Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(2,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.106) (0.45 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.4 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].Cl>O.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH3:24])[CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Methyl 4-(2-(benzyloxycarbonylamino)ethyl)benzoate ((3.2 g, 10.2 mmol) was added to tetrahydrofuran (34 mL) and reacted with methyl iodide (3.8 mL, 61.2 mmol), then sodium hydride (2.0 g, 51 mmol) was added batch-wise and the reaction mixture was stirred for 3 h at room temperature, and then water (1 mL) was added. The mixture was stirred at room temperature for 1 h, adjusted to pH=3 with 1N hydrochloric acid and the mixture was extracted by ethyl acetate (50 mL×3), washed by water and evaporated the solvent. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 10:1 to 2:1, acetic acid was added) to obtain 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.3 g, yield 72%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.79-2.85 (m, 5H), 3.49 (m, 2H), 4.95-5.04 (t, J=19 Hz, 2H), 7.24-7.37 (m, 7H), 7.83-7.86 (m, 2H), 12.8 (s, 1H); LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: [C:1]([NH:3][C:4](S(C)=O)=[N:5][CH3:6])#[N:2].[CH3:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:16][S:17][CH2:18][CH2:19][NH2:20]>CC#N>[C:1]([N:3]=[C:4]([NH:20][CH2:19][CH2:18][S:17][CH2:16][C:12]1[N:13]=[CH:14][NH:15][C:11]=1[CH3:10])[NH:5][CH3:6])#[N:2]
Reactant: CN=C(NC#N)S(C)=O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 79.8 %

Procedure:
A solution of N-cyano-N'-methyl-methylsulfinylformamidine (493 mg) and 2-(5-methylimidazol-4-ylmethylthio)ethylamine (684 mg) in CH3CN (20 ml) was stirred for 4 hrs. at room temperature. After concentration under a reduced pressure, the residue was subjected to chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The product obtained was recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (684 mg). Yield 79.7%, m.p. 136°-138° 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:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
A solution of 11-bromoundecanoic acid (53 g, 0.2 mol) and concentrated sulphuric acid (1 ml) in ethanol (250 ml) was heated to reflux for 24 hr. After cooling to room temperature, the mixture was concentrated to half its original volume by evaporation under reduced pressure. The residue was poured into water (400 ml) and extracted with diethyl ether (3×300 ml). The combined extracts were then washed with saturated sodium bicarbonate solution (3×200 ml) and water (3×200 ml). After drying over MgSO4 the solvent was evaporated under reduced pressure to give a yellow coil (55.5 g, 95%)
Reaction SMILES: [CH2:1]([N:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:12]([O:14]C)=[O:13])=[O:5])[CH3:2].[Li+].[OH-]>CO>[CH2:1]([N:3]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCN(C(=O)N1CCCC[C@H]1C(=O)OC)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(C(=O)N1CCCC[C@H]1C(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
To (S)-methyl 1-(N-ethyl-N-phenylcarbamoyl)piperidine-2-carboxylate (0.15 g, 0.5 mmol) dissolved in methanol (2.0 mL) was added a solution of LiOH (1.0 N, 8.0 equiv). The reaction was heated to 50° C. and stirred at this temperature for 4 h. The solvent was then removed and pH was adjusted to 4 by addition of 1N HCl. The mixture was extracted with dichloromethane and evaporation of the solvent afforded (S)-1-(N-ethyl-N-phenylcarbamoyl)piperidine-2-carboxylic acid (0.1 g, 72% yield). 1H NMR (500 MHz, CD2Cl2) δ 1.00-1.10 (m, 4H), 1.40-1.55 (m, 3H), 2.10 (m, 2H), 2.5 (m, 1H), 3.2 (d, 1H), 3.50-3.55 (m, 2H), 3.65-3.70 (m, 1H), 4.4 (t, 1H), 7.10-7.25 (m, 3H), 7.30-7.45 (m, 2H), 12.5 (br s, 1H).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.O>[CH:10]1([C:8](=[O:9])[CH2:7][C:1]([O:4][CH3:5])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of dimethyl carbonate (361 g) in toluene (1250 ml) added cyclopropyl methyl ketone (125 g) and stirred for 15 min at 25° C. Cooled the reaction mixture to 10° C., added potassium tert.butoxide (100 g) to it under nitrogen atmosphere. Heated the reaction mixture to 75° C. and stirred for 14 hrs. Cooled the reaction mixture to 25° C. and slowly poured it into chilled water (750 ml). Cooled the reaction mixture to 0° C. and adjusted the pH to 2.5 by using 50% HCl solution. Raised the temperature to 25° C. and stirred for 45 minutes. Separated the both organic and aqueous layers. Extracted the aqueous layer with toluene (500 ml). Washed the organic layer with water (500 ml). Distilled off the toluene completely from organic layer under reduced pressure to get the title compound.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][C:11]1[N:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[N:13][CH:12]=1.[CH3:19][C:20]1[N:21]=[C:22]([N:28]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:29]2=[O:40])[S:23][C:24]=1[C:25](O)=[O:26]>>[CH3:19][C:20]1[N:21]=[C:22]([N:28]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([F:37])([F:38])[F:39])[C:29]2=[O:40])[S:23][C:24]=1[C:25]([NH:18][CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([CH3:10])[N:16]=1)=[O:26]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: Cc1cncc(CN)n1
Agent: NCc1cncc(F)c1
Product: Cc1cncc(CNC(=O)c2sc(N3CCN(CCCC(F)(F)F)C3=O)nc2C)n1
Yield: 34 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (6-methylpyrazin-2-yl)methanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 34% yield: mp 123-123° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.39 (s, 1H), 6.75-6.72 (m, 1H), 4.70 (d, J=4.9 Hz, 2H), 4.17-4.12 (m, 2H), 3.64-3.59 (m, 2H), 3.44-3.39 (m, 2H), 2.63 (s, 3H), 2.57 (s, 3H), 2.25-2.09 (m, 2H), 1.92-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.4, 155.6, 152.9, 152.6, 148.7, 143.4, 142.7, 128.6, 124.9, 117.6, 42.9, 42.3, 42.0, 31.4, 30.9, 21.2, 20.2, 20.1, 17.3; MS (ES+) m/z 442.7 (M+1).
Reaction SMILES: [ClH:1].[CH:2]1[C:16]2=[C:17]3[C:9]([C:10]4[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]([CH2:18][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[CH:3]=1.[CH:26]1C2=C3C(C4C2=CC=CC=4)=CC=CC3=C(C=O)C=1.NC(CC)(CO)CO>>[ClH:1].[CH2:25]([C:20]([NH:19][CH2:18][C:4]1[CH:3]=[CH:2][C:16]2[C:15]3[C:10]([C:9]4[C:17]=2[C:5]=1[CH:6]=[CH:7][CH:8]=4)=[CH:11][CH:12]=[CH:13][CH:14]=3)([CH2:21][OH:22])[CH2:23][OH:24])[CH3:26]
Reactant: O=Cc1ccc2c3c(cccc13)-c1ccccc1-2
Reactant: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: CCC(N)(CO)CO
Agent: Cl
Product: CCC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2

Procedure:
Using the reductive amination procedure described in 1D, 3-fluoranthenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-ethyl-2-((3-fluoranthenylmethyl)amino)-1,3-propanediol hydrochloride mp 250°-252° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:31][CH:30]=1>>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)=[O:19])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(C(=O)c2cccc(C(F)(F)F)c2)C(C)C(=O)O)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1cccc(C(F)(F)F)c1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(m-trifluoromethylbenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(m-trifluoromethylbenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(m-trifluoromethylbenzoyl)2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 119° to 121°).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(N(CC)CC)C>O1CCCC1>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[CH2:14][CH2:13]1
Reactant: ClCCCBr
Reactant: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(CCCCl)CC2
Yield: 52.6 %

Procedure:
A mixture of 7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 7.3 mmol), 1-bromo-3-chloropropane (0.80 ml, 8.1 mmol) and triethylamine (3 ml, 21.5 mmol) in anhydrous tetrahydrofuran (25 ml) was heated at reflux for 5 h. The mixture was cooled, evaporated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml) and the combined organics washed with brine (150 ml), dried (Na2SO4) and evaporated in vacuo. Purification by chromatography on silica gel using 10-70% ethyl acetate in hexane gradient elution gave the title compound as a pale orange oil (1.22 g, 53%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[CH2:19]1[CH2:23]OC[CH2:20]1.[Li]N([Si](C)(C)C)[Si](C)(C)C.C(Br)C=C>CCOC(C)=O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:23][CH:19]=[CH2:20])[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCCCC(=O)N2CCOC2=O)OCCO1
Reactant: C1CCOC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-3 (6.0 g, 23.3 mmol) and THF (125 mL) at -78° C. was added LiN(TMS)2 (18.9 mL, 37.8 mmol, 1.0M in THF) dropwise over 10 minutes. After 20 minutes, allyl bromide was added. After 10 minutes, the reaction was warmed to 0° C. After 4.0 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes) gave 2-4 as an yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:43](=[O:45])[CH3:44])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(N)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(NC(C)=O)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To [3-(4-amino-2-{[methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-phenoxy)-phenyl]-acetic acid ethyl ester (0.156 g, 0.33 mmol) and triethylamine (0.07 mL, 0.49 mmol) in CH2Cl2 (2 mL) was added acetyl chloride (0.02 mL, 0.33 mmol), and the reaction was stirred at room temperature for 2 minutes. LCMS analysis showed some starting material remained, so additional acetyl chloride (0.01 mL) was added, and the reaction was stirred for 30 minutes, until no starting material was seen by analytical LCMS. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was dried and concentrated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH:34]([CH3:38])[C:35]([OH:37])=[O:36]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH:34]([CH3:38])[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC(C(=O)O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 40.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.73 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.34 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH2:4]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH2:4]1
Reactant: Nc1nc2c(Oc3cc(C4=CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(C4=CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[6-(4-trifluoromethyl-cyclohex-1-enyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, Example 1(e), (85 mg, 0.22 mmol) in toluene was added acetic anhydride (82 μL, 0.86 mmol). The mixture was heated at 90° C. with stirring for 1 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 435 (M+1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Yield: 50 %

Procedure:
Starting material ratios as low as 1.1/1.3/1 (moles of AlCl3 :1,4-dichlorobenzene:benzoyl chloride) have been found sufficient to produce 2,5-dichlorobenzophenone in about 50% yield under the conditions provided by the present invention; the same ratio of starting materials has been found to give a 64% yield of 2,5-dichlorobenzophenone if the benzoyl chloride is added slowly to a mixture of AlCl3, 1,4-dichlorobenzene and a small amount of benzoyl chloride.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[N:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[C:9]=[S:10]>CCOC(C)=O>[NH2:7][C:6]1[S:10][C:9]([NH:8][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: S=C=Nc1cccc2ccccc12
Reactant: N#CC(N)C(N)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2cccc3ccccc23)sc1N
Yield: 48.7 %

Procedure:
To a suspension of 2-amino-2-cyanoacetamide (0.25 g, 2.53 mmol) in EtOAc (8 mL), was added 1-isothiocyanatonaphthalene (0.467 g, 2.53 mmol), and the mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography eluted with 2% MeOH in DCM to give 0.35 g (48% yield) of the titled compound.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33]C)=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)[CH:8]3[N:9]=2)=[C:5]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[N:4]=[CH:3]1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]5[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:29]=5)[CH2:20][CH2:19]4)[CH:8]3[N:9]=2)=[C:5]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[N:4]=[CH:3]1
Reactant: COCCOc1ccc(N2CCN(CCN3C(=O)N(C)N4C5=C(c6ccco6)N=CN(N)C5=NC34)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)N(CCN2CCN(c3ccc(OCCO)cc3)CC2)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a solution of compound 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (Example A1) (0.075 g, 0.140 mmol), in DCM (10 ml) was added BBr3 (0.15 ml, 0.154 mmol) drop wise at 0° C. and stirred at 25° C. for 20 hours. The reaction mixture was quenched with sat. NaHCO3 (25 ml) and extracted with DCM (3×20 ml). The crude product was purified by column chromatography to obtain 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-hydroxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (70 mg, 90%) as an off white solid
Reaction SMILES: C[CH2:2][CH2:3][CH:4]([C:6]1(CC)C(=O)NC(=O)[NH:9][C:7]1=O)[CH3:5].Cl[C:18](Cl)(Cl)[CH:19]([OH:21])O.C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)CO)=CC=C([N+]([O-])=O)C=1>>[NH2:9][CH2:7][CH2:6][C:4]1[CH:5]=[CH:18][C:19]([OH:21])=[CH:2][CH:3]=1
Reactant: CCCC(C)C1(CC)C(=O)NC(=O)NC1=O
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: *CC*
Agent: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Product: NCCc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Rats were anesthetized with a mixture of pentobarbital (30 mg/kg) and chloral hydrate (120 mg/kg) by intraperitoneal injection. The left carotid artery and jugular vein were cannulated with fine polytene tubing (artery) or fine silicone rubber tubing connected to polyethylene tubing (vein), the distal end of which was brought under the skin to an anchor point behind the neck. The tubing was filled with heparinized saline solution, and plugged with a fine steel rod. The animals were treated with 20 mg chloramphenicol by intramuscular injection and allowed to recover from the operation overnight. The following day, the rats were placed in a high-walled container permitting free movement. The arterial catheter was connected to a pressure transducer via a 100 cm length of saline-filled, fine-bore polyethylene tubing, and the venous catheter connected to a 1 ml syringe via a similar length of tubing, which, together with the syringe, contained a solution of tyramine hydrochloride in saline (1 mg/ml). Following an equilibration period of 30 to 40 minutes, tyramine injections (50 or 100 μg) were given and blood pressure responses recorded. An interval of at least 15 minutes was maintained between injections after return of blood pressure to control values. Control pressor responses were established, then one of the drugs was injected intraperitoneally, and tyramine responses were repeated over the next 4 hours. The area under the blood pressure response curve was estimated, and the ratio of this area after treatment to before treatment and to 1 to 3 hours after injection of the compounds, was determined using the average of 3 to 4 values obtained in the control period.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]#[N:20])=[CH:8][CH:7]=1.[N:22]([Sn](C)(C)C)=[N+:23]=[N-:24]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[NH:24][N:23]=[N:22][N:20]=2)=[CH:8][CH:7]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCC#N)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2nnn[nH]2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 139.6 %

Procedure:
To a solution of (E)-3-{4-[1-(2-cyano-ethyl)-pyrrolidin-2-yl]-phenyl}-acrylic acid methyl ester (1.0 g, 3.5 mmol) in xylene (35 mL) was added azidotrimethyltin (1.09 g, 5.30 mmol) and the reaction solution was stirred at 130° C. for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in an aqueous sodium hydroxide solution, washed with ethyl acetate, and neutralized with 1 N hydrochloride. A yellow oil was separated from the aqueous layer which was extracted with methylene chloride:ethanol (4:1) several times. The organic layers were combined with the yellow oil, dried over sodium sulfate, filtrated and concentrated in vacuo to give 1.6 g of a yellow oil, which was used to the next step without further purification. LCMS (m/z): 328.0 (M+1).