Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([N:35]2[CH:39]=[C:38]([C:40](Cl)=[O:41])[C:37]([CH2:43][CH2:44][CH3:45])=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:40]([C:38]3[C:37]([CH2:43][CH2:44][CH3:45])=[N:36][N:35]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:39]=3)=[O:41])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CCCc1nn(-c2ccccc2)cc1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CCCc1nn(-c2ccccc2)cc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-phenyl-3-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 592.2 (M+H)+.
Reaction SMILES: C(=O)([O-])O.[Na+].O1CCCC1.[NH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14].[CH3:20][C@@H:21]([C@@H:28]1[C@@:32]2([CH3:50])[CH2:33][CH2:34][CH:35]3[C@@:40]4([CH3:49])[CH2:41][CH2:42][CH:43]([O:45][C:46](Cl)=[O:47])[CH2:44][C:39]4=[CH:38][CH2:37][CH:36]3[CH:31]2[CH2:30][CH2:29]1)[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>O>[CH3:27][CH:25]([CH2:24][CH2:23][CH2:22][C@H:21]([C@@H:28]1[C@:32]2([CH3:50])[C@H:31]([C@H:36]3[C@H:35]([CH2:34][CH2:33]2)[C@:40]2([CH3:49])[C:39]([CH2:44][C@@H:43]([O:45][C:46]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[O:47])[CH2:42][CH2:41]2)=[CH:38][CH2:37]3)[CH2:30][CH2:29]1)[CH3:20])[CH3:26]
Reactant: NCC(=O)NCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80.8 %

Procedure:
Sodium hydrogencarbonate (0.168 g) and tetrahydrofuran (20 ml) were added to a suspension of glycylglycine (0.15 g) in water (20 ml). After tetrahydrofuran (20 ml) and cholesteryl chloroformate (0.898 g) were added to the resulting transparent solution at 0° C., the mixture was stirred for an hour. The reaction mixture was concentrated under reduced pressure and, methanl (10 ml) and chloroform (10 ml) were added to the residue. By filtration, the transparent solution was obtained. The solvent was distilled off to give crude crystals (0.98 g). The crude crystals were then purified by silica gel chromatography to give N-(cholest-5-ene-3β-oxycarbonyl)glycylglycine (0.5 g) as white powders.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH:4]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:3][CH2:2]2.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CC#N>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:3]2[CH:4]([C:8]([NH:10][C:11]3([C:14]4[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=4)[CH2:12][CH2:13]3)=[O:9])[CH2:5][CH:6]3[CH:1]([CH2:7]3)[CH2:2]2)=[CH:34][CH:33]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-(1-(3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (racemic mixture) (D100) (155 mg, 0.49 mmol) in dry MeCN (4 ml), Cs2CO3 (241 mg, 0.74 mmol) and 4-(trifluoromethyl)-benzylbromide (0.09 ml, 0.59 mmol) were added in sequence and the resulting mixture was stirred at RT for 4 hrs. The residue obtained after solvent evaporation was loaded on Biotage SNAP-Si column (25 g) eluting with a mixture cHex/EtOAc from 65/35 to 40/60. Collected fractions after solvent evaporation afforded the title compound (D139) (racemic mixture) (215 mg).
Reaction SMILES: [CH:1](N1C2C=CC=CC=2N=N1)=[O:2].[F:12][C:13]1[CH:14]=[C:15]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:22][NH:21][CH2:20]1>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:22][N:21]([CH:1]=[O:2])[CH2:20]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C=O)C3)c(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
N-Formylbenzotriazole (115 mg, 0.78 mmol) was added to a stirred suspension of (S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) in THF (5 mL) and stirred overnight. The solvent was removed and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 2-5% methanol-chloroform to give the title compound as a white foam. FAB-HRMS: theory 336.1356 (M+1); meas. 336.1357.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@:24]12[CH2:32][C@@H:28]([O:29][C:30]1=[O:31])[C@H:27]([OH:33])[C@H:26]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:25]2.O>C(Cl)Cl>[Si:35]([O:34][C@H:26]1[C:27](=[O:33])[C@H:28]2[CH2:32][C@:24]([OH:23])([C:30](=[O:31])[O:29]2)[CH2:25]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@]2(O)C[C@@H](OC2=O)[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@]2(O)C[C@@H](OC2=O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of Dess-Martin periodinane reagent (6.60 g, 15.5 mmol) in anhydrous CH2Cl2 (100 mL) was added compound 2 (3.86 g, 13.4 mmol). The mixture was stirred at room temperature for 18 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed several times with water, dried (MgSO4), and evaporated to give an oily residue which slowly crystallized on cooling (3.67 g, 95%). TLC indicated high purity of the obtained ketone 3 which could be used in the next step without further purification. Analytical sample was obtained by recrystallization from hexane. 3: m.p. 92-95° C.; 1H NMR (400 MHz, CDCl3) δ0.040 and 0.133 (3H and 3H, each s, 2×SiCH3), 0.895 (9H, s, Si-t-Bu), 2.15 (1H, dd, J=12.4, 10.4 Hz, 2α-H), 2.42 (1H, d, J=12.5 Hz, 8α-H), 2.54 (1H, ddd, J=12.4, 9.0, 3.9 Hz, 2β-H), 2.86 (1H, ddd, J=12.5, 6.7, 3.9 Hz, 8β-H), 4.54 (1H, dd, J=10.4, 9.0 Hz, 3β-H), 4.73 (1H, d, J=6.7 Hz, 5α-H); 13C NMR (125 MHz) δ−5.6 (Si—CH3), −4.8 (Si—CH3), 18.2 [C(CH3)3], 25.6 [C(CH3)3], 42.3 (C8), 43.0 (C2), 70.3 (C3), 71.8 (C1), 78.7 (C5), 177.1 (C═O), 202.4 (C4); MS (EI) m/z (relative intensity) no M+, 271 (M+−CH3, 4), 229 (92), 201 (28), 157 (100); HRMS (ESI) exact mass calcd for C9H13O5Si (M+−t-Bu) 229.0532, measured 229.0539; Anal. Calcd for C13H22O5Si×H2O: C, 51.29, H, 7.95. Found: C, 51.09, H, 7.90.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3]CC)=[O:2].[OH-].[Na+].O>C(O)C>[C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(C(=O)O)[nH]c2ccccc12

Procedure:
Ethyl 2-Carboethoxy-3-indoleacetate (0.7 gm) in absolute ethanol (10 ml) was combined with 50% aqueous sodium hydroxide. The mixture was heated to reflux on a steam bath for 15 minutes. The resulting solution was poured into water (50 ml) and the aqueous solution was washed with ether (2×30 ml). The aqueous solution was made acidic by the addition of concentrated hydrochloric acid and chilled to effect crystallization. The resulting white solid was recovered by filtration to provide the product. Analytical data are reported in Table I.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([NH:36][CH2:37][C:38]([F:39])([F:41])[F:40])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)O)c3)cc12
Reaction time: 2 h
Yield: 83.7 %

Procedure:
TFA (921 μl, 11.9 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoate (130 mg, 0.239 mmol) in DCM (2.4 ml) at rt. The reaction was allowed to stir for 2 h then concentrated azeotroping with toluene to dryness. The resulting solid was triturated with DCM to give the expected product 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (97 mg, 0.20 mmol, 83% yield) consistent by LCMS and NMR. LC-MS retention time: 1.73 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s, 1H), 8.37-8.30 (m, J=4.5 Hz, 1H), 8.05-7.94 (m, 4H), 7.70-7.66 (m, 3H), 7.34 (t, J=8.9 Hz, 2H), 6.67 (s, 1H), 4.23-4.10 (m, J=3.0 Hz, 2H), 2.80 (d, J=4.8 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C:36](=[O:64])[C:37]#[C:38][C@H:39]([CH3:63])[C@H:40]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C@@H:41]([CH3:54])[CH2:42][C@@H:43]([CH3:53])[CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CC(O)C>[Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:64])[C:37]#[C:38][C@H:39]([CH3:63])[C@H:40]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[C@@H:41]([CH3:54])[CH2:42][C@@H:43]([CH3:53])[CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C#CC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C#C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ynone 32 (5.28 g, 5.71 mmol) was taken up in i-PrOH (58 mL). The (S,S)-Noyori catalyst (0.77 g, 1.15 mmol, 20 mol %) was added in one portion and the solution was stirred overnight. The solvent was removed under vacuum, and the crude residue was purified by flash chromatography on silica gel (hexane/EtOAc 97:3), affording propargylic alcohol 33 (4.18 g, 79%) as a pale yellow oil: IR (CHCl3) 3469, 2955, 2856, 1471, 1448, 1252, 1084, 836, 774 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.55 (m, 6H), 7.36 (m, 9H), 5.71 (m, 2H), 4.59 (m, 1H), 4.03 (quint, J=3.9 Hz, 1H), 3.65 (d, J=3.9 Hz, 2H), 3.58 (dd, J=4.6, 3.2 Hz, 1H), 3.55 (dd, J=10.1, 5.1 Hz, 1H), 3.38 (dd, J=9.7, 6.8 Hz, 1H), 2.71 (m, 1H), 2.50 (m, 1H), 2.32 (d, J=5.4 Hz, 1H), 1.88 (m, 1H), 1.80 (m, 2H), 1.55 (m, 1H), 1.23 (d, J=7.1 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 0.98 (m, 34H), 0.20 (s, 3H), 0.17 (s, 3H), 0.16 (s, 3H), 0.14 (s, 3H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.0, 128.6, 127.8, 127.1, 126.9, 88.1, 86.8, 83.0, 72.6, 68.3, 65.8, 65.1, 59.5, 41.9, 40.3, 38.7, 33.5, 33.2, 32.1, 26.0, 25.9, 18.4, 18.1, 17.7, 17.4, 15.7, 15.3, 14.2, −3.9, −4.0, −4.4, −4.5, −5.3; LRMS (ESI) 949.7 [M+Na]+, 413.3, 243.1; HRMS (ESI) calcd for C56H90O5Si3Na 949.5994 [M+Na]+, found 949.6018; [α]20D−10.0 (c 1.2, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][CH2:27][CH:26]([O:25][CH3:24])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(C)CCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: COC(C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxybutan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (d, J=6.32 Hz, 3H) 1.52-1.70 (m, 2H) 3.17 (s, 3H) 3.26-3.36 (m, 3H) 7.72 (d, J=8.59 Hz, 2H) 8.07 (d, J=6.57 Hz, 2H) 8.27-8.50 (m, 2H) 8.61 (t, J=5.43 Hz, 2H) 8.76-8.96 (m, 1H) 13.46 (br. s., 1H). MS m/z [M+H]+ 392.1.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH:20]4[CH:16]([CH2:17][NH:18][CH2:19]4)[CH2:15][CH2:14]3)[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[C:36]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:35]=[C:34]([CH2:44][CH3:45])[CH:33]=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH2:44]([C:34]1[CH:33]=[C:32]([NH:31][C:30]([N:18]2[CH2:19][CH:20]3[CH:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=5)[CH2:8]4)[CH2:14][CH2:15][CH:16]3[CH2:17]2)=[O:29])[CH:37]=[C:36]([C:38]2[N:42]([CH3:43])[N:41]=[N:40][N:39]=2)[CH:35]=1)[CH3:45]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: Fc1ccc(C[C@@H]2CCCN(C3CCC4CNCC43)C2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cc(NC(=O)N2CC3CCC(N4CCC[C@@H](Cc5ccc(F)cc5)C4)C3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.2 %

Procedure:
A mixture of (3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]octahydrocyclopenta[c]pyrrole (53 mg, 175 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (56 mg, 175 μmol), triethylamine (49 μL, 350 μmol) and acetonitrile (2 mL) was stirred at room temperature. After 18 hours, the mixture was concentrated to provide a residue. The residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and was dried over sodium sulfate and concentrated to provide a residue. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a tan glass (56 mg, 75%). 1H NMR (300 MHz, CDCl3) δ7.83 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 7.09 (m, 2H), 6.96 (m, 2H), 6.52 (broad s, 1H), 4.22 (s, 3H), 3.61 (m, 2H), 3.5-3.2 (m, 2H), 3.0-2.6 (m, 6H), 2.6-2.4 (m, 3H), 2.0-1.5 (m, 10H), 1.27 (m, 3H), 0.93 (m, 1H). Mass spec (ES+) m/z 532.4 (M+H+, 100%)
Reaction SMILES: C(C1CCC(=O)CC1)CC.[2H]O[2H].C(OC1C=CC(Br)=CC=1)C.[C:24]1([C:30]2(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1(c2ccccc2)CCCCC1
Agent: CCCC1CCC(=O)CC1
Agent: CCOc1ccc(Br)cc1
Agent: [2H]O[2H]
Solvent: ClCCl
Product: C1=C(c2ccccc2)CCCC1

Procedure:
4-Propylcyclohexanone is dissolved in a solvent, e.g., dichloromethane, and heated with heavy water (D2O) in the presence of a base to obtain 4-propylcyclohexanone-2,2,6,6-d4, which is then reacted with a Grignard reagent prepared from 1-ethoxy-4-bromobenzene. The resulting d4 -phenylcyclohexanol derivative is dehydrated to obtain a d3 -phenylcyclohexene derivative. The d3 -phenylcyclohexene derivative is catalytically reduced, and the cis-compound is removed to obtain 1-(trans-4-propylcyclohexyl-2,2,6-d3)-4-ethoxybenzene. ##STR60##
Reaction SMILES: C([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:6]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5]1)(=O)C.C(=O)(O)[O-].[K+].C(O)(=O)C>CO.O>[CH:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:7]2[C:6]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:53])([CH3:55])[CH3:54])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:37])[CH3:36])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5][NH:4][C:8]=2[CH3:9])=[CH:16][CH:15]=1)([CH3:20])[CH3:19]
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(OC(C)C)cc2)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OC(C)C)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a suspension of 1-acetyl-4-[(4-isopropoxyphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.00 g) in methanol (10 mL) was added potassium bicarbonate (0.038 g) under stirring at room temperature. The suspension turned into a solution by heating to reflux, and the mixture was stirred for further 2 hours. After confirming the completion of the reaction, a solution of glacial acetic acid (0.022 g) in water (10 mL) was added to the mixture at 60° C. to precipitate the crystals. The suspension was cooled to room temperature, and stirred under ice-cooling for 1 hour. The crystals were collected by filtration, and the obtained crystals were washed with a mixed solution of 2-propanol and n-heptane, and dried under reduced pressure to give 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.890 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].[CH3:25][O:26][C@H:27]1[CH2:31][CH2:30][NH:29][C@@H:28]1[C:32]([NH2:34])=[O:33]>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:29]5[CH2:30][CH2:31][C@H:27]([O:26][CH3:25])[C@H:28]5[C:32]([NH2:34])=[O:33])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: CO[C@H]1CCN[C@@H]1C(N)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CCN(c2cc3c(cn2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)[C@@H]1C(N)=O
Yield: 27 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and (2S,3S)-3-methoxy-pyrrolidine-2-carboxylic acid amide with added triethylamine were reacted. The crude product was washed with water, filtered then triturated in diethyl ether and methanol to give 408 as a white solid (40 mg, 27%). LCMS: RT=2.68 min, [M+H]+=439. 1H NMR 400 MHz (CDCl3) δ: 9.31 (1H, s), 7.86 (1H, s), 7.59 (1H, s), 6.99 (1H, br, s), 6.08 (1H, s), 6.03 (1H, m), 5.37 (1H, br, s), 4.67 (1H, s), 4.53-4.49 (2H, m), 4.40-4.39 (2 H, m), 4.29 (1H, m), 3.62-3.57 (1H, m), 3.52-3.51 (1H, m), 3.39 (3H, s), 2.23 (2H, m), 1.57 (6H, dd, J=6.68, 3.32 Hz)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(O)cc1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(OCCCCBr)cc1
Reaction time: 16 h

Procedure:
7.0 g (0.05 mol) of 4-(methylthio)phenol are stirred in 80 cc of absolute dimethylformamide for 30 minutes with 2.8 g (0.05 mol) of pulverized potassium hydroxide. 16.2 g (0.075 mol) of 1,4-dibromo butane are added dropwise over the course of 15 minutes and the mixture is stirred at 20° for 16 hours. After the addition of approximately 150 cc of water, the reaction mixture is extracted with ether, the extract is washed with ice-cold 1N sodium hydroxide solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. After chromatography of the residue on silica gel with hexene/ethyl acetate (99:1) and (98:2) and subsequent crystallization from petroleum ether, pure 1-(4-bromo-butyloxy)-4-(methylthio)-benzene is obtained. M.P.: 33°-34° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].C(ON1C(=O)C2=CC=CC=C2C1=O)(=[O:11])C.C(O)(=O)C1C=CC=CC=1>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:2]
Reactant: CC(=O)ON1C(=O)c2ccccc2C1=O
Reactant: CCc1ccccc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 1.062 g (10 mmol) of ethylbenzene, 0.205 g (1 mmol) of N-acetoxyphthalimide, 0.025 g (0.1 mmol) of cobalt(II) acetate tetrahydrate, 0.025 g (0.1 mmol) of manganese(II) acetate tetrahydrate and 15 ml of acetic acid was stirred at 130° C. in an atmosphere of air [2 MPa (gauge pressure)] for 8 hours and thereby yielded benzoic acid in a yield of 85% (analyzed by gas chromatography) with a conversion from ethylbenzene of 96%. In this procedure, acetophenone was not produced.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO>[Pd].O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)Nc1nc2ccc([N+](=O)[O-])cc2[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc2cc(N)ccc2[nH]1
Yield: 35.4 %

Procedure:
A mixture of 13.3 g (47.8 mmol) of (5-nitro-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester and (6-nitro-1H-benzimidazol-2-yl)-carbamic acid tert-butyl ester, 100 ml of methanol, 100 ml of tetrahydrofuran and 1 g of 10% Pd/C catalyst is hydrogenated. After completion of the reaction, the catalyst is filtered off, washed with tetrahydrofuran and the filtrate is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and chloroform:methanol=10:1 as eluent to yield 4.72 g (40.4%) of (6-amino-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester (Rf. 0.5), Melting Point: 159° C. (diethyl ether) and 4.2 g (36.0%) of (5-amino-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester (Rf. 0.4) Melting Point: 168° C. (diethyl ether)