Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[OH:22])[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[O:22][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
NaH (0.432 g, 18 mmol) is stirred with absolute DMF (12 ml) at ambient temperature and then 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764 g, 6 mmol) in DMF (12 ml) is added. After the development of gas has ceased, a solution of 2-bromopyridine in absolute DMF (8 ml) is added at RT. After 3 hours at RT this reaction mixture is poured onto H2O (100 ml) and extracted 3 times with CH2Cl2 (60 ml). The combined organic phases are dried with Ha2SO4, concentrated by rotary evaporation and the residue is purified by flash chromatography (90 g silica gel, CH2Cl2 /MeOH=9/1).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21][C:20]1=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[Na+].CO>[CH2:13]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29](=[O:31])[CH:30]=[CH:1][C:3]3[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:26][CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21][C:20]1=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.3 %

Procedure:
Methyl 4-formylbenzoate (22 mg, 13.4 mmol) was added to a solution of N-hexyl-6-acetyl 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 6a, 40 mg, 13.3 mmol) in 2 mL of 1 N NaOH and 4 mL of methanol. After stirring at room temperature for 18 h, the reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chormatography (50:49:1 hexane/ethyl acetate/acetic acid) gave the title compound as a light yellow solid (18.9 mg, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:14][CH:15]([C:21]([CH3:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([NH2:1])[C:3]=1[C:4]#[N:5])([CH3:14])[C:21](=[O:22])[CH3:23])[CH3:20]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Reactant: CCOC(=O)C(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10 mmol) and ethyl 2-methylacetoacetate (3.6 g, 25 mmol) in DMF (10 mL) was added finely powdered K2CO3, and the mixture stirred vigorously for 24 h. The deep red mixture was diluted with EtOAc and washed in turn with 2M HCl, water and brine. The residue after evaporation was purified by flash chromatography in hexane/EtOAc 3:1 to yield 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (1.39 g, 46%), MS (NH3 CI) 323 (M+NH4+), 293 (M+NH4—NO+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]([F:16])([F:15])[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.Cl>ClCCl.O>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:14][NH:13][C:11](=[O:12])[C:10]([F:15])([F:16])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:23])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NNC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F)c1ccc(F)cc1
Yield: 55.4 %

Procedure:
In 7 ml of dichloromethane was suspended 0.33 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide. To the suspension was added 0.12 g of triethylamine. Thereto was dropwise added 0.19 g of 4-fluorobenzoyl chloride at 5°-10° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of dichloromethane and 10 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.25 g of N'-(4-fluorobenzoyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:29]C)=[N:25][CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:31])=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl.C(N(CC)CC)C>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[C:20]([CH3:31])=[C:21]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc[nH]c2=O)c1C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (40 mg, 0.09 mmol) in dioxane (1 mL) was added 4M HCl and the reaction was stirred at 90° C. for 3 hours. To the mixture at room temperature, 0.5 mL of triethyl amine was added and the reaction was concentrated under reduced pressure. The crude residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (50-100%). ESI-MS m/z calc. 439.4. found 440.3 (M+1)+. Retention times: 1.39 minutes. H NMR (400 MHz, DMSO) 8.67 (s, 1H), 7.80 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.44-7.32 (m, 4H), 6.23 (t, J=6.6 Hz, 1H), 2.27 (s, 3H), 1.96 (s, 3H), 1.51-1.48 (m, 2H), 1.16-1.14 (m, 2H).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 26 h
Yield: 80.7 %

Procedure:
To a solution of estrone (11, 2.70 g, 10 mmol) in DMF (40 mL) were added potassium carbonate (2.76 g, 20 mmol) and benzyl bromide (1.8 mL, 15 mmol) at room temperature. The reaction mixture was stirred for 26 h, then quenched with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 2.91 g of 40 (81% yield) mp: 126-127° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O-:5])=[O:4].[Na+].[I-].[Na+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C(=CC(=C(C=1)C)C)C)C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[Cl:1][CH2:2][C:3]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: ClCc1ccccc1
Reactant: O=C([O-])CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cc1cc(C)c(C)cc1C
Agent: [Cl-]
Solvent: O
Product: O=C(CCl)OCc1ccccc1
Reaction time: 7 h
Yield: 10 %

Procedure:
A mixture consisting of sodium chloroacetate (2.344 g, 20 millimoles, Aldrich, 98%), sodium iodide (0.152 g, 1 millimole, Aldrich, 98%) and water (249.3 g) was introduced to a three-necked 500 mL flask. The organic phase consisting of benzyl chloride (10.139. g, 80 millimoles, Aldrich, 97%), durene (GC standard, 0.781 g, 6 millimoles, Aldrich, 98%), and Adogen 464 (0.900 g, 2 millimoles, Aldrich) was added to the aqueous phase and the two phase system was stirred mechanically (600 rpm, a calibrated photo-tachometer) for about seven hours at 45° C. The organic phase:aqueous phase weight ratio was 1:21. The aliquots were taken at 0, 30, 97, 186, 300 and 400 minutes after the addition of the organic phase. After a brief centrifugation the phases were separated and the organic phase of each aliquot was injected into the GC instrument. The yield of benzyl chloroacetate based on the limiting reactant (sodium chloroacetate) was 55%, the conversion of the chloroacetate anion was 67%. Benzyl chloroacetate was accompanied by small quantities of benzyl iodide and benzyl alcohol and an unidentified product. Its yield was above 10%.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1OCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2c1OCC2
Yield: 79.6 %

Procedure:
Methyl 2,3-dihydro-benzofuran-7-carboxylate (12 g, 68 mmol) was reduced with LAH (5.14 g, 136 mmol) in THF similar to the above procedures to give the product as a dark oil (8.13 g, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([CH3:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)O

Procedure:
Ethyl 4-benzyloxy-2-methyl-6-[3-(quinolin-2-ylmethoxy)-benzyloxy]-benzoate (2.4 g, 4.5 mmole, example 64) is added to ethanol (50 ml) and 11N sodium hydroxide (4.4 ml, 44 mmole) and refluxed for 8 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane with a small amount of water and is acidified to pH6 with 1N HCl. The organic layer is dried over MgSO4 and the solvent removed in vacuo. The crude product is purified by column chromatography (silica, 1% methanol in dichloromethane) to provide the title compound. m.p. 146–149° C.; 1H NMR (300 MHz, CD3OD) d 8.34 (d, 1H), 8.04 (d, 1H), 7.91 (d, 1H), 7.78–7.70 (m, 2H), 7.61 (t, H), 7.37–7.20 (m, 7H), 7.05–6.91 (m, 2H), 6.51 (d, 1H), 6.47 (d, 1H), 5.35 (s, 2H), 5.09 (s, 2H), 5.03 (s, 2H), 2.29 (s, 3H); MS (ESI) 506 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41](O)[CH2:42][CH3:43].[ClH:45].O1CCOCC1>>[ClH:45].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:41][CH2:42][CH3:43])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:39])([F:40])[F:38]
Reactant: CCCO
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 45 °C
Reaction time: 4.5 h

Procedure:
703 mg (1.24 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoro ethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 1.86 mL (24.8 mmol) of 1-propyl alcohol were mixed, 12.4 mL (49.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 45° C. for 4.5 hours.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccc2[nH]ccc12
Product: CN(C(=O)Oc1cccc2[nH]ccc12)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxyindole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (48%, off-white solid). HPLC-MS: m/z=267.1 (M+1); Rt: 3.57 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:8][CH:9]([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])(=[O:7])[CH3:6]>CN(C)C=O>[C:5]([O:8][CH:9]([CH2:14][CH2:15][N:1]=[N+:2]=[N-:3])[C:10]([O:12][CH3:13])=[O:11])(=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(CCOS(C)(=O)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN=[N+]=[N-])OC(C)=O
Temperature: 70 °C
Yield: 134.3 %

Procedure:
1.91 g of sodium azide was added to a dimethylformamide (10 ml) solution of 2.54 g of methyl 2-(acetyloxy)-4-[(methylsulfonyl)oxy]butanoate, and stirred under heat at 70° C. for 8 hours. The reaction liquid was restored to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated saline water and dried, and the solvent was evaporated away under reduced pressure to obtain 2.70 g of methyl 2-(acetyloxy)-4-azidobutanoate as a brown oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 25.6 g of 19-acetoxyandrost-4-ene-3, 17-dione in 4 liters of methanol cooled to 0° C is added 3.1 g of sodium borohydride, and the mixture is stirred at 0° C for 1 hour after which 30 ml of acetic acid is added and the methanol removed under reduced pressure. The resulting residue is taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed. The solid residue is dissolved in 2 liters of chloroform treated with 125 g of manganese dioxide and stirred for 2 hours. The reaction mixture is filtered, and the solvent removed under reduced pressure. The residue is chromatagraphed on alumina using benzene-ether (1:1) as the eluant. The product is recrystallized from acetone-hexane to give 19-acetoxy-17β-hydroxyandrost-4-en-3-one, M.P. 125°-127° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(Cl)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C1=NNC(=O)CC1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-chlorobenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to the procedure described in Example 2(ii) to give 6-[2(3-t-butylamino-2-hydroxypropoxy)-5-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[CH:7]=1)#[N:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([C:1]#[N:2])=[CH:7][C:6]=2[CH:8]=1
Reactant: N#Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc2cc(N)ccc2o1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A heterogeneous reaction mixture of 2-cyano-5-nitrobenzofuran (0.150 g, 0.789 mmol), iron powder (0.220 g, 3.9 mmol), NH4Cl (0.221 g, 3.9 mmol) in EtOH/H2O (5 mL each) was vigorously stirred at 60-70° C. for 1 hour. The resulting solution was filtered through a pad of Celite when hot and then washed with methanol. The filtrated was concentrated to dryness under a vacuum and resuspended into H2O (20 mL), saturated and the solid was isolated by filtration to obtain 5-amino-2-cyanobenzofuran. 1H NMR (DMSO-d6): δ 7.80 (s, 1H), 7.36 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=2.7 and 9.0 Hz), 6.76 (d, 1H, J=2.1 Hz), 5.16 (bs, 2H); LCMS: purity: 95%, MS (m/e): 159 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)nc1)C(F)(F)F
Yield: 81.5 %

Procedure:
According to Reference Example 8-12, by use of 6-bromo-3-pyridinecarboxaldehyde (1.00 g, 5.37 mmol), (trifluoromethyl)trimethylsilane (935 μL, 6.45 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 537 μL, 0.537 mmol) and tetrahydrofuran (20 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=19/1) was performed to give 2-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound DD) (1.12 g, yield: 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:24]=1[CH:25]=O>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(C2CCN(C)CC2)ccc1C=O
Product: COc1cc(C2CCN(C)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 49 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (125 mg, 0.427 mmol) and 2-Methoxy-4-(1-methyl-piperidin-4-yl)-benzaldehyde (109.5 mg, 0.469 mmol) were reacted to produce 106 mg (49%) of the title compound. mp: 232-235° C., 1H NMR (300 MHz, CDCl3): 10.67 (s, 1H), 8.33 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.42 (m, 1H), 6.38 (m, 1H), 6.35 (m, 1H), 5.48 (d, J=8 Hz, 1H), 5.18 (t, J=8 Hz, 1H), 5.05 (s, 1H), 4.06 (s, 3H), 3.19 (s, 1H), 3.03 (d, J=10 Hz, 2H), 2.91 (m, 2H), 2.57 (m, 1H), 2.37 (s, 3H), 2.34 (s, 1H), 2.10 (m, 2H), 1.89 (m, 4H), 1.76 (d, J=8 Hz, 1H), 1.27 (s, 2H). MS: 507 (M+H), HPLC: 1.86 min (G method)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([C:29]([N:19]2[CH2:20][CH2:21][C:11]3([NH:10][C:9]4[CH:8]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:15][C:14]=4[C:13](=[O:16])[NH:12]3)[CH2:17][CH2:18]2)=[O:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC2(CCN(C(=O)c3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
A stirred solution of 6′-(pyridin-4-yl)-1′H-spiro [piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.0500 g, 0.170 mmol) and triethylamine (0.070 mL, 0.51 mmol) in tetrahydrofuran (4 mL) was cooled to 0° C. in an ice bath. A solution of benzoyl chloride (0.0260 g, 0.190 mmol) in tetrahydrofuran (0.1 mL) was added, and the reaction was allowed to warm to room temperature overnight. Then, the solvent was removed and the obtained residue was diluted with methanol (25 mL) and the mixture was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solids were removed by filtration. The filtrate was concentrated to give a yellow solid, which was triturated with water and collected by filtration. This solid product was recrystallized from hot methanol/hexanes to give the title compound (0.0315 g, 45%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].Cl[C:16]1N=C(Cl)C=C[N:17]=1.CN(C)C.[C-]#N.[K+]>CCOCC.O>[C:16]([C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)#[N:17]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOc1ccnc(Cl)n1
Agent: CC[O-]
Agent: CN(C)C
Agent: [C-]#N
Solvent: CCOCC
Solvent: O
Product: CCOc1ccnc(C#N)n1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 2-chloro-4-ethoxy pyrimidine (20 g from the reaction of 1 equivalent of sodium ethoxide with 2,4-dichloropyrimidine at 0°-5° C.) in ether (50 ml) was added to ice cooled trimethylamine (50 ml of a 30% aqueous solution). After stirring the mixture for 2 hours a solution of potassium cyanide (9.0 g) in water (50 ml) was added and the resulting mixture was stirred vigorously at room temperature. After 16 hours the reaction mixture was extracted with ether (3×50 ml) and the combined extracts were washed with brine, dried and concentrated to give 2-cyano-4-ethoxypyrimidine (14.6 g, 77% yield) as a pale yellow liquid which gradually crystallised (m.p. 35° C.); 1H NMR (270 MHz): δ1.42(3H,t), 4.49(2H,q), 6.89(1H,d), 8.49(1H,d) ppm.