Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].F[B-](F)(F)F.[H+].[F:15][C:16](I)([F:18])[F:17].OO>F[B-](F)(F)F.[Fe+2].F[B-](F)(F)F.CS(C)=O>[F:15][C:16]([F:18])([F:17])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: F[B-](F)(F)F
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
0.11 g (1.0 mmol) of uracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.21 ml of a 42% tetrafluoroboric acid aqueous solution, 2.0 ml of dimethyl sulfoxide, 3.0 ml of a 2.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) tetrafluoroborate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 94%) was confirmed in the same manner as in Example 1.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])/[CH:18]=[C:19](\[C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)/[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([O:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:32])[CH2:18][C@@:19]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:4][N+:1]([O-:3])=[O:2])[C:20]([F:22])([F:21])[F:23])=[CH:13][C:12]=1[CH3:33])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 336 h

Procedure:
Alternatively, to a solution of 1-cyclohexyl-3-[(S)-(6-methoxy-4-quinolyl)-[(1S,2S,5S)-5-vinylquinuclidin-2-yl]methyl]thiourea (10 mg, prepared according to the literature: Journal of Organic Chemistry 2008, 3475) and nitromethane (0.6 ml) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (100 mg). The solution was heated for 8 days at 50° C. then allowed to stand at room temperature for 14 days. Water was then added and the resulting mixture was extracted with diethyl ether and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (28 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.06 minutes (major enantiomer), 7.19 minutes (minor enantiomer) indicated that the reaction proceeded with 89% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C(C([O-])=O)(F)(F)F.[NH4+].[NH4+].[OH-].CP(C)C>O1CCCC1.CCOC(C)=O>[CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33][NH2:51])[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: CP(C)C
Agent: O=C([O-])C(F)(F)F
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(=C\c1csc(CN)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 35 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
To a stirred suspension of epothilone F (5.0 g, 9.55 mmol, 86.2% potency) in tetrahydrofuran (50 ml) was added diphenylphosphoryl azide (2.28 ml, 2.89 g, 10.5 mmol, 1.1 equivalents) at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.73 ml, 1.74 g, 11.46 mmol, 1.2 equivalents) was then added over 10 min. The mixture was stirred for 10 min. and then allowed to warm to 35° C. and stirred for 6.5 hours. The mixture was cooled to 20° C., and a mixture of aqueous solution of CF3COONH4 (4M, 10 ml) and NH4OH (4M, 10 ml) was added. After the mixture was stirred for 5 min, trimethylphosphine (1M in tetrahydrofuran, 10.03 ml, 10.03 mmol, 1.05 equivalents) was added over 10 min at 20° C. The mixture was allowed to stir at 35° C. for 2 hours and then at 5° C. for 14 hours. EtOAc (200 ml) and aqueous NH4OH (1 M, 10 ml) were added. The organic layer was washed with aqueous NH4OH (1 M, 30 ml). The combined aqueous layers were extracted with EtOAc (2×30 ml). The combined organic layers were washed with a mixture of brine (20 ml) and H2O (20 ml). The solvents were removed to yield ˜60 ml on a rotary evaporator, and EtOAc (60 ml) was added. The solvent was removed again to ˜65 ml, and the resulting slurry was crystallized from EtOAc/heptane to give 21-amino epothilone B (3.75 g, 87% yield corrected for input potency) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[NH4+].[Cl-].[NH4+].[OH-].CP(C)C>O1CCCC1.CCOC(C)=O>[CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33][NH2:51])[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: CP(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C/C(=C\c1csc(CN)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 98.3 %

Procedure:
To a stirred suspension of epothilone F (2.5 g, 4.77 mmol, 86.2% potency) in tetrahydrofuran (25 ml) was added diphenylphosphoryl azide (1.14 ml, 1.45 g, 5.25 mmol, 1.1 equivalents) at room temperature. The mixture was stirred for approximately 5 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.86 ml, 0.87 g, 5.73 mmol, 1.2 equivalents) was then added over 10 min. The mixture was stirred for 10 min, and then allowed to warm to 40° C. and stirred for 3 hours. The mixture was cooled to 30° C., and a mixture of aqueous solution of NH4Cl (2M, 2.5 ml) and NH4OH (2M, 2.5 ml) was added. After the mixture was stirred for 10 min at 30° C., trimethylphosphine (1M in tetrahydrofuran, 5.01 ml, 5.01 mmol, 1.05 equivalents) was added over 10 min. The mixture was allowed to stir at 30° C. for 3 hours and then at room temperature for 15 hours. EtOAc (100 ml) and aqueous NH4OH (1 M, 20 ml) were added. The organic layer was washed with aqueous NH4OH (1 M, 20 ml). The combined aqueous layers were extracted with EtOAc (20 ml). The combined organic layers were washed with H2O (20 ml) and dried over MgSO4. The solvents were removed on a rotary evaporator, and the residue dried in vacuo to provide the crude 21-amino epothilone B (2.45 g) as an off-white solid. The crude 21-amino epothilone B (2.45 g) was crystallized from EtOAc/heptane to give 21-amino epothilone B (1.86 g, 86.5% yield corrected for input potency) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: Cc1ccccc1
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and toluene (125 ml) is stirred at about 80° C. for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as toluene are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. After cooling to 80° C., n-heptane (100 ml) is allowed to run in. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 1 hour. The product is isolated by filtration and washed with n-heptane (100 ml). The product is dried in vacuo at about 60° C. Yield: 22.31 g=50.7% (beige powder).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:13]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1(OC)CCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[CH2:19]([S:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[O:9][CH3:10])=[C:13](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(Br)ccc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC1CCCC1
Solvent: O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Temperature: 90 °C
Yield: 91.1 %

Procedure:
A RBF charged with xantphos (9.97 g, 17.23 mmol), pd2(dba)3 (5.26 g, 5.74 mmol), 4-bromo-1-iodo-2-methoxybenzene (74.9 g, 239 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (60.000 g, 191 mmol), cesium carbonate (100 g, 306 mmol), and 400 ml cylopentyl-methylether was heated to 90° C. overnight. The reaction mixture was then poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was triturated with IPA leaving a yellow solid that was collected and dried (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (86.95 g, 174 mmol, 91% yield). m/z (ESI) 500.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12].N([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromo-4-hydroxybenzaldehyde (6.30 g) in acetic acid (45 ml) was added dropwise with 70% nitric acid (5.85 ml) on a water bath, then added with sodium nitrite (62 mg), and further stirred for 2 hours. The reaction mixture was poured into ice water (300 ml), and precipitates were taken by filtration, and washed with water (50 ml×3). The precipitates were dried under reduced pressure for 24 hours to obtain the title compound (Intermediate 26, 5.88 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[Cl:13][C:14]1[C:19]([C:21]([OH:23])=[O:22])=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1
Reactant: O=C=O
Reactant: Clc1cncc(Cl)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of diisopropylamine (13.0 mL, 92.6 mmol, 2.3 eq.) in anhydrous THF (300 mL) at −78° C. under N2 was added dropwise a solution of 1.6 M nBuLi in hexanes (57.9 mL, 92.6 mmol, 2.3 eq.). After 1 hour a solution of 2,6-dichloropyrazine in anhydrous THF (6.0 g, 40.3 mmol) was added dropwise over 30 minutes. After stirring at −78° C. for 1 hour, the reaction mixture was poured onto crushed dry ice (solid carbon dioxide), and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with water (100 mL) and washed with ethyl acetate (3×100 mL). The aqueous layer was cooled to 0° C., acidified with 2N HCl until pH ˜2, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant crude was purified by column chromatography (Si-PPC, gradient 0% to 50%, methanol in dichloromethane) to give the desired product as a beige solid (3.16 g, 40.6%). 1H NMR (CDCl3, 400 MHz) δ ppm 8.60 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCCC.Cl>[C:21]([C:17]1[C:16]([Cl:20])=[N:15][C:14]([Cl:13])=[CH:19][N:18]=1)([OH:23])=[O:22]
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)c1ncc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.78 g) in tetrahydrofuran (40 ml) is added dropwise a 1.6M solution of n-butyl lithium in hexane (4.82 ml) in a dry ice-acetone bath over a period of 3 minutes. The mixture is stirred in the same bath for 30 minutes. To the mixture is added dropwise a solution of 2,6-dichloropyrazine (0.50 g) in tetrahydrofuran (5 ml) at the same temperature over a period of 15 minutes, and the mixture is stirred for one hour. The reaction mixture is poured into dry ice, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with a 10% aqueous hydrochloric acid solution in order to adjust the pH value thereof to about 2, and then extracted with ethyl acetate. The combined organic layers are extracted with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous extract is washed with ethyl acetate, acidified with a 10% aqueous hydrochloric acid, and extracted with ethyl acetate. The combined organic layer is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is triturated with a mixture of chloroform and hexane (1:1) to give 2-carboxy-3,5-dichloropyrazine (234 mg) as a slightly brown crystalline powder, m.p. 139-141° C., MS (m/z): 191 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[C:12](=O)([O-])[O-:13].[K+].[K+]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cl)c2o1
Yield: 82 %

Procedure:
21.3 g of 2-amino-4,5,6-trichlorophenol, 27.6 g of anhydrous potassium carbonate and 150 ml of ethyl acetate were placed in a 300 ml round-bottom flask and a solution of 9.9 g of diphosgen (trichloromethyl chloroformate) dissolved in 50 ml of ethyl acetate was added dropwise to the mixture with stirring under cooling on ice-water bath. The resulting mixture was heated at reflux temperature for one hour and the reaction solution was then cooled and subjected to suction filtration to remove insoluble salts. The filtrate was concentrated to dryness under reduced pressure to afford yellowish white crystals, which were recrystallized from methanol/acetone to give 19.6 g of 5,6,7-trichlorobenzoxazolone as white crystals with a melting point of 253°-254° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-fluoro-benzaldehyde (1.0 eq.) in MeOH (0.2M) at 0° C. was added portionwise NaBH4 (2.0 eq.). The mixture was stirred at rt for 1 h, poured in HCl (1M) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Ca+2:5].C(=O)=O>O>[C:1](=[O:2])([OH:4])[O-:3].[Ca+2:5].[C:1](=[O:2])([OH:4])[O-:3]
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])O

Procedure:
Dolomite, marble and calcium carbonate are carbonized at 25° C. by spraying water and introducing CO2 (99 vt %) simultaneously. Pure aqueous solution of calcium bicarbonate (CaO: 11 g/L, Fe: 0.5 ppm, Al: 0.6 ppm) can be obtained after clarification and filtration.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[CH:14][S:15][C:8]=12.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH3:1])[S:15][C:8]=12
Reactant: Clc1ccnc2ccsc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (0.71 ml, 1.77 mmol) in THF (20.0 mL) was cooled to −78° C. and 7-chlorothieno[3,2-b]pyridine (200 mg, 1.18 mmol) was added dropwise. The mixture stirred at −78° C. for 1 h to afford a yellow suspension. A solution of iodomethane (0.22 ml, 3.54 mmol) in THF (1.0 mL) was added dropwise via syringe, and the mixture stirred at −78° C. for 3 h.; LCMS showed completion of the reaction. The reaction was quenched with water and warmed to RT. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. This material was purified via column chromatography (RediSep 40 g column, gradient elution with 10-50% ethyl acetate-hexane) to afford 7-chloro-2-methylthieno[3,2-b]pyridine as white solid. MS [M+H]=184.1; Calc'd for C8H6ClNS: 183.7.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].B(F)(F)F.CCOCC.[C:14]([O:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=O)(=[O:16])[CH3:15].CCCCCC.CC(=O)OCC>C(Cl)Cl>[C:14]([O:17][CH2:18][CH2:19][C:20]1([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[S:4][CH2:1][CH2:2][S:3]1)(=[O:16])[CH3:15]
Reactant: SCCS
Reactant: CC(=O)OCCC(=O)c1ccc(F)cc1
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCC1(c2ccc(F)cc2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
1.79 g (19.0 mol) of ethane-1,2-dithiol and 680 mg (4.76 mmol) of boron trifluoride etherate were added in succession at 0° C. to a solution of 2.0 g (9.5 mmol) of 3-(4-fluorophenyl)-3-oxopropyl acetate in DCM (40 ml). The mixture was then stirred for 16 h at RT and subsequently neutralized with a 10M aq. NaOH sol. Extraction with DCM (3×100 ml) was then carried out and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 24:1) of the residue yielded 1.8 g (6.3 mmol, 66%) of 2-(2-(4-fluoro-phenyl) -1,3-dithiolan-2-yl)ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.318 g, 0.0012 mol) and MeI (0.088 mL, 0.0014 mol, 1.18 eq) were added to DMF (5 mL) and the solution cooled to −10° C. NaH (0.03 g, 0.0013 mol, 1.07 eq) was added and the RM was stirred at 0° C. for 30 min and rt for 30 min. The solvent was evaporated under reduced pressure and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried (MgSO4) and evaporated under reduced pressure to give the product as a purple oily residue (0.25 g, 75%); 1H (DMSO-d6): δ 1.55 (4H, m, 2CH2), 1.7 (2H, m, CH2), 1.9 (2H, m, CH2), 2.63 (2H, t, J=5 Hz, CH2), 3.17 (3H, s, CH3), 3.65 (2H, t, J=5 Hz, CH2), 4.74 (1H, m, CH), 8.14 (1H, s, CH); MS+ve: 281.2; Rt=3.11 min (Analytical—1).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:6]([CH3:7])[CH3:5])[C:13]=1[O:14][C:1]([Cl:4])=[O:2])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 20% solution of phosgene in toluene (139 mL, 0.269 mol) was added to a stirring solution of propofol (40 g, 0.225 mmol) in toluene (80.0 mL) under a nitrogen atmosphere at 0° C. N,N-Dimethylaniline (34.0 mL, 0.269 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature slowly and stirred for 14 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The crude product (2) was carried to the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 1H), 7.19-7.17 (m, 2H), 3.04-3.01 (m, 2H), 1.25 (d, J=7.2 Hz, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O:9]=[C:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][C:25]2[C:29]3=[N:30][CH:31]=[CH:32][CH:33]=[C:28]3[O:27][C:26]=2[C:34](OC)=[O:35])=[O:23])[CH2:18][CH2:17]1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34]([C:26]2[O:27][C:28]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[C:25]=2[NH:24][C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][C:10]3=[O:9])[CH2:17][CH2:18]2)=[O:23])=[O:35])=[N:3][CH:4]=1
Reactant: COC(=O)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Reactant: Cc1ccc(N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)c2oc3cccnc3c2NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)nc1
Reaction time: 0.5 h

Procedure:
2-Amino-5-methylpyridine (81 mg) is dissolved in chloroform (5 ml). After adding 0.98 M trimethyl alminum-hexane solution (763 μl) under ice-cooling, the reaction solution is stirred under ice-cooling for 10 minutes, and then at room temperature for 0.5 hours. To the resulting reaction solution is added methyl 3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxylate (150 mg) obtained in Reference Example 79, and the mixture is stirred at room temperature for 2 hours and at 50° C. under heating for 5 hours. To the reaction solution is added 10% hydrochloric acid (3 ml) under ice-cooling, and the mixture is stirred at room temperature for 0.5 hours. The reaction solution is then neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in diethyl ether, and collected by filtration to give the title compound (110 mg).