Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][N:49]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:48][CH2:47]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1N1CCN(CCCOc2cccc(-c3noc4ccsc34)c2)CC1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-(2-fluorophenyl) piperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (98:2). Combine the appropriate fractions and concentrate to give the title compound (0.45 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=438 m/e.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][O:5][N:6]=[C:7]([C@H:11]1[C:16](=[O:17])[CH2:15][C@H:14]([CH2:18][CH:19]([S:21][CH2:22][CH3:23])[CH3:20])[CH2:13][C:12]1=[O:24])[CH2:8][CH2:9][CH3:10].[OH:25]O>CC(C)=O>[Cl:1][CH:2]=[CH:3][CH2:4][O:5][N:6]=[C:7]([C@H:11]1[C:12](=[O:24])[CH2:13][C@H:14]([CH2:18][CH:19]([S:21]([CH2:22][CH3:23])=[O:25])[CH3:20])[CH2:15][C:16]1=[O:17])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)SCC)CC1=O
Reactant: OO
Solvent: CC(C)=O
Product: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)S(=O)CC)CC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In this example, a mixture containing 2.2 g of trans-2-[1-(3-chloroallyloxyimino)butyl]-5-(2-ethylthiopropyl) cyclohexane 1,3-dione and 1 ml of aqueous 30% hydrogen peroxide in 10 ml of acetone was stirred at room temperature for about 21/2 days and then concentrated by evaporation. The residue was mixed with 50 ml of ethyl ether, washed with 30 ml of saturated aqueous sodium bicarbonate solution, then washed with 30 ml of water, dried over magnesium sulfate and evaporated to dryness affording 1.9 g of the title compound.
Reaction SMILES: CO[CH:3]([O:29][CH3:30])[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[S:7]>C(O)=O>[CH3:30][O:29][CH:3]1[S:7][C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[N:5][CH2:4]1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=S)NCC(OC)OC)cc3)CC2)cc1
Solvent: O=CO
Product: COc1ccc(N2CCN(c3ccc(NC4=NCC(OC)S4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 17.6 parts of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea and 120 parts of formic acid was stirred for 1 hour at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in 133 parts of dichloromethane. The mixture was neutralized with a sodium hydrogen carbonate solution. The precipitated product was filtered off, washed with water and dichloromethane and crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 8.5 parts (52.0%) of 4,5-dihydro-5-methoxy-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-thiazolamine; mp. 177.5° C. (int. 5).
Reaction SMILES: [C:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16](O)[C@@H:15]([CH3:27])[O:14][C@@H:10]1[S:11][CH2:12][CH3:13])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+]>C(Cl)Cl.CN(C=O)C>[N:57]([C@@H:16]1[C@@H:15]([CH3:27])[O:14][C@H:10]([S:11][CH2:12][CH3:13])[C@H:9]([O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5])[C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:58]=[N-:59]
Reactant: CCS[C@H]1O[C@H](C)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCS[C@H]1O[C@H](C)[C@@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Yield: 79.1 %

Procedure:
Treatment of 12 (0.50 g, 1.26 mmol) in pyridine (1.02 mL, 12.61 mmol) and DCM (6.5 mL) with trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol) followed by treatment of triflate residue in DMF (16 mL) with sodium azide (0.41 g, 6.31 mmol) according to the general procedure for introduction of the C-4 azide group gave compound 13 as colorless oil (0.42 g, 79%). Rf=0.32 (Hexane/EtOAc, 4:1, v:v). [α]27D=+13.1 (CHCl3, c=5.1 mg/mL). 1H NMR (300 MHz, CDCl3): δ 1.67 (t, 3H, J=7.5 Hz, SCH2CH3), 1.30 (d, 3H, J5,6=5.7 Hz, H-6), 2.10 (s, 3H, CH3C(O)CH2CH2C(O)O), 2.44-2.49 (m, 2H, CH3C(O)CH2CH2C(O)O), 2.57-2.67 (m, 4H, SCH2CH3, CH3C(O)CH2CH2C(O)O), 3.11-3.24 (m, 2H, H-4, H-5), 3.48 (t, J3,4=9.0, J2,3=9.0 Hz, H-3), 4.27 (d, 1H, J1,2=9.9 Hz, H-1), 4.68 (d, 1H, J=11.1 Hz, PhCH2), 4.71 (d, 1H, J=11.1 Hz, PhCH′2), 4.94 (dd, 1H, J1,2=9.9, J2,3=9.0 Hz, H-2), 7.22-7.29 (m, 5H, Harom); 13C NMR (75 MHz, CDCl3): δ 14.8 (SCH2CH3), 18.7 (C-6), 23.9 (SCH2CH3), 28.0 (CH3C(O)CH2CH2C(O)O), 29.8 (CH3C(O)CH2CH2C(O)O), 37.8 (CH3C(O)CH2CH2C(O)O), 67.7 (C-4), 72.2 (C-2), 74.9 (PhCH2), 75.1 (C-5), 82.3 (C-3), 83.2 (C-1), [127.9, 128.0, 128.2, 128.4, 137.5 (Carom)], 171.5 (CH3C(O)CH2CH2C(O)O), 206.1 (CH3C(O)CH2CH2C(O)O); MALDI-TOF/MS: m/z: found [M+Na]+ 444.1, C20H27N3O5S calcd for [M+Na]+ 444.15.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.[CH3:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>CC(O)C>[CH3:32][C:30]1[N:31]=[C:26]([CH:25]=[N:1][N:2]2[CH2:3][CH2:4][N:5]([CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH:12]=[C:11]([C:19]#[N:20])[C:10]4[CH:21]=[CH:22][CH:23]=[CH:24][C:9]3=4)[CH2:6][CH2:7]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(C=O)n1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cccc(C=NN2CCN(C3c4ccccc4C=C(C#N)c4ccccc43)CC2)n1
Reaction time: 4 h

Procedure:
A mixture of 30 parts of 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile, 21 parts of 6-methyl-2-pyridinecarboxaldehyde, 1 part of glacial acetic acid, and 250 parts of 2-propanol is heated at the boiling point under reflux with stirring for 4 hours, then stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of tetrahydrofuran and hexane to give 5-{4-[(6-methyl-2-pyridylmethylene)amino]-1-piperazinyl}-5H-dibenzo[a,d]cycloheptene-10-carbonitrile as light brown crystals melting at 200°-202°.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:46])[CH2:32][C@@H:33]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:4][C:3]([CH2:2][O:45][C:42]3[CH:43]=[CH:44][C:39]([C@@H:33]([C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[CH2:32][C:31]([N:26]4[C@@H:25]([CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:29][O:28][C:27]4=[O:30])=[O:46])=[CH:40][CH:41]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCCCc1ccc(-c2ccc(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 60.5 (0.16 mmol), 7.5 (52 mg, 0.13 mmol), and Cs2CO3 (135 mg, 0.41 mmol) in DMF (1.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 60.6 (26 mg, 32%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.48 (d, 2H), 7.28 (m, 5H), 7.19 (m, 4H), 7.14 (d, 1H), 7.04 (d, 1H), 6.96 (d, 2H), 6.13 (d, 1H), 5.17 (s, 2H), 4.75 (t, 1H), 4.61 (m, 1H), 4.13 (m, 2H), 4.02 (dd, 1H), 3.54 (dd, 1H), 3.20 (dd, 1H), 2.76 (dd, 1H), 2.62 (t, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ncccc2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccnc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3-methoxy-pyridin-2-yl)-methanone (Example 195) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C17H23N6O4S [(M+H)+] 407.1496, observed 407.1501.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][C:7](=[O:12])[C:8]#[C:9][CH2:10][CH3:11].S(=O)(=O)(O)O>C1C=CC=CC=1.CCOCC>[CH3:6][C:7]([OH:12])([C:8]#[C:9][CH2:10][CH3:11])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CCC#CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C#CCC(C)(O)C#CCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution consisting of 6.06 parts of magnesium, 15 parts by volume of ether and 0.06 part of mercuric chloride, stirred at room temperature in an atmosphere of nitrogen, was added 0.5 part by volume of a solution consisting of 29.74 parts of propargyl bromide and 70 parts by volume of ether. The resulting mixture was then cooled to -10° to -15° and the remaining propargyl bromide solution was slowly added over a period of 45 minutes. At the end of the addition period, stirring was continued at -10° for about 15 minutes longer. To that mixture was then added, with stirring, over a period of 45 minutes at -3° to -5°, a mixture consisting of 22 parts of 3-hexyn-2-one and 60 parts by volume of benzene. At the end of the addition period, stirring was continued for about 20 minutes at -3°, and the reaction mixture was then poured carefully into cold dilute sulfuric acid. The aqueous phase was separated, extracted with ether and the combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Vacuum distillation of the residue afforded 4-methyl-1,5-octadiyn-4(RS)-ol, characterized by infrared absorption maxima of about 3620, 3330, 2250, 1385, 1355, 1085, 940, and 770 cm.-1.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N+:24]([O-])=O)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:27])[C:7]=2[N:6]=[C:5]1[CH2:28][CH2:29][CH3:30].CC(C)CN1C2C3C=CC(OC4C=CC([N+]([O-])=O)=CC=4)=CC=3N=C(N)C=2N=C1CCC>>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[C:5]([CH2:28][CH2:29][CH3:30])=[N:6][C:7]=3[C:8]([NH2:27])=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2c(N)nc3cc(Oc4ccccc4[N+](=O)[O-])ccc3c2n1CC(C)C
Agent: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Product: CCCc1nc2c(N)nc3cc(Oc4ccccc4N)ccc3c2n1CC(C)C

Procedure:
A modification of the general method described in Example 41 was followed using 1-(2-methylpropyl)-7-(2-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine, prepared as described in Example 36, in lieu of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. When the reaction was complete, the reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol and methanol:dichloromethane. Following treatment with the ion exchange resin, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 98:2 to 94:6). The white, waxy solid was recrystallized from acetonitrile to yield 0.150 g of 7-(2-aminophenoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 197-199° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[C:14]([N+:33]([O-:35])=[O:34])=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[CH2:38]([O:40][C:41]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)=[O:42])[CH3:39].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[C:14]([N+:33]([O-:35])=[O:34])[C:13]([C:47]4[CH:48]=[C:43]([CH:44]=[CH:45][CH:46]=4)[C:41]([O:40][CH2:38][CH3:39])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])c1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
Cesium carbonate (1.69 g, 5.19 mmol) was added to Pd(Ph3P)4 (250 mg, 0.216 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (2.00 g, 4.33 mmol), 3-(ethoxycarbonyl)phenylboronic acid (1.01 g, 5.19 mmol). Dioxane (36 mL) and water (7 mL) was added at rt and the mixture was degassed 3×. The reaction was heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, Tilt and concentrated. The crude solid was triturated with DCM to give the titled compound (1.70 g, 85%). 1H NMR (400 MHz, DMSO-d6) δδ ppm 8.55-8.61 (1 H, m), 8.54 (1 H, s), 8.00-8.09 (3 H, m), 7.95 (1 H, s), 7.73 (1 H, s), 7.61-7.70 (2 H, m), 7.45 (2 H, t, J=8.91 Hz), 4.35 (2 H, q, J=7.19 Hz), 2.83 (3 H, d, J=4.52 Hz), 1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.62 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 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 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Temperature: 78 °C
Yield: 93.9 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.345 g, 3.59 mmol) and ethyl formate (0.862 mL, 10.77 mmol) were dissolved in anhydrous ethanol (7.19 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.70 mL, 17.9 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.358 g, 3.37 mmol, 94%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccccc2C(=O)O)CC1
Reaction time: 0.75 h
Yield: 86.7 %

Procedure:
To a stirring solution of methyl 2-[4-Boc-piperazine-1-ylcarbonyl]aminobenzoate (2.42 g, 6.7 mmol) in methanol (15 mL) was added 5 N sodium hydroxide (15 mL). After 45 min, the solution was partially concentrated in vacuo to a volume of about 10 mL and the solution was diluted with water and washed with diethyl ether. The aqueous phase was then acidified with conc HCl and extracted with ethyl acetate. The ethyl acetate solution was then washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 2.03 g (87%) of an off-white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=O.[H-].[Na+].CS(C1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1)(=O)=O.[OH-].[Na+]>CN(C)C=O>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:1]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[N+:11]([O-:13])=[O:12])[N:25]=1
Reactant: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Nc2ccc(C)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N-formyl-4-methyl-2-nitroaniline (25.00 g) was dissolved in dimethylformamide (400 ml), and sodium hydride (60% purity, oily) (6.11 g) was added thereto at room temperature. After stirring for 10 minutes, 2-methylsulfonyl-4,6-dimethoxypyrimidine (30.28 g) was added at room temperature, followed by stirring for 3 hours. A 10% NaOH aqueous solution was added thereto, and the crystals were collected by filtration, washed with water and dried to obtain 37.50 g of the desired product as a yellow powder (m.p. 158-161° C.).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[C:14]3[C:33]2[O:37][CH:36]=[N:35][CH:34]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[C:14]3[C:33]2[O:37][CH:36]=[N:35][CH:34]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(O[C@@H]5CCN(C(=O)OC(C)(C)C)C[C@H]5F)c4n3)cnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To (trans)-tert-butyl 3-fluoro-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-4-(oxazol-5-yl)quinolin-8-yloxy)piperidine-1-carboxylate (4 mg, 0.007 mmol) in DCM (1 mL) was added TFA (1 mL), followed by a 30 minute stir. The crude reaction was concentrated and purified by flash column chromatography (DCM/MeOH/NH4OH 10:1:0.1) affording the desired product (60%). MS APCI (+) m/z 504.2 (M+1) detected.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CO>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.3 %

Procedure:
To a solution of 4-methyl-2-phenylbenzoic acid methyl ester (1.83 g, 8.09 mmol), prepared as in Example 227A, in methanol (16 mL) was added aqueous 4N sodium hydroxide (5 mL) and the reaction mixture was stirred for 60 hours, after which additional aqueous 4N sodium hydroxide (5 mL) was added and the mixture was heated at reflux for 5 hours. The reaction mixture was cooled to ambient temperature and the methanol was evaporated in vacuo. The aqueous residue was acidified with 4N sulfuric acid and extracted with ethyl acetate (3×). The combined organic extracts were dried, filtered, and concentrated in vacuo to give 4-methyl-2-phenylbenzoic acid (1.67 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31]C)=[O:30])([CH2:26][CH:27]=[CH2:28])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC(C(OC)=O)(CC=C)C[C@@H]1CCCCN1C(OCC[Si](C)(C)C)=O)=O)(C)(C)C.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([OH:31])=[O:30])([CH2:26][CH:27]=[CH2:28])[CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: C=CCC(C[C@@H]1CCCCN1C(=O)OCC[Si](C)(C)C)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CO
Product: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate 1.1 g of 2-trimethylsilanylethyl (S)-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate were dissolved in 33 ml of methanol and cooled to 0° C. 2.3 ml of a 2 N solution of trimethylsilyldiazomethane in hexane were added dropwise. The mixture was allowed to reach room temperature in the course of 3 h, and then a further 2.3 ml of the trimethylsilyldiazomethane solution were added dropwise. The mixture was stirred for 1 h and then the reaction was stopped by adding 1 ml of acetic acid. After stirring for 30 min, the solvents are removed in vacuo and the residue was chromatographed on silica gel.