Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])C=C.CCCCCC.CCOCC>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]1([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH:12][CH2:14][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[Si](C)(C)C
Reactant: C=CCC(O)CCc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: C[Si](C)(C)CC=CCC(O)CCc1ccccc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a round-bottomed flask containing 1-phenyl-hex-5-en-3-ol (495 mg, 2.8 mmol, 1 eq) in DCM (12 mL) was added allyltrimethylsilane (1.79 mL, 11.2 mmol, 4 eq). Hoveyda-Grubbs' Catalyst (44 mg, 0.07 mmol, 0.025 eq) was subsequently added as a solid and left to stir at room temperature under an atmosphere of argon. After 72 hours a further equivalent of allyltrimethylsilane was added (0.445 mL, 2.78 mmol). After 7 days the reaction mixture was concentrated under reduced pressure to a dark brown oil. Column chromatography (hexane:ether, 100:0, 9:1, 85:15) gave 1-phenyl-7-(trimethylsilyl)-hept-5-en-3-ol as a colourless oil (445 mg, 61% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 0.006 (s, 9H, SiMe3), 1.47-1.49 (d, 2H, CH2SiMe3, J=8 Hz), 1.74-1.84 (mn, 2H, CH2CH2CHOH), 2.06-2.14 (m, 1H, CHOHCH2CH), 2.20-2.31 (m, 1H, CHOHCH2CH), 2.66-2.74 (m, 1H, PhCH2), 2.79-2.86 (m, 1H, PhCH2), 3.57-3.63 (m, 1H, CHOH), 5.21-5.28 (dt, 1H, CH2CHCH, J=15.2 Hz, 8 Hz), 5.50-5.58 (dt, 1H, CH2CHCH, J=15.2 Hz, 8 Hz), 7.18-7.24 (m, 3H, Ph), 7.27-7.31 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3) δ −2.0 (SiMe3), 23.0 (CH2SiMe3), 32.1 (PhCH2), 38.3 (PhCH2CH2), 41.0 (CHOHCH2), 70.2 (CHOH), 123.8 (CHCH), 125.7 (Ph), 128.4 (Ph), 130.9 (CHCH), 142.2 (Ph). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 0.012 (s, 9H, SiMe3), 1.47-1.49 (d, 2H, CH2SiMe3, J=8 Hz), 1.74-1.84 (m, 2H, CH2CH2CHOH), 2.06-2.14 (m, 1H, CHOHCH2CH), 2.20-2.31 (m, 1H, CHOHCH2CH), 2.66-2.74 (m, 1H, PhCH2), 2.79-2.86 (m, 1H, PhCH2), 3.64-3.69 (m, 1H, CHOH), 5.30-5.35 (dt, 1H, CH2CHCH, J=10.4 Hz, 8 Hz), 5.61-5.66 (dt, 1H, CH2CHCH, J=10.4 Hz, 8 Hz), 7.18-7.24 (m, 3H, Ph), 7.27-7.31 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3) δ −1.82 (SiMe3), 18.7 (CH2SiMe3), 32.1 (PhCH2), 31.5 (CHOHCH2), 38.4 (PhCH2CH2), 70.8 (CHOH), 122.4 (CHCH), 125.7 (Ph), 128.3 (Ph), 129.3 (CHCH), 142.1 (Ph); IR (v, cm−1) 3383 (OH), 3063 (ArH), 1667 (C═C), 1604 (Ar), 1496 (Ar), 850 (Si—C). MS (GCT, CI+) m/z 280.2101 [M+NH4]+ HRMS required for C16H26OSiNH4: 280.2097, found 280.2101.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14]B(O)O.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.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>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:14])[CH:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(=O)n(C)ccc2c1
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh3)4 (93.0 mg, 0.08 mmol), K2CO3 (232.0 mg, 1.68 mmol) and H2O (2 drops) in dioxane (10.0 mL) was microwaved at 120° C. for 1 h. Purification by silica gel chromatography (PE:EA=5:1) gave the title compound (120.0 mg, 82.8%) as a light yellow solid. LCMS: 174.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH2:31][O:32][CH3:33])[N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C(=O)([O-])[O-:35].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH2:31][O:32][CH3:33])[N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:35])[CH:8]=1)=[O:5]
Reactant: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(3-fluoro-6-(methoxymethyl)pyridin-2-yl)benzamide (Example 89, 200 mg, 0.43 mmol) in DMSO (4 mL) was added potassium carbonate (120 mg, 0.87 mmol) followed by H2O2 (1.79 mL, 17 mmol, 30% w/w in water) slowly, maintaining the internal temperature below 30° C. The reaction was stirred at room temperature for 3 hours before quenching with the addition of water (15 mL). The solution was extracted into ethyl acetate (3×15 mL), the organic extracts were collected, dried over sodium sulphate, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate 0-10% MeOH in EtOAc followed by preparative HPLC. The residue was dissolved in DCM (5 mL) and washed with water (4 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound (29 mg, 14%).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:18]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][C:29]([CH3:34])([CH3:33])[O:30]2)=[CH:25][C:24]=1/[C:38](/[CH3:43])=[C:39](/[F:42])\[CH:40]=O)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH:35]([CH3:36])[CH3:37])=[CH:28][C:29]([CH3:33])([CH3:34])[O:30]2)=[CH:25][C:24]=1/[C:38](/[CH3:43])=[C:39](/[F:42])\[CH:40]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Product: CCCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (183 mg, 0.70 mmol) and (2E)-3-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 100, 86 mg, 0.24 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8]NCC(O)C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:16][CH:17]([CH2:38]OC1C2C(=CC=CC=2)C=CC=1)[CH2:18][NH:19][C:20]1[C:21]2[N:22]=[CH:23][N:24]([C:34]=2[N:35]=[CH:36][N:37]=1)[C@@H:25]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]1[OH:27]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:38][CH:17]([OH:16])[CH2:18][NH:19][C:20]2[C:21]3[N:22]=[CH:23][N:24]([C:34]=3[N:35]=[CH:36][N:37]=2)[C@@H:25]2[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]2[OH:27])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(ONCC(C)O)cc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(O)COc4cccc5ccccc45)ncnc32)[C@H](O)[C@@H]1O
Product: CC(=O)c1ccc(OCC(O)CNc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
By substituting (4-acetylphenoxy)-2-hydroxypropylamine (3.65 g, 0.017 mole) for the 2-hydroxy-(1-naphthalenyloxy)propylamine of Example 1 and following the method of Example 1, N6 -[3-(4-acetylphenoxy)-2-hydroxypropyl]-adenosine was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H](NCCCC(=O)O)c1ccccc1
Yield: 70.9 %

Procedure:
The product of example 128A (480 mg, 1.49 mmol) and NaOH (299 mg, 7.47 mmol) in MeOH (10 mL) was stirred at ambient temperature for 1 hour. The mixture had HCl (1M) added and was extracted with EtOAc. The organic was washed with brine, dried (MgSO4), filtered and concentrated to afford 310 mg (71%) of the title compound. MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12]/[N:13]=[C:14]2\[NH:15][C:16](=[O:28])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:22]\2[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=O)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:15]3[C:16](=[O:28])[C:17]4[NH:18][CH:19]=[N:20][C:21]=4[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:14]3=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: CCCCCn1/c(=N/NC(=O)Cc2ccc(OC)cc2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Yield: 95.5 %

Procedure:
The mixture of 2-(4-methoxyphenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide (0.66 g, 1.4 mmol) in toluene (30 mL) was refluxed overnight. The reaction mixture was concentrated to give the crude product as a solid. The solid was washed with ethyl acetate and dried to yield the desired product (490 mg, 92%). LCMS calculated for C19H23N6O2 (M+H): 367.2. found: 367.2.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:26](OCC)=[O:27]>C1COCC1.CCCCCC>[C:15]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:26]=[O:27])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1nnnc1C=C(c1ccccc1)c1ccccc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=O)=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)-ethene (3.75 g; 14.29 mmole) in dry THF (40 mL) was cooled to -78° C. and treated with n-butyllithium (6.3 mL of a 2.5 M soln. in hexane; 15.75 mmole) and the resulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (1.5 mL; 18.58 mmole) was added and the mixture stirred at -78° C. for 2 hours. The reaction was quenched with 2N HCl and the solvent removed by evaporation. The residue was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 25-35% EtOAc-hexane as eluent to afford starting material (1.35 g; 36%) and the desired title compound (1.65 g; 39%); m.p.=185°-186° C. (crystallized EtOAc-hexane). MS (EI): m/e=290 for M+ ;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30](O)=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:38])=[O:31])[C:18]([C:33]([F:35])([F:34])[F:36])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
2-(2-(2-(2-((3-(4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I68) (75.0 mg, 169 μmol) was dissolved in DMF (1 mL) then HATU (129 mg, 339 μmol), DIPEA (57 uL, 339 μmol) and ammonium chloride (181 mg, 3.39 mmol) were added. The resulting mixture was stirred at room temperature overnight then the volatiles were evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 10% NaHCO3, the layers were separated and the organic layer was dried (MgSO4) then evaporated under reduced pressure to give a cream solid. The cream solid was adsorbed onto silica and chromatographed on silica gel (0-10% MeOH/DCM) to give the title compound (17) (23.3 mg, 28%) as a cream solid; 1H NMR (400 MHz, CD3CN) δ 8.57 (s, 1H), 8.34 (s, 1H), 7.58 (s, 1H), 7.30-7.16 (m, 5H), 7.09 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.2, 1.9 Hz, 1H), 3.61 (s, 2H), 3.27 (t, J=4.9 Hz, 4H), 3.19-3.03 (m, 4H), 2.92 (bs, 4H), 2.91 (s, 3H). LCMS Method C: rt 4.43 min; m/z 499.7.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])=[CH:18][CH:17]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(SC)C=CC=CC=1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])=[CH:34][CH:35]=1
Reactant: O=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(O)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.5 %

Procedure:
Trifluoroacetic acid (5 mL) and thioanisole (3 drops) were added to quinoline-6-carboxylic acid 4-benzyloxybenzylamide (2.67 g, 7.25 mmol) synthesized in Example E-8, the solution was stirred at room temperature for 14 hours, followed by stirring at 50° C. for 4 hours, lastly, and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, then, was neutralized with an aqueous solution of saturated sodium bicarbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (433 mg, 22%) was obtained as a colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[C:9]([C@H:11]([NH:24][C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[N:8]=[N:7]1)C.[Li+].[BH4-].Cl.[OH-].[Na+]>C1COCC1>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([NH:24][C@@H:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][CH2:4][OH:3])[CH:10]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[CH:14][N:13]=2)=[O:37])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)Cn1cc([C@H](NC(=O)Cc2ccc(C(C)(C)C)cc2)c2ccc(OCC(F)(F)F)cn2)nn1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(CCO)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a solution of ethyl(4-{(S)-{[(4-tert-butylphenyl)acetyl]amino}[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)acetate (0.190 g, 0.356 mmol) in 1.0 ml of anhydrous THF at RT was added 2.0N LiBH4 in THF (0.214 ml, 0.427 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with 1.0N HCl (2.0 ml, 2.000 mmol), stirred for 30 min. and 2.0 N NaOH (2.0 ml, 4.000 mmol) was added. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.047 g (27%) of the title compound. ES-MS [M+1]+: 492.3. This intermediate was carried over to the next step without further purification and characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)(O)[O-].[Na+]>O.CO.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[C:32](=[O:34])[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2cc(O)c(O)cc12

Procedure:
A solution of 4-(3-bromophenylamino)-6,7-dihydroxy-3-quinolinecarbonitrile (1.78 g, 5.0 mmol), dimethylaminopyridine (60 mg, 0.50 mmol), 5.0 ml of acetic anhydride, and 10 ml of pyridine was stirred at reflux temperature for 1.5 h and concentrated to dryness. The residue was stirred with 50 ml of methanol, 5 ml of water, and sodium bicarbonate (2.1 g, 25 mmol) at 25° C. for 16 h and concentrated to dryness. The residue was stirred with water containing acetic acid to give pH-4-5, and the resulting solid was filtered off, washed with water, and dried. A solution of the resulting solid in THF was passed through a pad of silica gel; the filtrate was concentrated to give a tan solid; mass spectrum (electrospray, m/e) M-H 396.3, 398.3.
Reaction SMILES: ClCCl.Cl([O-])(=O)(=O)=O.[CH2:9]([C:11]1(CCC#N)[C:20]2[C:19]3[NH:21][C:22]4[C:27]([C:18]=3[CH2:17][CH2:16][N+:15]=2[CH2:14][CH2:13][CH2:12]1)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:10].[OH-].[Na+]>O>[CH2:9]([C:11]1([CH:13]([CH3:12])[C:14]#[N:15])[C:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:19]=2[N:21]=[C:22]2[C:27]=3[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC1(CCC#N)CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(C(C)C#N)CCCN2CCC3=c4ccccc4=NC3=C21

Procedure:
40 ml. of dichloromethane are added to a suspension of 1.00 g. of 1-ethyl-1-(2-cyanoethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3 -a)quinolizinium perchlorate in 100 ml. of distilled water, and the pH of the mixture is adjusted to 10 to 11 with 40% sodium hydroxide solution. During this operation the mixture is cooled with water and stirred in argon atmosphere. After some minutes of stirring the separated red organic phase is removed, and the aqueous phase is extracted with 20 ml. of dichloromethane. The organic solutions are combined, dried over magnesium sulfate, and the solvent is evaporated in vacuo. The obtained 0.75 g. of red, oily residue is triturated with 1 ml. of methanol, and the resulting orange-red crystals are filtered off. 0.72 g. of (1-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained; m.p.: 122-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=5)=[C:20]([O:38][CH3:39])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:40]=O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]5[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=5)[CH3:40])=[C:20]([O:38][CH3:39])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCNCc1ccc(C(C)C)cc1
Reactant: C=O
Solvent: O=CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)Cc1ccc(C(C)C)cc1
Yield: 81 %

Procedure:
The product from Example H17 (12 mg) was dissolved in 37% formaldehyde (1 mL) and 88% formic acid (1 mL). The solution was refluxed for 2 h. The solvents were removed by rotary evaporation and the product was purified by silica gel column chromatography giving the title compound (10 mg, 81%). 1H NMR (CDCl3) δ 1.25 (6H, d), 2.40 (3H, s), 2.90 (2H, m), 3.65 (2H, m), 3.90 (3H, s), 4.21 (2H, m), 6.91-7.00 (3H, m), 7.19-7.34 (4H, m), 7.46 (2H, d, J=8.4 Hz). 7.55 (1H, s), 7.68 (2H, d, J=8.6 Hz), 8.15 (1H, s). LCMS m/z=574 (m+H+).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)=[O:37])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Yield: 79.8 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.353 g, 0.826 mmol), 4-iodo-4′-fluorobutyrophenone (0.27 g, 0.826 mmol), and potassium carbonate (0.17 g, 1.24 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.39 g, 80%); MS for C35H46FN3O4 m/z 592 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[Na+].[ClH:22].C1(C2NC(C)=C(C([Cl:36])C)N=2)C=CC=CC=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C1CNCCN1
Temperature: 25 °C
Yield: 55 %

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol :water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4- 1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl!piperazine trihydrochloride (55% yield), which melted at 215° C.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([C:23]2[S:27][C:26]([CH2:28][C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:29](=[O:31])[CH2:28][C:26]2[S:27][C:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1ccc(-c2ccccc2)s1)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Yield: 68.6 %

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of Step B of Example 1, 0.567 g of 5-phenyl-2-thiophene-acetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.571 g of trans-(±) N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-5-phenyl-2-thiophene-acetamide and then 0.457 g of its hydrochloride melting at ≃ 249° C.