Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([OH:39])[CH:37]=2)[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:39][C:36]1[CH:37]=[C:38]2[C:33]([CH2:32][CH2:31][N:30]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])=[CH:34][CH:35]=1
Reactant: Oc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(O)cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.37 mmol) 2,3-dihydro-1H-indol-6-ol, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2.[N:18]([O-:20])=[O:19].[Na+].[N+]([O-])(O)=O.[OH-].[NH4+]>>[F:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c([N+](=O)[O-])c(F)ccc2n1
Temperature: 20 °C

Procedure:
To 3.5 l of fuming sulfuric acid were added, with cooling, 600 g (3.73 moles) of 6-fluoroquinaldine in small portions (5 to 10 g). To this mixture was added about 0.1 g of sodium nitrite, followed by the dropwise addition of 261 ml of fuming red nitric acid over a period of six hours. The temperature of the mixture was maintained at 5° to 10° C. during the addition. The mixture was stirred at 20° C. for sixteen hours, then poured into 3 gallons of ice. Ammonium hydroxide was added, with cooling, to basify the mixture. The precipitated solid was separated by filtration, and dissolved in about two liters of warm toluene. The solution was dried over magnesium sulfate, filtered and evaporated to provide a yellow solid (6-fluoro-5-nitroquinaldine, m.p. 105°-108° C.) which was recrystallized from 1,2dicholoroethane. The structural assignment was confirmed by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(Cl)Cl.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:33]1([CH2:32][CH2:31][NH:39][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
Made in the same manner as EXAMPLE 62 using 2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (37.2 mg), CH2Cl2 (2 mL), triethylamine (72 μL), phenethylamine (39 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg) and 4-dimethylaminopyridine (˜1 mg). Run for 18 h then concentrated under reduced pressure and purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 21.6 mg of the title compound. 1H NMR (500 MHz, CDCl3 partial): δ 8.48 (br s, 1H); 8.40 (d, J=5.5 Hz, 1H); 7.84 (m, 2H); 7.56 (m, 2H); 7.42 (t, J=7.7 Hz, 1H); 6.80 (d, J=5.5 Hz,1H); 6.10 )br s, 1H); 5.69 (br s, 1H); 5.23 (br s, 1H); 3.72 (m, 2H); 2.94 (t, J=7.0 Hz, 2H); 1.65 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O)=[C:4]([CH3:17])[CH:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O.C(O)C>[CH2:18]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: CCCCN
Solvent: O
Solvent: CCO
Product: CCCCNC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 4.90 grams (0.02 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3oxopropanoate prepared in Example I (Compound No. 75), 358 grams (4.9 moles) of n-butylamine, 150 milliliters of ethanol and 5 drops of water was stirred at room temperature for about 16 hours. After this period, rotary evaporation gave a crude product as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give 3.08 grams (0.009 mole) of N-butyl 3-[(4-bromo-2-methylphenyl)amino]-3- oxopropanamide having a melting point of 123° C.-125° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][CH:4]([CH2:7][C:8]2[CH2:9][S:10][C@@H:11]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:12]3[C:13]=2[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[O:3]1>C(O)C.C1C=CC=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH2:9][S:10][C@@H:11]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:12]3[C:13]=2[C:14]([O:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[O:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC3C=CC(=O)O3)CS[C@H]12
Agent: [Pd]
Agent: [Rh]
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC3CCC(=O)O3)CS[C@H]12
Yield: 39.1 %

Procedure:
Diphenylmethyl 3-[(5RS)-2,5-dihydro-2-oxofuran-5-yl methyl]-7β-phenylacetamidoceph-3-em-4-carboxylate (Example 2(a)), (1.58 g) in 50% ethanol/benzene (100 mls) was treated with tris(triphenylphosphine)rhodium (I) chloride (0.75 g) and 10% palladium on carbon (0.2 g) and hydrogenated for several hours at room temperature. The reaction was monitored by t.l.c. analysis until formation of the slightly more polar product was complete. The solution was filtered through a small pad of silica gel and then concentrated. Purificationby `flash` chromatography afforded the title compound as a brown solid, (0.62 g, 39%); a sample recrystallized from ethyl acetate was shown to be a single isomer by spectroscopic analysis, m.p. 84°-89° C., νmax (KBr) 3400 (br), 3299, 1782, 1770, 1735, 1719, 1661, 1619, 1533, 1494, 1453 and 1373cm-1 ; δH (CDCl3) 1.75 (1H, m), 2.23 (2H, m), 2.43 (2H, m), 3.02 (1H, dd, J2.3, 13.8Hz), 3.52 (2H, ABq, J18.7Hz), 3.66 (2H, ABq, J16.2Hz), 4.66 (1H, m), 4.93 (1H, d, J4.7Hz), 5.87 (1H, dd, J4.7, 9.2Hz), 6.11 (1H, d, J9.2Hz), 6.84 (1H, s) and 7.25-7.5 (15H, m); [mass spectrum: +ve ion (3NOBA, Na+) MNa+ 605].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH:36]=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCOC(C)=O>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:2]=2[NH:1][CH:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:34][CH2:33]2)[CH3:36])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 61.5 %

Procedure:
Using a similar procedure to that described in Example 47-C, 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.7 g, 8.8 mmol) and 1-(tert-butoxycarbonyl)-piperidine-4-acetaldehyde (3.0 g, 13 mmol) afforded, after trituration with EtOAc:methylene chloride, 2.8 g (61%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].[CH3:10]O>>[OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: CO
Product: COC(=O)[C@H]1NCC[C@@H]1O

Procedure:
To a stirred solution of trans-3-hydroxy-L-proline (15 g, 0.114 moles) in methanol (200 mL) was added borontrifluoride diethyl ether (42 mL, 0.343 moles) and the reaction mixture was refluxed for 48 h. Once the starting material had disappeared (monitored by TLC) the reaction mixture was concentrated to get the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1>CO.[Pd].[C]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [Pd]
Solvent: CO
Product: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 8 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (2 g, 9.25 mmole) was dissolved in methanol (50 ml) under argon. Pd/carbon (100 mg, 5%) was added and the reaction mixture was hydrogenated for 8 hours at 2 bar. The product was worked up by filtering the solution through silica gel and washing with methanol (10×20 ml). The filtrate was concentrated by evaporation and dried. 5-chloro-3-piperidine-4-yl-1H-indole was obtained in a yield of 2 g (100%) with an m.p. of 156°-158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1C=CC(C)=CC=1.[C:21]([NH2:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)O>CC(N(C)C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][C:28]3[CH:27]=[CH:26][CH:25]=[CH:23][C:22]=3[C:21](=[O:29])[N:30]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccccc1O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccc(C)cc1
Product: O=c1nc(-c2ccc([N+](=O)[O-])cc2)oc2ccccc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
36.6 g of 4-nitrobenzoyl chloride are added to 48 g of p-xylene over 5 minutes and the suspension warmed to 80° C. To this suspension is then added, over 90 minutes, at 80° C., a solution of 13.2 g of salicylic acid amide in 7.2 g of dimethylacetamide, with stirring. The temperature is then raised to 135° C. over 1 hour and the mixture stirred at this temperature for a further 6 hours. After this time, the mixture is treated with 48 g of p-xylene, cooled to 80° C., the precipitated solids filtered, washed with p-xylene and dried, to yield 25.87 g of 2-(4-nitrophenyl)-4H-1,3-benzoxazin-4-one melting at 249-251° C. and having the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:45]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
(4-Chloro-phenyl)-phenylamino-acetic acid (I256) (1.22 g, 4.97 mmol), HOBT (0.99 g, 6.46 mmol) and DCC (1.33 g, 6.46 mmol) are dissolved in THF (250 mL). The reaction is stirred for 15 minutes and then (R)-quinuclidin-3-ol (1.26 g, 9.93 mmol) is added. The reaction is stirred at RT for 4 days. The solvent is evaporated and the residue is taken up with EtOAc. The insoluble is filtered off, the solution is washed with 1M K2CO3 and brine. The organic phase is dried (Na2SO4), filtered and evaporated to dryness. The crude is purified by flash chromatography (DCM/MeOH=98/2 to 90/10) to afford compound C259 as a yellow solid (462 mg, 25% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([C:9](=[O:11])[CH3:10])=[CH:8][C:4]=2[CH:3]=1.Cl[C:15]1[C:16](=[O:34])[N:17]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[C:9]([C:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([NH:1][C:15]3[C:16](=[O:34])[N:17]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:18](=[O:26])[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:4]=2[CH:8]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cc2cc(NC3=C(c4ccccc4)C(=O)N(Cc4cccnc4)C3=O)ccc2o1
Temperature: 130 °C
Yield: 7.3 %

Procedure:
1-(5-Aminobenzo[b]furan-2-yl)ethan-1-one (0.94 mmol, 164 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min. 0.3 mL water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 15 mg (7%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.64 (d, 1H), 8.52 (dd, 1H), 8.01 (bs, 1H), 7.80-7.75 (m, 1H), 7.35 (dd, 1H), 7.31-7.23 (m, 2H), 7.08-6.93 (m, 7H), 4.77 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][NH:27][C:28]([NH2:30])=[S:29]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:13]
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
3-Fluoro-4-nitrobenzenecarboxylic acid (8.4 g, 45 mmol) and 1,1′-carbonyldiimidazole (10 g, 64 mmol) were mixed in 100 mL DMF. The mixture was stirred at 20° C. for 1 hour. A clear yellow solution formed. To this mixture was added thiosemicarbazide (8.3 g, 91 mmol). The resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was concentrated under vacuum to remove almost all the DMF. The remaining residue was treated with 2 N HCl with stirring until the solution reached pH 4. Upon standing, a yellow solid formed. The pure product was obtained as a yellow solid after filtering, washing with water, and drying (8.02 g, 68% yield). LCMS (API-ES) m/z (%): 259.1 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (s, 1H) 7.90 (d, J=8.41 Hz, 1H) 7.99 (s, 1H) 8.04 (d, J=11.93 Hz, 1H) 8.28 (t, J=8.02 Hz, 1H) 9.47 (s, 1H) 10.76 (s, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][C:15]1[N:20]=[C:19]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:14][C:15]1[N:20]=[C:19]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1cccc(N2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of N-hydroxyphthalimide (35.0 g, 214 mmol), 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (74.8 g, 236 mmol), cesium carbonate (146.8 g, 450 mmol) and potassium iodide (1.78 g, 10.7 mmol) in acetonitrile (350 mL) was stirred at room temperature for 18 h. Water (300 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to yield 2-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione as a colourless solid [85.0 g; 94% of theory; HPLC/MS m/z=400 (M+H); log P(HCOOH)=2.44].
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[C:23]([OH:25])=O.C(Cl)Cl.[NH2:29][C@H:30]([C:34]([OH:36])=[O:35])[CH:31]([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[C:23]([NH:29][C@H:30]([C:34]([OH:36])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:25]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@H](C(=O)O)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
DMAP (367 mg, 3.0 mmol) and EDAC (748 mg, 3.9 mmol) were added as solids to a solution of 1,3-dimethylindole-2-carboxylic acid (568 mg, 3.3 mmol) in DMF (5 mL), and the resultant mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of the methyl ester of valine (553 mg, 3.3 mmol, in 5 mL of methylene chloride) was added to the mixture, and the mixture was first stirred for one hour at 0° C. then for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate washes were in turn washed with 5% KHSO4 solution saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give the title product as a yellow syrup (900 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[C:34]2([CH3:41])[CH3:40]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[C:34]4([CH3:40])[CH3:41])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1C(=O)c2c(N)cccc2C1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4(C)C)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 148A). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.71 (br s, 1H), 8.94 (br s, 1H), 8.35 (s, 1H), 7.43 (dd, J=6.2, 1.9 Hz, 1H), 7.06-7.30 (m, 4H), 6.80 (br s, 2H), 3.80-3.95 (m, 4H), 3.13 (s, 3H), 3.01 (d, J=21.5 Hz, 2H), 1.27 (s, 6H), 1.14 (t, J=7.1 Hz, 6H). MS (ES+): m/z 578.16 [MH+] HPLC: tR=3.27 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)c(OC)n1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 134. NMR (CDCl3): 1.46 (m, 2H, CH2), 1.60-1.69 (m, 6H, 3×CH2), 1.83 (m, 2H, Ch2), 2.12 (t, 2H, CH2, J=10.91 Hz), 2.28 (m, H, CH), 2.53 (m, 4H, 2×CH2), 3.04 (d, 2H, CH2, J=11 Hz), 3.82 (s, 2H, CH2), 3.87-3.89 (m, 4H, 2×CH2), 4.02-4.04 (m, 4H, 2×CH2), 4.08 (s, 3H, CH3), 4.11 (s, 3H, CH3), 7.30 (s, H, ArH), 8.93 (s, H, ArH). MS: (ESI+): MH+=540.51
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([C:17]([CH3:19])=O)=[CH2:16].P(=O)(O)(O)O.[As](=O)(O)(O)O>>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:17]([CH3:19])=[CH:15][CH:16]=[N:7]2
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Reactant: C=CC(C)=O
Agent: O=P(O)(O)O
Agent: O=[As](O)(O)O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Yield: 30 %

Procedure:
Compound II was treated with commercially-available methyl vinyl ketone in the presence of phosphoric acid and arsenic acid to afford the intermediate 5,6-dimethoxy-4-methyl-8-nitroquinoline (III), a new compound, as a pure crystalline material in 30% yield. This successful reaction is novel in that the steric hindrance provided by the 2-methoxy group of 4-amino-5-nitroveratrole and by the methyl group of methyl vinyl ketone would be expected by those skilled in the art to prevent the ring-closure reaction to form III from occurring.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (44.0 mg, 0.079 mmol) in DCM (6 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at rt for one hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (23 mg, 0.042 mmol, 54% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.53 (s, 1H), 7.29-7.40 (m, 2H), 7.25 (s, 1H), 7.20 (s, 1H), 4.63 (s, 2H), 3.74 (s, 1H). LC-MS (ES+) m/z 429.00, [M+H].