After addition, the temperature was increased to 190° C., mantained for 30 minutes and the reaction mixture was cooled and extracted with chloroform. The organic solution was extracted with 2N sodium hydroxide aqueous solution, washed with diethyl ether, acidified with 2N hydrochloric acid aqueous solution and extracted with chloroform. The organic extracts were washed with water, dried (Na2SO4) and the solvent was removed in vacuo to give 1-n-propyl-3-(4-chlorophenyl)-xanthine (19.5 g; yield 64.3%). After recrystallization from 90% ethanol, the melting point is 233°-234° C.
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].[C:8](=[O:10])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][O:1][C:8](=[O:9])[O:10]1)=[O:4]
Reactant: O=C=O
Reactant: COC(=O)C1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COC(C)(C)C
Product: COC(=O)C1COC(=O)O1
Reaction time: 96 h
Yield: 94 %

Procedure:
20 g of the methyl epoxypropionate were mixed with 20 g of tert-butyl methyl ether and 1 g of tetrabutylammonium bromide. The homogeneous mixture was transferred to a 100 ml pressurized reactor and carboxylated for 4 days at 40° C. and a CO2 pressure of 20 bar. Following carboxylation, a two-phase system was obtained; the upper phase consisted of tert-butyl methyl ether, and the lower phase consisted of 4-methoxycarbonyl-2-oxo-1,3-dioxolane (purity 94% (GC), yield 94%).