Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:20]1([C:26]([N:28]=[C:29]=[O:30])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:26]([NH:28][C:29](=[O:30])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=O)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.116 g, 0.41 mmol, 1 equiv.) and PhCONCO (0.06 mL, 0.5 mmol, 1.2 equiv.) were dissolved in THF (2 mL) and stirred at 50° C. for 16 h. The solvent was removed and the product was purified by preparatory HPLC (0-40% EtOAC:hexanes). The product was isolated as a white solid (0.105 g, 59% yield). 1H NMR (400 MHz, CDCl3) δ 13.26 (s, 1H), 9.81 (s, 1H), 8.13 (d, J=7.0 Hz, 2H), 7.65 (d, J=6.7 Hz, 3H), 4.72 (s, 2H), 2.75 (s, 2H), 1.64 (s, 9H), 1.32 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O-].[Na+]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-fluorobenzaldehyde (3.54 gm, 28.5 mmol) and 1,1-diphenylacetone (5.000 gm, 23.8 mmol) in absolute EtOH (50 ml) was treated with a solution of EtONa in EtOH (21% solution, 900 μl, 2.4 mmol). After stirring at room temperature for 22 hours, the mixture was concentrated to 35 ml and the solution was treated with HOAc (200 mg). The solution was cooled to 0° C. and the precipitate that had formed was collected by filtration and washed with cold EtOH. The title compound was obtained as a pale yellow solid (5.787 gm, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:36]4[C:35](=[C:34]([CH3:33])[CH:39]=[CH:38][CH:37]=4)[NH:40][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][CH2:20][C:21](=O)[CH3:22])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]2[S:33][C:21]([CH3:22])=[CH:20][N:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1cnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)s1

Procedure:
The title compound was prepared by a similar method to Example 29 from (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-oxopropyl)-2-piperidinecarboxamide [see Preparation 81] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane:ethyl acetate, in 5% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-1,3-thiazol-2-yl)piperidine as a white solid.
Reaction SMILES: C([O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:16][N:15]([C:17]3[C:18]([F:25])=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=3)[CH2:14]2)=[CH:8][CH:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:18]1[C:19]([CH2:23][OH:24])=[CH:20][CH:21]=[CH:22][C:17]=1[N:15]1[CH2:14][CH:13]([O:12][C:9]2[CH:8]=[CH:7][C:6](=[O:5])[NH:11][CH:10]=2)[CH2:16]1
Reactant: CC(C)(C)Oc1ccc(OC2CN(c3cccc(CO)c3F)C2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc(OC2CN(c3cccc(CO)c3F)C2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
(3-{3-[(6-tert-Butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 1M aqueous NaOH solution and CHCl3 were added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (428 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19](C=O)[CH3:20].CNC.C1COCC1>>[CH3:18][N:19]([CH3:20])[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)benzoic acid (1 g, 4.21 mmol) in DMF (10 ml) CDI (1.025 g, 6.32 mmol) was added. The mixture was stirred at RT for 2 hours. Dimethylamine 2M in THF (3.16 ml, 6.32 mmol) was added, and the mixture stirred at RT for 3 hours. The mixture was poured onto water and extracted with AcOEt (2×). Organic phase was dried over Na2SO4 and evaporated under vacuum to give g 1.25 of Int. 73 which crystallizes on standing.
Reaction SMILES: [F:1][C:2]([F:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3]O.FC(F)(F)C(O)=O.[NH:21]1[CH2:25][CH2:24][C@@H:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:22]1>>[F:1][C:2]([F:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][N:21]1[CH2:25][CH2:24][C@@H:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:22]1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: OCC(F)(F)CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(CC(F)(F)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=364.2 (M+H+) was prepared from 2,2-difluoro-4-phenyl-butan-1-ol and (3R)-4-(pyrrolidin-3-ylsulfanyl)-phenol trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][NH:15][CH2:14][CH2:13][N:9]3[S:10](=[O:11])(=[O:12])[C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCN2C(Cc3ccc(C(F)(F)F)cc3S2(=O)=O)C1
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CNCCN21
Reaction time: 1 h

Procedure:
To a solution of phenylmethyl 3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate 6,6-dioxide (59.0 mg, 0.134 mmol) in methanol (2 mL) under a nitrogen atmosphere was added 10% Pd-C (6 mg). The nitrogen atomosphere was exchanged for hydrogen (provided by a balloon) using 3 pump/purge cycles. The reaction was stirred for 1 h. The hydrogen atmosphere was exchanged for nitrogen and the reaction was filtered through Celite® AFA. The pad was rinsed with methanol (1 mL). The combined filtrates were concentrated in vacuo to provide the title compound: LCMS (pos. ion spectrum) m/z 307.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1Cl
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (1.81 g, 0.0077 mol), 4chlorophenyl isothiocyanate (1.59 g, 0.0094 mol) and toluene (10 ml) was refluxed for 2.5 hours, cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.54 g (90%), m.p. 177° 179 ° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:5][CH:4]=1.Br>O>[NH:16]1[CH:17]=[C:13]([CH2:12][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:11]=3)[CH2:7][CH:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:15]1
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)C(c1ccccc1)C2
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1)C(Cc1c[nH]cn1)C(c1ccccc1)C2
Temperature: 135 °C

Procedure:
A mixture of 4-[(2,3-dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)methyl]-1H-imidazole (370 mg as base) and 48 wt. % hydrobromic acid (15 ml) was heated at 130-140° C. for 2 hours with stirring. The cooled reaction mixture was poured into water and made basic (pH 8). The resulting precipitate was filtered and washed with water. The product was purified by flash chromatography (elution with a dichloromethane—methanol gradient).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:7].[ClH:48]>C(OCC)(=O)C.CCCCCC>[ClH:48].[ClH:48].[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][NH:18]2)[CH2:10][C@H:9]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(C/C=C/[C@@H]3COCCN3C(=O)OC(C)(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C[C@@H]2CN(C/C=C/[C@@H]3COCCN3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 5 h

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]-2-propenyl]-2-(3,4-dimethylbenzyl)piperazine (1.36 g) in ethyl acetate (13 ml) was treated 4N hydrogen chloride in ethyl acetate (3.12 ml) at room temperature for 18 hours and then at 40° C. for 5 hours. The solution was diluted with hexane and stirred for 1 hour. The resulting precipitate was collected by filtration and dried under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(2E)-3-[(3R)-3-morpholinyl]-2-propenyl]piperazine dihydrochloride (1.11 g) as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)c1ccccn1

Procedure:
A solution of pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide (7.7 g, 25.3 mmol) in 90% ethanol (110 mL) was hydrogenated (60 psi) over 10% palladium on carbon (0.8 g) at 50° C. for 4 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel, using methanol/dichloromethane (DCM),5/95, as the eluant, to give the product as a beige solid, 2.54 g (47%). MS m/z 215 (MH+). 1H NMR(DMSO-d6) δ 6.76 (d, 2H), 7.54 to 7.76 (m, 3H), 8.05 (t, 1H), 8.14 (d, 1H), 8.72 (d, 1H), 9.30 (s, 1H) and 10.41 (s, 1H). Anal. calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 66.99; H, 4.56; N, 12.81.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].C(N(CC)CC)C>C(#N)C>[O:30]=[C:29]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:13]2[CH2:14][CH2:15][C:16](=[O:17])[C:12]=2[CH:3]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[NH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)-methyl)benzonitrile hydrochloride (intermediate 13, 11.8 g, 26.1 mmol based on 90% purity) in acetonitrile (100 mL) and 1,1′-carbonyldiimidazole (5.28 g, 32.6 mmol) is treated with triethylamine (0.9 mL, 6.5 mmol), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered, washed with water and dried. The residue is purified by recrystallization from hot toluene (130 mL). Yield: 8.6 g; ESI mass spectrum [M+H]+=398; Retention time HPLC: 1.06 min (V011_S01). LH4BRM00213
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:35]([O:37]C(C)C)=[O:36])([C:29]([O:31]C(C)C)=[O:30])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:29]([OH:31])=[O:30])([C:35]([OH:37])=[O:36])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]1[CH2:53][CH2:54][O:55][CH2:56][CH2:57]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-morpholinoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (9 mg, 0.011 mmol) in 1,4-dioxane (1 mL) and MeOH (0.5 mL) was added 1N NaOH (0.5 mL, 0.500 mmol)). The mixture was stirred at 50° C. for 3 h. The crude product was purified by Prep HPLC using method 14 to give desired product in 74% yield as a solid. MS: m/e 703.6 (M+H)+, 2.42 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 5.96 (s, 1H), 5.54 (dd, J=6.1, 1.6 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.80-3.67 (m, 4H), 3.15-3.01 (m, 2H), 2.94-2.76 (m, 2H), 2.76-2.58 (m, 8H), 2.52 (br. s., 2H), 2.22-2.14 (m, 1H), 2.10-1.87 (m, 2H), 1.83-1.07 (m, 19H), 1.76 (s, 3H), 1.24 (s, 3H), 1.18 (s, 4H), 1.09 (s, 6H), 0.85 (s, 3H).
Reaction SMILES: Cl.C(=O)(O)O.[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH2:16])[CH2:10][CH2:9][CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+]>O.C1COCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH:16][C:23]([NH2:24])=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N#C[O-]
Reactant: COc1ccc(CN)cc1OC1CCCC1
Agent: Cl
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC(N)=O)cc1OC1CCCC1
Yield: 97 %

Procedure:
25 ml of 5N HCl was added to a solution of 31.54 g of 3-cyclopentyloxy-4-methoxy-benzylamine carbonate and 8.30 g of sodium cyanate in 440 ml of water and 50 ml of THF over 15 minutes. After 3 hours another 0.83 g of sodium cyanate was added. After 20 hours the solid was collected, washed with water containing 5% of THF, suspended in 2.2 liters of ether and collected to give the title compound as a white solid (28.55 g) mp 134-5° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)c2ccccc12
Product: COc1ccc(CNc2ccccc2C(=O)O)c2ccccc12

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 4-methoxy-1-naphthaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 169.9, 154.4, 150.7, 134.4, 131.8, 131.6, 126.7, 125.8, 125.7, 125.2, 125.1, 123.3, 122.0, 114.4, 111.6, 110.1, 103.7, 55.4, 43.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=C)[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=[O:26])[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: C=Cc1csc2c1c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C=O)csc32)cc1
Reaction time: 4 h
Yield: 67.9 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (850 mg, 2.51 mmol) was suspended in tetrahydrofuran (17 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (1.24 g, 5.78 mmol) was heated in water (8.5 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was at 40° C., osmium(VIII) oxide (737 μl, 2.50% w/w, 0.08 mmol) was added and the mixture was stirred vigorously for 4 hours. It was diluted with water (300 mL) and the resulting solids were collected via vacuum filtration to yield the aldehyde (0.58 g, 68%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3 H), 5.42 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 8.29 (s, 1H), 8.61 (s, 1H), 10.58 (s, 1H). LCMS (MH+, 341.1).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][N:9]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCCNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpiperidine (Example 24A, 0.24 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.308 g, 1.00 mmol), under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.12-7.33 (m, 20H), 4.23 (s, 2H), 4.13 (s, 2H), 3.35-3.46 (m, 4H), 2.57-2.64 (m, 2H), 2.45-2.51 (m, 2H), 1.72-1.85 (m, 2H), 1.46-1.56 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15][CH3:16])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[OH:34]O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15]([CH3:16])=[O:34])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Reactant: OO
Solvent: C1CCOC1
Product: CS(=O)c1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Temperature: 73 °C
Reaction time: 12 h

Procedure:
To the title compound from Example 255 (0.18 grams) dissolved in anhydrous THF (10 mL) was added 30% aqueous hydrogen peroxide (3 mL) and the resulting solution was stirred for 12 hours at 73° C. The solution was concentrated in vacuo, diluted with CH2Cl2, and washed with water. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the title compound after preparative plate chromatography (silica gel) using 3% MeOH—CH2Cl2 (0.04 grams, 26%, MH+ 492).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.