Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:21]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([O-:28])=[C:14]([C:21]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[Na+:30]
Reactant: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](CO)NC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 72 %

Procedure:
In a manner similar to that described in example 474, from 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1S)-2-hydroxy-1-methylethyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (436 mg, 1.13 mmol described in example 359) and sodium hydroxide (1.08 mL of a 1 N solution) was prepared sodium 7-[(4-fluorophenyl)methyl]-3-({[(1S)-2-hydroxy-1-methylethyl]amino}carbonyl)-l -methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (331 mg, 72% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.41 (d, J=7.2 Hz, 1 H), 8.16 (s, 1 H), 7.59 (s, 1 H), 7.33-7.29 (m, 2 H), 7.11-7.07 (m, 2 H), 4.79 (m, 1 H), 3.93 (m, 1 H), 3.41 (m, 1 H), 3.28 (s, 3 H), 3.24 (m, 1 H), 1.03 (d, J=6.8 Hz, 3 H); MS m/z 386 (M+1).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:26]1[NH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][CH2:32][CH:31]([CH2:35][NH2:36])[CH2:30]2>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:36][CH2:35][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][NH:27][N:26]=3)[CH2:30]2)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: NCC1CCc2n[nH]cc2C1
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:27]2[CH2:28][CH2:29][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-piperidine in ethanol in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+383.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N:54]([C@@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])=[C:55]=[O:56]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:20][C:21]([C@@H:23]3[CH2:32][C:31]4[CH:30]=[C:29]5[O:33][CH2:34][C@H:35]([C:37]6[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=7)=[CH:41][CH:42]=6)[O:36][C:28]5=[CH:27][C:26]=4[CH2:25][N:24]3[C:55](=[O:56])[NH:54][C@@H:57]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH3:58])=[O:22])[C:3]([OH:2])=[O:53])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: C[C@@H](N=C=O)c1ccccc1
Product: C[C@@H](NC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino [2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was added ((R)-1-isocyanato-ethyl)-benzene (5 equiv) and the reaction stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (26 mg). LCMS (m/z): 884.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Br)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Br)s1

Procedure:
56.3 Using general method H. 5-bromo-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 521.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1OC
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,4-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 128 mg of the title compound (yield: 84%).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:36][OH:37].N1C=CC=CC=1>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][CH2:12][NH:11][C:9]([C:6]3[NH:7][N:8]=[C:4]([C:1](=[N:36][OH:37])[CH3:2])[CH:5]=3)=[O:10])[N:15]=2)=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28])#[N:26]
Reactant: NO
Reactant: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
5-Acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide (0.17 g, 0.43 mmol) was dissolved in ethanol (15 ml). Sodium acetate (0.071 g, 0.86 mmol) and hydroxylamine hydrochloride (0.060 g, 0.86 mmol) was added and the reaction mixture was stirred at RT for 1.5 h. After addition of pyridine (5 ml) stirring was continued for 65 h. The reaction mixture was evaporated to dryness, co-evaporated two times with toluene and dissolved the residue in ethyl acetate. It was then washed two times with water, dried with Na2SO4 and purified with CombiFlash using DCM and methanol as eluents affording 0.034 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.11-2.15 (m, 3H), 3.68-3.71 (m, 2H), 4.39 (t, 2H), 7.05-7.06 (m, 1H), 7.88 (d, 1H), 8.17-8.20 (m, 1H), 8.32-8-35 (m, 1H), 8.68 (d, 1H).
Reaction SMILES: [Cl-].[NH4+].C(O)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N+:21]([O-])=O)[CH:12]=1>[Fe].O>[NH2:21][C:13]1[CH:12]=[C:11]([C:7]2[O:6][CH:10]=[CH:9][CH:8]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(-c2ccco2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccco2)cc1N
Temperature: 25 °C
Yield: 63.4 %

Procedure:
Water (0.56 mL), ammonium chloride (18 mg), and iron powder (94 mg) were added to an ethanol (2.1 mL) suspension of methyl 4-(furan-2-yl)-2-nitrobenzoate (0.14 g), followed by heating to reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ammonium chloride (18 mg), iron powder (31 mg), and water (0.28 mL) were added thereto, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the obtained residue, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-95% hexane/ethyl acetate] to obtain 78 mg of methyl 2-amino-4-(furan-2-yl)benzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][CH2:12][CH2:13][OH:14]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NCCO
Product: NCc1ccc(Cl)cc1NCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-amino-ethanol analogously to the preparation of Intermediate 113.1. colorless powder; ES-MS: M−=199.1; HPLC: AtRet=1.90 min.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH2:13]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Agent: O=S(=O)(O)O
Product: CCC1(CC)C(=O)Nc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 3,3-diethyl-1,3-dihydro-indol-2-one (10.0 g, 52.84 mmol, A. Mertens et al., J. Med. Chem. 1987, 30, 1279-1287) in conc. sulfuric acid (50 ml) was added slowly a mixture of nitric acid (65%, 5.12 g, 3.63 ml, 52.84 mmol) and conc. sulfuric acid (10 ml) at 0° C. After 2 h at room temperature the mixture was poured into ice water. The precipitate was filtered off, washed with water and dried to yield 11.7 g 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (49.95 mmol, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:15][C:16]([Cl:21])([Cl:20])C([O-])=O.[Na+].O>CN(C)C=O>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:16]([Cl:21])([Cl:20])[Cl:15]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(O)C(Cl)(Cl)Cl)cc1OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.3 %

Procedure:
In 1.2 l of dimethylformamide, 196 g of 2,4,5-trimethoxybenzaldehyde were dissolved, followed by the addition of 241 g of sodium trichloroacetate salt under ice cooling. The resulting mixture was stirred at room temperature for 9 hours. After the reaction, 2 l of water were added to the reaction mixture under ice cooling. The solid so precipitated was collected by filtration, followed by washing with water and diethyl ether, whereby 272 g of 1-(1-hydroxy-2,2,2-trichloroethyl)-2,4,5-trimethoxybenzene were obtained (yield: 86%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10]([CH3:23])([CH3:22])[C:11]([NH:13][NH:14]C(OC(C)(C)C)=O)=[O:12].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][C:10]([CH3:23])([CH3:22])[C:11]([NH:13][NH2:14])=[O:12]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(C)(C)CCN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCN1C(=O)C=CC1=O)C(=O)NN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (154 mmol) of tert-butyl 2-[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,2-dimethylbutanoyl]hydrazinecarboxylate were dissolved in 2 ml of dichloromethane, and 0.4 ml of trifluoroacetic acid was added. The reaction mixture was stirred at RT for 30 min and then concentrated. 55.2 mg (93% purity, 99% of theory) of the title compound were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[NH:6][C:7]=1[CH3:8].C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[CH3:8][C:7]1[NH:6][C:5]2[N:4]([C:3]=1[CH3:2])[C:22](=[O:25])[CH:23]=[CH:24][C:9]=2[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1
Reactant: C#CC(=O)OC
Reactant: Cc1cccc(C(=O)Cc2nc(C)c(C)[nH]2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C(=O)c2ccc(=O)n3c(C)c(C)[nH]c23)c1

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.13 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methylphenyl)ethanone hydrochloride (example XXII), 65 mg (1.20 mmol) of sodium methylate and 95.3 mg (1.13 mmol) methyl propiolate.
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34](S(C2C=CC=CC=2)(=O)=O)[C:33]([C:47](=[O:60])[C:48]2[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH3:57])=[C:50]([O:58][CH3:59])[CH:49]=2)=[CH:32]3)(=O)=O)C=CC=CC=1.[OH-].[Na+].O>C(O)C>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26])[C:15]([C:13]1[N:12]=[C:11]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([C:47]([C:48]2[CH:49]=[C:50]([O:58][CH3:59])[C:51]([O:56][CH3:57])=[C:52]([O:54][CH3:55])[CH:53]=2)=[O:60])=[CH:32]3)[NH:10][CH:14]=1)=[O:16]
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc4c(c3)cc(C(=O)c3cc(OC)c(OC)c(OC)c3)n4S(=O)(=O)c3ccccc3)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)c2c[nH]c(-c3ccc4[nH]c(C(=O)c5cc(OC)c(OC)c(OC)c5)cc4c3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (16xaa) (1 mmol) in ethanol (20 mL) was added sodium hydroxide (10 equiv) and stirred overnight in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (250 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) or recrystallized from water and methanol to give a white solid. Yield: 30-95%.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Na].[CH3:12][O:13][C:14](=[O:23])[C:15]([CH:18](OC)OC)=[CH:16]O.O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:16]=[N:9][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:10][CH:18]=1)=[O:23]
Reactant: N=C(N)c1cccnc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cccnc2)nc1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
To a solution of nicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100° C. under N2 for 3 hours. After this time the reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.7 g, 51%). MS: 216 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:14][C:15](O)=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH2:18][NH:19][C:20]([NH2:22])=[S:21].C(=O)([O-])[O-].[Na+].[Na+]>>[N:8]1([CH2:14][C:15]2[S:21][C:20]([NH2:22])=[N:19][N:18]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NNC(N)=S
Reactant: O=C(O)CN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CN2CCOCC2)s1
Yield: 27.3 %

Procedure:
(4-Morpholinyl)acetic acid trifluoroacetic acid salt (1.0 g) and thiosemicarbazide (0.25 g) are heated in polyphosphoric acid (2.0 g) at 70° C. for 1 h. The mixture is cooled to room temperature and basified with sodium carbonate, which is extracted with CH2Cl2. The organic layer is dried (MgSO4), concentrated, and the residue is chromatographed (CH2Cl2/methanol, 9/1) to give 150 mg of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 201 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:24](O)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:29]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: CC(C)(C)C(=O)O
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C(C)(C)C)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 22 mg (0.22 mmol, 1.1 eq.) of pivalic acid were reacted according to General Method 1. Yield: 37 mg (34% of theory)
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:29]2([CH3:30])[C@:16]([CH3:35])([C:17]3[C:26](=[CH:27][CH2:28]2)[C@:25]2([CH3:31])[CH:20]([C:21]([CH3:34])([CH3:33])[C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:47](O)[CH2:48][OH:49]>C1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:8]/[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:29]2([CH3:30])[C@:16]([CH3:35])([C:17]3[C:26](=[CH:27][CH2:28]2)[C@:25]2([CH3:31])[CH:20]([C:21]([CH3:33])([CH3:34])[C:22]4([CH2:23][CH2:24]2)[O:49][CH2:48][CH2:47][O:32]4)[CH2:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])[CH3:7]
Reactant: OCCO
Reactant: CCOC(=O)/C(C)=C/CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C(=O)CC[C@]4(C)C3=CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C(C)=C/CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C5(CC[C@]4(C)C3=CC[C@]12C)OCCO5
Temperature: 25 °C

Procedure:
General Ketalization. Ketone 9E (0.257 g, 0.535 mmol, 1.0 equiv) was dissolved in benzene (27 mL). After the ketone was completely dissolved, p-toluenesulfonic acid (0.0102 g, 0.0535 mmol, 0.1 equiv) and ethylene glycol (0.298 mL, 5.35 mmol, 10 equiv) were added and the solution was heated to reflux for 20 h using a modified Dean-Stark apparatus. The mixture was then allowed to cool to room temperature, and was then concentrated using a rotary evaporator. The residue was then diluted with CH2Cl2 (30 mL) and washed with saturated sodium bicarbonate solution (3×30 mL). The organic layer was washed with a saturated brine (30 mL), dried with MgSO4, and vacuum filtered through a pad of Celite. The filtrate was concentrated with a rotary evaporator to give 10E as a pure white crystalline product (0.246 g, 88% yield). 10Z was prepared by an analogous procedure in 83% yield. (6R,E)-Ethyl-2-methyl-6-((10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-1,2,4,5,6,10,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-yl)hept-2-enoate (10E): mp 75-79° C. IR (KBr) νmax 3047, 2963, 2924, 2898, 2888, 1705, 1652, 1197, 1141, 1101, 1098, 1050, 1028, 964, 952 cm−1. 1H NMR (CDCl3) δ 6.75 (dt, J=1.3, 7.5 Hz, 1H), 5.45 (m, 1H), 5.31 (d, J=6.3 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.96 (m, 3H), 3.88 (m, 1H), 2.27-2.17 (m, 2H), 2.11-1.84 (m, 8H), 1.81 (d, J=1.1 Hz, 3H), 1.75-1.31 (m, 7H), 1.29 (t, J=7.1 Hz, 3H), 1.22-1.1 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H), 0.92 (d, J=6.5 Hz, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.60 (s, 3H). 13C{1H} (CDCl3) δ 168.3, 145.9, 142.8, 142.5, 127.4, 120.2, 116.0, 113.1, 64.9, 64.7, 60.4, 50.8, 50.3, 47.4, 43.8, 41.8, 37.8, 37.0, 36.2, 34.9, 34.0, 31.5, 27.9, 27.2, 25.7, 25.6, 23.1, 22.9, 22.7, 20.4, 18.3, 15.6, 14.3, 12.3. HRMS calcd for C34H5304 (M+H)+525.3938. found 525.3922.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O.C(OCC)C>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: NCCCCOc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.8 g of 4-(4-nitrophenoxy)-butaneamine hydrochloride (Example 34) in 200 ml of water is treated successively with 9 ml of 10N NaOH, and a solution of 7.5 g of 4-methylbenzenesulfonyl chloride in 200 ml of diethylether. The reaction is stirred at room temperature for 3 hours, the precipitate collected, washed with water and diethylether, and air dried. Recrystallization from 50% aqueous ethanol gives the desired product as a solid, m.p. 87°-88° C.; yield, 1.2 g.
Reaction SMILES: [CH3:1][C:2]12[CH:11]=[CH:10][CH:5]([CH:6]=[C:7]1[CH2:8][OH:9])[C:4]([CH3:13])([CH3:12])[C:3]2=[O:14].[H][H]>[C].[Pd].C(O)(C)C>[CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][CH:7]1[CH2:8][OH:9])[C:4]([CH3:13])([CH3:12])[C:3]2=[O:14]
Reactant: [H][H]
Reactant: CC12C=CC(C=C1CO)C(C)(C)C2=O
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2(C)CCC1CC2CO
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A mixture of 30 g of 1,3,3-trimethyl-6-hydroxymethyl-bicyclo-(2.2.2)-octa-5,7-dien-2-one, 0.5 g of 5% of palladium-carbon and 300 ml of isopropyl alcohol is added to a stirred autoclave. The autoclave is pressurized to 400 pounds per square inch with hydrogen and heated to 100° C for 6 hours. At the end of this time, the mixture is filtered, stripped of solvent and vacuum distilled, yielding about 27 g (90%) of the product, 1,3,3-trimethyl-6-hydroxymethyl-bicyclo-(2.2.2)-octan-2-one, having the structure: ##SPC41##