Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.COC1C=C(C=CC=1OC)C[NH2:32]>CC(N(C)C)=O.FC(F)(F)C(O)=O.C(OC(=O)C)C>[NH2:32][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: COc1ccc(CN)cc1OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Nc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
A stirred solution of Example 5 (0.055 g, 0.143 mmol) in dimethylacetamide (2 ml) was treated with 3,4-dimethoxybenzylamine (0.22 ml, 1.43 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was reduced in vacuo and taken up in neat trifluoroacetic acid (3 ml). The mixture was stirred at 70° C. for 48 h, cooled and reduced in vacuo. The residue was taken up in ethylacetate (25 ml), washed with saturated sodium bicarbonate solution (15 ml), dried over sodium sulfate and reduced in vacuo. Silica gel (10 g) column chromatography (10% MeOH in EtOAc) afforded the title compound as an orange solid in 9% yield, >95% purity. LC-MS m/z=368.0 [M+H]+; RT=2.58; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 4.67 (2H, bd), 5.81 (1H, s), 7.23-7.25 (1H, m), 7.33-7.36 (1H, m), 7.51 (2H, b), 7.79 (1H, bd), 8.09 (1H, bd), 8.38-8.62 (4H, bm)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH3:28].[Cl-].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[CH3:28][C:14]1[N:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[S:17][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
5-Hydroxyindole (200 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL) with the chloride 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.50 g, 1.7 mmol) and Cs2CO3 (2.37 g, 7.27 mmol) The reaction mixture was stirred at RT overnight. Ether (50 mL) and H2O were added and stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organics was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product as a white solid (0.3 g, 51% yield).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH:18]=[C:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:47])C=1.[OH-].[Na+].CO>ClCCl>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH:17]3[O:47][C@H:18]3[C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H]2OC2[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 2 %

Procedure:
To a solution of 3β-benzoyloxy-4,4dimethylcholesta-5,16-diene (250 mg, 4.8 mmol) in dichloromethane (5 mL) at ice bath temperature was added mCPBA (180 mg, 5.2 mmol) and the whole stirred for 3 hours. 2N NaOH (5 mL) was added and the aqueous phase extracted with dichloromethane. Concentration under reduced pressure gave a residue which was tritured with methanol and purified by flash chromatography to give 3β-benzoyloxy-4,4-dimethyl-16α-epoxycholesta-5-ene (50 mg).
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:15])CCC.S(=O)(=O)(O)[OH:17]>O.C(OCC)(=O)C>[Cl:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[CH:6]=[O:17]
Reactant: CCCC/N=C/c1c(Cl)cccc1CC
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cccc(Cl)c1C=O
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 19.7 g (88.1 mmol) butyl-[1-(2-chloro-6-ethyl-phenyl)-meth-(E)-ylidene]-amine in 70 ml water at 0° C. was added dropwise 18.9 ml concentrated sulphuric acid. The mixture was then heated at reflux for 90 min before being cooled to room temperature and diluted with ethyl acetate. The mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 11.4 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (3H, t, CH3), 2.97 (2H, q, CH2), 7.20 (1H, d, ArH), 7.30 (1H, d, ArH), 7.39 (1H, dd, ArH), 10.65 (1H, s, CHO).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1N[C:10](=O)[CH2:9]2.IC.[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[C:18]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:10])[C:4]([CH3:12])([CH3:3])[C:19]1=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1cccc2c1NC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1cccc2c1N(C)C(=O)C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.00 g (50.0 mmol) sodium hydride (55%, suspension in mineral oil) were added at 0° C. to 2.34 g (3.58 mmol) 7-methyl-1,3-dihydro-indol-2-one in 20 mL DMF and the mixture was stirred for 30 min. Then 3.00 mL (48.2 mmol) iodomethane were added and the mixture was stirred for 2 h at RT. Ice water was added to the reaction mixture, then it was extracted with DCM and aqueous sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:36](=[O:39])[CH:37]=[CH2:38])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Brc1cccc(Nc2ncnc3cnc(NCCCN4CCOCC4)cc23)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CCCN1CCOCC1)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-[(3-bromophenyl)amino]-6-[(3-morpholinopropyl)amino]pyrido[3,4-d]pyrimidine (400 mg, 0.90 mmol), (prepared from 4-[(3-bromophenyl) amino]-6-fluoropyrido[3,4-d]pyrimidine and 3-morpholinoprop-1-ylamine) DMAP (40 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (1.2 mol eq., 1.08 mmol, 89 μL). After 1 hour stirring, a further two portions of acid chloride (89 μL each) were added over the next 2 hours, and the reaction was then stirred at 20° C. for 1 hour, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/EtOAc (1:9) to MeOH/EtOAc (1:5) to give N-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-N-[3-morpholinopropyl]acrylamide] (142 mg, 32%) as a cream powder, mp (CH2Cl2/hexane) 178-180° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:12]([C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[N:13][CH:14]=1.C(N(CC)C(C)C)(C)C.[F:51][CH:52]([F:68])[C:53]1[C:54]2[C@H:64]3[CH2:65][C@H:63]3[C:62]([F:67])([F:66])[C:55]=2[N:56]([CH2:58][C:59](O)=[O:60])[N:57]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:12]([C@@H:15]([NH:25][C:59](=[O:60])[CH2:58][N:56]2[C:55]3[C:62]([F:66])([F:67])[C@@H:63]4[CH2:65][C@@H:64]4[C:54]=3[C:53]([CH:52]([F:68])[F:51])=[N:57]2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[N:13][CH:14]=1
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Compound 49B (60 mg, 0.1 mmol) was dissolved in 1 mL of DMF and cooled to 0° C. To it was added N,N-diisopropylethylamine (0.09 mL, 0.5 mmol) followed by a solution of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (26 mg, 0.1 mmol) and HATU (56.5 mg, 0.15 mmol) in 1 mL of DMF. To it was added 0.5 mL of ethanol and 0.1 mL of 15% NaOH aqueous solution and stirred for 5 min. The reaction mixture was acidified with 5% citric acid and then extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ 8.23 (dd, 1H), 7.09 (q, 1H), 6.97 (d, 1H), 6.83-6.53 (m, 2H), 6.37 (m, 2H), 6.17 (d, 1H), 4.80-4.66 (m, 3H), 3.38 (s, 2H), 3.06 (dd, 1H), 2.97 (d, 4H), 2.91 (m, 1H), 2.55-2.42 (m, 2H), 1.44-1.34 (m, 1H), 1.12-1.00 (m, 1H). MS (m/z) 753.14 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[NH:17][N:18]=2)=[CH:10][CH:9]=1)[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:40]>C(O)C.O.C(OCC)(=O)C>[ClH:40].[ClH:40].[ClH:40].[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[NH:17][N:18]=2)=[CH:12][CH:13]=1)[CH3:28]
Reactant: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCN(CC)CCNCc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C

Procedure:
A mixture of N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide (2.75 g, Example 29) and dry tetrahydrofuran (100 ml) was stirred at room temperature under nitrogen and lithium aluminium hydride (3.4 g) was added portionwise. The reaction mixture was then boiled under reflux for about 2.5 hours, then cooled in an ice/water bath. Ethyl acetate (100 ml) and water (100 ml) were added. Then the organic phase was separated off, washed with brine (25 ml), dried, filtered and evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica using ethyl acetate/ ethanol/ triethylamine (7:2:1) as eluant to give a pale yellow gum. The gum was dissolved in warm ethanol (5 ml), hydrochloric acid (conc, 0.6 ml) was added and the solvent then removed under reduced pressure. The gummy solid residue was boiled up with ethanol (10 ml) and cooled in ice. The precipitated solid was collected by filtration, washed with ethanol and dried to give 3-{4-[(2-diethylaminoethyl)aminomethyl]phenyl}-1,4-dihydroindeno[1,2-c]pyrazole trihydrochloride, m.p. 225° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@@H:24]([C@H:26]1[O:30][C:29](=[O:31])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:27]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:25])=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]([C@H:26]1[O:30][C:29](=[O:31])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:27]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:25]
Reactant: [N-]=[N+]=NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Triphenylphosphine (600 mg, 2.4 mmol) was added to a stirred solution of (R)-5-(2-azido-(S)-1-hydroxyethyl)-3,4-dibenzyloxy-5H-furan-2-one (5) (750 mg, 2 mmol) in THF (10 ml) and after a few minutes gas was evolved. The stirring was continued until the effervescence had ceased (typically 2-3 h) and water (2 ml) was then added and the mixture stirred for a further 1 hour. The THF was removed under reduced pressure and the residue partitioned between dichloromethane (25 ml) and water (25 ml). The organic phase was separated, dried (MgSO4), filtered and any volatile components evaporated under reduced pressure (45° C. at 8 mm/Hg) to leave a viscous orange residue which was purified by chromatography on silica. Initial elution with a dichloromethane:methanol (19:1) mixture removed the less polar by-products and the product was then isolated by elution with a dichloromethane:methanol (3:1) mixture as a pale yellow oil (150 mg; 21%) (Rf0.25).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36]>>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:43][CH:44]=1)[CH3:36]
Reactant: COCCOCCN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COCCOCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C30H33N3O5
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39]>>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-ethylpiperazine according to conditions described in general procedure C. Mp: 185-186° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=6.9 Hz, 3 H), 2.31 (bs, 6 H), 3.27 (t, J=4.0 Hz, 6 H), 3.50 (bs, 2 H), 3.77 (t, J=4.4 Hz, 4 H), 6.22-6.24 (m, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.56-7.63 (m, 3 H), 7.84-7.86 (m, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.27-8.29 (m, 1 H), 10.48 (s, 1 H).
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@H:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH3:11])[C:6]=2[CH:19]=1.C(OC([N:28]1[C:32]([NH2:33])=[CH:31][C:30]([CH:34]2[CH2:36][CH2:35]2)=[N:29]1)=O)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH:34]1([C:30]2[NH:29][N:28]=[C:32]([NH:33][C:2]3[C:3]([F:20])=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C@H:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[CH3:11])[C:6]=4[CH:19]=3)[CH:31]=2)[CH2:36][CH2:35]1
Reactant: C[C@@H](c1ccc(F)cc1)n1cnc2cc(F)c(Br)cc21
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(F)cc1)n1cnc2cc(F)c(Nc3cc(C4CC4)[nH]n3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A mixture of (S)-6-bromo-5-fluoro-1-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole (Method 44; 0.200 g, 0.59 mmol), 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (0.166 g, 0.741 mmol), Pd2 dba3 (0.011 g, 0.012 mmol), Xantphos (0.021 g, 0.036 mmol), and Cs2CO3 (0.483 g, 1.48 mmol) in toluene (5 ml) was heated at reflux for 18 hrs. To this was added 10 ml of EtOAc and saturated NH4Cl solution (10 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulted residue was dissolved in the mixture of DCM:TFA (3:1 v/v, 4 ml), stirred at 25° C. for 2 hrs, concentrated, and treated carefully with saturated NaHCO3 solution (5 ml). The aqueous layer was extracted with DCM (10 ml), dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (EtOAc) to give the title compound as a white solid (0.135 g, 60%). NMR (400 MHz) 11.71 (br, 1H), 8.30 (s, 1H), 8.04 (rb, 1H), 7.91 (s, 1H), 7.40 (d, J=12 Hz, 1H), 7.31 (m, 2H), 7.18 (m, 2H), 5.67 (m, 1H), 5.53 (s, 1H), 1.93 (br, 3H), 1.84 (m, 1H), 0.92 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 379; Found: [M+H]+ 380.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@H:8]([O:11]C(=O)CC)[CH2:7][C@@H:6]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][C:17]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][C@@H:6]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][C:17]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:2][CH3:3]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](OC(=O)CC)CCN2C(=O)CC)c(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2CCC)c(OCc2ccccc2)c1
Yield: 88.3 %

Procedure:
Using the procedure of Example 5, 723 mg (1.46 mmole) of N-propionyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-propionyloxypiperidine and 129 mg (3.40 mmole) of lithium aluminum hydride gives 582 mg (88%) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The enzyme preparation to be determined is added to 100 mM TES buffer (pH 7.0) containing 5 mM L-proline, 5 mM 2-ketoglutaric acid, 1 mM ferrous sulfate and 5 mM L-ascorbic acid to make 100 μl in total, and the mixture was allowed to stand at 35° C. for 10 minutes. The reaction mixture is heated at 100° C. for 2 minutes so as to stop the reaction, and the amount of cis-3-hydroxy-L-proline produced in the reaction mixture is determined by high performance liquid chromatography (hereinafter referred to as HPLC).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])c(OC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Oc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4-nitro-1,3-phenylene diacetate (1.0 g) in chloroform (25 mL) was added aluminium chloride (2.23 g) with ice-cooling under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 h. Then to the reaction mixture was added water (100 mL) and extracted with methylene chloride (30 mL×2). The combined organic layer was washed with 1N hydrochloric acid (25 mL) and saturated brine (25 mL) successively, dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using hexane/ethyl acetate (20:1) to give the title compound (610 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]2)[N:25]=1.[F-].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:38]4[CH2:39][CH2:40][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42][CH2:43]4)[CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](n2cc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c(C)n2)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.18/541.20 (100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).