Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][C:25]([OH:27])([CH3:28])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(O)CN
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 7 %

Procedure:
As described in example 10, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and 1-amino-2-methyl-propan-2-ol instead of DL-2-amino-1-propanol, was converted to the title compound (7.5 mg, 7%) which was obtained as a colorless solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][C@@H:24]([CH3:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15](Br)=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.C[Li].O>C(OC)(C)(C)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][C@@H:24]([CH3:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15]([CH3:27])=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(C(F)(F)F)cc3N21
Reactant: CI
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc2c(cc1C(F)(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Yield: 67.5 %

Procedure:
(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.38 g, 0.8 mmol) and methyl iodide (0.25 g, 1.6 mmol) were dissolved in tert-butylmethylether (3 mL). A solution of methyl lithium in diethylether (0.66 mL, 1.6 M) was added with cooling (0° C.) and stirring. The mixture was stirred for ½ h at 0° C., water (25 mL) was added and the mixture was extracted with diethylether (2×20 mL). Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (n-hexane/diethylether 4:1) yielded the title product as light yellow oil (0.20 g, 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>CN(C)C=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
16.1 g (60 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 15.9 g (90 mmol) of 1-benzyl-piperazine and 7.3 ml (90 mmol) of pyridine are stirred into 60 ml of dimethyl formamide at 100° C. A further 5.8 g (33 mmol) of 1-benzyl-piperazine is added after 7 hours and stirring of the reaction mixture is continued for 12 hours at 100° C. When the reaction mixture is cold it is poured out on 300 ml of ice water and the solid which precipitates is suction filtered. The aqueous phase is extracted twice with 200 ml of dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution, dried, filtered and concentrated by evaporation in vacuo. The solid residue obtained is recrystallized from 500 ml of ethanol together with the solid initially obtained. 23.4 g (95%) of orange red crystals melting at 220° to 221° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[CH2:22][CH:21]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])[CH2:20][CH2:19]2>>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:6]1[CH:10]=[C:9]([NH:11][C:29](=[O:30])[CH:28]([NH:27][CH:21]2[CH2:20][CH2:19][C:18]3[C:23](=[C:24]([F:26])[CH:25]=[C:16]([F:15])[CH:17]=3)[CH2:22]2)[CH2:32][CH2:33][CH3:34])[N:8]=[CH:7]1)[CH3:5]
Reactant: COC(=O)C(C)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)C(=O)OC)cn1

Procedure:
2-(4-Nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 435.5 m/z (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:29]5[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH3:38][O:37][C:16]1[CH:17]=[C:18]([C:21]2[S:25][C:24]3=[N:26][CH:27]=[C:28]([C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[N:23]3[N:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)nn23)cn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCNCC5)c(OC)c4)nn23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
4-{2-Methoxy-4-[5-(6-methoxy-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (11 mg; 0.0204 mmol; 1 eq) was dissolved in anhydrous DCM (1 ml) and 4M HCl (0.051 ml, 0.204 mmol, 10 eq) was added. The reaction mixture was stirred at RT for 2 h. The excess of acid was co-evaporated with DCM (×3) to give the desired product (9 mg, 100%) as a white solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.24 min, [M+H]+ m/z 438.2; 1H NMR (300 MHz, MeOD) δ 8.98 (s, 1H), 8.54 (m, 1H), 8.25 (m, 1H), 7.66 (m, 2H), 7.28 (m, 2H), 4.76 (m, 1H), 4.10 (s, 3H), 3.94 (s, 3H), 3.45 (m, 2H), 3.21 (m, 2H), 2.17 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:17])[CH2:15][CH2:14][CH:13]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:12][CH2:11]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2nc3ccccc3o2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nc4ccccc4o3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-benzooxazol-2-yl-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:20]2)=[CH:14][CH:13]=1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH2:44][CH2:45][N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[NH:48][C:47]1=[O:55]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:2]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][N:27]([CH2:43][CH2:44][CH2:45][N:46]4[C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=5[NH:48][C:47]4=[O:55])[CH2:26][CH2:25]3)[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:20]2)=[CH:16][CH:17]=1)([CH3:1])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 2-methyl-2-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate (0.22 g, 0.46 mmol) and potassium carbonate (0.095 g, 0.69 mmol) in N,N-dimethylformamide (4 mL), was added 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.139 g, 0.46 mmol). After stirring at 55° C. for 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.26 g, 86%); 1H NMR (DMSO-d6): δ 1.35 (s, 9H), 1.49 (s, 6H), 1.56 (d, 2H, J=13.6 Hz), 1.82 (t, 2H, J=6.4 Hz), 2.32-2.34 (m, 2H), 2.45-2.50 (m, 2H), 2.66-2.72 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.45 (s, 2H), 4.53 (s, 2H), 6.77-6.84 (m, 5H), 6.96 (d, 3H, J=3.2 Hz), 7.17-7.24 (m, 5H), 10.79 (s, 1H); MS for C38H47N5O5 m/z 654.18 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:19]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:6]([CH2:4][OH:3])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (1.00 g, 2.64 mmol) in THF (15 mL) at 0° C. were added portion wise LiAlH4 (211 mg, 5.56 mmol). Stirring was continued for 2 hours, and the reaction mixture was quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. Flash chromatography (SiO2, EtOAc) to yield 0.70 g (79%) of the title product as a white solid ES-MS m/e: 336.3 (M+H+).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)(C)C>[CH2:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C1CCCCC1

Procedure:
One mole of 4-hydroxybenzoic acid was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catalyst. This reaction was carried out in isopropyl alcohol at a temperature of 130°-140° C. and a hydrogen pressure of 20-40 kg/cm2 (gauge) After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to recover the solvent. The resulting residue was recrystallized from a mixture of benzene and hexane to obtain cyclohexane-4-carboxylic acid. This product had a melting point of 67.0°-68.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][NH2:13].[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][NH:13][C:32]([NH:31][C:23]1[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=1[CH:28]([CH3:30])[CH3:29])=[O:33]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCC(CN)c1cccc(OC)c1OC
Solvent: Cc1ccccc1
Product: CCCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccc(OC)c1OC
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To 0.65 g (2.6 mmol) of (+)-2-(2,3-dimethoxyphenyl)-heptylamine was added dropwise a 5.2 ml of 0.502M toluene solution of 2,6-diisopropylphenyl isocyanate at room temperature and the whole was stirred overnight. The reaction mixture was concentrated and the resulting residue was crystallized from methanol. The crystals were collected by filtration and washed with n-hexane to give 0.512 g (43.5% yield) of (+)-1-(2-(2,3-dimethoxyphenyl)heptyl)-3-(2,6-diisopropylpheyl)urea.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[C:5]([Cl:3])(=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCCC/C=C\CCCCCCCC(=O)Cl
Temperature: 40 °C
Reaction time: 0.92 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 13.15 ml (180 mmol) of thionyl chloride, and a water condenser, is placed 28.45 ml (100 mmol) of palmitoleic acid. Addition of the thionyl chloride is completed with heating to about 40° C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 55 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, (Z)-hexadec-9-enoyl chloride. This acyl chloride, 10.95 g (40 mmol), is put into a dry separatory funnel and combined with 75 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: C[N:2]1[C@@H:7]2[CH2:8][C:9]([CH2:11][C@H:3]1[CH2:4][CH2:5][CH2:6]2)=[O:10].[CH2:12]([O:14][C:15](Cl)=[O:16])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([N:2]1[CH:7]2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:11][C:9](=[O:10])[CH2:8]2)=[O:16])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: CN1[C@@H]2CCC[C@H]1CC(=O)C2
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C2CCCC1CC(=O)C2
Yield: 86.5 %

Procedure:
186.8 g of pseudo-pelletierine and 264 g of freshly distilled chloroformic acid ethyl ester are slowly heated to a boil in 1 liter of absolute toluene within one hour. A vigorous evolution of gas sets in. The mixture is heated to a boil under reflux for a further 16 hours, then cooled and filtered. The filtrate is concentrated in a vacuum, and the residue is purified through vacuum distillation to obtain 223 g (86.5 percent) of light-yellow oil (b.p. 101° C. at 2.7 Pa.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:26]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:29]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[C@@H:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:27]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[C:26]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:29]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:28]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:27]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To an oven-dried 25 mL round-bottomed flask equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed methyl(triphenylphosphoranylidene)acetate (199 mg, 0.597 mmol) and toluene (5 mL). To this heterogeneous solution was added a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate (93 mg, 0.199 mmol) in toluene (3 mL). The reaction mixture was heated to reflux and stirred overnight. The volatiles were then removed in-vacuo and the yellow oil was purified by Combiflash (10 to 30% ethyl acetate in hexanes) to afford 83 mg (80%) of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate. LCMS (ESI): 424 (M-CO2t-Bu+2H+), 468 (M-t-Bu+2H+), 524 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.Cl.[OH:13][NH2:14]>N1C=CC=CC=1.C(O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5](/[CH:6]=[N:14]/[OH:13])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Br)cc1F
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: c1ccncc1
Product: O/N=C/c1cc(F)c(Br)cc1F
Yield: 53.5 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzaldehyde (7.0 g, 31.67 mmol), hydroxyl amine hydrochloride (2.42 g, 34.84 mmol) in pyridine (35 mL) and ethanol (35 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, eluting with 5-100% ethyl acetate in hexanes) to provide the title compound as a yellow solid (4.0 g, 53%): ESIMS m/z 238 [(M+2H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Li]CCCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]([OH:20])([CH3:21])[CH3:18])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 4-Bromo-1-methyl-2-trifluoromethyl-benzene (3.4 g, 14.2 mmol) in THF was added n-BuLi at −78° C. After the reaction mixture was stirred at −78° C. for 30 minutes, dry acetone was slowly added. The resulting content was maintained at −78° C. for 3 hours and slowly warmed up to RT overnight. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was then washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude solid was purified via flash chromatography (15% EtOAc in n-hexane) yielded the title compound as an oil (2.7 g, 86%).
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][Al:5]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: Oc1ccccc1-c1ccccc1
Product: CC(C)C[Al](Oc1ccccc1-c1ccccc1)Oc1ccccc1-c1ccccc1

Procedure:
In a manner analogous to that described in Example 1, 17.5 g of triisobutylaluminum and 30 g of 2-phenyl-phenol are reacted to give bis(2-biphenylyloxy)isobutylaluminum and this is then reacted with 11.2 g of pyridine-N-oxide-2-thiol to give the title compound. The isolation of the product is carried out in an analogous manner. The yield of bis-(2-biphenylyloxy)(2-pyridinethiolato)aluminum N-oxide is 30.25 g, about 69.9% of theory, of a white finely granular powder with a melting point of 219°-221° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C(N(C(C)C)CC)(C)C.[CH2:20]([O:27][C:28]([N:30]([CH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)[C:31]([NH:33]C(OCC1C=CC=CC=1)=O)=[NH:32])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O-].[Na+]>C(#N)C.CO>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([NH:1][C:51]([C@H:48]3[CH2:47][CH2:46][C@H:45]([CH2:44][N:30]([C:28]([O:27][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[C:31]([NH2:33])=[NH:32])[CH2:50][CH2:49]3)=[O:52])=[C:3]2[CH:10]=[CH:9]1
Reactant: N=C(NC(=O)OCc1ccccc1)N(C[C@H]1CC[C@H](C(=O)Cl)CC1)C(=O)OCc1ccccc1
Reactant: Nc1ccnc2[nH]ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N(C[C@H]1CC[C@H](C(=O)Nc2ccnc3[nH]ccc23)CC1)C(=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of 4-amino-1H-pyrrolo[2,3-b]pyridine (2.46 g) dissolved in acetonitrile (100 ml) was added diisopropylethylamine (6.5 ml). The mixture was stirred at 40° C. Trans-4-(1,3-dibenzyloxycarbonylguanidinomethyl)cyclohexanecarboxylic chloride (19.86 g) was added to this solution and the mixture was stirred at 50° C. for 2 hours. Then, diisopropylethylamine (6 ml) and trans-4-(1,3-dibenzyloxycarbonylguanidinomethyl)cyclohexanecarboxylic chloride (15.03 g) were added thereto and the mixture was stirred at 50° C. for 2 hours. The solvent was distilled away under reduced pressure and the residue obtained was dissolved in methanol (100 ml). Sodium methoxide (1.05 g) was added to this solution and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The solvent was distilled away under reduced pressure, chloroform (200 ml) was added thereto and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3.61 g of trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-benzyloxycarbonylguanidinomethyl)cyclohexanecarboxamide, melting point 160°-162° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>P([O-])([O-])([O-])=O>[CH2:1]([O:8][C@H:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](C)OCc1ccccc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
Ethyl 2-benzyloxypropionate (300 mg) was suspended in 0.1 M phosphate buffer (pH 6.5) (30 mL). “Lipase Fine Grade” (trade name, product of SEIKAGAKU CORPORATION, Rhizopus delemer; 6 mg) was added, followed by stirring at 30° C. for 24 hours. Ethyl acetate was added to the reaction mixture, denatured proteins were removed by filtration through celite. The mixture was adjusted to pH 7.0 with a 1 N aqueous solution of sodium hydroxide, followed by extraction. The organic layer was washed with a 5% aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. The solvent was distilled off to afford the title compound as an oil (102 mg, 98.8% ee).