Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Fe]
Agent: [Ru+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Fe, R=i-Pr, Ar=3,5-Me2C6H3—, 1.3 μmol, 0.33 mol %) were dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 65° C. After the mixture was cooled to room temperature, p-methoxyacetophenone (0.4 mmol), tetrahydrofuran (2 mL) and an aqueous solution of sodium bicarbonate (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 12 h under H2 (20 atm) at 40° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-methoxyphenyl)ethanol was obtained and the ee value (ee=99.1%) was measured by GC analysis.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCCl>[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]([C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2NC1=O
Yield: 99.7 %

Procedure:
1-Adamantylcarbonyl chloride (795 mg) and pyridine (0.33 ml) were added to 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in anhydrous 1,2-dichloroethane (20 ml). The mixture was refluxed with heat for one hour. After the reaction mixture was allowed to cool, crystals so precipitated were collected by filtration, to thereby obtain 1.58 g of the titled compound as a white solid (yield: 99.8%).
Reaction SMILES: [CH:1]1(CN2C(=O)C3NC(C4C=CC(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC)=CC=4)=NC=3N(CC3CCCCC3)C2=O)CCCCC1.[CH:62]1([CH2:68][N:69]2[C:77](=[O:78])[C:76]3[N:75]=[C:74]([C:79]4[CH:89]=[CH:88][C:82](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:80]=4)[NH:73][C:72]=3[N:71]([CH2:90][CH:91]3[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]3)[C:70]2=[O:97])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1.C1(CN2C(=O)C3N=C(C4C=CC=C(/C=C/C(N5C=CN=C5)=O)C=4)NC=3N(CC3CCCCC3)C2=O)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CO>[CH3:1][O:86][C:85](=[O:87])/[CH:84]=[CH:83]/[C:82]1[CH:81]=[CH:80][C:79]([C:74]2[NH:73][C:72]3[N:71]([CH2:90][CH:91]4[CH2:92][CH2:93][CH2:94][CH2:95][CH2:96]4)[C:70](=[O:97])[N:69]([CH2:68][CH:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[C:77](=[O:78])[C:76]=3[N:75]=2)=[CH:89][CH:88]=1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccc(-c2nc3c([nH]2)c(=O)n(CC2CCCCC2)c(=O)n3CC2CCCCC2)cc1
Agent: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
In the manner of Example 36, part (b), (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid was converted to (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder. Such a sample (2.50 g, 4.62 mmol) was stirred at reflux in acetonitrile (75 ml) with potassium carbonate (1.28 g, 9.25 mmol) and methanol, (10 ml) for 24 hours. The mixture was cooled to room temperature and filtered and the filtrate-wash was adjusted to pH ˜3 by addition of 6N hydrochloric acid. The resulting precipitate was filtered and washed with methanol and dried to give (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid methyl ester (1.70 g, 74%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J=8.2 Hz, 2H, phenylCH), 7.83 (d, J=8.4 Hz, 2H, 2 phenylCH), 7.63 (d, J=15.9 Hz, 1H, CH═), 6.70 (d, J=15.9 Hz, 1H, CH—), 3.95 (d, J=7.0 Hz, 2H, CH2N), 3.75 (d, J=6.8 Hz, 2H, CH2N), 3.70 (s, 3H, CH3), 2.0-1.50 and 1.20-0.80 (m, 22H, 2C6H11).
Reaction SMILES: C1O[CH:4]([C:5]2[C:6]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[N:7][N:8](C(OC)=O)[CH:9]=2)[O:3]C1.N1CCCCC1>O1CCOCC1.O>[N+:19]([C:16]1[O:15][C:14]([C:6]2[C:5]([CH:4]=[O:3])=[CH:9][NH:8][N:7]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1

Procedure:
React 3.1 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal in 50 ml of dioxan and 25 ml of water with 1.73 g of piperidine for 20 minutes at room temperature (20° C) and then proceed according to the method of part (a) above to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde with a melting point of 185° to 187° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)([CH3:8])[CH3:7])=O.[N+:17]([C:20]1[CH:21]=[N:22][NH:23][CH:24]=1)([O-:19])=[O:18].CC(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:6]([N:22]1[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:24]=[N:23]1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 149 %

Procedure:
Di-tert-butyl azodicarboxylate (1.59 g, 6.91 mmol) was added to a solution of 4-nitro-1H-pyrazole (601 mg, 5.32 mmol), 2-propanol (319 mg, 5.32 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) in tetrahydrofuran (25 mL) over 3 minutes and the mixture was stirred at room temperature for 16 h. After this time, the reaction was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, 1:4 ethyl acetate/heptane to 7:3 ethyl acetate/heptane) to afford 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g, >100%) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.24 (s, 1H), 4.58 (m, 1H), 1.42 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53]C)=[O:52])[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:51]([CH2:50][CH2:49][CH2:48][CH2:47][N:4]([CH:1]1[CH2:2][CH2:3]1)[S:5]([C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])(=[O:6])=[O:7])([OH:53])=[O:52]
Reactant: COC(=O)CCCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 81.3 %

Procedure:
A mixture of 208 mg of methyl 4-{2-[4-({[2-({3-[cyclopropyl(5-methoxy-5-oxopentyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 2.1 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and then to the obtained residue were added water, 300 mg of citric acid, dichloromethane, and THF in this order, and the organic layer was separated and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol). The crude product was washed with diethyl ether to obtain 163 mg of 4-{2-[4-({[2-({3-[(4-carboxybutyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a colorless crystal.
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:4]=21.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:5]2[N:6]=[C:7]3[C:3]([C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2c3c(Br)cccc3nn2cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Temperature: 105 °C
Yield: 26.7 %

Procedure:
400 mg (1.12 mmol) 10-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, intermediate example Int-1-3, 172.1 mg (1.17 mmol) 4-cyanophenylboronic acid, 91 mg (0.112 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 354.6 mg (3.35 mmol) sodium carbonate in 12 mL degassed dioxane and 1.68 mL water were heated in the microwave for 45 min. at 105° C. The reaction mixture was poured on a mixture of water/saturated ammonium chloride/dichloromethane and stirred vigorously for 30′. The organic phase was separated, washed twice with brine and dried (sodium sulfate). After filtration and evaporation of the solvent the residue was purified by HPLC yielding 114 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-n2cnc(C)c2)c(C#N)c1

Procedure:
In analogy to example 5a, 2-fluoro-5-methyl-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup the title compound was obtained as a white solid (yield: 48%). MS: m/e=198.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:17].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[C:3]([I:17])=[CH:4][C:5]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[I:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)c1cc(I)c(O)c(I)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(COc1c(I)cc(C(=O)c2ccccc2)cc1I)OCc1ccccc1
Reaction time: 15 h
Yield: 37.8 %

Procedure:
To a solution of (4-hydroxy-3,5-diiodophenyl)-phenyl-methanone (as prepared in Example 6, 2.25 g, 5.0 mmol) and benzyl 2-bromoacetate (1.71 g, 7.5 mmol) in 50 mL DMF was added cesium carbonate (4.1 g, 13 mmol). The resulting suspension was stirred for 15 hours, then the reaction mixture was poured into ˜150 mL 1 M HCl. A pale oil formed, and the supernatant was removed by decantation. The oil was crystallized from hot isopropanol, yielding the title compound as colorless crystals (1.13 g, 38%). 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 7.77-7.74 (m, 2H), 7.63 (tt, J=7.4, 1.2 Hz, 1H), 7.54-7.50 (m, 2 H), 7.45-7.35 (m, 5H), 5.33 (s, 2H), 4.71 (s, 2H). TLC (4:1 Hex:EtOAc), Rf 0.52. LRMS (EI+) calc'd for [C22H16I2O4+H] 598.9, found 598.8.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O.Cl.[NH2:26]/[C:27](/[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1)=[N:28]/[H].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:28]=[C:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[N:26]=2)[CH:13]=[CH:12][S:11]3)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: [H]/N=C(/N)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(-c2nc3sccn3c2C(=O)C=CN(C)C)ccc1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Yield: 87.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (0.537 g, 1.55 mmol) and tert-butyl 4-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.650 g, 2.33 mmol) was diluted with 13 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (780 μl) to form a reaction mixture. The reaction mixture was heated to reflux for 24 hours. Volatiles were removed in vacuo and the residue was taken up in 50 ml of ethyl acetate and 50 ml of water. The phases were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product was purified by flash chromatography on silica gel (gradient 50% to 75% ethyl acetate in hexanes) to yield 0.713 g of a pale yellow solid (88%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.71 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.2, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.19-7.12 (m, 2H), 6.39 (d, J=5.1 Hz, 1H), 3.98-3.87 (m, 3H), 3.83 (s, 3H), 2.91 (t, J=11.5 Hz, 2H), 1.94-1.87 (m, 2H), 1.47-1.35 (m, 2H), 1.42 (s, 9H). LCMS: 525 [M+H].
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](OC=O)(=[O:41])C>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH:39]=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: CC(=O)OC=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(C=O)CCC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To 3.0 g (6.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 586) dissolved in 25 ml of ethyl acetate and cooled to 0° C., was added 2.4 g (30 mmole) of pyridine and 4.0 g (28 mmole) of formic acetic anhydride mixture (Example 621a). After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 2.5 g of the desired compound, mp 161°-163° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(Cl)cc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(Cl)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-chlorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (10.8 g, 24.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.17 g. (85.2%). EA, MS(FD).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F>C(#N)C>[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:5]1[CH2:6][CH2:7][C@@H:3]([OH:2])[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC[C@@H](O)C2)c(F)c1
Yield: 95.6 %

Procedure:
(3R)-3-Hydroxypyrrolidine hydrochloride (20 g, 0.163 M) was suspended by stirring in acetonitrile (200 ml) under nitrogen at 50°, and treated with N,N-diisopropylethylarnine (52.5 g, 0.41 M) and 3,4-difluoronitrobenzene (25.9 g, 0.153 M). The mixture was heated at 90° for 17 hours, then the solvent evaporated. The residue was dissolved in dichloromethane (500 ml) and washed with 5% aqueous sodium dihydrogen phosphate (300 ml), which caused partial precipitation. The precipitate was filtered, washed, and the combined aqueous layers re-extracted with dichloromethane (200 ml). The organic layers were evaporated, and the residue combined with the previously filtered material, and dried by azeotroping with toluene to give the desired product (35 g), of sufficient quality for use without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[O:19]1[CH2:20][CH2:21][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: BrCCOCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol), bis(2-bromoethyl)ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml, 237 mmol) in N,N-dimethylformamide (200 ml) was stirred for 16 hours at 70° C. The reaction mixture was cooled down to room temperature, concentrated and the product was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution (15% aq.), dried and concentrated. The product was used in next step without purification.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>C(O)(=O)C>[O:5]=[S:13]1[CH2:14][CH2:15][N:10]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:11][CH2:12]1
Reactant: N#CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: N#CC1(c2ccc(OCCCN3CCS(=O)CC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Sodium perborate tetrahydrate (221 mg, 1.43 mmol) and glacial acetic acid (5 ml) was heated to 50 to 60° C. and 4-[4-(3-Thiomorpholin-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (500 mg, 1.43 mmol) was added in one portion and the heating was maintained for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was added to ice water (15 ml) and extracted with EtOAc (3×5 ml), which was discarded. The aqueous phase was basified to pH 8-9 with 2M sodium hydroxide and extracted with DCM (3×25 ml), dried over MgSO4, filtered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1 to 92:6:2) to provided the title compound (300 mg, 58%) as a white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.92 (d, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.15-3.03 (m, 2H), 2.94-2.67 (m, 6H), 2.63 (t, 2H), 2.16-1.92 (m, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[C:12]([S:16]Cl)[CH:11]=1>>[CH3:18][C:10]1[CH:11]=[C:12]([S:16][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: Cc1cccc(SCl)c1
Product: COC(=O)c1c[nH]c(Sc2cccc(C)c2)c1

Procedure:
By the method of this Example and Examples 3 and 8, methyl pyrrole-3-carboxylate is reacted with m-toluenesulfenyl chloride to yield methyl 5-(3-methylphenylthio)-pyrrole-3-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[Sn](CCCC)(CCCC)CCCC)=[CH:12]\[C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:16](=[O:29])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[N:49]=[C:48]([O:50][CH3:51])[C:47]([C:52](=[O:54])[CH3:53])=[CH:46][CH:45]=1.[F-].[Cs+].O>CN(C)C=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.[Cu](I)I.C(OCC)(=O)C>[C:52]([C:47]1[CH:46]=[CH:45][C:44](/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[CH:12]/[C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:16](=[O:29])[CH2:15][CH2:14]2)=[N:49][C:48]=1[O:50][CH3:51])(=[O:54])[CH3:53]
Reactant: COc1nc(Br)ccc1C(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)=O)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (170 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-26 (1.00 g), 1-(6-bromo-2-methoxypyridin-3-yl)ethanone obtained in Reference Example 4-40 (674 mg), cesium fluoride (447 mg) and copper iodide (308 mg) in N,N-dimethylformamide (10 mL) in a nitrogen atmosphere, and the mixture was stirred at 65° C. for one hour. The reaction solution was left to cool, and then water and ethyl acetate were added, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a pale yellow amorphous (773 mg).