Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH:22]CC(O)=O)=[N:3]1.[OH-].[Na+]>CCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:22])=[N:3]1
Reactant: Cn1nc(NCC(=O)O)c2c(Oc3ccc4ccccc4c3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(N)c2c(Oc3ccc4ccccc4c3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[1-Methyl-4-(naphthalen-2-yloxy)-1H-indazol-3-ylamino]-acetic acid (A25) To a 50 mL round-bottomed, one-necked flask containing K-3 (90 mg, 0.25 mmol) was added 1:1 EtOH/H2O (2 mL). To this stirring suspension was added 15% aqueous NaOH (0.133 mL, 0.5 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated on the vacuum line and the resulting solid was suspended in H2O (2 mL) and 1N HCl was added until a pH of 1-2 (litmus paper) was reached. The mixture was stirred at room temperature for 30 min and then filtered. The resulting solid was dried to afford 65 mg (75%) of A25 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 3.77 (s, 3H), 3.93 (s, 2H), 5.63 (br s, 1H), 6.18 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0, 8.0 Hz, 1H), 7.41 (dd, J=8.8, 1.2 Hz, 1H), 7.51 (m, 2H), 7.63 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 12.45 (br s, 1H), LC/MS (86%) (ESI+) Calcd. for 347.4; Found: 348.7 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([NH:14][CH:15]([CH3:17])[CH3:16])=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:5]=[N:6][CH:7]=1>C(N(CC)CC)C>[CH3:17][CH:15]([NH:14][C:3]1[CH:2]=[CH:7][N:6]=[N:5][C:4]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH3:16]
Reactant: CC(C)Nc1c(Cl)cnnc1N1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccnnc1N1CCNCC1

Procedure:
Following the general procedure of PREPARATION 28 and making non-critical variations but starting with 1-[5-chloro-4-(1-methylethyl)amino-3-pyridazinyl]piperazine (PREPARATION 32, 1.7 g) and triethylamine (0.81 g), the title compound is obtained, NMR (CDCl3) 1.28, 2.06, 3.05, 3.11, 3.59, 4.75, 6.39, and 8.49δ; CMR (CDCl3) 22.2, 43.2, 46.2, 50.6, 103.7, 138.7, 148.4 and 154.5δ.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCC)C>[C:39]1([NH:45][C:46]([C:2]2[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[C:4]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:3]=2)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.00 g (0.0023 mol) of 2-bromo-4-{methyl(phenylmethyl) amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 20 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 2.2 ml of a 1.6M-hexane solution of BuLi (0.0023×1.5 mol) was added to the solution, followed by stirring the obtained mixture for about 10 minutes. After 0.62 g (0.0023×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH:13]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C1(OC)C=CC=CC=1>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:32]([S:31][CH2:30][CH:13]([CH2:14][CH2:15][CH2:16][NH2:17])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])(=[O:34])[CH3:33]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[2-Acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline tert-butyl ester (2 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (6 ml). The solution is stored at room temperature for one hour, the solvents are removed in vacuo and the residue is precipitated from ethyl acetate-ether to yield 1-(2-acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccncc2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 4-mercaptopyridine (0.67 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.33 g, 90%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20](=O)[CH3:21])[CH2:16][CH2:15]1.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:20]([CH:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]3)([CH3:21])[O:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CC(=O)C1CCNCC1
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C)(C1CCNCC1)OCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.5 %

Procedure:
A mixture of 200 g of 3,4-dimethoxybenzeneethanol and 163.7 g of 1-(4-piperidinyl)ethanone in 800 ml of ethanol saturated with anhydrous hydrochloric acid was stirred for 15 h at ambient temperature. The mixture was concentrated under vacuum, and the concentrate was diluted with 500 ml of ethanol after which the hydrochloride precipitated. After filtration the hydrochloride was dissolved in water and sodium hydroxide until the pH was 12. The base was extracted with dichloromethane, and the organic phase was washed with water, dried and evaporated to yield 251 g (86.5%) of crude 4-(3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzopyran-1-yl)piperidine.
Reaction SMILES: N(OC(C)(C)C)=[O:2].N[CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]1=[O:26].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:24]([O:23][C:21]([CH2:20][N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][C:9](=[O:2])[C:10]1=[O:26])=[O:22])[CH3:25]
Reactant: CC(C)(C)ON=O
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
t-Butyl nitrite (31 ml) was added with stirring to a solution of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one (55 g) in chloroform (1000 ml) and acetic acid (2.8 ml). The reaction mixture was refluxed under nitrogen for 3.5 hours, and then cooled to 0°. While stirring was maintained, m-chloroperbenzoic acid (43.5 g) was added in five portions during 0.5 hour. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (500 ml), concentrated aqueous ammonia (2×250 ml), and saturated brine (250 ml). The organic solution was dried over sodium sulfate, treated with charcoal, and evaporated under reduced pressure to give an oil which was triturated with ether to give 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2,3-dione, m.p. 112°-114°.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[OH:19].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[O:9][CH3:8])=[O:4]
Reactant: CCC(Br)C(=O)Br
Reactant: COc1cc(C)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Br)C(=O)Oc1c(OC)cc(C)cc1OC
Reaction time: 1.5 h

Procedure:
2-Bromobutyryl bromide (31.1 ml) was added to a stirred solution of 2,6-dimethoxy-4-methylphenol (45 g) in dry dichloromethane (500 ml), whereupon triethylamine (37.3 ml) was added dropwise over 30 minutes, maintaining the internal temperature below 10° C. using an ice-salt bath. During the addition a white precipitate formed. After addition was complete the reaction mixture was stirred for 1.5 hours, then filtered. The solid was washed with diethyl ether (200 ml) and the filtrate washed twice with saturated sodium bicarbonate solution (100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the crude product as an oil (79.4 g). To remove any residual starting phenol, the oil was dissolved in diethyl ether and washed with sodium hydroxide solution (0.1 M; 3×100 ml), then water (4×100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the title compound as a yellow oil (72.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([C:19]#[CH:20])([OH:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:28]1([N:38]=[C:39]=[O:40])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([O:18][C:39](=[O:40])[N:38]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:19]3=[CH2:20])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C#CC1(O)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C=Nc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Product: C=C1N(c2cccc3ccccc23)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 5 h
Yield: 76.5 %

Procedure:
A mixture containing 11.0 g of 1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-ethynyl-4-hydroxypiperidine, 6.0 g of 1-naphthyl isocyanate, 0.2 g of anhydrous potassium acetate and 36 ml of C-picoline is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, the residue is taken up in benzene, filtered through an aluminum oxide column and then evaporated under reduced pressure. The residue is recrystallized from methanol under clarifying by activated carbon to give the title product in 76.5% yield, m.p.: 99°-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[Br:22].C(OCC)(=O)C.[H][H]>[C].[Ru].C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Br:22]
Reactant: [H][H]
Reactant: Brc1ccc2ccccc2c1-c1c(Br)ccc2ccccc12
Agent: [Ru]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2
Temperature: 30 °C
Reaction time: 20 h

Procedure:
A 500 ml capacity stainless steel autoclave was charged with 35 g (0.085 mol) of 2,2'-dibromo-1,1'-binaphthyl, 5.25 g of 5%-ruthenium-carbon (manufactured by NECHEMCAT), 130 ml of ethyl acetate and 130 ml of 95% ethanol. After carrying out 20 hours of hydrogenation at a temperature of 100° C. under a hydrogen pressure of 50 kg/cm2, absorption of 4 mols of hydrogen per mol substrate was confirmed. The reaction mixture was cooled to 30° C. to remove the catalyst by filtration, the resulting filtrate was allowed to stand overnight at room temperature and then 30.6 g of the thus precipitated crystals were collected by filtration (yield, 85.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH3:12]>C(O)C>[NH2:12][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
To a solution of commercially available 2,6-dichloro-5-nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13.8 g, 83%). The compound thus obtained was suspended in an acetic acid solution (130 mL) of 30% hydrogen bromide. The suspension was stirred at 100° C. for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained was recrystallized from ethyl acetate to give the title compound (14.93 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(CO)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2ccc(C#N)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 5.5 g of 1-(4-cyanophenyl)-4-hydroxymethyl-piperidine and 5.16 g of triethylamine in 150 ml of methylene chloride, 5.84 g of methanesulphonic acid chloride are slowly added dropwise at ambient temperature and with stirring. After it has all been added the mixture is left to stand overnight and the solvent is removed under reduced pressure. The residue is chromatographed with methylene chloride/methanol (50:1) over silica gel. Yield: 6.95 g (93% of theory), Mass spectrum: (M+H)+ =295
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH2:14])=[NH:13].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[CH3:1][CH:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[NH:14][C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:13]=1
Reactant: CC(C)COc1ccccc1NC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (89 g) in denatured alcohol (300 ml) is added dropwise diethyl ethoxymethylenemalonate (93 g), and the mixture is refluxed with stirring for 3 hours. After cooling, the precipitate is collected by filtration, washed with denatured alcohol and petroleum ether and dried to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (94 g). M.p. 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].Cl.[N:18]([O-])=[O:19].[Na+].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N:18]=[O:19])[N:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[O:4]
Reactant: CCN(CC)c1cccc(NC(=O)OC)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=O)c(NC(=O)OC)c1
Yield: 98.8 %

Procedure:
While stirring a mixture of 6.0 g of 3-(methoxycarbonylamino)-N,N-diethylaniline, 10 ml of water, and 2.0 ml of concentrated hydrochloric acid at 0° C, 2.0 g of sodium nitrite was added to the mixture. When the first crystals were deposited in the mixture, 50 ml of water was further added to the mixture followed by stirring for 30 minutes. Thereafter, the reaction mixture obtained was poured into 300 ml of water followed by stirring well, neutralized by the addition of sodium bicarbonate, and extracted with ethyl acetate. After washing with water, the extract was dried by Glauber's salt and the solvent was distilled off using an evaporator to provide a yellow-green oily product. The crude product was purified by silica gel chromatography to provide 6.7 g (yield: 98%) of a product as a green solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8])[CH3:2].[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[O:11].C1(C=CC(O)=CC=1)O>C(Cl)Cl>[CH2:14]([O:13][C:9]([CH:10]1[CH:7]([CH3:8])[CH:6]=[CH:5][CH:4]([O:3][CH2:1][CH3:2])[O:11]1)=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CC=CC=COCC
Reactant: CCCCOC(=O)C=O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: CCCCOC(=O)C1OC(OCC)C=CC1C

Procedure:
Following the procedure of Example 12, a solution of 26.7 g. (0.226 mol) of 1-ethoxy-1,3-pentadiene (purity, 95%), 32.5 g. (0.25 mol) of butyl glyoxylate and 0.250 g. of hydroquinone in 250 ml. of methylene chloride was refluxed for 48 hours to give 28.0 g. of a mixture of 1-ethoxy-1,3-pentadiene and butyl glyoxylate and 20.32 g. of distilled 2H-pyran butyl ester (b1.0 = 100°-110° ) as an oil. Yield based on 1-ethoxy-1,3-pentadiene, 34%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]([C:15]1[O:16]C=CC=1)[C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH2:21].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.O>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[C:15]([OH:16])=[O:21])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: COC[C@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a stirred solution of NalO4 (969.0 mg, 4.5 mmol, 6.0 equiv) in H2O/CCl4/CH3CN (3/2/3, 21 mL) was added RuCl3 (53.0 mg, 0.26 mmol, 0.34 equiv). After stirring for 15 minutes, a solution of ((1S,2R)-1-furan-2-yl-3-methoxy-2-methyl-propyl methylcarbamic acid tert-butyl ester (214.0 mg, 0.76 mmol) in CH3CN (4 mL) was added. After 15 minutes, the mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed successively with saturated aqueous NaHSO3, brine, dried over Na2SO4, and concentrated in vacuo to give (2S,3R)-2-(tertbutoxycarbonyl-methyl-amino)-4-methoxy-3-methyl-butyric acid (180.0 mg).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:16])=[O:15])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][NH:28][CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:38]([O-])(=O)C.[Na+].C(O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:15])=[O:16])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][N:28]([CH3:38])[CH2:27]2)=[O:25])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(=O)[O-]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(c3ncc(Br)cc3F)CNC2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CC(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)(c2ncc(Br)cc2F)C1
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To a mixture of example 13 (0.05 g, 81.8 μmol, Eq: 1.00), sodium acetate (14.8 mg, 180 μmol, Eq: 2.2) and acetic acid (10.8 mg, 10.3 μl, 180 μmol, Eq: 2.2) in dichloromethane (0.5 ml) was added at 25° C. aqueous formaldehyde solution (36%; 19.1 mg, 17.5 μl, 229 μmol, Eq: 2.8). The mixture was stirred for 45 min, then sodium triacetoxyborohydride (55.5 mg, 262 μmol, Eq: 3.2) was added in one portion at 0-5° C. The cooling bath was removed after 10 min and stirring was continued at 25° C. for further 18 h. The reaction mixture was quenched with aqueous 0.5 M NaOH-solution (2 ml), stirred for 2 min, then the layers were separated. The aqueous layer was extracted with three portions of AcOEt (each 5 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative HPLC to yield the title compound as a colorless amorphous solid (0.0206 g; 40%). m/z=626.1 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH:24]([O:30][CH2:31][CH3:32])[C:25]1[N:29]=[CH:28][NH:27][N:26]=1)[CH3:22].C(N(CC)CC)C>ClCCl>[CH2:31]([O:30][CH:24]([O:23][CH2:21][CH3:22])[C:25]1[N:29]=[CH:28][N:27]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:26]=1)[CH3:32]
Reactant: CCOC(OCC)c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A solution of trityl chloride (43.4 g) in dichloromethane (120 ml) was added dropwise, over thirty minutes, to a stirred solution of 1,2,4-triazole-3-carboxaldehyde diethyl acetal (21.67 g, prepared as described by Mukahami et al, Heterocycles, 1981, 15, 301) and triethylamine (25 ml) in dichloromethane (200 ml). After stirring for a further three hours, the mixture was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. A solution of the residual oil in ether (250 ml) crystallised to give 1-trityl-1,2,4-triazole-3-carboxaldehyde diethyl acetal (22.14 g, m.p. 120-124° C.). Trimethylsilyl bromide (14 ml) was added rapidly to a stirred solution of this acetal (6.2 g) in toluene (80 ml). After a further fifteen minutes, the solution was poured into a rapidly-stirred mixture of saturated sodium carbonate solution (200 ml), solid sodium carbonate (10 g) and ethyl acetate (150 ml). The mixture was stirred rapidly for ten minutes, the phases separated and the organic layer washed with water, dried over magnesium sulphate, and evaporated under reduced pressure. The residual oil was chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give the title compound (2.57 g). The deacetalation can also be carried out using pyridinium p-toluenesulphonate in acetone.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[C:10]([F:24])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>CO>[F:1][C:2]1[C:11]([CH2:12][NH2:13])=[C:10]([F:24])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1c(F)cc2ncccc2c1F
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1c(F)cc2ncccc2c1F
Yield: 88.4 %

Procedure:
To a solution of 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 15.73 mmol) in CH3OH (150 mL) was added hydrazine monohydrate (0.50 g, 15.73 mmol). The solution was heated at reflux for 3 h. After cooling, the mixture was filtered through celite. The filtrate was concentrated in vacuo. EtOAc was added to dilute the residue, filtered and concentrated in vacuo to afford (5,7-difluoroquinolin-6-yl)methanamine (2.70 g, 88%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (d, 1H), 8.38 (d, 1H), 7.59 (d, 1H), 7.43 (m, 1H), 4.12 (s, 2H). LCMS (method B): [MH]+=195.0, tR=0.17 min.