Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][Sn](C)(C)C>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Br)c2nccn2c1
Reactant: C[Sn](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)c2nccn2c1

Procedure:
Microwave a mixture of 6-methyl-8-bromoimidazo[1,2-a]pyridine (1.0 g, 4.76 mmol), tetramethyl tin (2.0 g, 11.2 mmol), and palladium tetrakis(triphenylphosphine) (0.28 g, 0.024 mmol) at 120° C. for 10 minutes at 300 watts. Subject the reaction mixture to flash silica gel chromatography to provide a quantitative yield of the title compound as a tan oil.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)[N:12]=1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37](N2C=CN=C2)=[O:38])=[CH:30][C:29]=1[Cl:44]>C1COCC1>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37]([O:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:11]3[C:10](=[O:24])[CH:9]=[CH:8][C:7]([Cl:6])=[N:12]3)[CH2:17][CH2:18]2)=[O:38])=[CH:30][C:29]=1[Cl:44]
Reactant: Nc1c(Cl)cc(C(=O)n2ccnc2)c2c1CCO2
Reactant: O=c1ccc(Cl)nn1CCCN1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=O)OCC2CCN(CCCn3nc(Cl)ccc3=O)CC2)c2c1CCO2
Yield: 42.6 %

Procedure:
1H-imidazole (2.72 g) was added to a solution of 6-chloro-2-[3-[4-(hydroxymethyl)-1-piperidinyl]propyl]-3(2H)-pyridazinone (2.62 g) in THF (100 ml). NaH (60%, 0.4 g) was added, under nitrogen atmosphere. The mixture was stirred for minutes. 1-[(4-Amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-1H-imidazole (2.64 g) was added and the resulting reaction mixture was stirred for 15 minutes at room temperature. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/(CH3OH/NH3)50/45/5). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a drop of ACN. The precipitate was filtered off, washed and dried, yielding 1.88 g (39%) of [1-[3-(3-chloro-6-oxo-1 (6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (compound 21, mp: 137 ° C.) In a similar way, [1-[3-(3-methyl-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]-methyl 7-amino-6-chloro-1,3-benzodioxole-4-carboxylate (compound 22) was also prepared.
Reaction SMILES: [C:1]([CH:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[C:17]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]4[N:23]=[C:22]3[CH2:32][CH3:33])[CH:18]=[CH:19][C:6]1=2)[CH3:4])#[N:2].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:32]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:6]3[N:5]([CH:3]([C:1]4[NH:40][N:39]=[N:38][N:2]=4)[CH3:4])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:16]=2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:33]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2C(C)C#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2C(C)c1nnn[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 62.2 %

Procedure:
5-(1-Cyanoethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (520 mg, 1.19 mmol) obtained in step 1 of Example 19 was dissolved in toluene (12 mL), and the solution was added with trimethylsilylazide (2.54 mL, 19.1 mmol) and dibutyltinoxide (177 mg, 0.71 mmol), followed by stirring at 70° C. for 2 days. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=25/1) to give the title compound (compound 22, 354 mg, 62%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>>[Br:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[N:21]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH:20]=[C:19]2[CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:29])[CH2:18][CH2:17]1
Reactant: CCOCCBr
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3c(Br)cccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2cccc(Br)c21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 1.4 g (3.1 mmol) of 2-{2-[4-(7-bromo-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 138, part A), 0.16 g (3.7 mmol) of NaH in 60% of mineral oil and 0.42 mL (3.7 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.34 g (28% of yield) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](C2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[C:48]([C:49]#[N:50])=[CH:47][C:46]([C:51]([F:54])([F:53])[F:52])=[N:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:43]2[CH:44]=[N:45][C:46]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:48]=2[C:49]#[N:50])=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(C2OC(C)(C)C(C)(C)O2)cc1S(=O)(=O)N1CCCCc2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 100 °C
Yield: 85.5 %

Procedure:
4-[5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-butyric acid tert-butyl ester (60.0 mg, 0.1 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (23 mg, 0.09 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol) and K2CO3 (56 mg, 0.4 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 100° C. for 16 hrs. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated, washed with brine (2×5 mL), dried over MgSO4, filtered, concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester 6-1 as a white foam (50 mg). MS: 593.9 (M+H-tBu)*; tR=6.98 min (method 4). NMR (CDCl3), δ, 8.791 (1H, s), 7.738-8.101 (2H, m), 7.060-7.272 (4H, m), 6.774-6.828 (1H, m), 4.213 (2H, m), 3.780 (2H, m), 2.833 (2H, m), 2.404 (2H, t), 1.912-2.029 (4H, m), 1.591-1.657 (2H, m), 1.448 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][OH:7].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([Si:23]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:26])[CH3:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl alcohol (2.15 g, 11.75 mmol) and imidazole (880 mg, 12.94 mmol) in dry dichloromethane (58 ml) at 0° C. was quickly added tert-butyldimethylchlorosilane in one portion and the mixture was stirred at for 1 hour. LC-MS analysis indicated complete conversion. The solution was washed with ice cold water (50 ml) dried over Na2SO4, adsorbed on silicagel and purified by HPLC with hexanes/ethyl acetate 20-30% gradient to give compound 5 as a light yellow solid (3.3 g, 94%). MS (EI+): 282 (M-Me); 240 (M-tBu); H-NMR (400 MHz, CD2Cl2): 7.85 (1H, d, J=8 Hz) 7.19 (1H, s) 6.98 (1H, dq, J=8 Hz, 0.4 Hz) 4.82 (2H, s) 3.99 (3H, s) 1.0 (9H, s) 0.17 (6H, s). C-NMR (400 MHz, CD2Cl2): 153.96, 150.05, 138.73, 126.32, 117.74, 111.26, 64.65, 57.06, 26.30, 18.90, −4.97.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=[O:9]>>[OH:9][CH:8]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: CCOC=O
Reactant: O=C1CCCCC1
Product: O=C1CCCCC1=CO

Procedure:
As in the previous example, 200 g (2.0 mol) of cyclohexanone was reacted with ethyl formate to give 140 g of 2-hydroxymethylenecyclohexanone, XXVIIb, bp 71°-74° C (0.6 mm). Forty grams (0.32 mol) of this substance was dissolved in 150 ml CH2Cl2. containing 30 g of pyridine and treated at -5° C with a solution of 64 g (0.34 mol) of p-toluenesulfonyl chloride and 16 g of pyridine in 150 ml CH2Cl2. The reaction was stirred overnight at this temperature. Work-up in the usual manner gave the enol tosylate XXVIIIb. This was not isolated but added directly to solution of 150 g (1.0 mol) NaI in dry acetone. After stirring overnight at room temperature this was worked up in the usual manner to give (E)-2-iodomethylenecyclohexanone, XXIXb, as a red oil. Again this was not isolated but was reduced with NaBH4 in EtOH to give crystalline dl-(E)-2-iodomethylenecyclohexanol, XXXb. Recrystallization from petroleum ether gave 40 g of white needles, mp 80° C.
Reaction SMILES: [CH2:1]([O:7]C1C=CC=C2C(NC(=O)C=12)=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C([NH2:23])CCC.C(OCC)C.[ClH:29]>C(O)C>[ClH:29].[CH2:1]([O:7][NH2:23])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2c(OCc3ccco3)cccc21
Reactant: CCCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NOCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.28 g of [-furfuryloxyphthalimide [prepared as described in step (i) above] were dissolved in 20 ml of ethanol, and 1.37 g of butylamine were added to the resulting solution. The mixture was then stirred for 1 hour at room temperature, after which diethyl ether was added. The mixture was then acidified by the addition of a 10% by volume methanolic solution of hydrogen chloride, and the resulting crystals were collected by filtration, to afford 2.62 g of the title compound. Nuclear Magnetic Resonance Spectrum (CD3OD, 270 MHz), δ ppm: 5.07 (2H, singlet); 6.54 (1H, doublet of doublets, J=2 & 3 Hz); 6.72 (1H, doublet, J=3 Hz); 7.67 (1H, doublet, J=2 Hz).
Reaction SMILES: [OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4].[OH-:34].[Na+]>>[OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]([NH2:12])=[O:34])[CH:3]([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.90 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.64 g of the title compound was obtained as a powder, melting at 153°-157° C.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[Cl:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: C/C(N)=C\C#N
Reactant: Nc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=CC#N)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-chloroaniline (8.55 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)CNCC[C@@H](N)CC(C)C
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 24.7 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based. [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 25%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (5 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m, 5H), 1.76-1.82 (m, 1H), 2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([C:14]#[N:15])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylacetonitrile (8.30 g) in tetrahydrofuran (80 ml) was cooled to −78° C. under an argon gas atmosphere, and a solution (1.9 M, 17.3 ml) of sodium hexamethyldisilazane in tetrahydrofuran was added dropwise. After the completion of the dropwise addition, the solution was stirred at 10° C. for 15 min, and cooled to −78° C. again. To the solution was added ethyl bromoacetate (5.48 g), and the mixture was stirred at room temperature for 16 hr. The reaction solution was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 100:0-70:30) to give the title compound (7.50 g, yield 67%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>>[CH3:29][N:30]([CH3:34])[C:31]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[C:2]([Cl:1])[CH:10]=3)=[O:12])[CH2:14][CH2:15]1)=[O:32]
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Reactant: CN(C)C(=O)Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)N(C)C)CC4)[nH]c3cc2Cl)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 37, from [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36), and dimethylcarbamoyl chloride, to afford the title compound as a light-yellow solid (62%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3]O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22]3[C@@H:21]4[CH2:23][C@@H:20]4[CH2:19][C:18]=3[C:17]([C:24](O)=[O:25])=[N:16]2)=[N:13][CH:14]=1.[C@@H]12C[C@@H]1CCC2=O.ClC1C=CC(NN)=NC=1>>[OH:6][CH2:5][C:2]([NH:1][C:24]([C:17]1[C:18]2[CH2:19][C@H:20]3[CH2:23][C@H:21]3[C:22]=2[N:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][N:13]=2)[N:16]=1)=[O:25])([CH3:7])[CH3:3]
Reactant: CC(N)(CO)CO
Reactant: O=C(O)c1nn(-c2ccc(Cl)cn2)c2c1C[C@H]1C[C@@H]21
Agent: NNc1ccc(Cl)cn1
Agent: O=C1CC[C@H]2C[C@@H]12
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(Cl)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using 2-amino-2-methylpropane-1,3-diol and (1aR,5aR)-2-(5-Chloropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. The aforementioned acid was prepared in a similar method as described in Method A and B using (1R,5S)-bicyclo[3,1,0]hexan-2-one and 5-chloro-2-hydrazinylpyridine. LCMS m/z=347.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=8.3, 4.4 Hz, 1H), 1.406 (s, 3H), 1.410 (s, 3H), 2.24-2.30 (m, 1H), 2.75-2.80 (m, 1H), 2.90 (d, J=16.6 Hz, 1H), 3.00 (dd, J=16.6, 6.4 Hz, 1H), 3.70 (s, 2H), 4.63 (bs, 1H), 6.92 (s, 1H), 7.78 (dd, J=8.7, 2.5 Hz, 1H), 7.87 (dd, J=8.8, 0.6 Hz, 1H), 8.41 (dd, J=2.5, 0.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1)[CH3:2].COS(OC)(=O)=O.C(OC1C=C(C=CC=1)OC1[CH:33]=[N+:34](OC)C=CC=1)C.[Na]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[C:9]([C:33]#[N:34])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc[n+](OC)c2)c1
Reactant: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Agent: [Na]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOc1cccc(Oc2cccnc2C#N)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 68 g of 3-(3-ethoxyphenoxy)pyridine 1-oxide and 40 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(3-ethoxyphenoxy)-1-methoxy pyridinium methosulfate is dissolved in 200 ml of water and is added dropwise to a cooled, stirred solution of 75 g sodium cyamide in 200 ml of water at 0°-5° C. under a nitrogen atmosphere. The mixture is stirred 16 hours and is extracted with 500 ml of dichloromethane. The dichloromethane layer is washed with 100 ml of water, dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)-2-pyridinecarbonitrile, bp 145°-150° C. at 0.2 mM, mp 83°-84° C. after recrystallization from methanol.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[Na].[CH3:11]O>>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:11])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Agent: [Na]
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-Imidazoleacetic acid, sodium salt, hydrate (compound ix, where R2 is H) (3.0 g, 18.1 mmol) in MeOH (50 ml) was cooled to about 0° C. and anhydrous HCl gas was bubbled into the mixture for about 15 minutes while maintaining reaction temperature below about 5° C. The reaction was stirred for about 12 hour at room temperature and then solvents were removed under reduced pressure to yield an oil which solidifies on standing. Mass spec 141.0 MH+, NMR (300 MHZ, DMSO-d6, 30° C.), 9.0-9.2 (1H, s), 7.47.6 (1H, s), 3.85-3.95 (2H, 3), 3.6-3.7 (3H, s).
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:18]=1[C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.N>C(Cl)Cl>[CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:17]=4[CH3:16])[CH2:22][CH2:23]3)[CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1C(=O)N1CCC(=O)CC1
Reactant: CCCCC1NC(=O)OC12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC1NC(=O)OC12CCN(C1CCN(C(=O)c3c(C)cccc3C)CC1)CC2
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one (12: R=H; R′=n-Bu; 1.09 g; 5.1 mmol)) in 30 mL DCM was added 1.24 g (5.4 mmol) of 1-(2,6-dimethyl-benzoyl)-piperidin-4-one followed by 2.1 mL (7.1 mmol) of Ti(IV)(O-i-Pr)4 The reaction mixture stirred under nitrogen for 18 h. of Sodium triacetoxyborohydride (1.6 g: 7.7 mmol) was added to the reaction mixture followed by glacial HOAc (0.365 mL; 6.4 mmol). The reaction mixture stirred for 24 h. Aqueous ammonia (20 mL; 10% aqueous solution) was added and the solution stirred for an additional 10 min. The mixture was filtered by gravity through a cartridge of ChemElute™. The organics were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with gradient elution (2% to 10% methanol in ethyl acetate with 0.4% ammonia) to provide 1.6 g (73%) of 4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decane-2-one: ms [M]+=428.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH2:5][Cl:6])[CH:3]=[O:4].[CH:8]([NH2:10])=[O:9]>>[OH:4][CH:3]([NH:10][CH:8]=[O:9])[C:2]([Cl:7])([Cl:1])[CH2:5][Cl:6]
Reactant: NC=O
Reactant: O=CC(Cl)(Cl)CCl
Product: O=CNC(O)C(Cl)(Cl)CCl
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture consisting of 16.2 gm of 2,2,3-trichloropropionaldehyde and 4.5 gm of formamide was stirred on a boiling water bath for 30 minutes. Recrystallization of the reaction product from benzene yielded 17 gm of the desired compound, m.p. 105°-109° C.