Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([NH:25][C@H:26]([C:31]([O:33]C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:22][O:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[N:22][O:23][N:24]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Reaction time: 2 h

Procedure:
To methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucinate (375 mg, 0.793 mmol) in MeOH (20 mL) was added an aqueous solution of LiOH (2.0 M, 2.0 mL, 4.0 mmol) and the reaction mixture was stirred for 2 hours. An additional aliquot of aqueous LiOH (2.0 M, 2.0 mL, 4.0 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was acidified (pH=4–5) with aqueous 10% HCl, brine was added and the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (Hex/EtOAc/AcOH, 50/49/1) to afford N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucine.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12

Procedure:
This synthesis is depicted in FIG. 1. Ketone 1 (500 mg, 1.84 mmol) was reduced with sodium borohydride (d, 75 mg, 2 mmol) in THF/MeOH 5:1 (18 ml) at RT. (2 h). The crude product was chromatographed on silica gel (60 g) using toluene/ethyl acetate 2:1. After traces of the axial alcohol 2 (9 mg, 2%), the pure equatorial alcohol 3 (388 mg, 77%) was eluted. An analytical sample was recrystallized from MeOH/water. M.p. 124°-125°, [a]D =+14.2° (c=1.12) ([2]: m.p, 125°-127°, [a]D17 =+11.2° (c=0.76)). - IR. (CDCl3): 3620m, 3430w, 1590w. - 1H-NMR. (360 Mhz): 0.77 (s, 3 H); 0.85 (s, 3 H); 3.60 t x t, J=11 and 5, 1 H); 5.70 (m, 1 H); 5.84 (m,1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([C:10]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:11])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC1

Procedure:
50.99 g (454.4 mmol) of potassium tert-butoxide were dissolved in 454 ml of abs. THF and cooled to 0° C. The solution was stirred vigorously, and 50 g (478.3 mmol) of cyclopropanecarbonyl chloride were added dropwise such that the reaction temperature did not exceed 50° C. (cooling required). After the addition has ended, the resultant suspension was stirred for another 30 min. After cooling, the reaction mixture was, under reduced pressure, concentrated to about one third of the original volume and then added to 2 liters of saturated aqueous ammonium chloride solution. The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the mixture was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure without heating (cold water bath). The residue was distilled at a bath temperature of about 85° C. and 42 mbar. This gave 43.1 g (63.2% of theory) of the target compound as a clear liquid.
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:22]C1CC(=O)NC1=O>CN(C=O)C>[Br:22]/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1
Reactant: COc1ncc(/C=C/C(=O)O)c(OC)n1
Reactant: O=C1CC(Br)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(/C=C/Br)c(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of E-5-(2-carboxyvinyl)-2,4-dimethoxypyrimidine (0.300 g; 1.43 mmol) in dry DMF (5 ml) was added K2CO3 (0.45 g: 5.25 mmol). After stirring at ambient temperature for 15 min. a solution of N.-bromosuccinimide (0.258 g; 1.45 mmol) in dry DMF (4 ml) was added dropwise over 10 min. The suspension was immediately filtered, the solid washed with DMF and the filtrate evaporated in high vacuum. The solid residue was purified by column chromatography by preloading on SiO2 and eluting with EtOAc-hexane (7:3, v/v). Product fractions were pooled and evaporated to give fine white crystals, yield 0.561 g (45%). FAB mass spectrum: m/z245 and 247 (M+H)+. Analysis, found: C,39.9; H, 3.6; N, 11.5% C8H9BrN2O2 requires C, 40.20; H, 3.70; N. 11.43%.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 65.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 μl, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 52 mg (64% yield) of the title compound. Purity 93%.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>>[CH3:8][C:7]1[C:2]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[N:3][CH:4]=[N:5][C:6]=1[CH3:9]
Reactant: Cc1ncnc(Cl)c1C
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)c1C
Yield: 15 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 4.8 g (0.03 mole) of p-aminobenzotrifluoride; the mixture was then heated at 100°-150° C. for about 3 minutes. The reaction mixture quickly became a solution and soon produced a precipitate which was separated and then made alkaline by the addition of 50 ml of a dilute aqueous solution of sodium hydroxide. The insolubles were collected by filtration, washed with water and then recrystallised from a 7:3 by volumemixture of ethanol and water, to give 1.2 g (yield 24%) of the desired Compound No. 38 in the form of a pale brown powder melting at 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=1)[CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([C:7]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[CH2:9][CH2:8]1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(CCBr)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1

Procedure:
In analogy to the procedure described in example 15.2, 4-bromo-2-(3-fluoro-4-nitro-phenoxy)-butyric acid tert-butyl ester was treated with potassium tert-butoxide in THF to afford the title compound as a brown solid. MS: m/e=298.3 [M+H+].
Reaction SMILES: C(OC([N:8]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]2)([CH3:16])[CH2:14][C:13](=[O:28])[CH2:12]3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:16][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][NH:8][C:25]4[C@:20]3([CH3:27])[CH2:21][CH2:22][C:23](=[O:26])[CH:24]=4)[C@@H:11]1[CH2:12][C:13](=[O:28])[CH2:14]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC(=O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12CC[C@H]3[C@@H](CNC4=CC(=O)CC[C@@]43C)[C@@H]1CC(=O)C2
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 6-t-butyloxycarbonyl-6-azaandrost-4-ene-3,16-dione (11, R2 =H) (693 mg, 1.79 mmoles) in methylene chloride (12 mL) was added trifluoroacetic acid (3mL) and the mixture stirred at room temperature for 1.75 hours. The mixture was evaporated in vacuo and the residue dissolved in methylene chloride and shaken with 10% NaHCO3. The resulting solid was filtered and dried in a vacuum oven at 60° C. to give (12, R2 =H) as a white solid. NMR (CDCl3): δ 0.98 (s, 3H, 18-Me); 1.36 (s, 3H, 18-Me); 4.88 (s,1H; NH); 5.09 (s, 1H, 4-H).
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.Br[CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][CH3:29])[CH2:13]1
Reactant: CCCBr
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4 (6.4 g, 0.023 mole), 1-bromopropane (5.7 g., 0.047 mole) and sodium bicarbonate (8.4 g, 0.10 mole) in DMF (100 ml) was stirred at 70° C. for three hours. The mixture was concentrated under high vacuum to an oil which was stirred with water then extracted with ether. The ether extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (6.3 g, 86%) which was distilled to yield an oil of 1-(m-chlorophenoxy)-3-(n-propyl)-2,3,4,5-tetrahydro-3-benzazepine, 190°-210° C./0.1 mm.
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].[F:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[C:17]([F:22])[C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:19]2[CH:20]=[C:13]([F:12])[C:14]([C:15]#[N:16])=[C:17]([F:22])[CH:18]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 2,4,6-trifluorobenzonitrile (157 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 143 mg, yield: 49%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.CO>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH:3]([O:5][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:4]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(Oc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
Similar to the procedure described in Example 103, rac-1,1,1,-trifluoro-2-propanol (Aldrich Chemical Company; 0.18 mL, 2.02 mmol) was added to a suspension of NaH (60% w/w in mineral oil) (81 mg, 2.02 mmol) in DMF (2.0 mL) and the resulting light-green solution was stirred at RT for 10 min. 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 2.5 h. The mixture was cooled to RT and partitioned between EtOAc (70 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and purified by reverse-phase using HPLC (Silicycle column, 20-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min), then dried in a Genevac Series II Evaporator. The residue was chromatagraphically purified then (silica gel; 0-10% MeOH in DCM) affording rac-2-(2-((1,1,1-trifluoropropan-2-yl)oxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16.0 mg, 0.043 mmol, 16.9% yield) as an amorphous yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.95 (br. s., 1H), 6.09 (dt, J=13.5, 6.8 Hz, 1H), 3.40-3.49 (m, 2H), 2.87 (t, J=6.7 Hz, 2H), 1.57 (d, J=6.7 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −77.03 (s, 3F). m/z (ESI, +ve ion) 376.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[CH2:15][O:16][C:17]1[C:22]([CH:23]([CH2:25][CH3:26])[CH3:24])=[CH:21][C:20]([Cl:27])=[CH:19][C:18]=1[Cl:28])=O)(C)(C)C.Cl>C(O)C>[CH:23]([C:22]1[C:17]([O:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])=[O:29])=[C:18]([Cl:28])[CH:19]=[C:20]([Cl:27])[CH:21]=1)([CH2:25][CH3:26])[CH3:24]
Reactant: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)NCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)NCCCCN
Reaction time: 1 h
Yield: 106.3 %

Procedure:
A mixture of 8.12 g of the product of Step F, 80 ml of ethanol and 20.1 ml of ethanolic, 2N hydrogen chloride was refluxed with stirring for one hour and was evaporated to dryness under reduced pressure. The residue was washed with methylene chloride to obtain 6.7 g of the desired hydrochloride. A mixture of 6.7 g of the hydrochloride, 100 ml of ethanol and 3.2 g of sodium bicarbonate was refluxed with stirring for 4 hours and the mixture was filtered hot. The filtrate was evaporated to dryness under reduced pressure and the 6.05 g of residue was chromatographed over silica. Elution with a 98-2 methanol-ammonium hydroxide yielded 4.74 g of the desired product.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19]>C(O)C>[NH2:19][C@@H:18]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:6]([OH:7])[CH2:8][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1
Reactant: CN
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(A)(ii) A suspension of 26.55 g of N-tert.butyl-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 1) in 100 ml of ethanol was treated with 25 ml of a 30% solution of methylamine in ethanol at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethanol, treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, made basic with solid sodium carbonate and then extracted with dichloromethane. The dichloromethane extract was washed with sodium chloride solution and evaporated to dryness. The residue was triturated with diethyl ether and, after filtration, there were obtained 17.48 g of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 402 [M+H]+.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:4][CH2:3]1>C1COCC1>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:3][CH2:4]3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCCCC3CC[SiH](Cl)CC3)CC2)cc1
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H](CCCC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
130 ml (0.13 mols) of a THF solution of 1M of 4-pentenylmagnesium bromide was dropped in a solution of 200 ml of THF and 14.0 g of zinc chloride to obtain an organozinc reagent. The resultant mixture was added to a solution of 41.0 g (0.1 mol) of 1-chloro-4-(4-(trans-4-(4-cyanophenyl)cyclohexyl)butyl)-1-silacyclohexane in 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments, followed by isolation through chromatography to obtain 40.8 g (yield: 95%) of the intended trans isomer product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15](=[O:17])[NH:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N+:18]1([O-])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2=[N:13][NH:14][C:15](=[O:17])/[C:16]/2=[C:19]2\[NH:18][C:27]3[C:22]([CH:21]=[CH:20]\2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: [O-][n+]1cccc2ccccc21
Reactant: CNS(=O)(=O)c1ccc(C2=NNC(=O)C2)cc1
Product: CNS(=O)(=O)c1ccc(C2=NNC(=O)/C2=C2/C=Cc3ccccc3N2)cc1

Procedure:
The title compound was synthesized using N-methyl-4-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide and quinoline N-oxide according to the procedure described in Example 23. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 (s, 3H) 7.09 (s, 1H) 7.48-7.60 (m, 2H) 7.76-7.81 (m, 3H) 7.83-7.90 (m, 4H) 8.25 (d, J=9.09 Hz, 2H) 11.90 (s, 1H); ESI-MS: m/z calc'd for C19H16N4O3S 380.42. found 381.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH3:3].[Na].[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:9]([NH:11][C:12]1([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]2C[O:23]2)[C:13]1=[O:25])=[O:10]>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:9]([NH:11][C:12]1([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]([OH:23])[CH2:1][S:2][CH3:3])[C:13]1=[O:25])=[O:10]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC2CO2)c2ccccc21
Reactant: CSC
Agent: [Na]
Solvent: CCO
Product: CSCC(O)CN1C(=O)C(CCC(=O)O)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
12 ml of an aqueous 15% sodium methyl sulfide solution was added to 24 ml of an ethanol solution of 1.635 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(2-oxiranylmethyl)-2-oxo-1H-indol-3-yl]propionate. The mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated, made acidic with aqueous 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried, filtered and then concentrated. The residue was purified by silica gel column chromatography [chloroform-methanol (10:1)] and recrystallized from ethyl acetate-hexane to afford 1.52 g of 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylthio-2-hydroxypropyl)-2-oxo-1H-indol-3-yl]propionic acid as colorless needles. Melting point: 168.5° to 169.5° C., IR (Nujol) (cm-1): 3400, 3300, 1710, 1650, 1615, FAB-MS (m/z): 499 & 497 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:40][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][C:34]=3[N:33]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:33]1[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH:40][C:32]=1[CH:29]1[CH2:30][CH2:31][N:26]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:7]3[C:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:9][N:4]4[N:3]=[C:2]([CH3:1])[N:24]=[C:5]4[N:6]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:28]1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: c1cc2nc(C3CCNCC3)[nH]c2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccncc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Yield: 33.7 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 181 mg (0.76 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after one, two, three, four and a half, five and a half, and seven and a half hours (two equivalents each). The solvents were evaporated and the usual workup and purification yields 108 mg of the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH:35]=[CH2:36])[CH2:33][O:32][C:31]1([CH3:38])[CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C1CCCCC1)C1CCCCC1.CN(C)C=O>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:37][C:31]1([CH3:38])[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@@H:34](/[CH:35]=[CH:36]/[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([N:12]3[CH2:18][CH2:17][CH2:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[CH2:13]3)[CH:3]=2)[CH2:33][O:32]1
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (310 mg, 1.0 mmol), (S)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (273 mg, 1.2 mmol), bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyl dicyclohexylamine (293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL) was heated with stirring in a 20 mL microwave process vial for 2.5 hours at 120° C. under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by flash column to give 380 mg of product as a white solid (yield was 76%). MS obsd. (ESI+) [(M+H)+] 500.