Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N1-(S-(4-methoxybenzyl)thiosalicyloyl)-N4-benzylpiperazine (compound 5) was prepared using the same procedure described above using: 10 mM(2.743 g) of S-(4-methoxybenzyl) thiosalicylic acid, 3 mM(728 mg) of 1-Benzylpiperazine and 20 mM (3.525 g)triethylamine. The product was dissolved in 5 ml of methylene chloride and purified by column chromatography on a silica gel column (eluent: Ethyl acetate) to give 870 mg(20.1%) of a white crystal. The product was then further purified by crystallization from hexane. The purified product had having a melting point of 84-85° C. and had the following specifications:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:11]1([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=C1CCCN1CC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCN1CC1(CCN2CCNCC2)CCCC1
Reaction time: 7 h

Procedure:
A mixture of 1-[[1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methyl]-2-pyrrolidinone (408 mg) and palladium hydroxide (41 mg) in methanol (5.5 ml) was stirred under hydrogen (4 kg) for 7 hours. After hydrogen was replaced with nitrogen, the mixture was filtered through Celite. The filtrate was concentrated in vacuo to provide a yellow oil. (345 mg/100%)
Reaction SMILES: O1CCCOC1.CC1(C)[O:13][C@H:12](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][O:9]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[OH:9][CH2:10][CH:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C@H:12]([OH:13])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2NC(=O)OC(C)(C)C)cc1
Agent: C1COCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(/C=C/[C@@H](O)C(CO)NC(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
1,3-Dioxane, 2-boc amino (10B) and 10 mol % TsOH were combined in 5.0 mL THF and 5.0 mL H2O and stirred at reflux until the starting material was consumed as indicated by TLC. The reaction mixture was quenched with 5% NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]([NH2:29])=O)[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]#[N:29])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:32])[F:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(N)=O)CC4)cc2)CC3)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C#N)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
The product from Example 14 (22 mg, 0.047 mmol) was stirred in DMF (0.3 mL) at RT in a capped vial. SOCl2 (0.05 mL) was added. The mixture was stirred at RT for 1.5 h. LC-MS showed completion of the reaction. Prep LC-MS purification (35–98% CH3CN in H2O) provided the title compound (15 mg, yield, 71%). LC/MS(ESI+) 453.4 (M+H)+, tR=5.24 min. 1H NMR (acetone-d6) δ 7.50 (d, J=9.2 Hz, 2H), 7.39 (m, 4H), 6.97 (d, J=8.8 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.17 (t, J=6.6 Hz, 2H), 1.71 (m, 2H), 1.48 (m, 2H) ppm. 19F NMR (acetone-d6) δ −77.16 ppm.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Product: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1

Procedure:
To 500 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 10 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water, chloroform, a tract of methanol, and aqueous saturated sodium bicarbonate were added. The chloroform layer was washed with brine, dried with sodium sulfate, and evaporated to give 626 mg of crude 4-chloro-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:22]=2)[CH:17]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:22]=2)[CH:17]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C=Cc2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1C=C(C=O)c2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To anhydrous N,N-dimethylformamide (0.129 mL, 1.51 mmol) at 0° C. was added phosphorus oxychloride (0.068 mL, 0.67 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (142 mg, 0.30 mmol) in dichloromethane (2 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (196 mg, 1.82 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 m]L). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (150 mg, 99% yield) as a yellow oil. The crude product was without further purification.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH3:5][O:6][N:7]=[C:8]([C:14]([CH2:16]Br)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH3:5][O:6][N:7]=[C:8]([C:14]1[N:4]=[C:1]([CH3:2])[S:3][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Thioacetamide (3.8 g.) was added to a solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (12.6 g.) in ethanol (50 ml.) and the mixture was stirred for 5 hours at 50° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (9.0 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cc(Br)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-bromo-2-formylbenzonitrile (200 mg, 0.95 mmol) and morpholine (248 mg, 2.85 mmol) in dichloroethane (10 mL), acetic acid (342 mg, 5.7 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (604 mg, 2.85 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (150 mg, 56%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[CH:14]([C:20](=[O:37])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([NH:31][CH3:32])[C:22]=1[S:33]([CH3:36])(=[O:35])=[O:34])[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16])(C)(C)C>C(Cl)Cl>[CH:17]1([C:15](=[O:16])[CH2:14][C:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[C:23]([NH:31][CH3:32])[C:22]=2[S:33]([CH3:36])(=[O:34])=[O:35])=[O:37])[CH2:19][CH2:18]1
Reactant: CNc1c(C(F)(F)F)ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c1S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1c(C(F)(F)F)ccc(C(=O)CC(=O)C2CC2)c1S(C)(=O)=O

Procedure:
5.0 ml of trifluoroacetic acid were heated at 55°-60° C. A solution of 5.3 g (8.0 mmol; 70% purity) of tert-butyl-3-cyclopropyl-2-(3-methylamino-2-methylsulfonyl-4-trifluoromethylbenzoyl)-3-oxopropanoate in 10 ml of CH2Cl2 was added dropwise and the mixture was then heated at reflux for 15 min. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. This gave 1.22 g of product in 95% purity.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[O:13]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:28][CH:29]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(OCCCc3ccccn3)cc2)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of α-picoline (1.0 g, 11 mmol) in dry tetrahydrofuran (20 ml), n-butyl lithium (8 ml, 11 mmol; 1.4 mmol/ml) was added at -50° C. under nitrogen stream until the reaction mixture turned red. After stirring at -50° C. for 30 minutes, 2-(4-phenoxyphenoxy)ethyl bromide (3.0 g, 10 mmol) was dropwise added thereto at -50° C., and stirring was continued at the same temperature for 2 hours and at 20° C. for 12 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give 2-[3-(4-phenoxyphenoxy)propyl]pyridine (1.6 g) as pale yellow oil. nD24.5 1.5861.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>>[S:8]1[C:7]([CH:10]=[O:11])=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:9]1
Reactant: O=Cc1cc(Br)cs1
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1cc(-c2ccsc2)cs1

Procedure:
[3,3′-bithiophene]-5-carbaldehyde was prepared using the general boronic acid coupling procedure with 4-bromothiophene-2-carbaldehyde and thiophen-3-ylboronic acid (56 mg, 102 mg theoretical, 54.9%). LC-MS m/z 195 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.Cl>O1CCOCC1.C1COCC1.CC(=O)OCC.O>[CH2:5]([C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([OH:10])=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 137.8 %

Procedure:
To a solution of 2-chloro-pyridine-4-carboxylic acid (2.55 g, 16.2 mmol) in dioxane (50 mL), Pd(dppf) (132 mg, 0.162 mmol) is added. The mixture is stirred under argon at rt and isobutyl zinbromide (6.55 g, 32.4 mmol, 65 mL of a 0.5 M solution in THF) is added dropwise. The mixture is stirred at rt for 1 h, then at 100° C. for 16 h. The mixture is cooled to rt and diluted with EA (250 mL) and cold water (0° C.). The mixture is acidified by adding aq. 25% HCl. The org. phase is separated and the aq. phase is extracted with EA (4×50 mL) followed by DCM (6×50 mL). The combined org. extracts are concentrated and dried. The crude product is purified by MPLC on silica gel to give the title compound (2.0 g) in form of a pale yellow oil. LC-MS: tR=0.47 min, [M+1]+=180.09. 1H NMR (CD3OD): δ 1.03 (d, J=6.8 Hz, 6H), 2.12-2.24 (m, 1H), 3.00 (d, J=7.3 Hz, 2H), 8.29 (dd, J=5.8, 1.5 Hz, 1H), 8.34 (s, 1H), 8.88 (d, J=5.8 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:39]1[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[N:41][C:42]([NH2:46])=[C:43]([NH2:45])[CH:44]=1>CN(C=O)C>[NH2:46][C:42]1[N:41]=[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[C:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[F:32])=[CH:44][C:43]=1[NH:45][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A solution of pyrazine-2-carboxylic acid (0.114 g, 0.924 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.178 g, 0.924 mmol) and 1H-1,2,3-benzotriazol-1-ol (0.096 g, 0.712 mmol) in DMF (6 mL) was heated at 40° C. for 15 minutes. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.356 mmol) in DMF (1 mL) was added and the mixture was stirred at room temperature overnight. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with 4% sodium bicarbonate aqueous solution and water, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (90:10 dichloromethane/methanol) to give the title compound (0.057 g, 41% of yield).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16](O)=O)=[C:14]([F:22])[CH:13]=1.N>>[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:14]([F:22])[CH:13]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-2,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.73 (dd, J=9.7, 5.9 Hz, 1H), 8.18 (dd, J=8.8, 6.1 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26](C)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[I-].[K+]>C(Cl)Cl.[Ag]=O>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:19][S:20]([C:23]1[CH:29]=[CH:28][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(OCCOCCOCCOCCOCCOCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Hexaethyleneglycol (11) (2.82 g, 10 mmol, 1 equiv.) was dissolved in CH2Cl2 (100 mL) under a N2 atmosphere, and silver oxide (3.48 g, 15 mmol, 1.5 equiv.) added followed by tosyl chloride (2.10 g, 11 mmol, 1.1 equiv.) and potassium iodide (332 mg, 2 mmol, 0.2 mmol). The solution was stirred at rt for 1 h then concentrated and filtered through celite eluting with ethyl acetate. The filtrate was concentrated in vacuo to give a pale yellow oil which was purified by column chromatography on silica (ethyl acetate) to give 12 (3.79 g, 87%) as a pale yellow oil.
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.[CH3:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:21][C:20]([CH3:23])([CH3:22])[C:19]([O:18][CH3:17])=[O:24])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
A solution of 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5, 0.2 mmol), 2-methyl-alanine methyl ester (0.2 mmol) and HBTU (CAN 94790-37-1, 114 mg, 0.3 mmol) in DMF (0.5 mL) was stirred for 20 h at room temperature. The crude reaction mixture was concentrated in vacuo by centrifugation and purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) to give the desired product together with some impurities (73 mg, 116%) as light yellow oil; MS (LC/MS): 333.1 (M+H).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][NH2:21].C(O)CCC>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:21][CH2:20][C:19]1[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1c(F)cccc1F
Agent: I
Solvent: CCCCO
Solvent: O
Product: N=C(NCc1c(F)cccc1F)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 2.86 g. of 2,6-difluorobenzylamine (prepared from 2,6-difluorobenzylamine hydrochloride) in 100 ml. of n-butanol and 20 ml. of water is heated at reflux for 66 hours. The solvent is removed under reduced pressure and the residual yellow oil is dissolved in aqueous ethanol and made basic with 10N NaOH. The resultant mixture is extracted with chloroform and the chloroform extract is evaporated under reduced pressure to give a yellow gum. This gum in ethyl acetate is purified by silica gel column chromatography, giving a colorless solid. This solid is recrystallized from aqueous ethanol, giving the desired product as colorless crystals, m.p. 168.5°-169.5° C.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH2:14]C(O)=O)[CH:10]=[CH:11][C:12]=1[OH:13].[OH-].[Na+].Cl>C(OC(=O)C)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C:1]([CH3:2])=[O:4])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Sodium acetate (50.5 g) was added to a solution of 3-bromo-4-hydroxyphenylacetic acid (28.5 g) in acetic anhydride (100 ml) and the mixture was refluxed with heating for 21 hours. After cooling to room temperature, 20% aqueous solution of sodium hydroxide was added to the reaction mixture to adjust to pH 11. The mixture was refluxed with heating for one hour. After cooling to room temperature, 10% aqueous solution of hydrochloric acid was added to the reaction mixture to adjust to pH 6. The mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous solution of sodium bicarbonate, and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-(3-bromo-4-hydroxyphenyl) acetone (22.2 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C-:24]#[N:25].[K+]>Cl.O>[C:24]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:25]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: N#Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 93.8 %

Procedure:
3-Amino-5-nitrobenzoic acid (3.64 g, 20 mM) was dissolved in concentrated hydrochloric acid (20 ml), diluted with water (75 ml), cooled to 0°, and added over 30 minutes to a solution of NaNO2 (1.38 g, 20 mM) in water (10 ml). The pH was adjusted to 6.2 with saturated Na2CO3 solution. A mixture of CuSO4.5H2O (10 g, 42 mM) in water (40 ml) and KCN (10 g, 154 mM) in water (20 ml) was heated to 65°, the solution of diazonium salt added over 15 minutes, and the mixture refluxed for 40 minutes. After cooling, and acidifying with 2M hydrochloric acid, the organics were extracted into ethyl acetate (2×200 ml). The combined extracts were washed with aqueous NaH2PO4, water, brine, and dried over Na2SO4. Evaporation gave 3-cyano-5-nitrobenzoic acid (3.6 g, 94%).