Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].N[C@H](C(NCC(NCC(N[C@H](C([NH:45][C@H:46]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=O)CC1C=CC=CC=1)=O)=O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1.N[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1>>[NH2:45][C@H:46]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
On the other hand, the filtrate and the washing liquid were well washed with chlorobenzene (5 ml) and then combined with each other, thereby a clear solution was obtained. When 10% aqueous sodium carbonate solution (12 ml) was added to the solution, a solid was deposited. After the mixture was allowed to mature by stirring at room temperature for 1 hour and then under ice-cooling for 1 hour, the deposited solid was filtered, and sequentially washed with chlorobenzene (2 ml) and water (2 ml), and dried under vacuum, thereby a white solid was obtained. The purity of the target Tyr(Bn)-Gly-Gly-Phe-Leu-OBn (SEQ ID NO: 2) was 88%, and the content of Tyr(Bn) was 4.9%. Further, the crystallization yield was 88%, and the acquisition yield relative to the Leu-OBn.TsOH salt was 58%.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15](Cl)=[N:14][C:13]=2[CH:12]=1)(=[O:5])=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:18]4[S:19][C:11]([CH2:10][NH:9][CH2:8][CH2:7][CH2:6][S:3]([N:2]([CH3:27])[CH3:1])(=[O:5])=[O:4])=[CH:12][C:13]=4[N:14]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 385. NMR: CDCl3: 1.99-2.01 (2 H, m, CH2), 2.78-2.81 (2 H, m, CH2), 2.82 (6 H, s, Me), 2.98-3.01 (2 H, m, CH2), 3.84-3.88 (4 H, m, CH2), 4.02-4.05 (4 H, m, CH2), 4.07 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 516.34
Reaction SMILES: [S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15].[OH:30]O>CO>[S:1]([C:16]1[CH:21]=[C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19]([OH:28])=[CH:18][C:17]=1[CH3:29])([C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][C:3]=1[CH3:15])=[O:30]
Reactant: Cc1cc(O)c(C2CCCCC2)cc1Sc1cc(C2CCCCC2)c(O)cc1C
Reactant: OO
Solvent: CO
Product: Cc1cc(O)c(C2CCCCC2)cc1S(=O)c1cc(C2CCCCC2)c(O)cc1C
Reaction time: 8 h

Procedure:
To a solution of crude oily 4,4'-thiobis(6-cyclohexyl-3-methylphenol) (10.5 g) in methanol (40 ml) is gradually added dropwise 30% hydrogen peroxide (6.5 g) at room temperature. The mixture is stirred for a while at the same temperature, and left standing at 50° C. for 3 hours and overnight at room temperature. The precipitated crystals are filtered off, washed with cool methanol and dried to give 4,4'-sulfinylbis(6-cyclohexyl-3-methylphenol), m.p. 151°-153° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH2:15]([N:19](CCCC)CCCC)[CH2:16][CH2:17][CH3:18].C(N)CCC>C(Cl)Cl>[CH2:15]([NH:19][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)CCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 3 h

Procedure:
11-Bromoundecanoic acid (45 mmol) was dissolved in dry CH2Cl2 (200 ml) and tributylamine (54 mmol). After the mixture had cooled at −10° C., isobutylchlorofomate (60 mmol) was added and allowed to react for 2 hrs. At this moment, excess N-butylamine (225 mmol) was added and later the cooling bath was removed. After 3 hrs, CH2Cl2 was added and the organic phase was washed with 1 N HCl, saturated NaHCO3, and water. After drying by MgSO4, the solvent was removed and the crude product was purified by column chromatography. The pure amide product was eluted with solvent, hexane (80)—EtOAc (20).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.CC1([N:34]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:34])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 68) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17); Solid (568 mg, 95%);
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[N:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Cl:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 2,6-bis(chloromethyl)pyridine (20 g, 113.6 mmol, 1 eq.) in 250 ml of DMF was added potassium phthalimide (21.04 g, 113.6 mmol, 1 eq.). The reaction was stirred at r.t. overnight then the solvent was evaporated and the residue taken in EtOAc. The insolubles were removed by filtration and the filtrate washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The resulting white solid was recrystallised from IPE/EtOAc (1/1) to give 2-{[6-(chloromethyl)pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (22.34 g, 68% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[N+:12]([C:9]1[CH:10]=[CH:11][C:2]([CH2:17][CH:16]=[CH2:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])([O-:14])=[O:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])cc1C(=O)OC

Procedure:
A mixture of Methyl 2-bromo-5-nitrobenzoate (0.60 g, 2.3 mmol), allyl tri-n-butyltin (0.92 g, 2.8 mmol), lithium chloride (0.29 g, 6.9 mmol), and palladium tetrakis (0.13 g, 0.12 mmol) was heated to reflux for 16 hours in toluene. TLC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, and separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14](N(OC)C)=[O:15])[N:11]([CH3:20])[C:10]=2[CH:21]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14](=[O:15])[CH2:1][CH3:2])[N:11]([CH3:20])[C:10]=2[CH:21]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Solvent: C1CCOC1
Product: CCC(=O)c1nc2ccc(Br)cc2n1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethylmagnesium bromide (1 M in THF, 11.0 ml) was added to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzo[d]imidazole-2-carboxamide (1.09 g) in THF (15 ml) at 0° C. The mixture was stirred at 0° C. under N2 atmosphere for 2 h. The mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.86 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH:6]2[CH3:15].FC(F)(F)[C:18](O)=[O:19].C1N2CN3CN(C2)CN1C3>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:18]=[O:19])[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH:6]2[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)C(C)CC(=O)N2C
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 110 mg (0.54 mmol) 6-methoxy-1,4-dimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 90 mg (0.64 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched first with water and then with 30 ml of saturated aqueous bicarbonate solution and extracted with chloroform (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue, 72 mg, was purified by silica gel column chromatography eluting with 4/6 ethyl acetate/hexane to afford 50 mg (40%) of a yellow solid which was used directly in the following step. Mass spectrum APCI m/e 234 (p+1). Enantiomeric separation was completed on a Chiralpak AD column eluting with 9/1 hexane/ethanol(EtOH) containing 1% diethylamine. The retention times were 12 minutes and 13.8 minutes respectively.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.C1COCC1.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A 20 drams vial was charged with methyl (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate (92 mg, 0.18 mmol), THF (1.8 mL) and MeOH (1.8 mL). NaOH 1M aq. (0.9 mL) was then added in one portion and the resulting mixture stirred for 30 minutes at room temperature. Organic solvents removed under reduced pressure and 5 mL of water added to the vial. Under magnetic stirring, citric acid solution (10%, aq.) added dropwise to reach ca. pH 3. The solid formed was recovered with a büchner funnel, washed with water and dried under high vacuum to provide (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido) propanoic acid as a white solid (76.9 mg, 86.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 9H) 2.44-2.48 (m, 2H) 3.38-3.47 (m, 2H) 4.33 (d, J=8.22 Hz, 1H) 6.54 (d, J=8.41 Hz, 1H) 7.17 (dd, J=8.90, 2.84 Hz, 1H) 7.44 (d, J=8.22 Hz, 2H) 7.55 (d, J=9.00 Hz, 1H) 7.74 (d, J=8.41 Hz, 2H) 7.84 (d, J=2.54 Hz, 1H) 8.08 (s, 1H) 8.44 (t, J=5.28 Hz, 1H) 8.84 (s, 1H) 12.18 (br. s., 1H); MS (M+1): 490.4.
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:8]=[CH:7][C:6]=1[C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34]C(C1C=NN(C3C=CC(Cl)=CC=3C)C=1C(C)(C)C)=O)[CH2:31]2>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:21]([C:6]1[CH:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=3)[C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:31]2
Reactant: Cc1cc(Cl)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Reactant: CC(C)(C)c1c(C(=O)O)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide was prepared from 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate #119) by the same process used for Intermediate #114.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([O:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[CH:19][CH:20]=1)([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 19.3 g of p-nitrocinnamic acid suspended in 300 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, upon which p-nitrocinnamoyl chloride precipitated. The precipitates thus obtained were dissolved in 300 ml of ethyl acetate, and 9.4 g of phenol was added to the resulting solution, after which 12 g of triethylamine was slowly added thereto at room temperature with stirring. After reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to obtain phenyl p-nitrocinnamate. Yield: 25.5 g (95%); melting point: 151°-152° C.; IR (cm-1): 1720, 1529, 1345.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1ccc(F)cc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35](Cl)=[O:36])[N:23]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:6][CH2:5]3)=[O:36])[N:23]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccnc1N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
126 mg 2-piperazin-1-yl-nicotinonitrile was added to 216 mg (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 150 μL triethylamine in 10 mL dichlormethane. The reaction was stirred 1 day at RT, the solvant was evaporated and the residue was purified by HPLC to give 93 mg of the desired product. (M+H)+: 486
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][C:12]=2[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1.O>[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:23][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.79 g, 18.77 mmol) was added to a stirred solution of phenylmethyl 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoate (may be prepared as described in Description 78; 0.81 g, 1.88 mmol) in tetrahydrofuran (50 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After the reaction mixture was cooled to room temperature, the solvent was removed and the residue was dissolved in water (100 ml) and stirred in an ice-water bath. 1N HCl (aq) was added to adjust the pH to 4. The solid was filtered, and dissolved in ethyl acetate (80 ml). The solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as a white solid, 486 mg.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[CH:12](N=C(O)N(C(C)C)C(C)C)([CH3:14])[CH3:13]>C(#N)C>[CH3:13][CH:12]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:14]
Reactant: COC(=O)c1sc(C)cc1O
Reactant: CC(C)N=C(O)N(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1sc(C)cc1OC(C)C
Yield: 75.6 %

Procedure:
Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (20.0 g, 116 mmoles) is dissolved in acetonitrile (450 mL) under argon. Triisopropylisourea (86.6 g, 465 mmoles) is added and the mixture stirred and heated under reflux. After 24 hours the mixture is cooled and the precipitate filtered off, rinsed with cold MeCN and discarded. The filtrate is stripped of solvent by rotary evaporator, then the excess triisopropylisourea is removed by distillation under reduced pressure. The remaining residue is dissolved in a small amount of ethyl acetate, cooled, filtered, and passed through a short column of silica gel. Evaporation of the effluent under reduced pressure leaves the product as an oil (18.8 g) sufficiently pure for further use.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.O.CCOCC.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:16]#[N:17])[C:7]=1[F:8]
Reactant: Fc1c(Cl)ccnc1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: N#Cc1nccc(Cl)c1F
Temperature: 100 °C

Procedure:
To a degassed solution of 2-bromo-4-chloro-3-fluoropyridine (7.3 g, 34.7 mmol) in DMF (50 mL) was added palladium tetrakistriphenylphosphine (4.01 g, 3.47 mmol) and zinc cyanide (4.07 g, 34.7 mmol) and heated to 100° C. for 20 minutes. After this time, more palladium tetrakis triphenylphosphine (4.01 g, 3.47 mmol) was added and heated to 100° C. for 90 minutes. The mixture was allowed to cool to room temperature and treated with water (200 mL) and ether (400 mL). The resulting mixture was filtered to remove insoluble solids, the filtrate was partitioned, and the aqueous layer was extracted with ether (400 mL). The combined ether extracts were washed with water (200 mL), dried (MgSO4), filtered, and the solvent removed in vacuo. This residue was purified by chromatography using silica gel column (330 g) eluting with a gradient of 10-100% CH2Cl2 in hexanes to provide the title compound. 1H NMR (CDCl3) δ=8.45 (d, 1H, J=5 Hz) and 7.65 (dd, 1H, J=5 Hz) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1>ClCCl>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:8](=[O:11])[CH:9]=[CH2:10])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Add triethylamine (0.82 mL; 2.0 equiv; 5.86 mmoles) followed by 2-propenoyl chloride (0.24 mL; 1.0 equiv; 2.93 mmoles) dropwise to a 0° C. solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.781 g; 1.0 equiv; 2.93 mmoles) in dichloromethane (29 mL). Stir the solution for 16 hours at ambient temperature, then dilute with dichloromethane, wash with brine, dry over sodium sulfate, filter, and concentrate to an orange oil. Purify the crude product by column chromatography to afford 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one (0.66 g; 70%): MS (m/z): 321 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cccnc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccnc1
Yield: 14 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with pyridine-3-boronic acid (available from Combi-Blocks Inc.; 49 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyridin-3-yl-benzoic acid (12 mg, 14%). 1H NMR (300 MHz, DMSO-d6), δ 13.27 (br s, 1H), 8.56-8.63 (m, 2H), 8.45-8.51 (m, 2H), 8.34 (d, J=1.9 Hz, 1H), 8.28 (dd, J=7.9, 1.9 Hz, 1H), 8.10 (dd, J=8.5, 2.1 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.48 (dd, J=7.7, 5.1 Hz, 1H).