Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: Cc1ccnc([Mg]Br)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3cc(C)ccn3)cc2OC1C(F)(F)F
Temperature: -78 °C
Yield: 4.9 %

Procedure:
The bromo (4-methylpyridin-2-yl)magnesium (10.4 mL, 2.6 mmole) was diluted by 5 mL THF and the solution was cooled to −78° C. ZnCl2 (340 mg, 2.5 mmole) was added to above solution and the mixture was slowly warmed to r.t and heated to 50 OC for 3 hrs. The mixture was cooled to −78° C. again and ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (1.0 g, 2.5 mmol) was added to above mixture and followed by PdCl2(PPh3)2 (18 mg, 0.025 mmole). The mixture was warmed to 50° C. for 3 hrs. LCMS indicated that around 40% product was formed. The reaction was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The filtrate was concentrated to afford the crude product, which was purified by RPHPLC eluted with 10 to 95% ACN in water with 0.05% TFA to give 50 mg the desired product as a brown oil (yield 5%), which had suitable purity to use without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][S:33]([CH3:32])(=[O:35])=[O:34])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Reaction time: 3 h

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 30 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-tert-butylaniline (51.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1,1-dimethylethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (21.1 mg).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=2[F:28])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=2[F:28])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(SC)cc1F
Agent: Cl
Solvent: CO
Product: CSc1ccc(Nc2c(C(=O)NOCCO)ccc3[nH]ncc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A solution of 4-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-indazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (45 mg, 0.112 mmol) in methanol (5 mL) was treated with hydrochloric acid (1M, 0.225 mL, 0.22 mmol) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue dissolved in methanol and to this solution was added water causing a precipitate to form which was filtered off. The filtrate was extracted twice with ethyl acetate, the combined extracts dried (Na2SO4), filtered and concentrated in vacuo. The crude product was combined with the earlier solid precipitate and subjected to flash chromatography (Si—PPC, gradient 0 to 10% methanol in DCM) to give a solid. The solid was triturated in diethyl ether to give a pale tan solid (23 mg, 55%). LCMS (Method A) RT 7.79 [M+H]+ 377. 1H NMR (MeOD, 400 MHz): 7.52-7.44 (1 H, m), 7.21-7.09 (3 H, m), 7.06 (1 H, dd, J=8.41, 2.08 Hz), 6.93 (1 H, d, J=8.88 Hz), 4.54 (1 H, s), 4.02-3.98 (2 H, m), 3.75 (2 H, dd, J=5.28, 4.05 Hz), 2.48 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.F[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2ccc3[nH]ccc3c2)c([N+](=O)[O-])c1
Temperature: 225 °C
Yield: 90 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 4-fluoro-3-nitrotoluene (0.465 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in which 4-fluoro-3-nitrotoluene was the only solvent and the reaction was heated at 225° C. under nitrogen for 18 hours. Chromatography using ether/hexanes [1:1 ] afforded the title compound (90%) as a red amorphous solid. Mp, decomposes 94° C.; Rf =0.55 in ethyl acetate/hexanes [1:1]; 13C NMR (CDCl3) δ143.4, 137.3, 134.2, 131.8, 131.1, 128.7, 126.1, 125.6, 120.8, 117.9, 116.2, 112.1, 102.8, 20.1; LRMS (m/z, relative intensity) 267 (M+, 45), 250 (5), 233 (20), 220 (13). HRMS calculated for C15H13N3O2 : 267.1005. Found: 267.0993.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18].Cl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=1
Reactant: Oc1cc(O)c2cc(Br)ccc2n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1

Procedure:
Prepared using general procedure 1; 6-Bromo-2,4-quinolinediol (3 g, 12.5 mmol), 3,4-dichloroaniline, 6.25 mL of 2 M HCl in Et2O were irradiated to 180° C. (400 W max) for 40 min. to afford 1.94 g (5.05 mmol, 40%). 1H NMR (300 MHz, DMSO): 11.36 (s, 1H), 8.83(s, 1H), 8.28(s, 1H), 7.70(dd, 1H, J=8.88, 1.61 Hz), 7.64(d, 1H, J=8.88 Hz), 7.55(d, 1H, J=2.02 Hz), 7.33(dd, 1H, J=8.88, 2.42 Hz), 7.25(d, 1H, J=8.88 Hz), 5.86(s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:79](=[NH:92])([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:80]1([C:79](=[N:92][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]3)=[CH:9][CH:8]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC1CCCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCC(c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Yield: 37.9 %

Procedure:
Ethyl [3-(4-{[(trifluoromethyl)sulphonyl]oxy}phenyl)cyclohexyl]acetate (322 mg, 0.85 mmol) was stirred in dry THF (8 mL) under a nitrogen atmosphere and caesium carbonate (387 mg, 1.19 mmol), palladium(II) acetate (12 mg, 0.05 mmol) and BINAP (32 mg, 0.05 mmol) were added followed by benzophenone imine (0.214 mL, 1.27 mmol). The reaction vessel was degassed 6 times and stirred under reflux for 16 h. The mixture was extracted with ether (2×100 mL) and washed with water (100 mL). The organic extracts were dried and concentrated by evaporation to give an oil that was purified by chromatography eluting with 0-30% EtOAc/isohexane to give the title compound (137 mg, 38%) as an oil; 1H NMR δ 0.81-2.48 (m, 9H), 1.12-1.21 (m, 3H), 2.58-2.72 (m, 1H), 3.97-4.12 (m, 2H), 6.57-6.65 (m, 1H), 6.94-7.04 (m, 1H), 7.10-7.18 (m, 1H), 7.29-7.36 (m, 1H), 7.37-7.78 (m, 10H); MS m/e MH+ 426.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]([C:18]1[C:19]2[CH2:20][CH2:21][NH:22][CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[C:19]2[CH2:20][CH2:21][N:22]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]
Reactant: COC(=O)c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COC(=O)c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (257 mg, 60%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:8]=[CH:9][N:10](COCC[Si](C)(C)C)[CH:11]=2)[CH:4]=[N:3]1.CN1C=C(C2N(COCC[Si](C)(C)C)C=NC=2)C=N1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]1[CH:11]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:8]=[CH:9]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)cn2)cn1
Agent: Cn1cc(-c2cncn2COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2c[nH]cn2)cn1

Procedure:
A mixture of 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1H-pyrazole and 1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole (170 mg, 0.7 mmol) from Step 2 of this Example were stirred in a 1:1 mixture of TFA and CH2Cl2 (5 mL) for 15 h. The mixture was then concentrated under reduced pressure to afford 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248 mg) as an oil and was used in the next step without further purification. LCMS (ESI) m/z 149 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].F[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27]#[N:28])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@@]1(C)C(N)=O
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D10, 60 mg, 0.187 mmol), 2-fluorobenzonitrile (45 mg, 0.374 mmol) and potassium carbonate (39 mg, 0.280 mmol) in DMF (2 ml) was heated under microwave irradiation for 30 min to 120° C. Water and ethyl acetate were added to the mixture, and the organic layer was washed with ice cold water. The solution was dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound (78 mg); Rt (HPLC): 5.44 min; Rf (cyclohexane:ethyl acetate=1:1): 0.21; MS: (ES/+) m/z: 444 [M+Na+]; C24H27N3O4 requires 421.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(O)C>[CH3:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCc2ccccn2)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)Nc1ccc(CCc2ccccn2)cc1
Yield: 92 %

Procedure:
A solution of 2-[2-(4-aminophenyl)ethyl]pyridine (5.8 g) and methyl isothiocyanate (2.6 g) in ethanol (60 ml) was refluxed for one hour. The reaction mixture was evaporated in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-[2-{4-(3-methylthioureido)phenyl}ethyl]pyridine (7.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>COCCOCCOC>[CH3:15][Si:16]([CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(CO)c1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: C[Si](C)(C)Cc1cccc(CO)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbenzylalcohol (6.10 g, 50 mmol) in anhydrous diglyme (200 ml) at -78° C. was added 1.5M butyllithium (100 ml) over 20 min. The resulting mixture was allowed to warm to -20° C. and stirred for 30 min. Then a mixture of trimethylchlorosilane (19.0 g, 175.0 mmol) and triethylamine (5.05 g, 50 mmol) was added and the final solution was stirred at room temperature for 3 hours. The reaction mixture was treated with ice water (200 ml), extracted three times with diethyl ether (100 ml) and the extracts washed twice with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (200 ml) and refluxed for 1 hour. Then the solvents were removed and 3-trimethylsilylmethylbenzylalcohol was purified by fractional distillation.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][OH:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:1]([S:7]([CH2:10][CH2:11][OH:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=1)([O-:15])=[O:14]
Reactant: O=S(=O)(CCO)c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Temperature: 90 °C
Yield: 30 %

Procedure:
2-(Phenylsulfonyl)-ethanol (2.5 g; 13 mmol) was dissolved in 5.5 ml of conc. sulphuric acid and treated in portions with potassium nitrate (2 g; 20 mmol). The reaction mixture was heated for 2 hours at 90° C., then poured onto ice and potassium carbonate was added. The mixture was extracted several times with ethyl acetate and the combined organic layers were concentrated to obtain 0.9 g (3.9 mmol, 30% yield) of 2-(3-nitro-phenylsulfonyl)-ethanol as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([NH:18][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: CC(C)N
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Temperature: 80 °C
Yield: 86.3 %

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (920.2 mg, 4.0 mmol) and isopropylamine (1.7 mL, 1.182 g, 20.0 mmol) in dioxane (10 mL) was heated at 80° C. for 26 hours and evaporated to result in a residue which was partitioned between saturated NH4Cl solution (200 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, and evaporated to afford crude title product (872 mg, 86%). 1H NMR (DMSO-d6) δ 1.22 (d, J=6.4 Hz, 6H, 2CH3), 3.42 (s, 3H, NCH3), 4.19 (m, 1H), 6.59 (s, 1H), 8.45 (s, 1H), 8.90 (d, J=7.6 Hz, 1H, NH); ESI-MS m/z 253.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:16][C:15]([C:27](O)=[O:28])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:33])[CH3:32].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:27]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:28])[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COCCOCCOCc1cc(C(=O)O)nn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCc1cc(C(=O)NC2CCN(C(C)C)CC2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 16 h

Procedure:
To 60 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 30 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 34 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 19 mg MS (ES+): m/e=566, chloro pattern.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:37])=O>CN(C)C=O>[Cl:37][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
9.7 g (0.02 mol) of 2-(4-carboxyphenyl)-2-[4-(4-nitrophenoxy)phenyl]hexafluoropropane were suspended in 47 cm3 of thionyl chloride, a few drops of dimethylformamide were added, and the mixture was refluxed until evolution of gas was no longer observed. The thionyl chloride was removed by distillation, and the residue was recrystallized from acetonitrile.
Reaction SMILES: O.O.[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+].[Na+].[Na+]>O>[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
1.45 grams of trisodium citrate dihydrate in 20 ml of distilled water was added to 18,900 grams of xanthan broth to give an equivalent citric acid concentration of 50 ppm; i.e., citric acid concentration of 50 ppm was prepared by adding 77 ppm trisodium citrate dihydrate. The citric treated xanthan sample in a 5 gallon polyethylene carbuoy was then vigorously agitated in a New Brunswick rotary shaker for 1 hour to insure proper mixing.