Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Cl[CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:14][CH:15]=1>C(#N)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:13]2[S:14][CH:15]=[C:11]([CH:10]=[O:5])[N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Solvent: CC#N
Product: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Temperature: 25 °C
Yield: 85.9 %

Procedure:
N-methylmorpholine-N-oxide (16.5 g, 141 mmol) was added to a solution (200 ml) of 4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole (13.99 g, 47 mmol) in acetonitrile, followed by heating under reflux for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, to thereby obtain 11.2 g (yield: 86%) of 2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde as a yellow solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=CC(S(OCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH2:15]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:14][C:13]#[CH:12]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1O
Product: C#CCCOc1cc(C=O)ccc1OC
Yield: 34.8 %

Procedure:
Isovanillin (0.95 g, 6.2 mmol) was alkylated with but-3-ynyl 4-methylbenzenesulfonate (2.1 g, 9.4 mmol) according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 3-(but-3-ynyloxy)-4-methoxybenzaldehyde (0.44 g, 35%) as a colourless crystalline solid; mp 63-65° C.; δH (400 MHz, CDCl3) 2.06 (t, J=2.8 Hz, 1H, C≡CH), 2.76 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.96 (s, 3H, OCH3), 4.22 (t, J=7.2 Hz, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.43 (d, J2,6=1.4 Hz, 1H, H2), 7.45 (dd, J5,6=8.0, J2,6=1.4 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 19.4, 56.2, 67.0, 70.3, 79.8, 110.9, 111.2, 127.1, 130.1, 148.4, 154.9, 190.7; vmax 1015, 1124, 1231, 1586, 1675, 2821, 3305 cm−1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:35]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)[C:36]#[CH:37]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([C:37]#[C:36][CH2:35][N:38]3[CH:42]=[CH:41][CH:40]=[N:39]3)=[CH:7][CH:6]=2)/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL) was degassed and 1-propargylpyrazole (144 mg, 1.36 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (62 mg, 0.054 mmol) and copper(I) iodide (20 mg, 0.108 mmol) were added and the resulting mixture was stirred at ambient temperature for 30 h. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (20 mL) and the formed solution was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-phenoxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]3[N:25]=[C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])[S:22][CH:23]=3)=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chlorophenyl isocyanate and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.912 (s, 1H), 8.870 (s, 1H), 8.820-8.792 (d, 1H), 8.318 (s, 1H), 8.052-8.024 (d, J=8.4 Hz, 2H), 7.590-7.561 (d, J=8.7 Hz, 2H), 7.521-7.492 (d, J=8.7 Hz, 2H), 7.356-7.326 (d, J=9 Hz, 2H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.319-2.273 (m, 1H), 1.000-0.953 (t, J=6.9, 7.2 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([OH:42])=O)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CNC.[CH2:46]([NH2:48])[CH3:47]>>[CH2:46]([NH:48][C:40](=[O:42])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1)[CH3:47]
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CCN
Agent: CNC
Product: CCNC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 61 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with ethylamine. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave the title compound (0.152 g, 61%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][Cl:1])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCl)cc1
Reaction time: 18 h

Procedure:
A solution of 4-(2-Chloro-ethyl)-benzoic acid (20 g, 108 mmol) in DMF (200 mL) is treated with K2CO3 (59.7 g, 432 mmol) and Mel (16.8 mL, 270 mmol) and stirred at 23 C for 18 h. The reaction mixture is diluted with EtOAc (450 mL) and washed with H2O (2×150 mL), saturated aqueous NaHCO3 (1×200 mL), brine (1×200 mL), dried (MgSO4), and concentrated to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13]
Reactant: Cn1ncc(Br)c1-c1sc(C(=O)O)cc1Br
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (238 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (293 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.62 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (silica) (3:1 hex/EtOAc) affording the title compound (229 mg, 60%): LC-MS (ES) m/z=695 (M+H)+.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[NH:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[NH:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH:23][CH:1]=[O:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1N2
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1N2
Temperature: 0 °C

Procedure:
Sodium formate (0.074 g, 0.108 mmol) was added to a suspension of compound of Example 37 (0.20 g, 0.547 mmol) in formic acid (2 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (50 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by trituration with chloroform/methanol (3:1) to obtain the title compound. Yield: 0.18 g (84%); mp: 280-282° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.48 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.91 (s, 2H, CH2, trans minor isomer), 4.97 (s, 2H, CH2, cis major isomer), 7.30 (d, 1H, Ar, trans minor isomer), 7.47 (d, 1H, Ar, trans minor isomer), 7.56 (s, 1H, Ar, cis major isomer), 7.63 (s, 1H, Ar, cis major isomer), 7.89 (s, 1H, Ar), 7.94 (s, 1H, Ar), 8.26 (s, 1H, CHO, cis major isomer), 8.29 (s, 1H, NH), 8.78 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.46 (s, 1H, NH, cis major isomer); MS: m/e (ES+) 395 (M+1); analysis: C17H14ClNO6S requires C, 51.72; H, 3.83; N, 7.10; Cl, 8.98; S, 8.12. found C, 51.24; H, 3.80; N, 6.79; Cl, 9.22; S, 7.84%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][C:24]=2[C:29]([F:32])([F:30])[F:31])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: O=C(Nc1ccc(F)cc1C(F)(F)F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-fluoro-2-trifluoromethyl-aniline (69 mg, 0.39 mmol). The title compound was obtained as a solid (60 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.55 (1H, s), 8.99 (2H, m), 8.64 (1H, s), 7.73 (1H, m), 7.64 (1H, m), 7.58 (1H, m). MS m/z: 510.02, 512.00 [M+H]+.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH2:11](N)[CH2:12][CH2:13]N.C(Br)C=C>>[N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][N:6]1[CH2:13][CH:12]=[CH2:11])([O-:3])=[O:2]
Reactant: NCCCN
Reactant: O=[N+]([O-])C=C1NCCCN1
Solvent: C=CCBr
Product: C=CCN1CCCNC1=C[N+](=O)[O-]

Procedure:
Method B, reacting hexahydro-2-(nitromethylene)pyrimidine (HNMP), prepared by Method A by reaction of NKDM with 1,3-propanediamine, with allyl bromide. Melting point: 125°-126°C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid methyl ester (575 mg, 1.62 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (778 mg, 18.5 mmol). The reaction mixture was stirred at 25° C. for 5 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=5 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (601 mg, quant.) as a light brown oil: EI-HRMS m/e calcd for C21H27NO3 (M+) 341.1990, found 341.1996.
Reaction SMILES: [CH3:1][C:2]([CH3:48])([CH3:47])[Si:3]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:4][CH2:5][CH:6]([C:31]([F:34])([F:33])[F:32])[NH:7]/[C:8](=[N:20]/C(=O)OCC1C=CC=CC=1)/[NH:9]C(=O)OCC1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[Si:3]([O:4][CH2:5][CH:6]([NH:7][C:8]([NH2:20])=[NH:9])[C:31]([F:34])([F:33])[F:32])([C:2]([CH3:1])([CH3:47])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](OCC(N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC(NC(=N)N)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
To a stirred solution of 346 (210 mg, 0.310 mmol) in 95% EtOH/THF (5 mL, 1:1) was added Pearlman's Catalyst (21.8 mg, 0.0310 mmol). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere of hydrogen pressure overnight. The mixture was then filtered through GF/F filter paper with 95% ethanol and the filtrate was concentrated to afford 127 mg (100%) of 1-(3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-yl)guanidine (348) as a white solid.
Reaction SMILES: [I-].[K+].[CH2:3]([C@:5]1([OH:37])[CH2:29][C@@H:9]2[CH2:10][CH2:11][CH2:12][C:13]3[C:14](=[CH:15][C:16]4[CH:17]=[N:18][N:19]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)[C:20]=4[CH:21]=3)[C@:8]2([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:7][CH2:6]1)[CH3:4].[O:38](C(C)(C)C)O>CC#N>[CH2:3]([C@:5]1([OH:37])[CH2:29][C@@H:9]2[CH2:10][CH2:11][C:12](=[O:38])[C:13]3[C:14](=[CH:15][C:16]4[CH:17]=[N:18][N:19]([C:22]5[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=5)[C:20]=4[CH:21]=3)[C@:8]2([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC[C@@]1(O)CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Reactant: CC(C)(C)OO
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@]1(O)CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3C(=O)CC[C@H]2C1
Yield: 6 %

Procedure:
Potassium iodide (1 M solution in water, 0.365 mL, 0.365 mmol) was added to a solution of (3R,4aS,12bS)-3-ethyl-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (13, R1=4-Fluorophenyl, R2=Pyridyin-2-ylmethyl, R3=Ethyl) (0.143 g, 0.305 mmol) and MeCN (3 mL) under air. 2-Hydroperoxy-2-methylpropane (0.717 mL, 5.18 mmol) was added dropwise over about 5 min. The reaction was mixed at rt for about 24 h. The reaction was quenched with sat. aq. sodium sulfite (5 mL) and then a 1:1 solution of sat. aq. NaHCO3/water (5 mL) was added. The solution was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 50-86% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 0-95% MeCN in aqueous NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aS,12bS)-3-ethyl-9-(4-fluorophenyl)-3-hydroxy-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-7(9H)-one (48, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Ethyl) (0.008 g, 6% yield). LC/MS, method 2, Rt=2.32 min.; MS m/z: 484 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=4.8 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 7.88-7.78 (m, 2H), 7.69 (s, 1H), 7.54 (s, 1H), 7.48-7.41 (m, 2H), 7.35 (td, J=7.6, 1.8 Hz, 1H), 7.10-7.04 (m, 1H), 6.34-6.30 (m, 1H), 3.95 (s, 1H), 3.02-2.86 (m, 3H), 2.74-2.64 (m, 2H), 2.47-2.43 (m, 1H), 2.12-2.03 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.62 (m, 1H), 1.55-1.46 (m, 2H), 1.39-1.25 (m, 2H), 1.20 (q, J=7.8 Hz, 2H), 0.73 (t, J=7.4 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:13]([N:15]([CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: O=Cc1ccc2c(n1)COC2=O
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC)Cc1ccc2c(n1)COC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
A solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (110 mg, 0.68 mmol) in dichloroethane (4 mL) is treated with diethylamine (75 μL, 0.68 mmol) followed by the addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). The reaction mixture is stirred at room temperature for 1.5 h. and then treated with saturated aqueous NaHCO3 solution. The aqueous layer is extracted twice with EtOAc (2×). The combined organic extracts are dried, and concentrated. The residue is chromatographed (silica gel, EtOAc/hexane). The product containing fractions are concentrated to give the title compound as white solid (90 mg, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCOc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCOc2ccccc2)CC1

Procedure:
1-(3-Phenoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-phenoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]3)[CH:19]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(C(C)C)CC4)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.5 %

Procedure:
Methyl 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate 7.56 g) was dissolved in a mixture of methanol (135 ml) and water (45 ml). 2N NaOH (36 ml) added and stirred at room temperature for 1 hour. The pH was adjusted to 2-3 using 2N HCl and the solvent evaporated in vacuo. The oil was triturated with a mixture of ethyl acetate (100 ml) and iso-hexane (100 ml) and the solid collected by filtration and dried under vacuum at 40° C. for 16 hours to give 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (9.9 g); NMR Spectrum: (DMSOd6) 1.33 (d, 6H), 2.14 (s, 3H), 3.15 (m, 2H), 3.46 (m, 5H), 3.98 (m, 2H), 7.55 (m, 2H), 7.68 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H), 8.18 (t, 1H), 11.56 (s, 1H); Mass Spectrum: M+H+ 407.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CCOCC.[Zn]>[Cl:1][C:2]1([Cl:7])[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8][C:3]1=[O:4]
Reactant: C=C1CCOCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CC2(CCOCC2)C1(Cl)Cl
Reaction time: 16 h

Procedure:
Zinc was activated according to a published procedure (Synthesis 1971; 415). Hydrated copper sulfate (14 g) was dissolved in water (150 mL) and added to zinc dust (60 g). The mixture was stirred for 2 hours under nitrogen. The activated zinc was isolated by filtration, washed with acetone and dried in a vacuum oven at 100° C. prior to use. The solution of 4-methylenetetrahydro-2H-pyran from Step A was dried with sodium sulfate and magnesium sulfate and filtered through Celite® (washing the cake with ether). This removed some orange solids which had precipitated. A solution of trichloroacetyl chloride (5.00 g; 27.5 mmol) in dry ether (250 mL) was added slowly (over 4 hours) to a stirred refluxing mixture of the 4-methylenetetrahydro-2H-pyran in dry ether (250 mL) and the activated zinc (5.00 g; 76.5 mmol) under nitrogen. The mixture was stirred for 16 hours at reflux. The solution was filtered through Celite® and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with 10:1 hexane/ethyl acetate to give impure product (160 mg) as a colorless oil which was continued directly on to the next step.