Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].BrBr>C(O)(=O)C>[CH3:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CC1CC(=O)NN=C1c1cccc(C#N)c1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1cccc(C#N)c1

Procedure:
A 15 g. portion of m-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal of Medicinal Chemistry 17, 281 (1974)] is suspended in 75 ml. of glacial acetic acid with stirring at steam bath temperature. Then 3.75 ml. of bromine in 25 ml. of acetic acid is added dropwise over a 15 minute period. The reaction mixture is heated on a steam bath for an additional 30 minutes then is poured onto crushed ice. The resulting solid is collected by filtration, copiously washed with water and dried to afford m-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a cream colored solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[O:40][CH3:41])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[CH:9]=4)[C:14]3=[O:18])=[CH:35][C:34]=2[O:40][CH3:41])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(N)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction of 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochromen-1-one with 4-(4-Amino-2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester by method AJ resulted in the desired product with the molecular weight of 549.67 (C31H39N3O6); MS (ESI): 550 (M+H+).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([NH2:38])[C:32]=1[CH3:39]>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([NH:38][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:26])[C:32]=1[CH3:39]
Reactant: COC(=O)c1c(C)ccc(N)c1C
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Product: COC(=O)c1c(C)ccc(NC(=O)c2nc(-c3ccccc3C)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1C
Yield: 65.4 %

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole4-carboxylic acid (Example 93) (374 mg, 1.00 mmol) was reacted with 3-amino-2,6-dimethyl-benzoic acid methyl ester (prepared from 2,6-dimethyl-benzoic acid by nitration, esterification and reduction) (179 mg, 1.00 mmol) according to the procedure of Example 20, step d. The crude product was purified by flash chromatography (silica, hexane/ethyl acetate 2:1) to afford colourless foam (344 mg, 64%). 1H NMR (300 MHz, CDCl3) 9.32 (1H, br s), 9.22 (1H, br s), 8.12 (1H, d), 7.55 (1H, d), 7.29 (3H, m), 7.08 (1H, d), 3.92 (3H, s), 3.12 (2H, m) 2.63 (3H, s), 2.28 (6H, s), 1.97 (3H, s), 1.74-1.44 (14H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C@:16]([NH:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])([C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])[C@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:15])[CH3:14].[CH2:53]=[O:54]>C1COCC1>[Si:40]([O:39][C@H:37]([C@@:16]([NH:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])([C:13](=[O:15])[CH2:14][CH2:53][OH:54])[C@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:38])([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:42]
Reactant: C=O
Reactant: CC(=O)[C@](NC(=O)N(C)C)([C@H](C)O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/c1ccccc1)NC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](NC(=O)N(C)C)(C(=O)CCO)[C@@H](/C=C/c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame-dried 250-mL round-bottomed flask was charged with diisopropylamine (5.8 mL, 41.3 mmol, 3.5 equiv) and THF (100 mL). The resulting solution was cooled to 0° C. and n-butyllithium (1.65 M in hexanes, 25.0 mL, 41.3 mmol, 3.5 equiv) was added dropwise. The reaction was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of ketone 6 (6.8 g, 11.8 mmol, 1.0 equiv) in THF (25 mL) was added dropwise, and the resulting mixture was stirred for 45 min and warmed to −45° C. Formaldehyde gas (CH2O(g), prepared by heating paraformaldehyde ((CH2O)n, 5.0 g, 166.7 mmol, 14.1 equiv) to 145° C. under a positive pressure of nitrogen) was bubbled through the reaction. The reaction was stirred at −45° C. until full conversion to product was indicated by TLC analysis, typically 1 h. The reaction was quenched by the addition of a saturated NH4Cl(aq.) (30 mL), and the resulting mixture was extracted with Et2O (3×30 mL). The combined organic extracts were dried with magnesium sulfate and concentrated in vacuo. The crude product was purified via flash chromatography (50:50 to 60:40 EtOAc:hexanes) to give alcohol 8 as a clear, viscous oil (4.9 g, 70%). Analytical data: [α]D19+11.2 (c=1.00, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.35-7.26 (m, 10H), 7.21 (t, J=7.0 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0, 9.0, 1H), 5.32 (s, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.02 (d, J=12.0 Hz, 1H), 4.98 (t, J=8.5 Hz, 1H), 4.40 (q, J=6.5 Hz, 1H), 3.85-3.82 (m, 1H), 3.73-3.71 (m, 1H), 2.93 (s, 6H), 2.82-2.70 (m, 2H), 1.23 (d, J=6.5 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 208.5, 158.7, 155.9, 136.8, 136.6, 132.3, 128.4, 128.3, 128.1, 127.9, 127.5, 127.1, 126.6, 74.2, 71.7, 66.6, 58.1, 55.2, 40.7, 36.6, 25.7, 19.2, 17.8, −3.7, −5.0; LRMS (ESI+) Calcd. for C32H47N3O6Si+H, 598.33. Found, 598.32. IR (thin film, cm−1) 3429, 2954, 1716, 1646, 1507, 1252, 966, 695, 530; TLC (50:50 hexanes:EtOAc): Rf=0.20.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([OH:16])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: O=C1CCC(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Temperature: 0 °C

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(4-oxo-cyclohexyl)-pyrrolidin-2-one (Example 14) (6.19 g, 18.19 mmol) in MeOH (200 mL) and cool to 0° C. under nitrogen. Add sodium borohydride (1.38 g, 36.39 mmol) and stir the solution at 0° C. for 4 hours. Add water (200 mL) and extract the aqueous layer with ethyl acetate (3×300 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 50-80% EtOAc-Hexane) to give 5.49 g (88%) of the title product as a white solid. 1H NMR (CDCl3) δ 7.37 (d, 1H), 7.22 (d, 1H), 7.17 (dd, 1H), 3.91-4.00 (m, 1H), 3.52-3.62 (m, 1H), 3.27-3.36 (m, 1H), 3.12-3.21 (m, 2H), 2.73-2.82 (m, 2H), 1.98-2.07 (m, 3H), 1.56-1.77 (m, 4H), 1.38-1.54 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].Cl.[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][NH:34][CH2:33][C:31]=2[N:32]=1.C(Cl)CCl.CN1CCOCC1>C(#N)C>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:34]1[CH2:35][CH2:36][C:30]2[CH:29]=[N:28][C:27]([C:26]([F:38])([F:25])[F:37])=[N:32][C:31]=2[CH2:33]1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cnc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A 1-L round bottom flask was charged with 15.5 g (46.5 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoic acid and 160 mL of acetonitrile. To the resultant suspension was added 14.5 g (60.5 mmol) of amine hydrochloride from Step B. The mixture was cooled to 5° C. and 12 g (62.8 mmol) of EDC and 6.9 mL (62.8 mmol) of N-methylmorpholine were added. After 2 h, the reaction was judged to be complete by LC-MS analysis. The mixture was partitioned between 100 mL of water and 160 mL of ethyl acetate. The organic phase was washed sequentially with 100 mL of saturated aqueous sodium bicarbonate solution and 100 mL of brine, dried over sodium sulfate, and concentrated in vacuo. Purification by Biotage flash chromatography (silica gel, 30–60% ethyl acetate/hexane) gave 20.3 g of the title compound as a white foam. LC-MS 419.4 (M+1-BOC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)cc1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.155 g, 0.289 mmol) and 2-tributylstannyl pyridine (0.210 g, 0.571 mmol) in dry toluene (8 mL) is purged with N2 and then tetrakis(triphenylphospine)pallium (0) (0.033 g, 0.029 mmol) is added. The reaction is heated to 100° C. and stirred for 20 hours under N2. The reaction is cooled, and the solvent is removed in vacuo to give crude 3-{2-methyl-4-[3-methyl-5-(2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester. This ester is dissolved in ethanol (8 mL), treated with 5 N NaOH (2 mL) and heated to reflux until saponification is complete. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to give crude product that is purified by preparative HPLC to afford 0.056 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1cscn1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and thiazole
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[C:13]3[N:14]([C:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=4)=[CH:19][N:20]=3)[CH:15]=[CH:16][N:17]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:18]2[N:14]3[CH:15]=[CH:16][N:17]=[C:12]([NH:11][CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[C:13]3=[N:20][CH:19]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COC(=O)c1ccc(CNc2nccn3c(-c4ccc(OC)c(OC)c4)cnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3c(NCc4ccc(C(=O)O)cc4)nccn23)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzoic acid methyl ester (0.20 g, 0.48 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (0.72 ml, 0.72 mmol, 1 M aqueous solution). The reaction was stirred at ambient temperature for 24 hours then diluted with water (30 mL) and washed with ethyl acetate (30 ml). The aqueous phase was acidified with 1 M aqueous HCl and extracted with ethyl acetate (3×30 ml), the organic layers were combined and dried with magnesium sulphate, filtered and concentrated in vaccuo. The product, 4-{[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzoic acid, is obtained as an off white solid (50 mg, 26%) (LC-MS m/z 405 [M+H]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[OH:3][CH2:4][C:6]1[O:7][C:8]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2cccc(OC)c2o1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2cc(CO)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
A mixture of 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg), lithium borohydride (36 mg) in tetrahydrofuran (4 ml) was stirred at ambient temperature overnight and then for 8 hours at 50° C. Saturated ammonium chloride solution was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane—ethyl acetate) to give 2-hydroxymethyl-7-methoxybenzofuran (310 mg).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:19]
Reactant: [H][H]
Reactant: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate 177 (0.29 g, 0.72 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate 178 (0.22 g, 98%) as a colorless foam.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([F:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([F:23])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cl)cc1
Reactant: Oc1ccc(F)cc1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2-chloro-5-fluoropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1) and 2-chloro-4-fluorophenol: 1H-NMR (CDCl3) δ 8.32 (1H, dd, J=8.1, 2.9 Hz), 8.19 (1H, d, J=7.3 Hz), 8.02–7.99 (3H, m), 7.45 (2H, d, J=8.3 Hz), 7.32–7.25 (2H, m), 7.14–7.08 (1H, m), 5.39 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].[OH:11][C@H:12]1[CH2:32][C@@:31]2([CH3:33])[C@@H:23]([CH2:24][C@@H:25]([OH:35])[C@:26]2([OH:34])[C:27](=[O:30])[CH2:28][OH:29])[C@H:22]2[C@H:13]1[C@:14]1([CH3:38])[C:19]([C@@H:20]([CH3:36])[CH2:21]2)=[CH:18][C:17](=[O:37])[CH:16]=[CH:15]1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][O:35][C@@H:25]1[CH2:24][C@@H:23]2[C@:31]([CH3:33])([CH2:32][C@H:12]([OH:11])[C@H:13]3[C@H:22]2[CH2:21][C@H:20]([CH3:36])[C:19]2[C@:14]3([CH3:38])[CH:15]=[CH:16][C:17](=[O:37])[CH:18]=2)[C@@:26]1([OH:34])[C:27](=[O:30])[CH2:28][OH:29])[CH3:2]
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2C[C@@H](O)[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)OCC

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.18 mole of precursor as described in Example 2A) in methanolether at 0°C is treated with 11β,16α,17,21-tetrahydroxy-6α-methylpregna-1,4-diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. The solution is evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][C:8](=[O:16])[N:7]=[C:6]2[N:17]([NH2:23])C(OCC)=O.CN(C)[CH:27]=[O:28]>>[CH3:24][N:2]([CH3:1])[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]2[NH:9][C:8](=[O:16])[N:7]3[C:27](=[O:28])[NH:23][N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: CCOC(=O)N(N)c1nc(=O)[nH]c2cc([N+](=O)[O-])c(N(C)C)cc12
Reactant: CN(C)C=O
Product: CN(C)c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)n1c(=O)[nH]nc21
Temperature: 25 °C
Yield: 65 %

Procedure:
350 mg (1.04 mmol) of ethyl (6-dimethylamino-7-nitro-2-oxo-1,2-dihydro-quinazolin-4-yl)-carbazate in 30 ml of dry dimethylformamide were heated at reflux for 3 hrs. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was triturated with a small amount of acetone and the red precipitate was filtered off and dried in a vacuum. 195 mg (65%) of 9-dimethylamino-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as a red powder.
Reaction SMILES: C([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1C(C)C)(C)C.C(C1C=CC2C(=CC=C(C(C)C)C=2)C=1)(C)C>C(C1C=CC2C(=CC(C(C)C)=CC=2)C=1)(C)C>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1ccc2ccccc2c1C(C)C
Agent: CC(C)c1ccc2cc(C(C)C)ccc2c1
Agent: CC(C)c1ccc2ccc(C(C)C)cc2c1
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene (800 g) and the catalyst from example 2 (40 g or 5% by weight on the naphthalene) are contacted with propylene at a temperature of 250° C. with an added pressure of propylene of 0.8×105Pa for 1 hour 30 minutes in a 2 liter Parr pressure autoclave operated under agitation. Analysis of the reaction mixture by gas chromatography gives a conversion of 82.3%, a yield in the 2,6-diisopropyl naphthalene of 15.0% and a yield in 2,7-diisopropyl naphthalene of 9.4%. The sum of the diisopropyl naphthalene represents 32.5% of the conversion. The selectivity to the 2,6-diisopropyl naphthalene is 18.2% and the selectivity to the 2,7-diisopropyl naphthalene is 11.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 103.4 %

Procedure:
5.6 g of 1-(4-nitrophenyl)-4-piperidone were suspended in 60 ml of dioxan under argon, treated with 2.6 ml of triethylamine and 0.6 g of palladium-on-charcoal (5%) and hydrogenated at room temperature and normal pressure. Filtration and concentration yielded 5.0 g of 1-(4-aminophenyl)-4-piperidinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH:27]3[CH3:30])=[CH:22][CH:21]=2)=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][C:20]([C:19]5[C:15]([CH3:14])=[N:16][O:17][C:18]=5[CH3:31])=[CH:21][CH:22]=4)[CH:27]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:26]1[NH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][CH2:32][CH:31]([CH2:35][NH2:36])[CH2:30]2>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:36][CH2:35][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][NH:27][N:26]=3)[CH2:30]2)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCc2n[nH]cc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[Cl:12].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.[AlH4-].[Li+]>[Cl:12][C:5]1[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(F)c(F)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-chloro-4,5-difluoro-benzoic acid methyl ester (119, 5.70 g, 0.0276 mol) in tetrahydrofuran (120.0 mL), 1.00 M of lithium tetrahydroaluminate in tetrahydrofuran (30.0 mL) was added slowly under an atmosphere of nitrogen. The reaction was stirred at room temperature for 4 hours, followed by adding sodium sulfate decahydrate. After 30 minutes, the reaction mixture was filtered, concentrated and purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%).