Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[CH3:19][O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0 M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained (~30 ml). After vigorous gas evolution had ceased, cooling was removed and the reaction mixture stirred for 1 h at room temperature. The mixture was then treated dropwise with glacial acetic acid until all yellow color had dissipated. It was then stirred 15 min. and concentrated in vacuo to a pale yellow oil. This material was purified by column chromatography on silica with 20% EtOAc/hexane as eluent. The appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:46])[CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:33]#[C:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:21]=2)[O:16]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:33]#[C:34][C:35]4[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=4)[CH:21]=3)[O:16][C:15]([CH3:14])([CH3:46])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-methylbromobenzene (237.0 mg, 1.38 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (177.5 mg, 2.77 mmol, 1.6 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (377.0 mg, 2.77 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-ylethynyl)-benzoate (Compound 264, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 120.0 mg (92%), was isolated by column chromatography (2.5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.98 (2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.5 Hz), 7.34 (1H, dd, J=2.1, 8.3 Hz), 7.25-7.21 (5H, m), 6.85 (1H, d, J=8.3 Hz), 5.62 (1H, s), 4.36 (2H, q, J=7.1 Hz), 2.41 (3H, s), 1.49 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (45 g, 0.17 mol) and copper cyanide (34 g, 0.34 mol) in DMF (450 mL) was heated to 150° C. for 24 h. The suspension was cooled, poured into water with stirring. The solid was filtered and dried to give 25 g (70%) of the title compound which was used for the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:21]([CH:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(F)cc1F

Procedure:
To a solution of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 570 mg (1.32 mmol) dissolved in toluene (12 mL) were added 0.43 mL (3.96 mmol) of 1-chloroethyl chloroformate and 0.68 mL (3.96 mmol) of Hunig's base.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=C1.O>CN(C)C=O>[O:5]([CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 64.9 %

Procedure:
To a solution of 1.00 g (10.2 mmol) of 1,4-butanediol in 20 ml of dry dimethylformamide were added 2.80 g (10.2 mmol) of tert-butyldiphenylsilyl chloride and 3.47 g (51.0 mmol) of imidazole in an atmosphere of argon. The mixture was allowed to react at 0° C. for 24 hours. To the solution was added water followed by extraction with dichloromethane. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol (100:1) yielded 2.17 g (6.62 mmol) of 4-(tert-butyldiphenylsiloxy)-1-butanol.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Cl>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-chlorobenzylmagnesium chloride (0.25 M in hexanes, 25 mL, 6.3 mmol) according to General Procedure 3. The resulting products were then converted to the title compound by hydrogenation according to General Procedure 6 (with Pt2O). The crude product was purified by column chromatography eluting with heptane-EtOAc, gradient 0 to 40% EtOAc to afford the title compound. 262 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.15 (m, J=12.57, 8.03, 6.17, 6.17 Hz, 1H) 2.52-2.64 (m, 1H) 2.64-2.72 (m, 2H) 2.74-2.83 (m, 2H) 3.81 (s, 3H) 6.39 (d, J=1.37 Hz, 1H) 7.07 (d, J=8.25 Hz, 1H) 7.21 (d, J=1.81 Hz, 2H) 7.22-7.26 (m, 1H) 7.28-7.32 (m, 1H) 8.75 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CC(=O)c1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[3-(1H-Pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 329(MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:56][CH2:57][NH:58]C(OC(C)(C)C)=O)[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:23][CH:22]=1)=[O:16])[CH3:14])=[O:11])=O)(C)(C)C.[ClH:66]>ClCCl.C(OCC)C>[ClH:53].[ClH:66].[NH2:8][C@@H:9]([CH2:56][CH2:57][NH2:58])[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:25][CH:26]=1)=[O:16])[CH3:14])=[O:11]
Reactant: C[C@H](NC(=O)[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@@H](N)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 4 h

Procedure:
420 mg (0.444 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-{(2S)-2,4-bis((tert-butoxycarbonyl)-amino)butanoyl}-L-alaninate were dissolved in 5 ml dichloromethane, and 4.442 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 4 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 322 mg (88% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:13]([O:15]C)=[O:14])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:2]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCC2(CC1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CC1)CC2)C(=O)O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
365.0 mg of methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoate (1.2 mmol) were dissolved in a mixture of 10.8 ml of THF and 3.6 ml of methanol. 3.6 ml of an aqueous 1 M LiOH solution (3 eq.) were added to this solution. The mixture was stirred at 45° C. (bath temperature) for one hour and then 3.6 ml of 1 M HCl solution were added. The mixture was concentrated under reduced pressure and codistilled with DMF twice more. The (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoic acid thus obtained was clean enough for the next reaction. Yield: 400 mg (quant.)
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Cl[C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:15](=[O:16])[CH:14]=[CH:13][S:12]1>ClCCl>[OH:16][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[S:12][C:11]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: c1cc2[nH]cnc2cn1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 6 g of 1H-imidazo[4,5-c]pyridine in 300 ml of anhydrous dichloromethane is slowly added a solution of 4.8 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate. The reaction mixture is stirred for 14 h at room temperature. The solvent is removed under reduced pressure and the residue is purified by flash chromatography [silica gel, elution gradient of toluene/ethyl acetate/acetic acid, 80/20/1 (v/v/v)] to 30/70/1 (v/v/v) to give the separated title compounds along with a small fraction of the isomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.ClCCl.[CH:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Reactant: OC1CCCC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
In a dry flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (350 mg 1.4 mmol) to which was added dichloromethane (10 mL) and cyclopentanol (0.25 mL, 2.8 mmol). The solution was stirred at 25° C. and as rhodium (II) acetate dimer (13 mg, 0.028 mmol) was added, the immediate evolution of gas was noted and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for 1 h, it was then poured into water and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL) and the organic layers were then combined, dried over sodium sulfate and concentrated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) to give rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (273 mg, 64% yield) as a clear colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0484.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[O:13])[C:7](=[O:11])[NH:8]2)=[N:4][CH:3]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[O:13])[C:7](=[O:11])[N:8]2[C:19]([NH2:20])=[O:25])=[N:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2cc(Cl)cnc2C1C(=O)c1ccco1
Agent: O=CNS(=O)(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ncc(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-3-(2-furoyl)-4-azaoxindole (Example 12) according to the procedure of Example 2C, using 400 mg (1.5 mmol) 6-chloro-3-(2-furoyl)-4-azaoxindole, 0.19 ml (2.25 mmol) N-chlorosulfonyl isocyanate and 15 ml acetonitrile. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO (5 ml), for 2 hours in a flask open to the air. The product was isolated by dilution with water filtration, and recrystallization from acetic acid. Yield: 160 mg (35%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[C:27]4[C:31](=[CH:32][C:23]=3[N:22]=2)[CH2:30][CH2:29][CH2:28]4)=[N:17][CH:18]=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][S:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]4[C:31](=[CH:32][C:23]=3[N:22]=2)[CH2:30][CH2:29][CH2:28]4)=[O:9])=[N:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)CCC4)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(CS(=O)c2nc3cc4c(cc3[nH]2)CCC4)nc1
Reaction time: 3 h
Yield: 65.1 %

Procedure:
50 ml of a 10% solution of m-chloroperbenzoic acid in ethyl acetate were added dropwise with intensive stirring and at 0°-5° C. to 6.7 g of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)-methyl]thio]indeno(5,6-d)imidazole, dissolved in 200 ml of methylene chloride. After stirring at 0°-5° C. for 3 hours, the mixture was poured into 1 l of methylene chloride, it was washed twice with 250 g of 2N soda, then neutral with water, dried over sodium sulfate and evaporated in vacuo. 6.5 g of crude product were recrystallized from acetonitrile. There were obtained 4.6 g (65.1% of theory) of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)methyl]sulfinyl]indeno(5,6-d)imidazole of melting point 190°-201° C.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]3[O:25]C(C)(C)C(C)(C)[O:18]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.O>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]([OH:18])[OH:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Temperature: 23 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To N-Boc-indole-5-boronic acid pinacol ester (172 mg, 0.500 mmol, 1.00 equiv) in acetone/H2O (5.0 mL/5.0 mL) at 23° C. was added NH4OAc (193 mg, 2.50 mmol, 5.00 equiv) and NaIO4 (535 mg, 2.00 mmol, 4.00 equiv). After stirring for 24 hr at 23° C., the reaction mixture was concentrated in vacuo to remove acetone. To the residual solution was added EtOAc (5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×5 mL). The combined organic phases are washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 70.0 mg of the title compound as a colorless solid (54% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].CO>O>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([NH2:30])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: O
Solvent: CO
Product: NC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl (2,4-dibenzyloxyphenoxy)acetate (2 g), concentrated ammonia (25 mL) and methanol (50 mL) is stirred at room temperature for 18 hours. The reaction mixture is diluted with water (50 mL) then evaporated to low bulk and filtered. The solid is washed with water and dried to give 2-(2,4-dibenzyloxyphenoxy)acetamide (1.1 g) as a white powder, m.p. 120° C. [Elemental analysis:- C,73.1; H,5.78; N,3.79%. Calculated:- C,72.7; H,5.83; N,3.85%].
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([OH:22])=O)=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:20]([C:16]2[S:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=4)=[CH:9][C:10]3=[O:23])=[N:18][C:17]=2[CH3:19])=[O:22])=[CH:29][CH:28]=1
Reactant: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (4-fluorophenyl)methanamine, the title compound was obtained as a colorless solid in 34% yield: mp 249-251° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.51-7.47 (m, 2H), 7.34-7.29 (m, 2H), 7.25-7.08 (m, 4H), 6.37 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=5.9 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 164.1, 163.2, 161.9, 160.9, 153.9, 150.4, 136.1, 132.1, 131.0, 130.9, 129.8, 123.6, 116.0, 115.7, 104.3, 97.5, 70.1, 42.4, 17.5; MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([OH:22])[CH2:18][CH2:19][CH:20]=[CH2:21].C(=O)(O)[O-].[Na+].CN1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[OH:22][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: C=CCCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1cnc(-c2ccc(C=CCCCO)cc2)nc1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of 14.7 g of 2-(4-bromophenyl)-5-(ethoxy)-pyrimidine, 5.7 g of 4-penten-1-ol, 10 g of sodium bicarbonate and 20 ml of N-methylpyrrolidone was treated with 0.3 g of triphenylphosphine and 0.12 g of palladium acetate. The reaction mixture was heated at 120° C. for 2 hours under a nitrogen atmosphere, then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 100 ml of concentrated sodium chloride solution each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol gave 12 g of 2-[4-(5-hydroxy-1-pentenyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6].ClCCl.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6]
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Using an ice-acetone bath, 48.6 ml of trifluoroacetic acid (TFA and 12.1 ml of 70% strength nitric acid are cooled to −10° C., 3.0 g (8.86 mmol) of the compound from example 25A, dissolved in 7 ml of TFA are added dropwise, and the mixture is stirred at 0° C. for 20 hours. The reaction solution is stirred into 400 ml of ice-water and 200 ml of dichloromethane and neutralized using about 200 ml of saturated sodium bicarbonate solution. The aqueous phase is separated off and extracted 3 times with dichloromethane, and the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel using toluene with added ethyl acetate in a gradient from 11 to 60%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:16])[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1)[CH3:2].[ClH:17]>>[ClH:17].[ClH:17].[CH2:1]([NH:3][CH2:4][C:5]1([OH:16])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH3:2]
Reactant: CCNCC1(O)CCN(C(=O)OCC)CC1
Agent: Cl
Product: CCNCC1(O)CCNCC1

Procedure:
4.6 g (20 mmol) of ethyl 4-ethylaminomethyl-4-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 35 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4O10.