Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P].[C:2]1([CH3:9])[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:13]O)(=[O:12])[CH3:11]>>[CH3:9][C:2]1[C:7]([OH:8])=[C:6]([OH:12])[CH:5]=[CH:4][CH:3]=1.[CH3:3][C:2]1[CH:11]=[C:10]([OH:13])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccccc1O
Reactant: CC(=O)OO
Agent: [P]
Product: Cc1cc(O)ccc1O
Product: Cc1cccc(O)c1O

Procedure:
In the presence of 0.2% by weight of the same phosphorus-containing acid ester as indicated in Example 4, 1 mol or orthocresol and 0.2 mol of peracetic acid were caused to react at 50°C. Within 75 minutes after the start of the addition of peracid, the reaction product was analyzed by gas chromatography. Consequently, it was found that the conversion of peracetic acid was 99.8% and that there were produced 3-methyl-1,2-dihydroxy benzene and 2-methyl-1,4-dihydroxy benzene in amounts corresponding to 40.0% and 29.3% respectively.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][CH2:7][NH2:8].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1>CC(O)C>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][NH:8][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=[CH:4]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCCc1cnc[nH]1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1NCCc1c[nH]cn1
Yield: 65 %

Procedure:
1.14 g (10.2 mmol) of histamine base and 1.62 g (10.2 mmol) of 2-chloro-3-nitropyridine are brought to reflux in 5 ml of 2-propanol for 3 h. Evaporation of the solvent under reduced pressure and purification of the solid residue by chromatography on a column of silica gel, eluted with chloroform containing increasing amounts of methanol (5, 10 and 20%), provide the title compound. M.p.: 178°-180° C. (yield 65%; ethanol:water).
Reaction SMILES: O1C[CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:49][O:50][CH:51]1CCNC[CH2:52]1>C(N(CC)CC)C>[CH3:49][O:50][CH:51]1[CH2:52][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC1CCNCC1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CCN(CC)CC
Product: COC1CCN(c2ccc(NC(=O)c3cccc(CSCCC(=O)O)c3)c(-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using 4-methoxypiperidine in place of morpholine and using triethylamine in place of potassium carbonate in the nucleophilic aromatic substitution step. 1H-NMR (300 MHz, CD3OD, ppm) δ 8.98 (d, J=4.1 Hz, 1H), 8.47 (d, J=9 Hz, 1H) 8.33 (s, 1H), 7.94 (s, 1H), 7.84 (m, 2H), 7.72-7.46 (m, 7H), 7.38 (d, J=7.5 Hz, 1H), 4.71 (s, 3H), 3.89 (s, 2H), 3.72 (m, 2H), 3.55 (m, 1H), 3.33 (s, 3H), 3.26 (m, 2H), 2.74 (t, 2H), 2.56 (t, 2H), 2.20 (m, 2H), 1.88 (m, 2H). MS (ES, m/z): 707 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][C:14]=3[C:5]=2[CH2:4]1.C(OC([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=O)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([C:43](O)=[O:44])[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[O:17][CH:3]([CH2:2][N:25]4[CH2:26][CH2:27][CH:28]([NH:31][C:43]([C:40]5[CH:41]=[CH:42][C:36]6[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=6[CH:39]=5)=[O:44])[CH2:29][CH2:30]4)[CH2:4][C:5]=3[C:14]=2[CH:13]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc2ncc3c(c2c1)CC(CBr)O3
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)O3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 1 and in analogy to Example 1 using 2-bromomethyl-8-methoxy-1,2-dihydro-furo[2,3-c]quinoline, 4-amino-piperidine-1-carboxylic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.C(OC(N1CC[C:43]2C=C(OCC3C=CC(C(OC)=O)=CC=3)C=C[C:42]=2[CH2:41][CH2:40]1)=O)(C)(C)C.COC(=O)C1C=CC(COC2C=CC3CNCCCC=3C=2)=CC=1>>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][N:8]([CH:6]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:14][CH2:13][C:12]=3[CH:15]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: COC(=O)c1ccc(COc2ccc3c(c2)CCCNC3)cc1
Product: COC(=O)c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1

Procedure:
Example 94 (E94) was prepared in an analogous manner to Example 88 (E88) from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) and 3-bromomethyl-benzoic acid methyl ester using the methods highlighted in Description 3 (D3), Description 4 (D4) and Example 88 (E88); MS (ES+), m/e 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[ClH:9]>CO.O=[Pt]=O>[ClH:9].[CH3:1][C@@H:2]1[NH:7][CH2:6][C@@H:5]([OH:8])[CH2:4][CH2:3]1
Reactant: Cc1ccc(O)cn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C[C@H]1CC[C@H](O)CN1
Temperature: 70 °C

Procedure:
To a solution of 6-methylpyridin-3-ol (20.0 g, 0.183 mol) in MeOH (200 mL) was added concentrated HCl (15.43 mL, 0.1850 mol) and PtO2 (2.40 g, 0.011 mol). The resulting mixture was heated to 70° C. at 50 PSI overnight. The reaction was filtered over solka-floc to remove the PtO2 and concentrated to a solid. The crude solid was taken on without further purification.
Reaction SMILES: C(O)(=O)C.O.[CH2:6]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1)[CH3:7]>[Fe].C(O)C>[CH2:6]([NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:18]([F:21])([F:19])[F:20])=[CH:11][N:10]=1)[CH3:7]
Reactant: CCNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCNc1ncc(C(F)(F)F)cc1N
Temperature: 70 °C
Yield: 67.8 %

Procedure:
A mixture of iron powder (700 mg), acetic acid (60 μl), ethanol (5 ml), and water (3 ml) was stirred with heating at 70° C., and then a mixture of N-ethyl-(3-nitro-5-trifluoromethylpyridin-2-yl)-amine (490 mg) and ethanol (10 ml) was added dropwise. The mixture was stirred with heating at 70° C. for 3 hours. The reaction mixture cooled to room temperature was filtered through Celite®, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.29 g of N2-ethyl-5-trifluoromethylpyridin-2,3-diamine (Compound (1F)-8).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[CH3:22][C@H:23]1[O:28][C@@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1>CN(C=O)C>[CH3:29][C@H:27]1[O:28][C@@H:23]([CH3:22])[CH2:24][N:25]([CH2:21][C@@H:19]([OH:20])[CH2:18][O:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:14][CH2:15][N:16]=4)[C:10]([NH2:13])=[N:11][C:12]=3[C:3]=2[O:2][CH3:1])[CH2:26]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Yield: 96.3 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 1.50 g, 5.20 mmol) and cis-2,6-dimethylmorpholine (6.4 mL, 52.0 mmol, 10 equiv.) in DMF (36 mL) was heated in two portions in a microwave reactor for 45 min. at 140° C. The resulting combined mixtures were concentrated under reduced pressure and purified using MPLC to give N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine (2.02 g, 96%): Preparative HPLC ret. time 4.29 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.10 (d, J=7.3 Hz, 3H), 1.14 (d, J=7.3 Hz, 3H), 2.69 (t, J=11.6 Hz, 1H), 2.76 (t, J=11.6 Hz, 1H), 3.23-3.32 (m, 2H), 3.43-3.54 (m, 2H), 3.80 (s, 3H), 3.81-3.87 (m, 1H), 3.88-3.97 (m, 1H), 4.31 (app dd, J=8.6, 12.1 Hz, 2H), 4.35-4.43 (m, 1H), 7.22 (J=9.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H); mass spectrum m/z 404 ((M+1)+, 100%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:17]([OH:24])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:24][C:17]1[C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:19][C:10]([Br:9])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (2.53 ml, 21.2 mmol) was added to a mixture of methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (3.0 g; 10.6 mmol) and cesium carbonate (6.9 g; 21.2 mmol) in DMF (30 ml), under stirring at room temperature. The reaction mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added. The organic phase was separated, washed with water and with a saturated NaCl solution. The organic phase was dried, filtered and concentrated to dryness. The crude material was purified by flash chromatography column over silica gel (eluting with a gradient hexane-ethyl acetate 10:1 to 2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=C)=[N:14]1.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]=[O:24])=[N:14]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C#CCOc1cc(-n2nc(CCC=C)[nH]c2=O)c(Cl)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1cc(-n2nc(CCC=O)[nH]c2=O)c(Cl)cc1Cl
Yield: 92.2 %

Procedure:
To a solution of 500 mg (1.48 mmol) of 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-2,4-dihydro-5-(3-butenyl)-3H-1,2,4-triazol-3-one in a mixture of 10 mL of tetrahydrofuran and 10 mL of water was added 696 mg (3.25 mmol) of sodium periodate and 167 mL of 0.18M aqueous solution of osmium tetroxide at room temperature. The mixture was stirred at the room temperature for 2h, and then diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel, eluting with a 96:4 v:v mixture of dichloromethane and methanol to give 464 mg of the title product of Step 1 as a white foam. 1H NMR (CDCI3, 400 MHz) δ 11.5 (broad s,1H), 9.8 (s,1H), 7.55 (s,1H), 7.2 (s,1H), 4.8 (s,2H), 2.9 (m,4H).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.ClC/C=C\CCl>O.C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: ClC/C=C\CCl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CSC1(S(C)=O)CC=CC1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (3.170g) was dissolved in 30 ml. of tetrahydrofuran, and at -15° C., 20 ml. of an n-hexane solution (1.3 millimols/milliliter) of n-butyl lithium was added. The mixture was stirred for 30 minutes at -15° to -5° C., and then 1.455g of cis-1,4-dichloro-2-butene was added. The mixture was stirred for 2.5 hours at -70° C. and then for 1.5 hours at room temperature. Methylene chloride (100 ml) and 30 ml. of water were added, and the mixture was shaken. The organic phase was separated, and the aqueous phase was extracted four times with 50 ml. of methylene chloride each time. The extract and the organic phase were combined, and dried with anhydrous sodium sulfate. The dried mixture was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride and ethyl acetate) to afford 1.560 g of 3-cyclopentenone dimethyl mercaptal S-oxide and a light yellow oily substance in a yield of 76%.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:18]([CH:26]2[CH2:28][CH2:27]2)[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])C.CC[O-].[Na+].C(O)(=O)C.O>C(O)C>[CH2:24]([O:23][C:21]([CH:20]1[CH2:19][N:18]([CH:26]2[CH2:28][CH2:27]2)[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:4]1=[O:5])=[O:22])[CH3:25]
Reactant: CCOC(=O)CCN(c1nc2cc(F)c(F)cc2cc1C(=O)OCC)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CN(C2CC2)c2nc3cc(F)c(F)cc3cc2C1=O
Temperature: 20 °C

Procedure:
A solution of 20 cm3 of 3-ethoxycarbonyl-6,7-difluoro-2-[N-cyclopropyl-N-(b-ethoxycarbonylethyl)amino]quinoline in 20 cm3 of absolute ethanol is added in the course of 60 minutes to a solution of 1.6 g of sodium ethylate brought to reflux in 40 cm3 of absolute ethanol. The solution obtained is stirred under reflux for a further 60 minutes. 2.6 cm3 of glacial acetic acid are then introduced in the course of 10 minutes. The reaction mixture is stirred for a further 15 minutes and, with the mixture still refluxing, 26 cm3 of water are then introduced in the course of 5 minutes. The suspension obtained is cooled to approximately 20° C. The precipitate is drained at approximately 20° C. and washed with twice 10 cm3 of water. The wet product is dried under reduced pressure (20 kPa) at approximately 60° C. 1.25 g of crude 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine are isolated in the form of a yellow solid, melting point 172° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[CH2:20]=O>CO>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:20][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[S:5]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CC(C)C(C(N)=S)c1ccccn1
Solvent: CO
Product: CC(C)C(C(=S)NCN1CCOCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.0 g. of 3-methyl-2-(2-pyridyl)thiobutanamide in 20 ml. of methanol is added, at one time, 0.45 g. of morpholine and 0.42 ml. of a 37 percent formalin solution. The reaction is stirred for 15 hours at 25°C., then refluxed on a steam bath for 20 minutes. The solvents are evaporated in vacuo and the residue is distilled to give 3-methyl-N-morpholinomethyl-2-(2-pyridyl)thiobutanamide, b.p. 110-+-112°C. (0.005 mm.).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(C)[CH:38]=CC(S(O)(=O)=O)=C[CH:34]=1.C([O-])(O)=O.[Na+]>C(O)(C)C>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][CH:33]([CH3:38])[CH3:34])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 1.25 h
Yield: 198.2 %

Procedure:
A solution of 214e (101 mg, 0.23 mmol) in isopropanol (10 ml) was stirred at room temperature with a catalytic amount of p-toluenesulfonic acid (10 mg). After 75 minutes, the reaction mixture was poured into saturated NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography (SiO2, CH2Cl2 to EtOAc) afforded 56 mg (51%) of 2100a as a white solid: 1H NMR (CDCl3; mixture of diastereomers) δ7.9-7.8 (2H,m), 7.6-7.5 (1H, m), 7.5-7.4 (2H, m), 7.1 (0.5H, d), 6.9 (0.5H, d), 6.4 (0.5H,d), 5.6 (0.5H, d), 5.3 (0.5H, s), 5.2-5.1 (1H, m), 4.95 (0.5H, m), 4.75-4.5 (1.5H, m), 4.35 (0.5H, t), 4.1 (0.5H, m), 3.98 (0.5H, m), 3.3-2.75 (4H, m), 2.5-2.4 (2H,m), 2.25 (1H, m), 2.1-1.9 (3H,m) 1.75-1.55 (2H,m).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29](C4C=CC=C(CN5CCN(C(OC(C)(C)C)=O)[C@@H](C)C5)C=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].Br[CH2:56][CH2:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[CH3:65][N:66]([CH:68]=O)[CH3:67]>>[F:52][C:28]1[C:29]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:65][N:66]3[CH2:68][CH2:13][NH:8][C@@H:9]([CH3:10])[CH2:67]3)[CH:20]=2)=[CH:30][C:25]([CH2:24][N:23]([CH2:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)=[CH:26][CH:27]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: BrCCCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CCCc4ccccc4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 70 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (76.1 mg, 0.106 mmol), NaH (8.29 mg, 0.345 mmol) and (3-bromopropyl)benzene (0.024 mL, 0.160 mmol) in DMF (1.0 mL) were reacted to give the desired product (47.2 mg, 70.0%). EI-MS m/z 633(M−H)+.
Reaction SMILES: CC1C=CC=C2C=1CC(=O)N2.[C:12]([O:19]CC)(=[O:18])[C:13](OCC)=O.[O-]CC.[K+].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31](C)[C:30]=1[CH3:36])([O-:28])=[O:27]>CCOCC>[CH3:36][C:30]1([CH2:13][C:12]([OH:19])=[O:18])[C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=[CH:32][CH2:31]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC[O-]
Agent: Cc1cccc2c1CC(=O)N2
Agent: [K+]
Solvent: CCOCC
Product: CC1(CC(=O)O)CC=CC=C1[N+](=O)[O-]
Yield: 45 %

Procedure:
Preparation of 4-Methyl-2-oxindole. Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternatively with 10% sodium hydroxide and 30% hydrogen peroxide until the dark color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. The sold was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].CC(OC)(C)C.C1COCC1.[NH2:24][C:25]1[C:26]([C:33](OC(C)=CC(=O)NC(C)(C)C)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1>O>[NH2:24][C:25]1[C:26]([C:33]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CSC(=N)N
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N

Procedure:
To NaOH (1 mol/l in water; 9.2 ml; 9.2 mmol) is added S-methylisothiourea sulphate (1.78 g; 6.1 mmol). The mixture is stirred until complete solution is achieved. TBME/THF (1:1; 30 ml) and then 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (2.00 g; 6.10 mmol) are added and the mixture is stirred at r.t. over night, then water (6 ml) is added. The precipitate formed is filtered off with suction, washed successively with water, methanol and then with diethyl ether and then dried at 50° C. (C7H9ClN6OS).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[CH:7]=[N:8]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (2.0 g, 7.4 mmol) in water (20 mL) and methanol (20 mL) was added a solution of 2 N sodium hydroxide (10 mL). The solution was warmed at reflux for 1 hour. The solution was cooled to room temperature and acidified with 1 N aqueous HCl (pH=3-4). The white solid was obtained by filtration, washed with MeOH (30 mL) and dried to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.