Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[CH3:23][C:24]1[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.O1CCCC1>[CH3:30][C:28]1[N:29]=[C:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1cccc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 41.1 %

Procedure:
To a mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.23 g, 0.79 mmol), 6-methyl-2-pyridinemethanol (0.13 g, 1.07 mmol) and triphenylphosphine (0.30 g, 1.14 mmol) in benzene (10 mL) under nitrogen was slowly added a solution of diethyl azodicarboxylate (0.22 g, 1.27 mmol) in tetrahydrofuran (6 mL). The resulting mixture was stirred at ambient temperature for 16.5 h. The solvents were removed under reduced pressure, and the residue was taken up into 2 M sodium carbonate (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic solution was washed with brine (50 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with hexanes/ethyl acetate (2:1) gave 1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.13 g, 41%) as a colorless solid: mp 183-185° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.56 (dd, J=7.8, 7.5 Hz, 1H), 7.23-7.16 (m, 2H), 7.10-7.00 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.32 (s, 1H), 5.23 (d, J=15.9 Hz, 1H), 4.958 (d, J=9.0 Hz, 1H), 4.956 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.8, 158.2, 155.4, 154.7, 144.8, 142.2, 138.4, 138.2, 132.3, 129.0, 124.0, 123.7, 122.9, 121.2, 118.8, 111.8, 109.8, 99.6, 80.3, 64.7, 64.1, 58.3, 45.7, 24.1; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[N:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1>C(O)C.[Pd]>[CH:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH2:11])=[N:4][CH:5]=1)([CH3:10])[CH3:9]
Reactant: C=C(C)c1cnc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(C)C)cnc1N
Yield: 95 %

Procedure:
3-methyl-2-nitro-5-(prop-1-en-2-yl)pyridine (221 mg, 1.24 mmol) was dissolved in ethanol (25 mL) and hydrogenated using a H-cube flow hydrogenator (settings: 20° C., 1 bar, 1 mL/min flow rate) and a 10% Pd/C CatCart (30 mm) as the catalyst. The collected solution was concentration in vacuo to give the title compound (177 mg, 95%). LCMS (2 min, formic) Rt 0.50 min, m/z (ES+) 151 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:5][C:4]1[CH:6]=[C:7]([I:9])[CH:8]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)cc(I)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a stirred solution of 3-bromo-5-iodo-aniline (0.60 g, 2.01 mmol) and pyridine (0.65 mL, 8.06 mmol) in CH2Cl2 (15 mL) at 0° C. was added methyl chloroformate (0.17 mL, 2.22 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 12 hours. The reaction mixture was washed with twice with 5 mL 1 M HCl and 5 mL brine. The organic layer was dried over Na2SO4 and concentrated to give 0.71 g (99%) of (3-bromo-5-iodo-phenyl)-carbamic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:50]=[CH:49][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([O:47]C)=[O:46])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CCN(CC)CC>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])=[O:31])=[CH:49][CH:50]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-L-phenylalaninate (20 mg, 0.029 mmol) was dissolved in 1.6 ml MeOH and 0.2 ml H2O. Et3N (0.2 ml, 1.44 mmol) was added and the mixture was stirred overnight. The mixture was heated to 80° C. for 7 h. The mixture was purified by preparative HPLC using a C8 column (25×300 mm). A gradient from 20% to 40% MeCN in 0.1 M ammonium acetate was used as mobile phase. The product fraction was concentrated and lyophilized to yield 7 mg (36%). M/z: 688.
Reaction SMILES: [C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)(C)C#N)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(C)(C)C#N)ccc1C(=O)O
Temperature: 65 °C
Yield: 78 %

Procedure:
Methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (340 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (98 mg, 4.1 mmol) was added and reaction mixture was heated at 65° C. for 1 hour. The crude material was diluted with 10 mL of water and was extracted two times with ether. The ether extracts were discarded and the aqueous layer was made acidic with 4M HCl. The product was then extracted into ethyl acetate, dried over sodium sulfate, filtered, and evaporated to dryness to yield 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid (78%) as a pale yellow solid. ESI-MS m/z calc 235.1. found 236.1 (M+1)+. Retention time: 1.29 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14]Br>>[Br:14][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]
Reactant: BrBr
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Product: O=C(O)c1cc(F)c(Br)c(F)c1F

Procedure:
The 4-fluoro substituent of 2,3,4,5-tetrafluorobenzoic acid was replaced by bromine by a series of reactions analogous to the sequence VIII→IX→X→II in Flow Sheet C, to produce 4-bromo-2,3,5-trifluorobenzoic acid (XI). The latter is then converted to a series of reactions analogous to the sequence IV→V→VI→VII of Flow Sheet A to yield an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5-trifluorobenzoyl)propenoate (XII). Selective cyclization of XII with lithium carbonate affords an alkyl 7-bromo-6,8-difluoro-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIII). Coupling with 2,6-dimethyl-4-(trialkylstannyl)pyridine then yields alkyl 6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIV). The latter is then converted to its mesylate (XV) with methanesulfonyl chloride. The mesylate is cyclized with hydrogen sulfide and sodium hydride to form the ester I (R'=H, X=S) which by hydrolysis is converted to the free acid (I; R and R'=H, X=S). The cyclization takes place by saturating a solution or suspension of XV with hydrogen sulfide, then treating it with excess sodium hydride while cooling the reaction in a Dry Ice bath and then allowing the reaction to warm to ambient temperature.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[C:37]([O:39]CC)=[O:38]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH:36]([CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:54])[C:50]([F:51])([F:52])[F:53])[C:37]([OH:39])=[O:38])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([CH3:27])=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:23]=4)[CH:20]=3)[C:11](=[O:28])[CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:32])[C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([CH3:27])=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:23]=4)[CH:20]=3)[C:11](=[O:28])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(NCc4ccc(Cl)s4)cc3=O)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(N(C)Cc4ccc(Cl)s4)cc3=O)cn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(((5-chloro-2-thienyl)methyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (11.5 mg) in DMF (1 ml) was added NaH (60% in oil, 1.7 mg) at 0° C. After the reaction mixture was stirred at 0° C. for 10 min, iodomethane (2.61 μl) was added to the reaction mixture. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was triturated with IPE, and the resulting solid was collected by filtration and washed with EtOAc-IPE to give the title compound (4.0 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([OH:19])=O)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.CS(C)=O>[F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:19])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Temperature: 45 °C

Procedure:
To a solution of 2-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (Example 65B) (75 mg, 0.181 mmol) in N,N-dimethylformamide (1.0 mL) was added methanesulfonamide (20.7 mg, 0.218 mmol), 4-dimethylaminopyridine (66.5 mg, 0.544 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (52.2 mg, 0.272 mmol). The solution was heated to 45° C. for 4 hours. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 um column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 12.30-12.18 (m, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.22 (d, J=3.6 Hz, 1H), 8.16 (s, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 5.10 (s, 2H), 3.29 (s, 3H), 2.64-2.56 (m, 2H), 2.46-2.32 (m, 2H), 2.05-1.87 (m, 2H); MS ESI(+) m/z 490.9 [M+H]+.
Reaction SMILES: C(OC[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16])C1C=CC=CC=1.C(O)(=O)C.Cl>O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[NH:12][CH:13]=[CH:14][N:10]=2)[OH:16])=[CH:28][CH:27]=1
Reactant: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
About 17 g. (0.042 mol) of 1-[(benzyloxy)methyl]-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol was boiled under reflux in a mixture of 85 ml. of glacial acetic acid, 8.5 ml. of water and 8.5 ml. of concentrated hydrochloric acid solution. Acetic acid was removed by evaporation and the base was liberated by addition of 2 N sodium hydroxide solution. It was crystallised from isopropyl alcohol. Melting point of the product was 162°-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1N
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a solution of 2-methylaniline (1.0 g) and triethylamine (0.95 g) in N,N-dimethylformamide (15 ml) was added benzyl bromide (1.9 g) at ambient temperature and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and it was washed with water and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (n-hexane:ethyl acetate=10:1) to give N-benzyl-2-methylaniline (795 mg) as a slightly yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][C:13]2[N:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][C:14]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)[CH3:2].Cl[C:31]1C=CC2N(C(CNC3N=C(C=O)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.CNCC>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][C:13]2[N:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][C:14]=2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:6]=1)[CH3:31])[CH3:2]
Reactant: O=Cc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1
Reactant: CCNCc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(C)cn23)n1
Agent: CCNC
Product: CCN(C)Cc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(C)cn23)n1
Yield: 40 %

Procedure:
The title compound was prepared in the same fashion as that described for compound 196 from 2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehyde and N-methylethanamine. (0.068 g, 40% yield). M/e+ 425.1 for C22H22ClFN6 (M+H)+; 1H-NMR (500 MHz, CDCl3, δ) 8.55 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.57 (d, J=9.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.83 (d, J=5.0 Hz, 1H), 5.26 (br s, 1H), 5.05 (d, J=6.0 Hz, 2H), 3.48 (s, 2H), 2.51 (q, J=7.0 Hz, 2H), 2.28 (s, 3H), 1.11 (t, J=7.0 Hz, 3H)
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.N([O-])=[O:25].[Na+].N>C(O)(=O)C.O>[OH:25][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(O)cc2[nH]1
Reaction time: 1 h

Procedure:
An amount of 3.2 (9.6 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was dissolved in 509 ml of glacial acetic acid, and then a solution of 1.38 gm (20 mmol) of sodium nitrite in 5.0 ml of water was added dropwise, under stirring. After one hour, the mixture was diluted with 100 ml of water, and the solution was refluxed for 1.5 hours. Subsequent to cooling, the solution was adjusted to a pH of 5 with concentrated ammonia and extracted three times, each time with 40 ml of methyl ethyl ketone, and the extracts are dried and concentrated by evaporation in vacuo. The oily residue was chromatographed over 500 gm of aluminium oxide (neutral) (eluant: methylene chloride with 8% ethanol).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.C(OC(=O)C)(=O)C.[N:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.Cl>C(O)(=O)C>[CH:9]([C:3]1[CH:2]=[CH:1][C:6]([CH:7]=[CH:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:5][CH:4]=1)=[O:10]
Reactant: Cc1ccncc1
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc(C=Cc2ccncc2)cc1

Procedure:
A mixture of 400 parts of terephthaldehyde, 120 parts of acetic acid and 300 parts of acetic anhydride was refluxed for two hours. 188 parts of 4-picoline were then added over a period of 45 minutes, and the dark brown mixture was refluxed for a further 2 hours. 3300 parts of 1M aqueous hydrochloric acid were then added. The desired product was extracted with toluene and treated with 5M sodium hydroxide to a pH between 5 and 6. The crude solid product was dissolved in hot ethyl acetate and the solution was filtered. Cooling of the filtrate gave the desired product, 4-(2-(4-formylphenyl)-ethenyl)-pyridine.
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](NC3C=C4C(=CC=3)C(CC(O)=O)CC4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C1(C)C(N=C=S)=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:62])C>>[C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:19])=[O:62])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCO
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc4c(c3)CCC4CC(=O)O)cc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1N=C=S
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 3) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography on silica eluting with a mixture of 5-10% tert-butyl methyl ether in dichloromethane to remove dicyclohexylurea. The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][Cl:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH3:18])[C:5]([CH2:9][Cl:10])=[CH:4][N:3]=1
Reactant: ClCc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)CN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)ncc1CCl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 3.47 g (17.57 mmol) of 2,4-dichloro-5-choromethyl-pyrimidine and 2.9 ml (21.08 mmol) triethylamine in 29 ml of THF is cooled to −5° C. and 2.2 ml (17.57 mmol) 2,2-dimethyl-propylamin is added over a period of 15 minutes. The reaction mixture is stirred at −5° C. for additional 2 h, then diluted with ethyl acetate and extracted once with brine. The organic layer is separated and dried over Na2SO4. Purification of the crude product by flash chromatography (hexanes/ethyl acetate) yields (2-chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as white crystalls.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:9][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
o-cresol (3.0 g, 0.028 mol) and anhydrous potassium carbonate (7.7 g, 0.056 mol) were dissolved into 50 ml of DMF and then iodomethane (3.9 g, 0.028 mmol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 3 g of the product (89%) by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: COC(=O)c1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(C)=O)cc1
Yield: 95.8 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxycarbonylphenyl)benzamide (291.0 mg, 0.58 mmol) and acetic anhydride (0.11 ml, 1.16 mmol), the procedure of Inventive Example 94 was repeated to obtain 303.0 mg (96.0%) of the title compound in a colorless amorphous form.