Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoate (301 mg, 0.5508 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (10 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (233 mg, 0.5508 mmol, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]([NH2:9])=[O:20])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The mixture of 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbonitrile (1.0 g, 3.85 mmol, 1.0 eq) and K2CO3 (2.0 g, 14.49 mmol, 3.8 eq) in DMSO (20 mL) was stirred at room temperature, and 30% hydrogen peroxide (3 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h, water was added and the suspension was filtered to afford 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carboxamide (950 mg, 89%). LC-MS (m/z)=279.0 [M+H]+.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1
Reactant: ClCCCCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccncc3)CC(C1)O2
Yield: 45.5 %

Procedure:
tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.35 g, 5.9 mmol, see Preparation A and Preparation C(iii) above) was mixed with 4-(4-chlorobutyl)pyridine (1.35 g, 7.37 mmol, see Example 10(i) above), Br, (0.094 g, 0.59 mmol ) and K2CO3 (3.26 g, 23.6 mmol). The mixture was refluxed under argon for 3 days. The reaction mixture was filtered, evaporated and purified by chromatography (DCM, 2-5% MeOH) giving 0.97 g (44%) of the sub-title compound.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=O)=O.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
Diphenylphosphine (0.94 mL, 5.40 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxybenzoate (1.531 g, 5.39 mmol, 1 eq), triethylamine (0.85 mL, 6.1 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.004 eq) in degassed MeCN (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:40]([NH:42][C@H:43]([C:48]([O:50]C(C)(C)C)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:19][S:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.O>FC(F)(F)C(O)=O.C(S)C>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:40]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:19][SH:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Solvent: O
Product: NC(=O)C[C@H](NC(=O)[C@H](CS)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reaction time: 4 h

Procedure:
2.2 g (2.9 mmol) of H-Tyr(tBu)-Cys(Trt)-Asn-OtBu are dissolved in a mixture of 25 ml of trifluoroacetic acid and 25 ml of ethyl mercaptan. After 4 hours, the mixture is tipped into 250 ml of water. The aqueous solution is extracted 3 times with ether and freeze-dried. Yield 1.05 g (91%).
Reaction SMILES: OO.C([C@@H]1COC(=O)N1[C:16](=[O:36])[C@H:17]([CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=1)C1C=CC=CC=1.[OH-].[Li+].S([O-])([O-])=[O:40].[Na+].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[CH:33]([C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=1)[C:16]([OH:36])=[O:40])([CH3:34])[CH3:35]
Reactant: COCCCOc1cc(C[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C(C)C)ccc1OC
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C(=O)O)C(C)C)ccc1OC
Reaction time: 3 h

Procedure:
0.434 litre of 30% hydrogen peroxide is slowly added to 300 g of 4(R)-benzyl-3-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionyl}-oxazolidin-2-one in 4.8 litres of tetrahydrofuran/water (3:1) at 0° C. After the addition of 31.2 g of lithium hydroxide, the mixture is stirred for 3 hours at 0°-20° C. 2.55 litres of 1.5M sodium sulfite solution are then added to the reaction mixture at 0°-15° C. and stirring is continued for a further 30 minutes. 1 litre of saturated sodium hydrogen carbonate solution is added and the tetrahydrofuran is evaporated off. The aqueous solution is washed repeatedly with dichloromethane and then acidified with 2N hydrochloric acid (pH 3.0). Extraction with dichloromethane and subsequent evaporation of the solvent yield the title compound: Rf (ethyl acetate/hexane=2:1)=0.30; m.p. 43.5°-44° C.
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].[OH-:17].[Na+]>CO>[C:10]1([CH:8]2[O:7][N:6]=[C:5]([C:3]([OH:17])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1=NOC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolecarboxamide (i.e. the product of Example 12, Step A) (60.0 g, 275 mmol) in methanol (300 mL) was added an aqueous sodium hydroxide solution (44 g of 50 wt. % aqueous NaOH in 50 mL of water) dropwise over 30 minutes while maintaining the temperature of the reaction mixture at 45° C. The reaction mixture was allowed to cool to room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure, and treated with 200 mL of water. The pH of the reaction mixture was adjusted using concentrated hydrochloric acid to about 1.0. The crude product was extracted into ethyl acetate (200 mL). The ethyl acetate solution was concentrated under reduced pressure, and the residue was triturated with hexanes. The resulting precipitate was filtered, washed with hexanes (2×20 mL), and dried under vacuum to give 46.5 g of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.NN>[Ni].C(O)C>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCCn1c(-c2ccccc2)cc2cc(N)ccc21

Procedure:
While stirring, 32.3 g (0.1 mol) of 1-(3'-dimethylamino-propyl)-2-phenyl-5-nitro-indole, prepared as in Example 1, was mixed with 15 g (0.3 mol) of hydrazine hydrate, 300 ml of pure absolute ethanol and a small quantity of Raney Nickel.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].C(C1C=C(C=C(C)C=1O)C#N)C.C1O[C@H]1CO>>[CH2:1]([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: CCc1cc(C#N)cc(C)c1O
Agent: OC[C@H]1CO1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@H](O)CNC(=O)CO

Procedure:
The title compound is obtained as a yellow oil (1.36 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and (S)-glycidol; LC-MS: tR=0.51 min, [M+H]+=326.00.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.OC1C=C(O)C=CC=1C1N=C(C2C=CC(O)=CC=2O)N=C(C2C=CC(Cl)=CC=2)N=1.OC1C=C(OCCO)C=CC=1C1N=C(C2C=CC(OCCO)=CC=2O)N=C(C2C=CC(Cl)=CC=2)N=1.OC1N=C(C2C=CC(OCCO)=CC=2O)N=[C:98]([C:113]2[CH:118]=[CH:117][C:116](C)=[CH:115][C:114]=2[CH3:120])N=1.OC1C=C(OCCO)C=CC=1C1N=C(C2C=CC(OCCO)=CC=2O)N=C(C2C=CC(Br)=CC=2)N=1.OC1C=C(OCCOC(=O)C)C=CC=1C1N=C(C2C=CC(OCCOC(=O)C)=CC=2O)N=C(C2C=CC(Cl)=CC=2)N=1.OC1C=C(O)C=CC=1C1N=C(C2C=CC(O)=CC=2O)N=C(C2C=CC(C)=CC=2C)N=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[C:11]1[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:120][CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:113][CH3:98])=[CH:17][C:16]=2[OH:22])[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:10]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: Cc1ccc(-c2nc(O)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Agent: CC(=O)OCCOc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(OCCOC(C)=O)cc3O)n2)c(O)c1
Agent: Cc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: OCCOc1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(OCCO)cc3O)n2)c(O)c1
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1

Procedure:
2,6-bis-(2,4-dimethylphenyl)-4-(2,4-dihydroxyphenyl)-s-triazine; 2,4-bis(2,4-dihydroxyphenyl)-6-(4-chlorophenyl)-s-triazine; 2,4-bis[2-hydroxy-4-(2-hydroxyethoxy)phenyl]-6-(4-chlorophenyl)-s-triazine; 2,4-bis[2-hydroxy-4-(2-hydroxy-4-(2-hydroxyethoxy)phenyl]-6-(2,4-dimethylphenyl)-s-triazine; 2,4-bis[2-hydroxy-4-(2-hydroxyethoxy)phenyl]-6-(4-bromophenyl)-s-triazine; 2,4-bis[2-hydroxy-4-(2-acetoxyethoxy)phenyl]-6-(4-chlorophenyl)-s-triazine, 2,4-bis(2,4-dihydroxyphenyl)-6-(2,4-dimethylphenyl)-s-triazine.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([CH2:29][CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])C.[OH-].[Na+]>CO>[CH2:29]([CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(CC)CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1)C(=O)O
Yield: 96 %

Procedure:
(Scheme 3 (P)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 2-Ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (100 mg, 0.24 mmole), Sodium hydroxide (2N, 0.5 mL, 1.0 mmole), Methanol (5 mL). Product was obtained as white solid (90 mg, 96%). Mass Spec: 391.25 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH:9]([C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)O)=[O:5])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1C(O)c1ccc2c(N)ncnn12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC1Cc1ccc2c(N)ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of 2-[(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-hydroxy-methyl]-cyclopropanecarboxylic acid ethyl ester (1.75 g, 6.3 mmol) in dichloromethane (17.5 mL) was added dropwise into a mixture of triethylsilane (3 g, 25 mmol) and TFA (17.5 mL) in ice water bath. It was stirred at rt for overnight. 2N sodium carbonate solution (10 mL) was added and organic layer was separated, dried and concentrated. The residue was purified by Biotage® to give desired product 0.43 g (26). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.75 (bs, 2 H), 6.80 (s, 1 H), 6.60 (m, 1 H), 4.0 (m, 2 H), 2.9 (d, 2 H), 1.5 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 261.07 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>C(O)C.[Ni].O>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCCN2CCOCC2)cc1
Temperature: 50 °C

Procedure:
A suspension of 5.00 gms. of (3-morpholin-4-yl-propyl)-(4-nitro-phenyl)-amine in 110 mL of ethanol is heated to 50° C. Once dissolution is achieved 5.49 mL hydrazine monohydrate is added to the solution. A Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the bubbling to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature. The reaction mixture is filtered through a pad of celite (rinsing the pad with methanol). N-(3-Morpholin-4-yl-propyl)-benzene-1,4-diamine (4.39 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 297.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 58.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cyclopentanone (1.11 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.31 g (58%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][C:19]([CH:21]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Reactant: Nc1ccccc1O
Product: Oc1ccccc1N=Cc1ccc(-c2ccccc2Cl)o1

Procedure:
Using 2-aminophenol and 5-(2-chlorophenyl)furan-2-carbaldehyde, 2.69 g of 2-{[5-(2-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 75%).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([CH3:64])=[C:46]([CH:63]=1)[O:47][C:48]1[N:53]=[C:52]2[S:54][C:55]([NH:57][C:58]([CH:60]3[CH2:62][CH2:61]3)=[O:59])=[N:56][C:51]2=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[CH:60]1([C:58]([NH:57][C:55]2[S:54][C:52]3[C:51]([N:56]=2)=[CH:50][CH:49]=[C:48]([O:47][C:46]2[CH:63]=[C:42]([NH:41][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=4)[CH:43]=[CH:44][C:45]=2[CH3:64])[N:53]=3)=[O:59])[CH2:61][CH2:62]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (44 mg, 0.185 mmol) in pyridine (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.185 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) produced in Example C47(i) was added to the obtained solution, and the mixture was stirred at 70° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (2 mL) was added, and the obtained precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (55 mg, 56%) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-]>C1(C)C(C)=CC=CC=1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:20][CH:19]1[C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1)=[O:26])[CH3:29]
Reactant: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CC1c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
1-(Toluene-4-sulfonyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine, (200 mg, 0.67 mmol), and ethyl diazoacetate, (730 μL, 7.0 mmol), were combined in 3 mL xylene and heated to 95° C. for 30 min, then to 115° C. for 4 hours. The solvent was evaporated onder vacuum and the residue purified by silica chromatography, (eluent: methylene chloride), affording 140 mg, (50%), 2-[1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl ]-cyclopropanecarboxylic acid ethyl ester as a mixture of cis and trans isomers. MS ES+385.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]#[N:26])=[CH:15][CH:14]=2)=[C:5]([C:10](O)=[S:11])[N:6]([CH3:9])[C:7]=1[CH3:8])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:34](C=O)C.[OH-].N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]#[N:26])=[CH:15][CH:14]=2)=[C:5]([C:10]([NH2:34])=[S:11])[N:6]([CH3:9])[C:7]=1[CH3:8])#[N:2]
Reactant: Cc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(O)=S)n1C
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(N)=S)n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-cyano-3-[4-(2-cyanophenyl)phenyl]-1-methyl-5-methylthiopyrrole-2-carboxylic acid (11.0 mmol, prepared in example A-163) in methylene chloride, add oxalyl chloride (2.0 mmol) and catalytic DMF. Stir this solution for 20 minutes at room temperature and then concentrate in vacuo. Dissolve the residue in methylene chloride and ammonia hydroxide (2.0 mmol). Stir this reaction for one minute. The reaction becomes cloudy. Concentrate in vacuo. Purify the residue via radial chromatography and recrystallize using ether and hexanes to yield the title compound. MS (m/e): 373.1 (M+1) 371.0 (M−1); 1H NMR δ 7.97 (d, 1H), 7.84 (s, 2H), 7.80 (t, 1H), 7.66 (m, 3H), 7.57 (m, 3H), 3.80 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C:13]([C:14]3[CH2:15][CH2:16][C@@H:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C@H:19]([OH:29])[C:18]4([CH3:31])[CH3:30])=[CH:12][CH2:11]1)[CH3:9])[CH3:4].[I-:32].[Na+].O>CC(C)=O>[I:32][CH2:2][C@@H:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C:13]([C:14]3[CH2:15][CH2:16][C@@H:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C@H:19]([OH:29])[C:18]4([CH3:31])[CH3:30])=[CH:12][CH2:11]1)[CH3:9])[CH3:4]
Reactant: [I-]
Reactant: C[C@@H](CCl)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CI)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 55 °C
Yield: 68.7 %

Procedure:
A mixture of (25R)-26-chloro-4,4-dimethyl-5α-cholesta-8,14-dien-3β-ol (50 mg, 0.1 mmol) and sodium iodide (0.8 g) in acetone (3 mL) were heated at 55° C. in a sealed reaction vessel for 3 days. Addition of water, extraction with diethyl ether and concentration under reduced pressure gave a residue which was crystallised 3 times from hexane to give the title compound (37 mg).