Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:17])=[CH2:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(=C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropenylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg (34%) of the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:10]([N+:19]([O-:21])=O)=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=1)([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pt]>[OH:21][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][C:11]=2[C:15]([F:18])([F:17])[F:16])[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: O=c1[nH]c2cccc(C(F)(F)F)c2n(O)c1=O

Procedure:
A solution of 3-ethoxalylamino-2-nitrobenzotrifluoride (0.28 g, 0.9 mmol) in 30 ml of 96% ethanol was hydrogenated at atmospheric pressure and room temperature in the presence of 28 mg of 5% platinum on carbon for 5 min. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. The residue was triturated with ether to give 77 mg 34%) of the title compound. M.p. 150° C. dec. 1H-NMR (DMSO-d6): 7.20-7.67 (m, 3H, ArH), appr. 12 (very broad s, 1H, NH); IR (KBr): 1700 cm-1 ; MS (m/e): 246 (28%, M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([O:13][Si:14]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])[CH2:11][OH:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](OC(CO)C(Cc1ccccc1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Solvent: CO
Product: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Yield: 67 %

Procedure:
The monosilylated diol of Step 2 was hydrogenated with 5% Rh-C at 60 psi and 60° C. in MeOH (135 mL). The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography, eluting with (15% EtOAc in hexane) to give the title alcohol (8.70 g, 67% yield, mp 61°-63° C). The 1H, 13C, and APT NMR spectral data were consistent with the proposed product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([O:21]C)=[O:20])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)cc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.9 %

Procedure:
Methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate (1.73 g, 5.50 mmol) was dissolved in THF/methanol (2:1, 30 ml). To the resulting solution was added 1N NaOH (20 ml) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetic acid (1.60 g, 97%) was obtained as a colorless crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[CH:6][CH2:7][CH2:8][CH3:9])[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].N12CCCN=C1CCCCC2>>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6]([CH2:14][N+:11]([O-:13])=[O:12])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC=CC(=O)OCC
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Yield: 99.4 %

Procedure:
To a stirred solution of hex-2-enoic acid ethyl ester (A) (450 g, 3.164 mol, 1 eq) in nitromethane (858 ml, 15.822 mol, 5 eq) cooled at 0° C., is added dropwise, under nitrogen, 481.8 g (3.164 mol, 1 eq.) of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture is allowed to react at room temperature for 3 h and is quenched with a 6M aqueous hydrogen chloride solution to obtain pH=4. The solution is extracted with diethyl ether (500 ml+2×300 ml). The organic layers are dried with MgSO4, filtered and concentrated to obtain an oil residue (672.13 g, HPLC purity=78.9%) which is purified by liquid chromatography eluting with dichloromethane. 639.41 g of 3-nitromethyl-hexanoic acid ethyl ester (B) are obtained (yield=99.4%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)CC3C[CH:7]([CH2:9][CH:3](C3)[CH2:2]1)[CH2:8]2.C1(COC2C(C3CC3)=CC(C(NS(CCOC)(=O)=O)=O)=C(F)C=2)CCCCC1>>[CH:1]1([CH2:11][O:12][C:13]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:21])=[O:22])=[O:18])=[C:15]([F:32])[CH:14]=2)[CH2:2][CH2:3][CH2:9][CH2:7][CH2:8]1
Reactant: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: O=C(NS(=O)(=O)CCO)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 121 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide, the title compound was obtained as colorless solid (0.03 g, 14%): 1H NMR (300 MHz, CDCl3) δ8.77-8.65 (m, 1H), 7.60-7.49 (m, 1H), 6.63-6.51 (m, 1H), 4.19-4.09 (m, 2H), 3.86-3.74 (m, 4H), 2.59-2.49 (m, 1H), 2.10-1.98 (m, 1H), 1.94-1.68 (m, 6H), 1.39-1.04 (m, 5H), 0.99-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 398.3 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[OH:19])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH2:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[O:19][CH2:29][O:30][CH3:31])[CH:2]=[CH2:3]
Reactant: COCCl
Reactant: C=CCc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(C)c2c(c(C)c1OCOC)C(C)(C)CC(=O)O2
Yield: 89.4 %

Procedure:
Compound C (8.26 g, 31.65 mmol) and DIPEA (57.2 mL, 317.7 mmol) were dissolved in 160 mL of methylene chloride. The mixture was cooled in an ice-water bath and stirred under N2. Methoxymethyl chloride (12.2 mL, 159 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature under N2 overnight. The mixture was diluted with 140 mL of methylene chloride and washed with 10% HCl solution (2×50 mL) and water (3×50 mL) and dried over MgSO4. Filtration and solvent evaporation gave a yellow residue, which was purified on a silica gel column (hexanes and ethyl acetate, 3/1, v/v) to give 8.61 g (87%) of a solid product. 1H NMR (CDCl3) δ5.96 (m, 1H), 5.07-4.95 (m, 2H), 4.90 (s, 2H), 3.63 (s, 3H), 3.47 (d, J=5.7 Hz, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([Cl:15])[C:12]([CH3:14])=O)C>C(O)(=O)C.CCOCC.CO.CN(C=O)C.CS(C)=O>[Cl:15][C:11]1[C:12]([CH3:14])=[N:1][C:2]2[N:3]([N:4]=[CH:5][N:6]=2)[C:10]=1[OH:9]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CO
Product: Cc1nc2ncnn2c(O)c1Cl
Reaction time: 0.25 h

Procedure:
3-Amino-1,2,4-triazole (4.2 g, 0.05 mol) and ethyl-2-chloro-acetoacetate (12.64 g, 0.0768 mol) were refluxed in acetic acid (15 ml) under a nitrogen atmosphere. The reaction mixture first turned into a clear yellow solution and after about 15 minutes a solid started precipitating. Reflux continued for one hour. The crude product was filtered off, washed with hot methanol (2×10 ml), and dried in an oven at 90° C. to give 5.9 g (64%) of pure TAI-3. TLC (in Et2O/MeOH, 70:30 v/v) showed only one spot. The compound is soluble in hot DMF and DMSO. mp=starts darkening at ˜308° C. and decomposes at temperatures >325° C.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:41]=[CH:40][C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>N.CO>[C@H:11]1([N:34]2[CH:41]=[CH:40][C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: CO
Product: O=c1ccn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Yield: 87.9 %

Procedure:
Compound 3 (0.87 g, 1.56 mmol) in NH3 /MeOH (100 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in H2O (50 ml), washed with ether (3×25 ml). and evaporated to give a white solid and it was crystallized from 95% EtOH to give pure compound 4 (0.335 g, 87.2%) as white crystal: m.p. 165°-166° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][CH2:11][CH2:10][S:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:16])(=O)=O.CC1C=CC(C2SCC[SH+]2)=CC=1>C(Cl)Cl>[Cl-:16].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:9][CH2:10][CH2:11][SH+:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2SCCS2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: Cc1ccc(C2SCC[SH+]2)cc1
Solvent: ClCCl
Product: [Cl-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 1.96 g (0.01 mole) of 2-(4-methylphenyl)-1,3-dithiolane in 20 ml of methylene chloride is cooled to 0° C. and 0.76 ml (0.0094 mole) of sulfuryl chloride is added in one portion. The mixture is stirred 1 hr at 5° C. It is diluted with methylene chloride and the ultraviolet spectrum measured: U.V. max 230,255,375 nm, the latter indicating the presence of 2-(4-methylphenyl)-1,3-dithiolanium cation.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([C:12]=1[C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]([C:26]([O:28]CC)=[O:27])[C:18]3=[O:31])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7]2.C(O)(C)(C)C.Cl>O>[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([C:12]=1[C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]3=[O:31])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc2ccccn2c1C(=O)c1ccc2c(c1)c(=O)c(C(=O)O)cn2C
Yield: 96.4 %

Procedure:
0.27 ml (3.22 mmol) of a 1N aqueous solution of sodium hydroxide is added, at ambient temperature, to 0.5 g (1.29 mmol) of ethyl 6-[(2-methylindolizin-3-yl)carbonyl]-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate in 9 ml of a mixture of t-butanol and water (1/1). The reaction medium is refluxed for 1 hour, acidified with a 1N aqueous solution of hydrochloric acid at ambient temperature, and then extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulphate, and concentrated under reduced pressure. The residue obtained is rinsed with ether and then dried under reduced pressure at 50° C. 448 mg of a yellow solid are obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:9]=2[NH:8]1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:9]=2[N:8]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]c(Cl)nc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
Phosphorus oxychloride (8.5 g, 55.6 mmol) was added to methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.03 g, 5.36 mmol) (reference: WO 2006/116412 A2), and the mixture was stirred at 85° C. for four hours. The reaction solution was diluted with ethyl acetate and THF, slowly added to cold water and neutralized with sodium bicarbonate. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was dissolved in toluene and the insoluble matter was removed. Concentration under reduced pressure gave 800 mg of the title compound as an oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[S:8]1CC(O)S[CH2:10][CH:9]1O.C(N(CC)CC)C>CCO>[NH2:2][C:1]1[S:8][CH:9]=[CH:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC#N
Reactant: OC1CSC(O)CS1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccsc1N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of methyl cyanoacetate (3.25 g, 32.3 mmol), 1,4 dithiane-2,5 diol (5 g, 32.8 mmol), triethylamine (1 mL, 7.71 mmol) in EtOH (50 mL) is stirred at 40° C. for 1 h. The cooled solution is eluted through a silica plug with CH2Cl2. The filtrate is stripped to dryness to give crude methyl 2-aminothiophene-3-carboxylate which is carried on to the next reaction. 1H NMR (DMSO) δ 7.26 (1H, s), 6.82 (1H, d, J=5.8 Hz), 6.28 (1H, d, J=5.8 Hz), 3.69 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[C:17]([CH3:18])[C:12]2=[C:11]([CH2:19][N:20]2[C:25](C)(C)[CH2:24][N:23]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:22]([CH3:34])([CH3:33])[CH2:21]2)[CH:10]=1.NC1(C)CCCN(CC2C=C(C3C=CC(O)=CC=3F)N=C3NN=C(C)C=23)C1.COCC(Cl)=O>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[C:17]([CH3:18])[C:12]2=[C:11]([CH2:19][N:20]2[CH2:25][CH2:24][CH2:33][C:22]([NH:23][C:28](=[O:32])[CH2:29][O:30][CH3:31])([CH3:34])[CH2:21]2)[CH:10]=1
Reactant: COCC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Agent: COCC(=O)Cl
Agent: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCCC(C)(N)C3)c12
Product: COCC(=O)NC1(C)CCCN(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)C1

Procedure:
The title compound was prepared in analogy to Example 75 (1-{4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-2-methoxy-ethanone) using 4-[4-(3-Amino-3-methyl-piperidin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-3-fluoro-phenol and methoxyacetyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:19](B1OC(C)(C)C(C)(C)O1)=[CH2:20].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:17][CH:16]([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([CH:19]=[CH2:20])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)Oc1ccc(Nc2ccc(Cl)nn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(Nc2ccc(OC(F)F)cc2)nn1
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-N-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (0.2 g, 0.736 mmol) in dioxane and water mixture were added vinylboronic acid pinacol ester (0.146 mL, 1.104 mmol), and K2CO3 (0.305 g, 2.209 mmol). The mixture was flushed for 15 min with nitrogen. PdCl2 (dppf)-CH2Cl2 adduct (0.060 g, 0.074 mmol) was then added and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate and purified by flash chromatography on silica gel using ethyl acetate in hexane to give N-(4-(difluoromethoxy)phenyl)-6-vinylpyridazin-3-amine as a white solid (0.12 g, 59%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.47 (d, J=1.20 Hz, 1H), 6.06 (dd, J=0.80, 23.80 Hz, 1H), 6.84-7.38 (m, 5H), 7.75-7.82 (m, 3H), 9.42 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][CH2:9][C:8]1=O.[OH-].[NH4+]>C1COCC1>[NH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCNc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCCN2
Temperature: 25 °C

Procedure:
To an ice cold solution of lithium aluminium hydride (4.68 g, 123 mmol) in dry THF (100 ml), under a nitrogen atmosphere, was added dropwise a solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (5.0 g, 30.9 mmol) in dry THF (50 ml). The mixture was allowed to warm to room temperature and then heated at reflux for 2 h. The mixture was then cooled to 0° C. and a solution of aqueous ammonium hydroxide (10 ml) in THF (60 ml) was added dropwise. The resultant suspension was stirred for 1 h and then filtered through a pad of celite. The filtrate was evaporated in vacuo to give a tan solid; yield 4.36 g (95%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][OH:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[CH3:31]OS(OC)(=O)=O>C(COC)OC.CN(C=O)C>[CH3:31][O:18][CH2:17][CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)[C:19]#[C:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(C(C#Cc2ccccc2)CCO)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COCCC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 18 h

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-phenylpent-4-ynol (175 mg, 0.5 mmol) in a mixture of glyme (7 ml) and DMF (2 ml) was treated with NaH (20 mg of a 60% dispersion in mineral oil), heated to 50° for 3 min, and cooled to 23°. MeI (0.5 ml) was added, and the mixture stirred for 18 hr. Me2SO4 (0.3 ml) was added, and the mixture was heated to 60° for 2 hr. The reaction was cooled, quenched with 50 ml cold 0.1N HCl, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent evaporated. Purification by flash chromatography (silica gel, 30% EtOAc in hexane) gave the titled compound, (26 mg 14%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.28 (m, 3 H), 6.96 (m, 2 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 3.98 (t, 1 H), 3.84 (s, 3 H), 3.62 (m, 1 H), 3.48 (m, 1 H), 3.40 (s, 3 H), 2.06 (m, 2 H), 1.72-2.00 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]2[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[CH2:31]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]3[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH2:31]2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C#N)cn5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 50 mg (0.2 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 19A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 39 mg (37% of theory) of the product as a solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2C(C2C=NC(OC)=CC=2)=CC2CCCC2)(=O)=O)C=CC=CC=1.C(O)C.O1CCCC1.[OH-].[Na+]>C(OCC)(=O)C>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[CH:11]1
Reactant: COc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: c1cnc2[nH]ccc2c1
Yield: 253.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (110 mg, 0.24 mmol), ethanol (6 mL), tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was heated at 40° C. for 4 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methoxy-pyridin-3-yl))-vinyl]-1H-pyrrolo[2,3-b]pyridine (72 mg, 94%) as a white solid: LC/MS m/e calcd for C20H21N3O [M+H]+ 320.41, observed 320.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCCl)Cc1ccc(C(F)(F)F)cc1
Yield: 50.8 %

Procedure:
Using 0.22 g of (4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.31 g of 1-bromo-3-chloropropane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(3-chloropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (85)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c1
Yield: 97.1 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0095 mL (0.072 mMol) 3-methylbenzoyl chloride, 0.022 gm (99%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C1(CCC([N:10]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=O)CCCC1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(N=[N+]=[N-])(=O)=O)(C)C>>[C:16]1([CH2:15][CH:14]2[CH2:13][O:12][C:11](=[O:22])[NH:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CCC1CCCC1)N1C(=O)OCC1Cc1ccccc1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Product: O=C1NC(Cc2ccccc2)CO1

Procedure:
Following the procedure described in Example 46 for the preparation of the corresponding cyclooctyl derivative, 2.1 g of S)-3-[3-cyclopentyl-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone and 2.5 g of 2,4,6-triisopropylbenzenesulfonyl azide yielded 1.23 g of [4S-3-(2S)]-3-[2-azido-3-cyclopentyl)-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone.