Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][O:26][C:27]([C:29]3[CH:30]=[N+:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)=[O:28])=[O:23])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[CH3:35][N:31]1[CH:32]=[CH:33][CH2:34][C:29]([C:27]([O:26][CH2:25][O:24][C:22]([N:20]([CH2:19][CH2:18][CH2:17][N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:12]=3[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]2=3)[CH3:21])=[O:23])=[O:28])=[CH:30]1
Reactant: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)OCOC(=O)c1ccc[n+](C)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C=CCC(C(=O)OCOC(=O)N(C)CCCN2c3ccccc3CCc3ccccc32)=C1
Yield: 95.3 %

Procedure:
Three-tenths gram (0.0005 mol) of the product of Example 54 in 30 mL water and 15 mL ethyl acetate was reduced with 0.25 g (0.003 mol) NaHCO3 and 0.35 g (0.002 mol) sodium dithionite at 0°-5° C., with deaeration, for a 60 minute period. The layers were separated and the aqueous layer was extracted twice with 30 mL portions of ethyl acetate. The combined organic layers were then extracted twice with 20 mL portions of cool deaerated water. Drying over Na2SO4 and removal of the solvent in vacuo afforded 0.22 g (95%) of the title compound, melting at 59°-63° C. (dec.) and having the structural formula: ##STR96##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([C:20]([O:22]CC)=[O:21])[S:19][C:11]1=2)([O-:3])=[O:2].O.[OH-].[Li+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([C:20]([OH:22])=[O:21])[S:19][C:11]1=2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Yield: 80 %

Procedure:
A mixture of the compound of Example 120 (150 mg, 0.357 mmol) and lithium hydroxide monohydrate (30 mg, 0.714 mmol) in dioxane (3 mL) and water (3 mL) was heated under reflux for 1.5 h. The dioxane was removed in vacuo, the aqueous residue acidified (2M HCl) and the precipitate filtered off and dried to give the title compound as a pale orange solid (112 mg, 80%). δH (DMSO-d6) 13.06 (1H, br s), 8.29 (1H, dd, J 1.3, 8.2 Hz), 8.02–7.93 (2H, m), 7.88–7.84 (1H, m), 7.46–7.35 (6H, m), 6.46 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.137 minutes, 393.0 (M+H)+.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH-:7].[Na+]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: [OH-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
50 kg of water glass having an SiO2/Na2O ratio of 2.06 and an active substance content of 45.5% were admixed with 0.2 kg of sodium hydroxide solution (48% strength) and spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate with an active substance content of 84%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). The chilled material (about 10 kg) is pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:16][CH3:17])[CH:7]=1
Reactant: CCI
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(Br)ccc1F
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a solution of 23A (4.4 g, 23 mmol) and K2CO3 (6.4 g, 46 mmol) in DMF (30 mL) was added ethyl iodide (2.49 mL, 31 mmol) at rt. The mixture was heated at 50° C. for 2.0 h. After cooling to rt, it was diluted with ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 3.86 g (77%) of 32A as viscous oil.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=2[O:11][CH3:12])[C:3]1=[O:17].[O:18]=[C:19]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].[BH4-].[Na+].Cl>CO.CC(C)=O>[O:18]=[C:19]([N:28]1[CH2:29][CH2:30][N:31]([C@@H:2]2[CH2:10][C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=3[O:11][CH3:12])[C@H:3]2[OH:17])[CH2:32][CH2:33]1)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(C=Cc1ccccc1)N1CCNCC1
Reactant: COc1cc2c(c(OC)c1OC)CC(Br)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc2c(c(OC)c1OC)C[C@@H](N1CCN(C(=O)C=Cc3ccccc3)CC1)[C@@H]2O
Reaction time: 16 h
Yield: 27.4 %

Procedure:
A mixture of 3.3 g (11 mmole) of 2-bromo-4,5,6-trimethoxy-1-indanone (Haworth et al., J. Chem. Soc. 1952 1583-1588), 2.16 g (10 mmole) of 1-(1-oxo-3-phenyl-2-propenyl)-piperazine, 0.92 g (11 mmole) of NaHCO3 in 8 ml of methanol is refluxed with stirring for 16 hours. After cooling, and maintaining the temperature at 0°-5° C., 0.77 g (20 mmole) of NaBH4 are added at portions, then the mixture is allowed to stand for 4 hours at room temperature under stirring. The mixture is cooled and made acidic by the addition of 15% aqueous HCl. After concentration under reduced pressure, the mixture is made alkaline by the addition of an aqueous 5% solution of sodium carbonate and extracted with methylene dichloride. The organic phase is washed with H2O to neutrality and dried over sodium sulfate. On evaporation under reduced pressure, 4.2 g are obtained as a mixture of diastereoisomers cis/trans which are separated by flash-chromatography through a column filled with silicagel 60 Merck 230-400 mesh, using chloroform:acetone 50:50 as the eluent. After crystallization from acetone, 1,2 g of cis-isomer are obtained (yield 27.4%), m.p. 162-163° C. On cristallization from acetone, 1.25 g of trans-isomer are obtained (yield 28.5%); m.p. 168°-170° C.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[Na+].CN(C=O)C.F[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1>CN(P(N(C)C)(N(C)C)=O)C.O>[C:2]([O:5][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: N#Cc1ccc(F)cn1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)Oc1ccc(C#N)nc1
Reaction time: 16 h
Yield: 62.4 %

Procedure:
To NaOtBu (1.57 g, 16.4 mmol) in HMPA (6 mL) was added DMF (6 mL), followed by 5-fluoropyridine-2-carbonitrile (1 g, 8.19 mmol) and the reaction mixture was stirred for 16 hours under an atmosphere of nitrogen. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL) and layers were separated. The organics were washed sequentially with water (50 mL) and sat. aq. NaHCO3 solution (50 mL) and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc/hexanes to give 5-tert-butoxypyridine-2-carbonitrile (0.90 g, 62%) as a yellow solid. ESI-MS m/z calc. 176.0. found 177.5 (M+1)+; Retention time: 1.3 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=2.7, 0.5 Hz, 1H), 7.67-7.56 (m, 1H), 7.41-7.31 (m, 1H), 1.52-1.38 (m, 10H). To 5-tert-butoxypyridine-2-carbonitrile (0.75 g, 4.26 mmol) in ethanol (10 mL) was added NaOH (4.3 mL of 5 M, 21.3 mmol) and the reaction mixture was heated at 85° C. for 1 hour. The reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate (50 mL). The organic layer was washed with mixture of brine solution (10 mL) and 6N HCl (3 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give 5-tert-butoxypyridine-2-carboxylic acid (0.82 g, 99%) as a yellow solid. ESI-MS m/z calc. 195.1. found 196.1 (M+1)+; Retention time: 0.62 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:24]=1[C:25]([OH:27])=[O:26].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[C:24]=1[C:25]([OH:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(Br)c1C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(Br)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
A suspension of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.84 mmols), 2-amino-6-bromobenzoic acid (2.53 g, 11.69 mmols), and N-ethyl-N-(1-methylethyl)-2-propanamine (7.55 g, 58.4 mmols) in 2-propanol (150 ml) was heated at 90° C. for 5 days. The solvent was removed, residue redissolved in DCM (150 ml), washed with 1M HCl(100 ml), organic layer separated, adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 10% MeOH/DCM). The crude product was then recrystallized from ethyl acetate/hexanes to obtain 2-bromo-6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (1.5 g, 49%). ESIMS (M+H)+=521.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:25][C:24]1[C:19]([N:15]2[CH2:16][CH2:17][CH:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][CH2:14]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccnc1Cl
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ncccc2Cl)CC1
Yield: 32.6 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was reacted with 2,3-dichloropyridine (201 mg, 1.36 mmol) to afford the title compound (90 mg), a white solid, in 33% yield.
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[CH:5]1[CH:6]=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([C:11]2[C:21]3[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=3[O:19][C:18]3[C:12]=2[CH:13]=[CH:14][C:15]([CH:17]=3)=[O:16])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:4]([O:29][C:27](=[O:28])[C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:11]1[C:12]2[C:18]([O:19][C:20]3[C:21]=1[CH:22]=[CH:23][C:24](=[O:26])[CH:25]=3)=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=2)[CH:3]=[CH2:2]
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reactant: CC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 65 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
Bromo-1-propene (0.78 mL, 9.0 mmol) was added dropwise under argon to a stirred mixture of fluorescein 16 (3.0 g, 9.0 mmol) and K2CO3 (1.24 g, 9.0 mmol) in dry DMF (40 mL). The resulting mixture was stirred for 4 h at 65° C. The mixture was concentrated, diluted with ethyl acetate, washed with 10% NaHCO3, brine, dried with anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane=2:1) to give 21 as a brown solid (0.70 g, 21%). 1H NMR (CDCl3, 500 MHz) δ 4.42 (d, J=6.0 Hz, 2H, CH2), 5.06 (m, 2H, 2CH), 5.53 (m, 1H, CH), 6.81 (m, 2H), 6.88 (m, 2H), 6.98 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 66.26, 103.90, 115.01, 119.49, 122.30, 130.02, 130.51, 130.65, 131.00, 131.38, 132.77, 134.48, 155.89, 158.06, 165.08, 175.84. ESIMS calcd for C23H17O5 [M+H]+ 373.1. Found 373.2.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])(=O)[CH3:2].[OH-].[Na+].O.[CH:13]1(C=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:2]1([CH:1]=[C:4]2[CH2:9][CH2:8][O:7][C:5]2=[O:6])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)C1CCOC1=O
Reactant: O=CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1=CC1CCCCC1
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 2-acetyl-γ-butyrolactone (15.4 g) in toluene (100 mL) was treated portionwise with sodium hydroxide (4.8 g) during 10 min and then refluxed with a Dean & Stark moisture receiver until the formation of water had stopped (about 1 h). After that the reaction mixture was treated dropwise with cyclohexanecarbaldehyde (15.0 g) during 1 h. Upon completion of the addition, the mixture was refluxed for 4 h, then cooled to room temperature and washed with water. After drying over magnesium sulfate, the obtained organic phase was filtered, concentrated on a rotary evaporator and distilled in vacuum to give 4.54 g (21%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([OH:49])[C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(F)n2)cc1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
To 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 30 g, 74.7 mmol) in 300 mL of tetrahydrofuran under an atmosphere of nitrogen at −20° C., isopropylmagnesium chloride (43.6 mL, 2 M in tetrahydrofuran, 87 mmol) was added and the reaction allowed to warm to 0° C. over 30 minutes. The reaction was cooled to −40° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (66, 17.96 g, 49.8 mmol) in tetrahydrofuran was added. The reaction was allowed to warm to 0° C. over an hour, then quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (67, 27 g, 42.5 mmol, 85% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[O:4][CH2:1][CH2:2][O:3]2)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(C2OCCO2)CC1
Yield: 78 %

Procedure:
Ethylene glycol (5 ml) and a catalytic amount of p-toluenesulfonic acid were added to 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.6 g, 22.6 mmol) in toluene (100 ml) and the mixture was heated at reflux under Dean and Stark conditions for 2.5 h. Solvents were removed in vacuo and the residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether) to yield the title compound (5.14 g, 78%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:27][C:28](=[O:39])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1)(C)(C)C.[OH-].[K+]>CCO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:22])/[CH:21]=[CH:37]/[C:34]3[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:28]([OH:39])=[O:27])=[N:32][CH:33]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone (319 mg, 1.085 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 253 mg, 1.08 mmol) and KOH 1.7 M (0.638 ml) in EtOH (10 ml) was stirred at 0° C. overnight. The resulting precipitate was filtered washing with hot EtOH and the powder was dissolved in DCM (10 ml) and treated with TFA (2 ml) for 6 h. The solvent was then removed in vacuo to give 388 mg of (E)-3-(5-{(E)-3-[4-(4-benzyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O>Cl.O.[Zn]>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][CH2:12]2
Reactant: COc1cc(Br)cc2c1OCCC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc2c1OCCC2
Yield: 47 %

Procedure:
According to the process of preparation I, from the amalgam of zinc prepared from 915 g (14 gram-atoms) of zinc, 91 g (3.8×10-1M) of mercurous chloride in 46 cm3 of concentrated hydrochloric acid and 1350 cm3 of water, after addition of 700 cm3 of water, 1100 cm3 of concentrated hydrochloric acid, 2500 cm3 of toluene and 450 g (1.8 M) of 6-bromo-8-methoxy-4-chromanon (III1), 200 g (yield=47%) of the expected product are obtained. M.p.=67° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C@@:11]2([CH3:22])[NH:20][C:19](=[O:21])[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.[CH2:23](Br)[C:24]#[CH:25]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@:11]2([CH3:22])[N:20]([CH2:25][C:24]#[CH:23])[C:19](=[O:21])[C:14]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: C#CCBr
Reactant: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Reaction time: 16 h

Procedure:
Sodium hydride (86.0 mg, 2.15 mmol, 60% dispersion in mineral oil) was added to a solution of (8R)-8-(3,5-difluorophenyl)-8-methyl-6,9-diazaspiro[4.5]decan-10-one (502 mg, 1.791 mmol, described in Intermediate 1) in 5 ml of DMF. When the gas evolution had ceased, propargyl bromide (320 mg, 2.15 mmol, 80 wt % in toluene) was added to the solution at ambient temperature. After 16 hours, the reaction was quenched with water (20 mL) and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of CH2Cl2:ethyl acetate—98:2 to 50:50. The clean fractions were concentrated in vacuo to yield the title compound. MS: m/z=319 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].COC(C1C=NC(NCC2C(C3C=CC=CC=3)=NOC=2C)=CN=1)=O.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52]>>[F:49][C:50]([F:54])([F:53])[CH2:51][NH:52][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Reactant: NCC(F)(F)F
Agent: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Product: O=C(NCC(F)(F)F)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 71 %

Procedure:
As described for example 9b, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (75 mg, 0.23 mmol), instead of 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (64 mg, 71%) which was obtained as a light yellow solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].[N:37]1(O)[C:41]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.CN.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:41][NH:37][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][N:9]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 60 h
Yield: 53.7 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (80 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (110 mg), methylamine hydrochloride (50 mg), triethylamine (85 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 2.5 days. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (100/0 to 95/5, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (110 mg, yield 52%) as colorless prism crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]([C:15]1[CH:16]=[N:17][N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12)[C:10]([CH:12]1[CH2:14][CH2:13]1)=O)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH:12]1([CH2:10][N:9]([CH2:7][CH3:8])[C:15]2[CH:16]=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)[CH2:13][CH2:14]1
Reactant: CCN(C(=O)C1CC1)c1cnn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CC1)c1cnn2ccccc12
Reaction time: 16 h
Yield: 41.5 %

Procedure:
To a suspension of LiAlH4 (0.70 g, 18.5 mmol) in THF (2.0 mL) was added a solution of N-ethyl-N-pyrazolo[1,5-a]pyridin-3-ylcyclopropanecarboxamide (0.77 g, 3.36 mmol) in THF (5.0 mL) at room temperature and stirred for 16 h. H2O (0.70 mL), 15% NaOH (0.70 mL) and H2O (2.1 mL) were added sequentially. Celite was added and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (E:H=1:4) to give 0.30 g (42%) of yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=7.0 Hz, 1H), 7.82 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.02–6.98 (m, 1H), 6.70–6.66 (m, 1H), 3.21 (q, J=7.1 Hz, 2H), 2.92 (d, J=6.6 Hz, 2H), 1.06 (t, J=7.1 Hz, 3H), 0.92–0.88 (m, 1H), 0.46–0.41 (m, 2H), 0.11–0.08 (m, 2H); MS (EI) m/z 216.19 (M++H).