Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC1N(CC2C=CC(C3C(C4N([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)N=NN=4)=CC=CC=3)=CC=2)C(C(OCC2OC(=O)OC=2C)=O)=C(C(O)(C)C)N=1.[OH2:61]>>[C:28]1([C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[OH:61])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Reaction temperature at which deprotection of trityl Olmesartan medoxomil takes place is preferable at about 0° C. to 60° C. more preferably at 10° C. to 30° C. In another preferred embodiment the combination of trityl Olmesartan medoxomil, water-immiscible organic solvent and acid is maintained for about 1 to 6 hours and more preferably 2 to 4 hours. Triphenyl carbinol formed dissolves in solvent toluene and the deprotected Olmesartan medoxomil is in aqueous solution. Both the layers are separated. Aqueous layer is washed with toluene and the pH of the aqueous layer is adjusted to about 5 to 6 using a base. Suitable bases include but are not limited to, alkali and alkaline earth metal hydroxides, carbonates, and hydrogen carbonate salts. Specific exemplary bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate. Potassium carbonate and sodium bicarbonate are preferred. After contacting the solution with the base, the solution is extracted with ethyl acetate twice. Combined ethyl acetate layers are washed with 5% sodium chloride solution. Olmesartan medoxomil is obtained by distillation of the solvent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12](I)=[N:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:32][CH:33]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:28]2[CH:33]=[N:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][CH:29]=2)=[N:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CCOC(=O)c1nc(I)sc1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1NC(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Ethyl 5-[(tert-butoxycarbonyl)amino]-2-iodo-1,3-thiazole-4-carboxylate (1 g, 2.5 mmol), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (1.1 g, 3.7 mmol), Pd2(dba)3 (0.23 g, 0.25 mmol), and tricyclohexylphosphine (0.18 g, 0.63 mmol) were combined in a flask. The flask was evacuated and backfilled with argon three times. Fully degassed dioxane (17 mL) and 1.27 M aqueous potassium phosphate (6.5 ml, 8.3 mmol) were added sequentially. The reaction was heated to 100° C. for 6 h. The mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography (silica, 0-75% ethyl acetate/hexanes) to afford the title compound as a yellow solid. LRMS (APCI) calc'd for (C20H27N4O5S) [M+H]+, 435.2; found 435.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:27]([C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])[C:5]=1[F:11]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1cccc(N)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To 3-amino-2-fluoro-benzoic acid methyl ester (72, 1.08 g, 6.4 mmol) in 40.64 mL of dichloromethane, pyridine (1.29 mL, 16 mmol) is added, followed by 2,5-difluorobenzenesulfonyl chloride (73, 3.391 g, 16 mmol). The reaction is stirred at room temperature overnight, then quenched with 1M aqueous hydrochloric acid. The organic layer is removed and the aqueous layer is extracted with dichloromethane. The organic layers are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (74, 0.956 g). MS (ESI) [M−H+]−=344.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][C:15](=O)[CH2:16][CH2:17][C@H:18]2[CH2:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:13])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH2:15][CH2:16][CH2:17][C@@H:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:26]([OH:28])[CH2:27]2)[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)CC[C@H]1CC(=O)c2ccccc2C1)c1ccc(F)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C[C@@H](NCCC[C@@H]1Cc2ccccc2C(O)C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N—((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)-3-((R)-4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanamide (830 mg, 2.131 mmol) was added to a suspension of LAH (162 mg, 4.26 mmol) in dioxane (15 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 25° C. and heated at 100° C. and further maintained for 12 h. The mixture was allowed to RT, cooled to 0° C. and slowly quenched with ethyl acetate (5 mL) followed by water (5 mL). Reaction mixture was extracted with ethyl acetate (30 mL), washed with brine solution (20 mL) and dried over Na2SO4 and concentrated to get crude compound which was used as it is in next reaction; m/z 378.6.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.CN(C)C=O>C(O)C.CS(C)=O>[CH2:2]([C:3]1[CH:4]=[CH:5][C:6]2=[N:10][C:9](=[O:11])[N:8]=[C:7]2[CH:12]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.05 g, 2.17 mg atom) was dissolved in ethanol (5 ml) and to this was added 6-methyl-1,3-dihydro-benzoimidazol-2-one (0.20 g, 1.35 mmol) and the solution was stirred at room temperature for 1 h. The solvent was removed in vacuo and the white solid was taken up in tetrahydrofuran (5 ml) and dimethyl sulfoxide (5 ml), and to this was added 1-bromododecane (0.34 g, 1.36 mmol) and the whole was stirred at room temperature for 2 h. N,N-Dimethylformamide (5 ml) was added to the mixture and the whole was stirred for a further 2 h. The mixture was filtered and the filtrate was evaporated in vacuo to give a yellow residue. The residue was placed on a silica column and chromatographed with 12.5% hexane-ethyl acetate to give (19) as a yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:9][S:8][CH2:7][C@H:3]1[C:4]([OH:6])=[O:5].[CH3:10]O>>[CH3:10][O:5][C:4]([CH:3]1[CH2:7][S:8][CH2:9][NH:2]1)=[O:6]
Reactant: CO
Reactant: O=C(O)[C@@H]1CSCN1
Agent: Cl
Product: COC(=O)C1CSCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was bubbled through a suspension of L-thioproline (990 mg, 7.55 mmol) in MeOH (30 mL) cooled at 0° C. for 5 min. The resulting clear solution was stirred at RT for 2 h, then concentrated carefully under reduced pressure. The obtained residue was dried in vacuo overnight to give a white solid, which was dissolved in MeOH (30 mL) and treated with Diaion® WA21J resin (6 g). The resulting suspension was stirred at RT for 30 min, then filtered. The filtrate was concentrated carefully under reduced pressure and the oily residue stripped with toluene (2×) to give a colorless oil.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=3)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: FC(F)(F)c1cc(I)ccc1OCCN1CCCC1
Product: FC(F)(F)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (180 mg, 0.47 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39 mmol).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11](O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:29][CH2:30][CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1.CO>O1CCCC1>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11]([NH:29][CH2:30][CH2:31][C:32]2[N:36]=[CH:35][NH:34][CH:33]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]cn1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To stirred solution of the product of step 1 (1.50 g, 4.34 mmol) in tetrahydrofuran (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.210 g, 5.25 mmol). After gas evolution ceased,p-toluenesulfonyl chloride (0.990 g, 5.20 mmol) was added and the mixture was stirred for 2 hours. At this time, histamine (1.93 g, 17.4 mmol) was added followed by methanol (10 mL). The reaction was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a pasty white solid. Flash chromatography over silica (methylene chloride/methanolic ammonia solution) provided 1.08 g (57%) of product as a colorless tacky foam: 1H NMR (CDCl3) δ 7.52-7.43 (m, 1H), 7.40-7.00 (m, 15H), 6.78-6.69 (m, 1H), 4.36-3.97 (m, 4H), 2.92-2.20 (m, 7H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1O.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2ccc(Br)c(S(=O)(=O)C(F)(F)F)c2s1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea (50 mg, 0.158 mmol) in pyridine (1 mL) were added 3 portions of (CF3SO2)2O (29 μL, 0.174 mmol) about 45 minutes apart. The reaction mixture was stirred for about 3 hours at about 35° C. The solvent was then evaporated. The crude material was purified by LC/MS to give 23 mg (32%) pure 14. 1H NMR (DMSO) δ 1.09 (t, 3H, J=8 Hz CH3), 3.19 (m, 2H, CH2), 6.79 (br s, 1H, NH), 7.67 (d, 1H, J=12 Hz, ArH), 7.80 (d, 1H, J=8 Hz, ArH), 11.20 (br s, 1H, NH). HPLC retention time 3.58 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C4COC4)CC3)cc2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 50.8 %

Procedure:
Following Example 148h, 300 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 287 mg of 327e were reacted to give 327f as a yellow solid (220 mg, 51%). LCMS: [M+H]+ 696
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>Cl>[OH:8][CH2:9][C:10]1[N:11]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1
Reactant: CC(C)c1cn(-c2ccncc2)c(COCc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cn(-c2ccncc2)c(CO)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
The compound (5) (20.0 g, 62.2 mmol) was suspended in 35% aqueous hydrochloric acid (100 ml). The solution was heated at 85° C. and stirred for 1 hour. The reaction mixture was cooled down to room temperature and water (100 ml) and toluene (44 ml) were added thereto with stirring. The aqueous layer was separated and neutralized with 30% aqueous sodium hydroxide, to which ethyl acetate (30 ml) was added with stirring. The obtained slurry was filtered, washed with cold water and dried to yield 2-hydroxymethyl-4-isopropyl-1-(pyridin-4-yl)-1H-imidazole (9) (11.7 g). Yield 81.4%.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:15])=[O:14])[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.Cl>CO>[CH3:16][C:6]1[CH:7]=[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:15])=[O:14])[CH:9]=[C:4]([CH3:3])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCS(C)=O)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCCS(C)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 M aqueous NaOH solution (480 μL) is added to a solution of methyl 2-((3S)-6-((1R)-4-(2,6-dimethyl-4-(2-(methylsulfinyl)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (180 mg) in methanol (5 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The mixture is neutralized with 1 M aqueous HCl solution and partitioned between diethylether and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40→10:90) to give the title compound. Yield: 80 mg; LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=539 [M+NH4]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=C(C)C=CC=2)=NOC=1C)=O)C>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(C)c2)noc1C
Product: Cc1ccc(-c2noc(C)c2CO)cc1
Yield: 37.8 %

Procedure:
As described for example 249d, 5-methyl-3-p-tolyl-isoxazole-4-carboxylic acid ethyl ester (12.6 g, 51.4 mmol) was converted, instead of 5-methyl-3-m-tolyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (3.95 g, 38%) which was obtained as a white solid. MS: m/e=204.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[C:10]([N+:25]([O-])=O)=[C:9](N)[CH:8]=2)[CH:4]=[N:3]1.C[OH:30]>[Pd]>[NH2:25][C:10]1[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[N:12][C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:8][C:9]=1[OH:30]
Reactant: CO
Reactant: Cn1cc(-c2cc(N)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Agent: [Pd]
Product: Cn1cc(-c2cc(O)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine (200 mg, 0.53 mmol) in methanol (10 mL) was added 10% Pd/C (20 mg, 0.1 eq). The reaction mixture was stirred at room temperature under 1 atm of H2 for 2 h, then filtered. The filtrate was concentrated to afford the title compound (170 mg), which was used for the next step without further purification. MS (m/z): 347 (M+1)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:19][CH2:20][C:21]1[N:26]=[C:25]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[CH:24]=[C:23]([CH3:34])[CH:22]=1)(=O)=O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:34][C:23]1[CH:24]=[C:25]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[N:26]=[C:21]([CH2:20][CH2:19][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=1
Reactant: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
Diethyl malonate (229 mg, 1.43 nimol) was added dropwise via syringe over 5 min to a suspension of sodium hydride (52 mg of 60% oil dispension, 1.30 mmol) in 2.0 mL of N,N-dimethylformamide, and the mixture was stirred at room temperature until it became clear. A solution of 200 mg (0.65 mmol) of 6-(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 59, Step A) in 1.0 mL of N,N-dimethylformamide was added to the reaction followed by 72 mg (0.19 mmol) of tetrabutylammonium iodide, and the reaction was stirred at room temperature for 3 h followed by 15 h at 65° C. The reaction was diluted with ethyl acetate (30 mL) and washed with 15 mL of saturated aqueous sodium bicarbonate and 15 mL of saturated aqueous sodium chloride. The combined aqueous layers were extracted with 30 ml of ethyl acetate and the combined organic layers were dried (sodium sulfate), decanted and concentrated. The residue was purified by flash column chromatography on 50 g of silica gel, eluting with 500 mL of 5% ethyl acetate/hexane and 700 mL of of 10% ethyl acetate/hexane to give 97 mg (40% yield) of diethyl (2-(4-methyl-6-(2,5-dimethylpyrrol-1-yl)-2-pyridinyl)ethyl)malonate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][C:6]2=[O:15].[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:8]1[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:23])([CH3:18])[CH3:17]
Reactant: COc1cc2c(cc1OC)C(=O)CNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(cc1OC)C(=O)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6,7-dimethoxy-2,3-dihydro-1H-isoquinolin-4-one (CA [206763-75-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 448.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=2)[C:6]#[N:7])[C@H:17]1[CH3:21])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc(F)cc1C#N
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(C#N)c1

Procedure:
Using 4-fluorophthalonitrile (500 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (870 mg) and lithium carbonate (341 mg), the title compound was obtained as a yellow solid (yield: 42 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH3:22])=[C:6]([CH:14]=[C:15]([CH3:21])[C:16]=1[C:17]([O:19]C)=[O:18])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[OH-].[Li+].[OH-].[Na+].Cl>O1CCOCC1.O.CO>[C:10]([O:9][C:7]([C:6]1[CH:14]=[C:15]([CH3:21])[C:16]([C:17]([OH:19])=[O:18])=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[CH3:22])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
1-tert-Butyl 4-methyl 3-(ethylamino)-2,5-dimethylterephthalate (142 mg, 0.463 mmol) was dissolved in dioxane (2 mL) and was cooled in an ice bath. 2N Lithium hydroxide (0.25 mL) was added and the mixture was stirred for 16 h and then methanol (0.5 mL) and 2N lithium hydroxide (0.25 mL) were added, and the mixture was stirred at ambient temperature for 1.5 h. The mixture was cooled in an ice bath and 1N sodium hydroxide (0.5 mL) was added and the mixture was stirred for 1 h and then was warmed to ambient temperature and was stirred for a further 1 h. The mixture was stirred at 50-55° C. for a further 16 h and then was cooled to ambient temperature and acidified with 1N hydrochloric acid to pH ˜4.5. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(tert-butoxycarbonyl)-2-(ethylamino)-3,6-dimethylbenzoic acid (115 mg, 0.392 mmol, 85% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 2.97 (q, 2H), 2.67 (s, 3H), 2.46 (s, 3H), 1.61 (s, 9H), 1.34 (t, 3H); MS (EI) for C16H23NO4: 294 (MH+).