Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1C=CC=CC=1)C(O)=O)=O)(C)(C)C.[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H:40]2COC(C)(C)[O:41]2)=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].N1(C(=O)CCl)CCC1>>[N:8]1([C:40](=[O:41])[CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C@@H:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:26])[C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH2:9][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(CCl)N1CCC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N2CCC2)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) 4-iodoaniline was used in place of 4-bromoaniline in step 2 and (ii) (R)-[4-(2-azetidin-1-yl-2-oxo-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid was used in place of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine. (R)-[4-(2-Azetidin-1-yl-2-oxo-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid was prepared by a method similar to that used for the preparation of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine in example 1 except that 1-azetidin-1-yl-2-chloro-ethanone was used in place of iodomethane.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CS(C)=O>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step B (0.28 mmol), and 3-aminomethylpyridine (0.59 mmol), in dimethylsulfoxide (1.5 mmol) and acetonitrile (2.5 mL) was stirred at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.103 g; 75%), m.p. 169-171° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[CH3:31][NH2:32].CO>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[CH:14]=[CH:13][NH:12][N:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:32][CH3:31])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2cc[nH]n2)c1C#N
Reaction time: 0.5 h

Procedure:
300 mg (0.639 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 2 ml of tetrahydrofuran, and 0.639 ml (1.278 mmol) of a 2 M solution of methylamine in tetrahydrofuran was added. After 30 minutes of stirring, methanol was added, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave 173 mg (58% of theory) of the target compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[NH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:15]=2[C:16]([NH2:18])=[O:17])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[NH:12][CH:13]=[C:14]([C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[C:15]=2[C:16]([NH2:18])=[O:17])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC(=O)CCC1CCCC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)c[nH]c1NC(=O)CCC1CCCC1
Yield: 79.2 %

Procedure:
0.210 g (0.56 mmol) of 2-(3-cyclopentylpropionylamino)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.055 g (0.0051 mmol) of 10% palladium on carbon in 25 cm3 of methanol. After hydrogenating for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with twice 10 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.151 g of 2-(3-cyclopentylpropionylamino)-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a brown powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.09 (m, 2H); from 1.39 to 1.84 (m, 9H); 2.39 (t, J=8.0 Hz, 2H); 5.14 (broad s, 2H); from 6.20 to 7.50 (very broad m, 2H); 6.23 (d, J=2.5 Hz, 1H); 6.59 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 10.9 (broad s, 1H); 11.3 (broad s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([F:25])=[O:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.00 g, 11.7 mmol) and pyridine (1.132 mL, 14.0 mmol) in dichloromethane (100 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (1.18 mL, 14.0 mmol). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (300 mL), washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane (200 mL), and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol, 96% yield) as a yellow, viscous oil. The product was found to react readily with methanol and on analysis was characterized as the methyl ester, which had an HPLC ret. time=2.56 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=272.3 (methyl ester).
Reaction SMILES: [C:1]([O:8][CH2:9]Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I-].[Na+].C(OC[I:21])(=O)C(C)(C)C>CC(C)=O>[C:1]([O:8][CH2:9][I:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCCCCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)OCI
Yield: 78 %

Procedure:
Chloromethyl hexanoate (205 mg, 1.25 mmol) was stirred with sodium iodide (900 mg, 6.0 mmol) in 3 mL of dry acetone for 4 hours at room temperature. Work-up followed the procedure detailed in EXAMPLE 3 above for the preparation of iodomethyl pivalate. Iodomethyl hexanoate, CH3 (CH2)4COOCH2I, was obtained as a yellow oil in 78% yield. NMR values were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:30])=O.CN(C)C=O>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8]([Cl:30])=[O:9])(=[O:3])[CH3:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
2-(Acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoic acid (475.5 mg, 1.24 mmol) obtained from Example 1-(11) was dissolved in tetrahydrofuran (5 ml), and the solution was cooled to 0° C., then oxalyl chloride (189.2 mg, 1.49 mmol) and N,N-dimethylformamide (15 μl) were added thereto with stirring. The mixture was warmed to room temperature and then stirred for 40 minutes. The solvent was distilled off under reduced pressure to give the crude 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:31][C:32]([NH2:34])=[O:33].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:31][C:32]([NH2:34])=[O:33])=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (3.80 g) in benzene (19 ml) was added thionyl chloride (0.90 ml) with stirring at ambient temperature and the mixture was stirred at the same temperature for one hour. To the mixture were added urea (1.80 g) and concentrated sulfuric acid (0.05 ml) successively. The mixture was heated under reflux for 5 hours. The reaction mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.85 g).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: NC1CCOCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(NC2CCOCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(tetrahydro-pyran-4-yl-amino)-nicotinamide was prepared starting from intermediate E and 4-aminotetrahydropyran. MS calcd. for C27H25ClN4O3 [(M+H)+] 489.2, obsd. 489.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[C:12]([CH2:14][O:15][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1
Reactant: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Reactant: Oc1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2Cl)cc(COc2ccccc2)cn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
24 mg of 3-(2-Chlorophenyl)-5-hydroxymethyl-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran. 9.4 mg of phenol, 33 mg of triphenylphosphine polymer (3 mmol/g resin) and 17 mg of 1,1′-azobis(N,N-dimethylformamide) were added thereto, followed by stirring at 60° C. overnight. Further, 50 mg of triphenylphosphine polymer (3 mmol/g resin) and 30 mg of 1,1′-azobis(N,N-dimethylformamide) were added, followed by stirring at 60° C. overnight. After cooling to room temperature, ethyl acetate was added thereto and the triphenylphosphine polymer was removed by filtration through Celite. The filtrate was washed with water and 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)n1
Reactant: NC(=O)C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (150 mg, 0.60 mmol), morpholine-3-carboxamide hydrochloride (100 mg, 0.560 mmol) and potassium carbonate (207 mg, 1.50 mmol) were taken up in DMF (3 mL) and the reaction was maintained at room temperature overnight. Water was then added and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:19]I.[Al]>CC(C)=O.[Ag-]=O>[CH3:19][O:10][C:9](=[O:11])[C@@H:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: O=[Ag-]
Agent: [Al]
Solvent: CC(C)=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 100.2 %

Procedure:
To a solution of Boc-Chg-OH (53 mg, 0.206 mmol) in acetone (3 mL) were added methyl iodide (195 μL, 3.1 mmol) and silver (I) oxide (53 mg, 0.229 mmol). The mixture was allowed to stir over night in a reaction flask that was covered with aluminium foil. Thereafter the solution was filtered through celite and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 15:1) provided methyl ester 54 (56 mg, 100%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].CN(C)C1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:35](=[O:38])[CH:36]=[CH2:37])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: C=CC(=O)Cl
Reactant: O=C(O)c1ccc(/C=C/c2ccc(OCCCCCCO)cc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A mixture of 4.38 g (12.8 mmole) of (E)-4-carboxy-4′-[6-hydroxyhexyloxy]stilbene (16), 1.87 g (15.4 mmole) of N,N-dimethylaniline, 1.38 g (15.4 mmole) of acryloyl chloride, 8 mg of 2,6-di-t-butyl-4-methylphenol and 9 ml of 1,4-dioxane was heated at 60° C. under a nitrogen atmosphere. After 3 hours the mixture was cooled and 10 ml of 1,4-dioxane were added. The product was collected on a filter and washed with 40 ml of ethanol. 3.6 g of product (71%) were obtained after drying over silica in a dessicator.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1.[C:29](=O)([O:32]C)[O:30][CH3:31]>C1COCC1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([O:30][CH3:31])=[O:32])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(C)ccn1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(OC)c1
Reaction time: 0.5 h

Procedure:
To the solution of lithium diisopropylamide (Aldrich, 2.0M, 122 mL, 244 mmol), THF (90 mL) and hexamethylphosphoric triamide (Aldrich, 16 mL, 89 mmol) at −78° C. under nitrogen was added, in 10 min, a solution of 2-methoxy-4-methylpyridine (10.0 g, 81 mmol) in THF (30 mL). After 30 min, a solution of dimethyl carbonate (Aldrich, 7.5 mL, 90 mmol) in THF (30 mL) was added over 15 min. The stirring was continued for 2 h at −78° C. before the reaction was quenched with MeOH (30 mL). The mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude product was purified by silica gel chromatography. MS: 182 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]1.[CH2:15]([S:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[CH2:15]([S:19][C:20]1[N:21]=[C:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]2)[CH:23]=[CH:24][N:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: NC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (480 mg, 12 mmol, 60% suspension) was added to a solution of 1H-indole-3-carboxylic acid amide (1.6 g, 10 mmol) in DMF (5 mL) at 0° C. and stirred for 20 min. A solution of 2-butylsulfanyl-4-chloro-pyrimidine (2.23 g) in DMF (5 mL) was added at 0° C., and the mixture allowed to warm to RT overnight. Water was added to the mixture, and the resulting white solid filtered off, washed with water (20 mL) and DCM (20 mL) and air-dried overnight to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (3.224 g, 98.77% yield) as a crude product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].C(O)CCC.[CH:21]([NH:23][NH2:24])=O.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([CH:21]=[N:23][N:24]=3)[N:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NNC=O
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1cc(-c2cccc(Cl)c2)nn2cnnc12

Procedure:
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 50 ml. of n-butanol and 1.08 g. of formylhydrazine is refluxed for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is added gradually until crystals separated. Cooling and filtering gives 1.20 g. of crystals, m.p. 173°-176° C. The crystals in methylene chloride are passed through a short column of hydrous magnesium silicate and the eluent concentrated with the addition of hexane to give 0.83 g. of crystals, m.p. 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(Nc1ccccn1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-pyridinamine (CAN 504-29-0) as starting materials, MS (D) m/e: 310.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[N:15]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1
Reactant: Cc1cc(-c2ccccc2Cl)c(NCC(F)(F)F)cn1
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2Cl)c(N(CC(F)(F)F)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-chlorophenyl)-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine (0.066 g, 219 μmol) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) in CH2Cl2 (1 mL) was added DIPEA (56.7 mg, 76.7 μL, 439 μmol) and the clear yellow solution was stirred at room temperature for 4 hours. Another batch of 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) and DIPEA (56.7 mg, 76.7 μL, 439 μmol) were added and stirring was continued for another 48 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (5%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1.O>C1COCC1>[I:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(I)c(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Methyl-2-iodobenzoic acid (100 g, 0.38 mol) is dissolved in THF (350 ml) and cooled in an ice bath. Borane-THF complex (380 ml of 1M in THF, 0.38 mol) is added dropwise. After addition is complete, the reaction is warmed to room temperature and stirred for 14 hours. The mixture is transferred to a large erienmeyer flask, cooled in an ice bath, and carefully quenched with water (250 ml). Evaporation of the THF on a rotovap gives a white suspension which is treated with additional water (1 L) and then filtered and dried in a vacuum dessicator over P2O5 to give 2-iodo-5-methylbenzyl alcohol as a white solid, m.p. 82-85°.