Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH2:17][CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)[CH2:55][CH2:54]1>CN(C)C=O>[C:63]([C:62]1[CH:61]=[CH:60][C:59]([CH:56]2[CH2:57][CH2:58][N:53]([C:8]([C:7]3[C:6]([CH2:17][CH3:18])=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:12]([CH:11]=3)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH2:54][CH2:55]2)=[CH:66][CH:65]=1)#[N:64]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6., 500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). HBTU (1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol, 3.00 equiv) were added to the reaction solution, and it was stirred for 5 min at 25° C. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10 equiv) was added to the above mixture. After stirring for 15 h at 25° C., the reaction was quenched by the addition of water. The mixture was extracted with 100 mL of ethyl acetate and the combined organic layers were washed with 4×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (4:1) as eluent to furnish 0.830 g (99%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([I:8])=[C:5](I)[N:6]=1.S(=O)(=O)(O)O.O.N.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([N+:16]([O-:18])=[O:17])[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nc(I)c(I)[nH]1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1nc(Cl)[nH]c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
2-Chloro-4,5-diiodoimidazole (354 mg) was suspended in concentrated nitric acid (d. 1.42)(5 ml), under ice-cooling, concentrated sulfuric acid (1 ml) was added, and was stirred at a room temperature for 15 hours. Reaction mixture was poured in ice-water, and ammonia water was added to adjust pH 3, the deposited matters were collected by filtration and dried, there was obtained 2-chloro-5-iodo-4-nitroimidazole (222 mg, yield: 81.2%) as yellow solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[O:20][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(O)c3cccc(Cl)c3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(OS(C)(=O)=O)c3cccc(Cl)c3)ccc21
Yield: 99.9 %

Procedure:
5-Amino-indazole-1-carboxylic acid tert-butyl ester was prepared following the procedure outlined by S. J. Brickner, WO9002744. 5-Amino-indazole-1-carboxylic acid tert-butyl ester was then coupled with 2-(3-chlorophenyl)-2-hydroxyacetic acid following the procedure as described in Example 1 to afford 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester. To a solution of 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (7.47 mmol) in dry THF (20 mL) at 0° C. was added pyridine (37.33 mmol, 5 equivalents) followed by methanesulfonyl chloride (22.40 mmol, 3 equivalents) added in a dropwise fashion. The resultant solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (3.58 g, qunatitative yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][O:12][CH2:13]/[CH:14]=[CH:15]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](/[CH:15]=[CH:14]/[CH2:13][O:12][CH3:11])[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC/C=C/c1cnc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=C)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2.C[OH:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH:13]=[O:18])=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: CO
Reactant: C=Cc1cc2c(nc1OC)CCC(=O)N2C
Solvent: ClCCl
Product: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A 1.1 g (5.0 mmol) solution of 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 50 ml of methylene chloride and 10 ml of methanol was cooled to −70° C. Ozone (via an ozone generator) was bubbled into the solution until a blue color was achieved. The reaction mixture was stirred at −70° C. for 30 minutes and quenched with 4.0 ml of dimethyl sulfide. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into 50 ml of water. The organic layer was dried (Na2SO4) and evaporated. This residue was chromatographed on silica using 10:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined to yield 0.52 g of 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde. TLC Rf=0.4 (1:1 ethyl acetate:hexane). 1H NMR (CDCl3) δ 10.18 (s, 1H), 7.7 (s, 1H), 4.05 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass spectrum: m/e=221.1, (p+1).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:28][O:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:8][C:7]=2[N:6]=1>C(O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:28][O:29][NH2:30])[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(CON)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Hydrazine hydrate (0.753 mL, 15.5 mmol) was added to a stirred suspension of tert-butyl 2-(4-amino-7-(benzyloxy)-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (3.15 g, 5.18 mmol) in ethanol (50 mL). The suspension was stirred at room temperature for 3 hours, then was filtered. The filtrate was concentrated under reduced pressure to yield 2.43 g of crude tert-butyl 2-[4-amino-2-[(aminooxy)methyl]-7-(benzyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate that was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:5][C:4]=2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOCc1nc2c(N)nc3cc(CCCO)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with ethyl 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate (1.0 g, 2.4 mmol) and anhydrous tetrahydrofuran (20 mL). The reaction mixture was cooled in an ice bath. Lithium aluminum hydride (92 mg, 2.4 mmol) was added in one portion. After 2 hours additional lithium aluminum hydride (92 mg, 2.4 mmol) was added in one portion. The ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched by successive dropwise addition of water (1 mL), 10% sodium hydroxide solution (1 mL) and water (3 mL). The reaction mixture was maintained at ambient temperature for 18 hours and then diluted with diethyl ether and water. The fractions were separated and the aqueous fraction was extracted with diethyl ether (3×25 mL). All of the organic fractions were combined and then concentrated to dryness under reduced pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, 0-20% CMA/chloroform) provided 0.8 g of 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propan-1-ol as a white crystalline solid, mp 177-178° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:18]=3)[S:14][C:13]=2[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[N:18]=3)[S:14][C:13]=2[CH:34]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(CNC(=O)OC(C)(C)C)cc4s3)n2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCCNc2nccc(-c3cc4ccc(CN)cc4s3)n2)CC1
Reaction time: 20 h

Procedure:
(2-{2-[3-(4-Methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophen-6-ylmethyl)-carbamic acid tert-butyl ester (1.36 g, 2.74 mmol) is dissolved in dichloromethane (20 mL) and TFA (3.2 mL) is added. After stirring for 20 hours, methanol is added and the mixture is passed through an SCX column. After eluting with methanol to remove the salts, 20% 2.0 M NH3/MeOH)/EtOAC is used to elute the product which is then passed through a 15 g silica gel column using the same solvent system. The title compound is obtained as a yellow solid (0.73 g, 68% yield). ES+(m/z) 397 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([C@@H:21]2[CH2:25][C@H:24]([F:26])[CH2:23][N:22]2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:6]=1)=[O:4].[H-].[Li+].S(OC)(O[CH3:43])(=O)=O.C(O)(=O)C>O1CCOCC1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:21]2[CH2:25][C@H:24]([F:26])[CH2:23][N:22]2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:8]([CH3:43])[C:9](=[O:20])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.75 h

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate, dissolved in dry dioxane, was added to a suspension of lithium hydride (1.2 eq.) in dry dioxane. The reaction mixture was stirred at 38° C. for 45 minutes and then cooled down to room temperature. Dimethyl sulfate (1.3 eq.) was added and the mixture was heated to 58° C. and stirred at this temperature for 3 hours. The reaction mixture was then cooled down and glacial acetic acid (0.2 eq.) was added, followed by water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate; the organic phase was dried over Na2SO4 and filtered to give, after concentration, a crude that was purified by flash chromatography (eluent petroleum ether:ethyl acetate from 4:6 to 2:8) to give the title compound as a 4.6:5.4 mixture of rotamers by NMR.
Reaction SMILES: [CH2:1]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:10]=2[O:9][C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:25].[K+].CO>>[OH:9][C:10]1[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([OH:24])=[O:25]
Reactant: CCCCCCC1C(=O)Oc2c(Sc3ccccc3C)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCCCCCC(C(=O)O)c1cccc(Sc2ccccc2C)c1O

Procedure:
3-n-Hexyl-7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(o-tolylthio)phenyl]octanoic acid, mp. 90°-91° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:24])[CH2:21][C:22]#[CH:23])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([Cl:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:24])[CH2:21][C:22]#[CH:23])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([Cl:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[Cl:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: C#CCN(C)c1cc(NC)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: C#CCN(C)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-propargylamino]-4-methylamino-5-amino-benzoic acid amide (50 mg, 0.13 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (41 mg, 0.13 mmol), DIC (20 μL) and DMF (2.0 mL).
Reaction SMILES: CC1(C)COB([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=2)[N:13]=4)OC1.Cl.N[OH:33].[OH-].[Na+]>[Cl-].[NH4+]>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[CH:29][C:8]([OH:33])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OCC(C)(C)CO3)cc1OCC2
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 127.7 %

Procedure:
To a solution of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (473 mg, 1.16 mmol) in IMS (10 mL) was added hydroxylamine hydrochloride (242 mg, 0.39 mmol) and sodium hydroxide (186 mg, 4.65 mmol) and the reaction mixture stirred at RT for 18 h. Further quantities of hydroxylamine hydrochloride (242 mg, 0.39 mmol) and sodium hydroxide (186 mg, 4.65 mmol) were added and stirring continued for 3 h. The reaction mixture was diluted with ammonium chloride solution (20 mL, saturated) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to yield 490 as a white solid (155 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.29 (1H, d, J=8.4 Hz), 7.88 (1H, s), 7.59 (1H, s), 6.64 (1H, dd, J=8.4, 2.6 Hz), 6.48 (1H, d, J=2.6 Hz), 5.99 (1H, sept, J=6.7 Hz), 4.44-4.32 (4H, m), 1.58 (6H, d, J=6.7 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.[OH-:41].[Na+]>CS(C)=O>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25]([OH:41])=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(c1c(-c2cnc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 22 %

Procedure:
A solution of 0.06 g (0.1 mmol) of [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 88) and 0.1 ml of 6M sodium hydroxide solution in 0.5 ml of DMSO was heated to 100° C. for 3 h. The DMSO was removed using an Isolute SPE 103 cartridge, and the crude product purified by preparative HPLC affording 0.01 g (22%) of the title compound as a colorless amorphous solid. MS: 543.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C)ccc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of 2-chloro-5-methyl-benzoic acid (3.0 g, 17.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 10 ml, 20 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 1 hour, methanol (20 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-chloro-5-methyl-benzoate (3.2 g, 100% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH:36](OC)[O:37]C)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:42])[C@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][CH:33]([CH:36]=[O:37])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C1CCN(c2ccc(C(=O)N[C@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CC1CCN(c2ccc(C(=O)N[C@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2R)-2-{[4-(4-(dimethoxymethyl)piperidin-1-yl)benzoyl]-amino}-butanedioic acid dibenzyl ester (0.215 g, 0.4 mol) in methylene chloride (10 mL) containing trifluoroacetic acid (0.165 mL, 2.0 mmol) was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo to give the product which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A solution of 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 4.5 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (130 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. The reaction mixture was filtered through a pad of celite and washed with methanol (2×30 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (20 g, petroleum ether/ethyl acetate 15:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 68%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 10.54 (br. s., 1H), 8.16 (t, 1H, J=3.6 Hz), 7.83 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=8.1 Hz), 7.02 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.91-6.74 (m, 3H), 6.32 (s, 1H), 4.20 (t, 1H, J=7.5 Hz), 3.73 (s, 3H), 2.10-1.95 (m, 2H), 1.60-1.51 (m, 1H), 0.96 (d, 3H, J=4.2 Hz), 0.89 (s, 3H, J=4.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)C.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: NCCCCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCCCCO)c(OC)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 5-aminopentan-1-ol (194 mmol), 2,4-dimethoxybenzaldehyde (213 mmol) and acetic acid (213 mmol) in methanol (500 ml) was stirred at 10° C. for 0.5 h. NaBH4 (22 g) was added portionwise at −10° C. and the mixture was stirred for 10 minutes. Then the reaction mixture was allowed to warm to 10° C. and stirred for 1.5 h. Saturated NaHCO3 was added and the mixture was stirred for 0.5 h. The mixture was extracted by CH2Cl2 (3×100 ml). The combined organic phase was washed by saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. Yield: 46 g (69% purity, 65% yield).