Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:30]1[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=1>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[CH3:36][C:35]1[C:30]([N:20]2[CH2:21][CH2:22][CH:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)[CH2:18][CH2:19]2)=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: CS(=O)(=O)c1ccc(N2CCC(C3CCNCC3)CC2)cc1
Reactant: Cc1nccnc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1nccnc1N1CCC(C2CCN(c3ccc(S(C)(=O)=O)cc3)CC2)CC1
Reaction time: 8 h

Procedure:
The 1-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine (80 mg, 0.25 mmol, prepared as for Example 1, Step 2) and cesium carbonate (243 mg, 0.75 mmol) were slurried in NMP (0.5 ml) and the 2-chloro-3-methylpyrazine (38 mg, 0.30 mmol) added. The mixture was stirred at 150 C overnight. The slurry was diluted with 15% saturated sodium bicarbonate:water (40 ml) and extracted with DCM (3×25 ml). The combined organic fraction was washed with 4:1 water:saturated sodium bicarbonate (2×), brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 5% acetone:DCM to yield the titled compound.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([NH:9][C@H:10]([C:16]([O-:18])=[O:17])[CH2:11][CH2:12][C:13]([O-:15])=[O:14])=[O:8].[Ca+2]>O>[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:8])[C:6]1[CH:19]=[CH:2][CH:3]=[N:4][CH:5]=1
Reactant: O=C([O-])CC[C@H](NC(=O)c1cncc(O)c1)C(=O)[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)CC[C@H](NC(=O)c1cccnc1)C(=O)O
Reaction time: 48 h

Procedure:
The study of acute daily toxicity of Compound I was carried out on white nondescript male mice with body weight 25-28 g, which lived in habitual conditions in vivarium and received feed and water ad libitum. Single dose of Compound I was administered intraperitoneally. The animals were under observation for 2 days after the dosing. The dose levels of Compound I used in the toxicity study were as follows: 800 mg/kg, 1000 mg/kg, 1200 mg/kg, 1500 mg/kg, 1600 mg/kg. Compound I was dissolved in distilled water and administered in 0, 1 ml per 10 g of the body weight of the animal when the doses 800 mg/kg and 1000 mg/kg, and in 0.2 ml per 10 g of the body weight when the doses 1200 mg/kg, 1500 mg/kg, 1600 mg/kg were used. Control animals received distilled water in the volume 0.2 ml per 10 g of the body weight.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[CH:15]([Mg]Br)=[CH2:16]>C1COCC1>[CH3:1][C:2]1[C:9]2[NH:10][CH:16]=[CH:15][C:8]=2[C:5]([C:6]#[N:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: CSc1cc(C)c([N+](=O)[O-])cc1C#N
Solvent: C1CCOC1
Product: CSc1cc(C)c2[nH]ccc2c1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-2-(methylthio)-5-nitrobenzonitrile (1.6 g, 7.68 mmol) in THF (80 mL) at −78° C. under nitrogen, was added rapidly 1M vinylmagnesium bromide in THF (30.7 mL, 30.7 mmol). After addition was complete, the reaction was stirred at −78° C. for 30 min. The reaction was then quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The pure title compound was isolated using FCC (0-50% EtOAc in heptanes). MS (ESI−) m/z 201.2 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:25]([CH2:27][CH2:28]O)[CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([N:25]([CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1)[CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN(C)CCO
Reactant: O=c1ccc2ccc(O)cc2o1
Product: CCCCCCCCCCCCN(C)CCOc1ccc2ccc(=O)oc2c1
Yield: 46.7 %

Procedure:
7-Hydroxycoumarin (6.0 g, 37.0 mmol) and 2-[N-dodecyl-N-methylamino] ethanol (9.0 g, 37.0 mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (6.7 g, 47%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][CH3:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([N:24]([CH3:25])[C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: CN[C@H](Cc1ccccn1)CN1CCN(c2ccccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of (2R)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-N-methyl-3-pyridin-2-ylpropan-2-amine (90 mg.; 0.26 mmol, from Example 17) in dichloromethane (3 mL) at 0° C. was added a solution of potassium carbonate (180 mg.; 1.3 mmol) in water (0.5 mL), followed by a solution of 1-methyl-1-cyclohexanecarbonyl chloride (41 mg.; 0.26 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, diluted with dichloromethane (5 mL), and the layers allowed to separate. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (10% methanol/ethyl acetate) to yield the free base of the title compound as a clear oil (68 mg.; 56%). Treatment with an equimolar amount of fumaric acid in acetonitrile afforded the fumarate salt as a white crystalline solid, m.p. 145–146° C.; MS (+) ESI [M+H]+ @ m/z 465; 1H NMR, 400 MHz, DMSO-d6. Analysis for C28H40N4O2.C4H4O4 Calculated: C, 66.18; H, 7.64; N, 9.65 Found: C, 65.95; H, 7.41; N, 9.54
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:29][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCCCC3)ccc12
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCCCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-cyclohex-1-enyl-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.78-8.80 (m, 1H), 7.96-7.95 (m, 1H), 7.76 (d, J=9.04 Hz, 1H), 7.59 (d, J=8.80 Hz, 1H), 3.25-3.40 (m, 2H), 2.85-2.95 (m, 1H), 2.01-2.15 (m, 2H), 1.86-1.99 (m, 10H), 1.55-1.60 (m, 2H), 1.40-1.45 (m, 2H), 1.23-1.26 (m, 3H). m/z: 421 [M+H]+
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:14][CH2:13][Br:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
A mixture of 1.52 g (10 mmol) of 4-acetoxyphenol, 2.22 g (11 mmol) 1,3-dibromopropane, and 2.98 g (21 mmol) of anhydrous potassium carbonate in dimethylformamide was stirred rapidly at room temperature for 4 hours. Ethyl acetate was added, and the salts present were removed by filtration. The solvent was removed under reduced pressure, and the residue chromatographed over silica gel. Elution with 15% ethyl acetate-hexane gave 270 mg of the title compound, which was homogeneous by thin layer chromatography (15% by volume of ethyl acetate/hexane on silica gel plates).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.C1(C)C=CC(S(O[CH2:20][CH2:21][CH:22]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O)=CC=1.[OH-].[Na+].Cl>C(O)C>[F:28][C:27]([F:29])([F:30])[CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:20][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:1][CH:2]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: OCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(CCOc1ccc(CO)cc1)C(F)(F)F
Reaction time: 6 h

Procedure:
In a round-bottomed flask, a solution of 2.4 g of p-hydroxybenzyl alcohol in 10 ml of ethanol and 5.3 g of ()-3-trifluoromethylheptyl p-toluenesulfonate were placed, and a solution of 0.8 g of sodium hydroxide in 10 ml of ethanol was added thereto dropwise, followed by 6 hours of heat-refluxing, cooling by standing and acidification with hydrochloric acid. The organic layer was extracted with diethyl ether. The resultant ether solution was dried with sodium sulfate and subjected to distilling-off of the solvent and purification by silica gel column chromatography to obtain 4.4 g of (+)-p-(3-trifluoromethylheptyloxy)benzyl alcohol. [α]D28 +1.0 °, [α]43527 +2.4° (c 5.0, chloroform).
Reaction SMILES: Br[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33].Cl.Cl.[CH3:38][N:39]([CH2:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)[CH3:40].C(=O)([O-])[O-].[K+].[K+]>>[CH3:38][N:39]([CH2:41][C@H:42]1[CH2:46][CH2:45][N:44]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[N:23]=[C:22]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=[CH:20][N:19]=4)[CH:11]=3)=[O:8])=[CH:5][C:4]=2[C:32]([F:35])([F:34])[F:33])[CH2:43]1)[CH3:40]
Reactant: Cc1ccc(NC(=O)c2ccc(CBr)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN(C)C[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[C@H](CN(C)C)C3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 47, except that 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 82) and (S)-3-(dimethylaminomethyl)pyrrolidine dihydrochloride (Reference Example 35) were used, and that potassium carbonate was used in an amount of 5 equivalents based on a raw material.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[O:24][C:25]3[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:17]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[O:24][C:25]3[CH:31]=[C:30]([CH2:32][C:33]([NH:14][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=4)=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:17]=1
Reactant: O=C(O)Cc1ccc2nc(Nc3cccnc3)oc2c1
Reactant: COC(=O)CCCOc1cccc(N)c1
Product: O=C(O)CCCOc1cccc(NC(=O)Cc2ccc3nc(Nc4cccnc4)oc3c2)c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with 2-(3-pyridylamino)-6-carboxymethylbenzoxazole according to the method described in example 7 to produce the methyl ester of 2-(3-pyridylamino)-6-{3-[3-carboxypropoxy]anilinocarbonyl methyl}benzoxazole
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([NH2:17])=O)[NH:11][C:10]3[N:18]([CH3:27])[N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:9]2=3)=[C:4]([CH3:28])[CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]#[N:17])[NH:11][C:10]3[N:18]([CH3:27])[N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:9]2=3)=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C1SCC(C(N)=O)Nc2c1c(-c1ccccn1)nn2C
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1C1SCC(C#N)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
To a solution of rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxamide (0.050 g, 0.055 mmol, Example #10) in DCE (0.5 ml)/pyridine (0.2 ml) at 0° C. was added POCl3 (0.051 ml, 0.545 mmol) dropwise. The icebath was removed about 5 min after the complete addition. The reaction was stirred at rt for about 16 h. The reaction was quenched by adding it dropwise to stirring H2O (20 mL). A saturated solution of NaHCO3 was added slowly until gas evolution had stopped. The reaction was extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to give rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carbonitrile (0.026 g, 0.028 mmol, 52%) as a white solid: LC-MS (Table 1, Method g): LC-MS (Table 1, Method g) Rt=2.52 min, m/z 440/442 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.50-8.47 (m, 1H), 7.85-7.82 (m, 1H), 7.79-7.71 (m, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.26-7.19 (m, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.82 (s, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.02-4.98 (m, 1H), 3.79 (s, 3H), 3.04 (dd, J=15.3, 4.9 Hz, 1H), 2.80 (dd, J=15.4, 2.2 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[NH2:13][CH:14]([C:29]1[N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=[C:32]([CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[N:33]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1>>[CH3:39][C:35]([CH3:38])([CH2:36][CH3:37])[CH2:34][C:32]1[N:33]=[C:29]([CH:14]([NH:13][C:9]([O:11][CH3:12])=[O:10])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[N:30]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH:31]=1
Reactant: COC(=O)Cl
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.02 mL, 0.16 mmol) followed by methyl chloroformate (5 μL, 0.05 mmol) were added to an ambient temperature solution of tert-butyl 2-{1-amino-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (24 mg, 0.05 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 20% ethyl acetate/hexane afforded tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methoxy carbonyl)amino]ethyl}-1H-imidazole-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[C:17](Cl)=[CH:18][C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[N:20][CH:21]=2)=[O:14])=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]2[O:14][C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:20]=[CH:21][C:16]=3[N:15]=2)=[CH:11][C:10]=1[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((5-((4-(benzyloxy)-3-fluorobenzoyl)amino)-4-chloropyridin-2-yl)oxy)propan-2-yl)carbamate (6.02 g), potassium carbonate (3.14 g) and copper(I) iodide (216 mg) in DMF (30 mL) was stirred at 160° C. for 2 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (1.35 g).
Reaction SMILES: [C:1]([O:7]C(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:12]([NH:14][CH3:15])[CH3:13]>C(O)(C)(C)C>[CH2:12]([N:14]([CH3:15])[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[O:4])[CH3:13]
Reactant: CCNC
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Product: CCN(C)C(=O)CC(C)=O
Temperature: 130 °C
Yield: 97.8 %

Procedure:
Into a 1 l stainless steel autoclave are introduced 158 g (1 mol) of tert-butyl acetoacetate and 61 g of N-ethyl-N-methylamine (1.05) mol), followed by heating at 130° C. for 6 hours; the pressure does not exceed 10 bars. The contents of the autoclave are transferred to a round-bottomed flask and the tert-butanol formed is evaporated under reduced pressure to give 140 g (98%) of N-ethyl-N-methylacetoacetamide which is sufficiently pure to be used in the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[ClH:10]>>[ClH:10].[NH2:8][C:5]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:3][CH:4]=1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: Nc1ccnn1-c1ccc(F)cc1

Procedure:
4-Fluorophenylhydrazine was converted to this product by the method described in Farmaco 22, 68, 1967. mp of HCl salt, 201°-210°
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:37]1[CH2:36][CH:35]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][CH:30]=2)[CH2:39][CH2:38]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Product: O=C(CCCN1CC=C(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (3) synthesized in Reference Example 3 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [C:1]([C:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:15].[Na+].[Na+].S(=O)(=O)(O)O>CCOCC.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1(O)CCCCC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1CCCCC1=O
Temperature: 25 °C

Procedure:
A solution of 31.25 g. (0.20 mole) t-butylcyclohexanol in 80 ml. of ethyl ether was cooled to 10° C. To this was added dropwise, with stirring, a solution of 21.0 g. (0.07 mole) sodium dichromate dihydrate and 15.75 ml. (0.30 mole) concentrated sulfuric acid in 100 ml. water while maintaining the reaction mixture below 25° C. The mixture was then warmed to room temperature, stirred for two hours, poured onto ice-water, ether layer separated, the aqueous phase extracted again with ether and the combined extracts washed with water, sodium bicarbonate and dried (MgSO4). Evaporation of the ether afforded 30.6 g. (99%) of the desired ketone.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][N:11]=C(N)N)[C:3]([OH:5])=[O:4]>[OH-].[Na+]>[NH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH:6][CH:2]([C:3]([OH:5])=[O:4])[CH3:1])[C:15]([OH:17])=[O:16]
Reactant: C[C@@H](N[C@@H](CCCN=C(N)N)C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(NC(CCCN)C(=O)O)C(=O)O
Reaction time: 36 h
Yield: 67 %

Procedure:
20 g of D-octopine in 100 ml of 1M NaOH was heated at 100° C. for 12-20 hr. The solution was evaporated to dryness to remove the ammonia and then dissolved in water. The pH was adjusted to 0.89 with 6M HCl and the solution was applied to a column of 200 g of Dowex-50 (H+ -form). The column was washed with water and then developed with 10% (v/v) aqueous ammonium hydroxide. The fractions that contained ninhydrin-positive material after removal of ammonia were combined, evaporated to dryness on a rotary evaporator, and then dissolved in 100 ml of water. The pH was adjusted to 5.2 with 3M HCl. After the addition of 5 volumes of ethanol, the solution was left at 0°-5° C. for 24 to 48 hr. A white solid was collected by filtration in an amount of 11.1 g, and identified as octopinic acid (67% yield, 99% pure). The absence of significant racemization at the chiral carbon atoms is supported by the fact that the product gave a single peak by HPLC in the 80% methanol in water, partisil SAX column solvent system that separates D-octopinic acid from L-allooctopinic acid and by its optical rotation ((α)D22 =20°, C 0.5, H2O; publ. 19°).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.227 ml 2-(3,4-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 515 mg colorless viscous oil (97%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC1C=CC(C[CH:19]2[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21][C:20]2=[O:28])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH:19]2[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21][C:20]2=[O:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1

Procedure:
The title compound was prepared using 4-(methylsulfonyl)benzaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).