Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:10]#[N:11])[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(C#N)n1
Temperature: 110 °C

Procedure:
2-Chloro-4,6-dimethylpyrimidine (3.3 g, 0.023 mol) was combined with zinc cyanide (2.7 g, 0.023 mol, 1 eq.) and tetrakis(triphenylphosphine)palladium (0) (2.7 g, 0.0023 mol, 0.1 eq.) in DMF (20 ml), and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to room temperature, diluted with EtOAc (70 ml) and washed twice with 2N ammonium hydroxide (50 ml). The EtOAc solution was washed with brine (20 ml) and concentrated in vacuum to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc/hexane) to afford 4,6-dimethylpyrimidine-2-carbonitrile. Yield: 0.8 g (26%). 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 6H), 7.21 (s, 1H). LCMS: (ES+) m/z=133.6 (M)+
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>O1CCOCC1>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(=O)O)cnc32)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53.6 mmol, Preparation #45) in 1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature. The organic solvent was removed under reduced pressure and the precipitate was collected, washed with water, and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.63 min; MS m/z 316 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12][NH:13][CH3:14]>CCO>[NH3:4].[CH3:12][N:13]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[CH3:14]
Reactant: O=C(O)c1ccc(CBr)nc1
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1ccc(C(=O)O)cn1
Product: N
Reaction time: 1 h
Yield: 70 %
Yield: 1 %

Procedure:
2nd step: To a stirred solution of 6-bromomethyl-nicotinic acid (350 mg, 1.62 mmol) in EtOH (3 mL) was added a solution of dimethyl-amine in EtOH (2 mL, 30% solution). Stirring was continued for 1 hour, concentrated under vacuo. Column chromatography (SiO2, CH2Cl2/MeOH: 8/2, aq. NH3 1%) yielded 205 mg (70%) of 6-dimethylaminomethyl-nicotinic acid as a light brown solid. ES-MS m/e: 181.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1cccc(Cl)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.S(Cl)([Cl:16])=O>CCOCC.CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(=O)O)c2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Cl)c2ccccc21
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A stirred suspension of 1-methyl-indazole-3-carboxylic acid (0.68 g, 3.86 mol) in anhydrous ether (50 ml) was treated with thionyl chloride (0.28 ml, 3.84 mol) and a few drops of dimethylformamide. After stirring for one hour the solid dissolved. The solvent was evaporated to give 1-methyl-indazole-3-carbonyl chloride as a yellow solid (0.75 g, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][C@H:16]1[C:21]([OH:23])=[O:22])=[O:14])([CH3:11])(C)C.C([O-])(O)=O.[Na+].C(Cl)(OCC1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=O>C(Cl)Cl.O1CCOCC1>[CH:44]1[C:45]2[CH:11]([CH2:8][O:12][C:13]([N:15]3[CH2:20][CH2:19][S:18][CH2:17][C@H:16]3[C:21]([OH:23])=[O:22])=[O:14])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCSC[C@H]1C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CSCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Trifluoroacetic acid (4 mL, 23.5 mmol) was added to a stirred solution of (R)-4-(tert-butoxy carbonyl)thiomorpholine-3-carboxylic acid (1.0 g, 4.05 mmol) in CH2Cl2 (20 mL), and the reaction mixture was stirred at room temperature for 2 h. Volatile byproducts were removed at reduced pressure and the residue was concentrated from toluene (2×20 mL) and dried under high vacuum for 30 min. The crude residue was dissolved in 1,4-dioxane (10 mL) and water (10 mL) was added followed by NaHCO3 (1.02 g, 12.15 mmol) and a solution of FMOC-Cl (1.04 g, 4.05 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to remove volatile organic solvent and the residue was washed with MTBE (2×20 mL). The aqueous layer was acidified with 1N aqueous HCl to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase column chromatography (C18; eluent: 10-100% acetonitrile/water) to afford the title compound (1.00 g) as a white semi-solid.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18]([OH:26])[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].C(O)C.[CH2:31]=O.[CH3:33][NH:34][CH3:35]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16](=[CH:15][C:14]=1[CH2:13]3)[C:17]([CH2:33][N:34]([CH3:31])[CH3:35])=[C:18]([OH:26])[CH:19]=[CH:20]2)=[O:11]
Reactant: C=O
Reactant: CNC
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1

Procedure:
A mixture of 10-hydroxycamptothecin (728 mg 2.0 mmol), prepared as described in Example 2, in glacial acetic (50 mL), ethanol (20 mL), 37% aqueous formaldehyde (3 mL) and 40% aqueous dimethylamine (3 mL) was stirred at room temperature for 20 h. The solvents were removed under reduced pressure; the residue was heated at 50° under high vacuum for 2 h and triturated with isopropanol (10 mL) to precipitate the title compound (561 mg, 64%) as a yellow solid. FAB mass spectrum: m/e 422 (MH+). 1H NMR (CDCl3 /CD3OD) δ1.0 (t, 3), 1.9 (m, 2), 2.5 (s, 6), 4.3 (s, 2), 5.2 (s, 2), 5.4 (q, 2), 7.6 (s, 1), 7.7 (q, 2), 8.5 (s, 1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[CH:8][C:7]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[CH:6][C:3]=1[C:4]#[N:5].[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([N:10]3[C:9]4[CH:8]=[C:7]([NH:19][C@H:20]([C:22]5[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=5)[CH3:21])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=4[N:1]=[CH:29]3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1cc(C#N)c(N)c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C#N)c2ncn(-c3cc(C4CC4)[nH]n3)c2c1)c1ccc(F)cc1
Yield: 27.2 %

Procedure:
The mixture of (S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzonitrile (Method 96, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol) in EtOH (50 ml) was heated at reflux for 36 hours. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (30 ml) and EtOAc (80 ml). The organic layer was separated, washed with brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as an off-white solid (1.05 g, 26%). 1H NMR (400 MHz) 12.80 (s, 1H), 8.45 (s, 1H), 7.43 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.12 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 4.58 (m, 1H), 1.97 (m, 1H), 1.44 (d, J=6.4 Hz, 3H), 1.03 (m, 2H), 0.75 (m, 2H). MS: Calcd.: 386; Found: [M+H]+ 387.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[C:19]([C:20]#[N:21])=[C:18]([CH3:22])[NH:17][C:16]([CH3:23])=[C:15]3[C:24]#[N:25])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>CO.O>[C:20]([C:19]1[CH:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:3]([OH:4])=[O:2])[C:15]([C:24]#[N:25])=[C:16]([CH3:23])[NH:17][C:18]=1[CH3:22])#[N:21]
Reactant: COC(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)O)c3c2)C(C#N)=C(C)N1
Temperature: 70 °C
Yield: 93 %

Procedure:
To 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid methyl ester (110 mg, 0.33 mmol) in MeOH—H2O (1:1, 8 mL) was added LiOH (1.08 g, 26.4 mmol) at rt. The reaction mixture was heated up to 70° C. for 2 days. After cooling to rt, the solution was acidified to pH 7 with 1 N HCl. After the removal of MeOH, the residue was purified by HPLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid (98 mg, 93%) (Cpd. No. 86, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.04 (s, 1H), 7.78 (s, 1H), 7.41 (d, 1H), 4.62 (s, 1H), 2.1 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].CCO.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](B(O)O)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[N:37][CH:38]=1)[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cncc2ccccc12
Temperature: 97.5 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (41 mg, 0.070 mmol) (Example 5) in 3:2 EtOH:toluene, 4-isoquinolineboronic acid (18.2 mg, 0.105 mmol) and 2.5 M sodium carbonate (0.175 mmol) were added. The solution was degassed, followed by the addition of a catalytic amount of tetrakis(triphenylphosphine)palladium. The solution was stirred at 95-100° C. until completion of the reaction. Upon cooling, the solvent was removed in vacuo. The desired product was obtained by preparative thin layer chromatography using 25% acetone/hexane. 1H NMR (CDCl3, 500 MHz) δ 9.36 (s, 1H), 8.38 (s, 1H), 8.10-8.13 (m, 1H), 7.68-7.80 (m, 4H), 7.26-7.64 (m, 5H), 4.22-4.48 (m, 4H), 3.64-3.78 (m, 3H). LC-MS (M+1) 587.2 (3.48 min).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1([F:45])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:24][CH2:23][C:22](=[N:25][OH:26])[CH2:21][CH2:20]1)=[O:18]>O1CCCC1.C(OCC)(=O)C>[F:45][C:9]1([F:8])[CH2:10][CH2:11][N:12]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=2/[C:15]/1=[CH:16]/[C:17]([N:19]1[CH2:20][CH2:21][C:22](=[N:25][O:26][CH2:4][C:5]([NH2:7])=[O:6])[CH2:23][CH2:24]1)=[O:18]
Reactant: NC(=O)CBr
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NOCC(N)=O)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Sodium hydride (47 mg) and 58 mg of bromoacetamide were added to a solution of 150 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine in 10 ml of tetrahydrofuran, and the mixture was stirred at 0° C. for three hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue was crystallized from diethyl ether to give 110 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperidin-4-ylidene)aminoxy]acetamide as a pale yellow powder.
Reaction SMILES: [OH:1][CH:2]([CH2:33][OH:34])[CH2:3][O:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:32])[CH2:15][CH2:16][C@@H:17]2[C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)[CH2:9]1.[S:35](Cl)([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36].O.C(OCC)(=O)C>N1C=CC=CC=1>[S:35]([O:34][CH2:33][CH:2]([OH:1])[CH2:3][O:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:32])[CH2:15][CH2:16][C@@H:17]2[C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)[CH2:9]1)([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](OCCOCC(O)CO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(O)COCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Yield: 88.9 %

Procedure:
To a solution of 1.7 g of 3β-(2-(2,3-dihydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared from 3γ-(2-hydroxyethoxy)-17β-(3-furyl)-5β-andostran-14β-ol, prepared as an intermediate in Ex.1, according to the sequence described in Ex. 2 and Ex. 15, in 13 ml of dry pyridine, 0.80 g of tosyl chloride were added at a temperature of 0° C. After 5 hrs 60 ml of water and 250 ml of ethyl acetate were added, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2)using n-hexane/ethyl acetate 70/30 as eluant to give 2 g of 3β-(2- (3-tosyloxy-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=O)[N:6]=[C:5]([C:12]([NH2:14])=O)[CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>ClCCl>[C:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:12]#[N:14])[N:6]=1)#[N:11]
Reactant: COc1cc(C(N)=O)nc(C(N)=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(C#N)nc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
4-methoxypyridine-2,6-dicarboxamide (900 mg, 4.6 mmol) was mixed with trifluoroacetic anhydride (2.32 g, 11.1 mmol) and pyridine (1.6 g, 20.2 mmol) in dichloromethane (20 mL) and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with water. Standard work up, afforded 461 mg of 2,6-dicyano-4-methoxypyridine.2,6-Dicyano-4-methoxypyridine (460 mg, 2.89 mmol) and 5M hydroxylamine hydrochloride (0.578 mL, 2.89 mmol) in ethanol (3 mL) and 1N sodium hydroxide (2.89 mL, 2.89 mmol), were stirred at room temperature overnight. Standard work up afforded 180 mg (32.4%) of 6-cyano-4-methoxypyrid-2-yl-amidoxime.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2Cl.[NH3:15]>[Cl-].[NH4+]>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:15]
Reactant: CC(O)Cn1cnc2c(Cl)ncnc21
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cn1cnc2c(N)ncnc21

Procedure:
9-(2-Hydroxy-1-propyl)-6-chloropurine (I, 9 g, 42.5 mmol) was dissolved in saturated methanolic ammonia and ammonium chloride (50 mg). The mixture was heated at 130° in a bomb for 6 hr. The resulting solution was evaporated to dryness and recrystallized from ethanol/acetone. Yield=6.68 g of a colorless crystalline product (81%); mp 193°-194°; uv (H2O; pH 5.5), λmax 260 nm; TLC in CHCl3 :MeOH (5:1); RfO.44.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[NH2:12][C:13]1([C:33](O)=[O:34])[CH2:17][C:16]([CH3:32])([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=2)[O:15][CH2:14]1>CO.C(Cl)Cl>[NH2:12][C:13]1([CH2:33][OH:34])[CH2:17][C:16]([CH3:32])([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=2)[O:15][CH2:14]1
Reactant: CCCCCCCCc1ccc(C2(C)CC(N)(C(=O)O)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C2(C)CC(N)(CO)CO2)cc1
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of lithium aluminum hydride (2.70 ml, 5.40 mmol) (Aldrich) was added carefully to THF (17.99 ml) under nitrogen. 3-amino-5-methyl-5-(4-octylphenyl)tetrahydrofuran-3-carboxylic acid (0.6 g, 1.799 mmol) was added in small portions causing vigorous bubbling. The reaction stirred for about 2 h. TLC in 10% MeOH in methylene chloride showed (Hannessian's stain visualization) reaction complete. The reaction was quenched by addition of water (200 uL) and the reaction stirred about 30 min. 10% NaOH (0.6 mL) was added and the reaction stirred about 30 min. Finally, water (200 uL) was added and the reaction stirred about 30 min. The resulting solid was collected by vacuum filtration and washed with ether. The filtrate was concentrated to a colorless oil. The residue was purified by flash column chromatography (40 g Redi-Sep) eluting with 10-20% methanol in methylene chloride and the product fractions combined. Solvents were removed under reduced pressure. The residue was redissolved in methylene chloride and filtered through a syringe filter into a vial and washed through with methylene chloride. Solvent was removed under reduced pressure to provide (3-amino-5-methyl-5-(4-octylphenyl)tetrahydrofuran-3-yl)methanol (0.192 g, 0.601 mmol, 33.4% yield) as a colorless oil that solidified on standing to a white solid:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19])#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NCc1ccc(C(=O)NC2CCCCCC2)cc1F
Reaction time: 0.5 h

Procedure:
Add 4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), 10% Pd/C (Degussa type E101, 250 mg), ethanol (25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (805 mg, 92%). MS (ES+) m/z: 265.3 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26].[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:21]1=[O:26]
Reactant: CN1CCCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCCN(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
20.4 g of diisopropylamine (0.1 mol) were dissolved in 200 ml of dry THF under nitrogen and cooled in a freezing mixture. 80 ml n-butyllithium in hexane (2.5 M, 0.2 mol) were added dropwise slowly. After the addition it was allowed to stir for 60 minutes and then 22.6 g N-methyl-2-piperidone (0.2 mol) were added dropwise. The reaction mixture was stirred for another 20 min in the freezing mixture. In a second flask, 87.7 g diethyl oxalate (0.6 mol) in 100 ml of dry THF were cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 300 ml ethyl acetate, the combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.) and 45 g of crude product were obtained. 10.4 g product was obtained as white crystals with a melting point of 23° C. after crystallization from diethyl ether/n-hexane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>N1CCCC1>[CH2:15]([NH:19][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:19]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:3][C:4]([CH3:14])=[N:5]2)=[CH:10][CH:9]=1)=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Solvent: C1CCNC1
Product: CCCCNC(=O)c1ccc2c(N3CCCC3)cc(C)nc2c1
Yield: 43 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (example 2, 200 mg, 0.80 mmol) was refluxed in butylamine (2 mL) for 6 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. The residue was chromatographed (SiO2, CH2Cl2/MeOH 19:1) to produce a yellow oil, which was heated in pyrrolidine (2 mL) at 70° C. for 16 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) afforded the title compound (108 mg, 43%). White solid, ISP-MS: m/e=312.3 ([M+H]+).