Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=[C:22](N)[C:17]=2[N:16]=[C:15]1[CH3:30].[Na+].[Br-:32].C([O-])([O-])=O.[Na+].[Na+]>O.Br>[Br:32][C:22]1[C:17]2[N:16]=[C:15]([CH3:30])[N:14]([CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=3[Cl:5])[C:18]=2[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=1
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: [Br-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of NaNO2 (0.37 g, 5.4 mmol) in water (0.5 ml) was added to a solution of 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazol-4-amine (prepared following the same procedure as for Example 7, 2.0 g, 5 mmol) in HBr (60 mL) at 0-5° C. and stirred for 15 min. The mixture was added dropwise to a solution of NaBr (1.5 g, 15 mmol) in HBr (60 ml) at 60° C., and then heated to 80° C. for 30 min. The mixture was cooled to rt and poured into a Na2CO3 solution (200 ml). The mixture was extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel chromatography eluted with EtOAc to give the product (1 g, 44%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 3.06 (t, 4H, J=4.8 Hz), 3.70 (t, 4H, J=4.8 Hz), 5.53 (s, 2H), 6.31 (dd, 1H, J=1.2, 7.8 Hz), 7.02 (d, 1H, J=2.1 Hz), 7.09 (d, 1H, J=2.1 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.60 (dd, 1H, J=1.2 Hz, 7.8 Hz); LC-MS: m/e=455 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[CH3:8][C:2]1[C:1]([N+:14]([O-:16])=[O:15])=[C:6]([OH:7])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cccc(O)c1[N+](=O)[O-]

Procedure:
Furthermore, there is disclosed in Journal of Chemical Society, 1277 (1923) that m-cresol is sulfonated with a fuming sulfuric acid and then the resulting sulfonated m-cresol is nitrated with a mixed acid (nitric acid plus sulfuric acid), but by this method 3-methyl-2-nitrophenol is obtained as a main product and only a small amount of 5-methyl-2-nitrophenol is obtained as a by-product, the total yield being very poor for the reason as mentioned above.
Reaction SMILES: [CH2:1]([N:8]([CH2:42][CH:43]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:47]([CH2:59][NH2:60])[CH:46]=1)[OH:44])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:16][CH:17]([OH:34])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([CH2:32][NH2:33])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:61][S:62](Cl)(=[O:64])=[O:63].Cl>N1C=CC=CC=1>[CH2:35]([N:15]([CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([CH2:32][NH:33][S:62]([CH3:61])(=[O:64])=[O:63])[CH:19]=1)[OH:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:42][CH:43]([OH:44])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[C:47]([CH2:59][NH:60][S:62]([CH3:61])(=[O:64])=[O:63])[CH:46]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NCc1cc(C(O)CN(CCCCCCN(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(CN)c2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cc(C(O)CN(CCCCCCN(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(CNS(C)(=O)=O)c2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
To a solution of 9.35 g. of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4-benzyloxyphenyl)-2-hydroxyethyl]-hexamethylenediamine in 50 ml. of pyridine is added 2.5 ml. of methanesulfonyl chloride at room temperature. After 18 hours the reaction mixture is added to an excess of 2N hydrochloric acid and extracted with chloroform. The extract is neutralized with sodium bicarbonate, washed, dried and evaporated to give N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamidomethylphenyl)-2-hydroxyethyl]-hexamethylenediamine. The latter, as the dihydrochloride, is hydrogenated with palladium-on-carbon to yield N,N'-bis[2-(4-hydroxy-3-methanesulfonamidomethylphenyl)-2-hydroxyethyl]-hexamethylenediamine dihydrochloride.
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].Cl>ClCCl>[OH:2][C:3]1[C:10]([OH:11])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(C=O)c(O)c1O
Reaction time: 2 h
Yield: 65.4 %

Procedure:
An anhydrous dichloromethane (50 ml) solution of 2,3,4-trimethoxybenzaldehyde (1.96 g, 10 mmol) under argon at room temperature was stirred for 10 min and boron trichloride (10 ml, 10 mmol, 1 eq; 1.0 M solution in dichloromethane) was added. After 2 h, the second equivalent of boron trichloride (10 ml, 10 mmol, 1 eq; 1.0 M solution of dichloromethane) was added. The dark reaction mixture was stirred overnight and then slowly poured into 10% sodium bicarbonate (aq) (4 g/36 ml). The resulting solution was acidified with concentrated hydrochloride acid to pH 1. The dichloromethane layer was separated, and the aqueous layer extracted with ethyl acetate (4×20 ml) and dried. Evaporation of solvent in vacuum gave brown oil, which was further separated by column chromatography (1:1 hexane-ethyl acetate) to afford a yellow solid. Recrystallization from ethyl acetate-hexane gave a pale yellow needle of 48 (1.1 g, 65.5%); Rf0.40 (hexane:ethyl acetate: 1:1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.[H-].[Na+].[CH3:18]I>C1COCC1>[Cl:1][C:2]1[N:3]([CH3:18])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
To 5 g of (65) in 100 ml THF was added 550 mg NaH and 2.5 ml methyliodide. The reaction was left with stirring overnight. Most of the THF was evaporated off, water was added, and the water phase extracted with EtOAc. The water phase was then acidified with acetic acid, which precipitated the pure product. Filtration and drying gave 770 mg of (66).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1cccc(Nc2cc(F)c(F)cc2C(=O)O)c1
Yield: 94.4 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-methoxy-aniline (1.91 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.48 g of the crude title compound.
Reaction SMILES: Br[C:2]1([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1.[N:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1[O:42][CH3:43])=[C:30]=[O:31].CN(C=O)C>ClCCl>[CH3:43][O:42][C:33]1[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:32]=1[NH:29][C:30]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:2]2[N:3]=[C:4]([N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=1)=[O:31]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1cccc(C2(Br)Cn3ccnc3C(n3ccnc3-c3ccncc3)=N2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccncc3)n2)c1
Yield: 89.1 %

Procedure:
A solution of 3-[6-Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (400 mg), 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (246 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-{3-[8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (468 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C@H:28]([CH3:32])[C:29](O)=[O:30].CN(C)C=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][O:27][C@H:28]([CH3:32])[C:29]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:20]=1)=[O:30]
Reactant: COc1ccc(-c2ccc3cnc(Nc4cccc(N)c4)nn23)cn1
Reactant: CO[C@H](C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(NC(=O)[C@@H](C)OC)c4)nn23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
N-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-benzene-1,3-diamine (50.0 mg, 0.150 mmol), (R)-(+)-2-Methoxypropionic acid (18.8 mg, 0.180 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.6 mg, 0.180 mmol) and N,N-Dimethylformamide (0.999 mL, 12.9 mmol) were combined in a vial and stirred at rt for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with sat'd NaHCO3 and filtered off resulting ppt. Took ppt up in CH2Cl2 and purified by ISCO silica gel chromatography (0-100%) EtOAc in hexanes to afford title compound (12 mg, 15%) LCMS=419.0 (M+H), HPLC rt=2.935 min, purity=99%. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.74 (d, J=2.1 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J=2.6 Hz, 8.9H, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.38-7.36 (m, 1H), 7.32-7.29 (m, 2H), 6.95-6.92 (m, 2H), 6.89 (d, J=8.6 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 1H), 3.45 (s, 3H), 1.48 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][NH:6]1)=[O:4].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=1.C(Cl)Cl.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:25][CH:24]=2)=[O:27])[CH2:7]\1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1CN[C@H](C(=O)OC)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CO/N=C1\C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Method A (e.g. methyl (2S,4EZ)-4-4-(methoxyimino-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate): A solution of methyl-(2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (0.564 g, 3.28 mmol), 2′-methyl[1,1′-biphenyl]-4-carboxylic acid (0.765 g, 3.60 mmol) and 4-dimethylaminopyridine (0.880 g, 7.21 mmol) in a 7:3 mixture of DCM and DMF (30 ml) was made. EDC (0.691 mg, 3.60 mmol) was added slowly at 0° C. The reaction mixture was stirred overnight at r.t. It was washed with water (twice 20 ml), dried over MgSO4, filtrated and evaporated in vacuo. The resulting crude product mixture, methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate, was purified by flash chromatography, unsing cyclohexane/EtOAc 8:2 as eluent. After several further chromatographies, (E)- and (Z)-isomers could be separated: methyl (2S,4E)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (261 mg, 22%) was isolated as a colorless powder in 98.3% purity by HPLC, and methyl (2S,4Z)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (237 mg, 20%) was isolated as a colorless powder in 98.3% purity by HPLC.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]3[C:22]([N:23]=2)=[CH:21][N:20]=[CH:19][N:18]=3)[CH2:10][CH2:9]1>O1CCCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:16]2[C:15]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][NH:5][C:2]([NH:1][CH3:4])=[S:3])[CH2:13][CH2:12]3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:30][CH:29]=1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A mixture of 0.7 parts of isothiocyanatomethane, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine and 90 parts of tetrahydrofuran was stirred for 4 hours at room temperature. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.3 parts (29%) of N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-N'-methylthiourea; mp. 205.5° C. (compound 179).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:30]([O:37][C:38](=[O:49])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:30]([O:37][C:38](=[O:49])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:48])[C@H:45]([CH3:47])[NH:46][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.035 mole of t-butyloxycarbonylalanine in 80 ml of dry tetrahydrofuran which has been cooled to -20° to - 30° is added 4 ml of N-methylmorpholine and then 4.6 ml of isobutylchloroformate. After stirring for 10 minutes there is added 0.035 mole of alanylproline benzylester hydrochloride and 4 ml of N-methylmorpholine in 60 ml of chloroform. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo and the residue taken up between ethyl acetate and 0.25 N hydrochloric acid. The organic layer is separated, washed with saturated sodium bicarbonate, water, dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylalanylalanylproline benzyl ester.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:31])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 5 (0.5 g, 0.0015 mole), meta-chloroper-benzoic acid (0.32 g, 0.0015 mole) and methylene chloride (25 ml) were stirred under argon for 12 hours. The excess peroxide was destroyed with a saturated potassium carbonate solution, the phases separated, washed with hexane and water, and dried over magnesium sulfate The solid was filtered, recrystallized from ethyl ether and methylene chloride and dried in vacuo, m.p. ca. 106°-108° C. Analysis calc. for C18H28O4S(340.48):
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C(O)(=O)[C:11](O)=[O:12].[C:16]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17]>>[C:16]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:17])[CH3:18].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12]
Reactant: O=C(O)C(=O)O
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: C=O
Temperature: 160 °C

Procedure:
Phenol (141 g; 1.5 moles) and 2.5 g of oxalic acid dihydrate were added to the resol layer, and the mixture was heated to perform co-condensation reaction of the p-tert-octylphenol resol with phenol. While distilling off the resulting water and volatile matter under atmospheric pressure and then under reduced pressure, the reaction mixture was heated to 160° C. to give 358 g of a pale yellow p-tert-octylphenol/phenol/formaldehyde co-condensate having a softening point of 85° C.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH3:5])#[C-:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[O:24][CH:2]=[N:1][C:3]=2[CH2:4][CH3:5])=[N:21][CH:22]=1
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A mixture of 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (1.98 g, 8.87 mmol), 5-bromopicolinaldehyde (1.65 g, 8.87 mmol), and K2CO3 (1.47 g, 10.6 mmol) in MeOH (45 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and concentrated in vacuo. Water was added to the residue and the product was extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® 25×60 column, 10%-50% EtOAc/hexanes) to yield 1.97 g (88%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 8.68 (dd, J=2.4, 0.5, 1H), 7.89-7.82 (m, 2H), 7.55-7.49 (m, 1H), 3.06 (q, J=7.5, 2H), 1.29 (t, J=7.5, 3H). MS (DCI+) m/z 253/255 (M+H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].CO.[CH3:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]3[S:32][C:30](=[O:31])[NH:29][C:27]3=[O:28])=[CH:23][CH:24]=2)=[N:14][CH:15]=1.CCOCC>CCCCCCC>[CH3:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]3[S:32][C:30](=[O:31])[NH:29][C:27]3=[O:28])=[CH:23][CH:24]=2)=[N:14][CH:15]=1.[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)([O-])[O-]

Procedure:
24 g of sulfuric acid was added slowly, at room temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone base with stirring. The mixture turned into a clear solution. 250 ml of ether was slowly added followed by 500 ml of heptane. A solid precipitated, and the suspension was stirred for 3 hours. The solid (98.4 g, yield was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 1113.5˜116.5° C. (recrystallized from methanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N>CO>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: CCOc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 10 °C

Procedure:
A mixture of 5.8 g (19.44 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-ethoxy-phenylamino)-pyrazole, 3.51 g (21.4 mmol) of 3-chloro-aniline hydrochloride and 40 ml of methanol is heated under reflux for 15 hours. Cooling to 10° C., filtering and washing the filter residue with methanol and diethyl ether yield the title compound; m.p. 232-233° C.; EI-MS: (M)+ =380.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20](B(O)O)=[C:19]([CH3:30])[CH:18]=1.O1CCOCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:30])[C:20]([C:3]2[CH:8]=[CH:7][N:6]=[N:5][CH:4]=2)=[CH:21][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: Brc1ccnnc1
Reactant: COC(=O)c1cc(B(O)O)c(C)cc1OC
Agent: [Pd]
Agent: Br
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)c(C)cc1OC
Temperature: 80 °C

Procedure:
A mixture containing 4-bromopyridazine hydrobromide (0.20 g, 0.83 mmol), cesium carbonate (1.1 g, 3.3 mmol) and 4-methoxy-5-(methoxycarbonyl)-2-methylphenylboronic acid (0.22 g, 1.0 mmol) was charged with dioxane (8.3 mL). Nitrogen gas was purged through the mixture for 15 min with stirring. Stirring was halted and tris(dibenzylideneacetone) dipalladium(0) (0.38 g, 0.04 mmol) was added, followed by ticyclohexylphosphine (0.04 g, 0.13 mmol) in toluene (0.15 mL). Stirring was resumed and the mixture was heated at 80° C. for 105 minutes under nitrogen gas. The reaction was cooled to RT, filtered and concentrated to a residue. The residue was purified on silica gel (5-100% ethyl acetate/hexanes) to afford methyl 2-methoxy-4-methyl-5-(pyridazin-4-yl)benzoate as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d) 9.32-9.14 (m, 2H), 7.75 (s, 1H), 7.46 (dd, J=5.0, 2.3 Hz, 1H), 6.95 (s, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 2.39 (s, 3H). LCMS retention time: 2.805 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 3 micron, C18, 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 259 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([C:14]#[C:15][Si](C)(C)C)=[CH:7][CH:8]=2)[O:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:20])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][C:6]([C:14]#[CH:15])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.16 g (4.1 mmol) of 2,2,4,4-tetramethyl-7-trimethylsilylethynyl-chroman (Compound 43) in 3 ml of isopropanol was added 5 ml of ethanolic KOH solution. The reaction mixture was stirred at room temperature for 24 hours and the alcohol was then removed under vacuum. The residue was extracted with 2×10 ml of ether and the combined ether extracts were washed with 15 ml of water and 20 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by Kugelrohr distillation to give the title compound as a white crystalline solid.