Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Methyl indole-5-carboxylate (1.40 g) was dissolved in 10 ml of dimethylformamide, followed by addition of 212 mg of sodium hydride (content: 95%) under ice-cooling and stirring for one hour. To the mixture, there was added 1.51 g of benzyl bromide, followed by stirring the mixture for 2 hours, pouring the reaction solution into 140 ml of a 5% ammonium chloride aqueous solution and extraction with ethyl acetate (50 ml×2). The resulting organic phase was washed with water (50 ml×2), dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give 2.09 g of methyl 1-benzylindole-5-carboxylate as orange-colored crystals. The yield thereof was found to be 99%.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:30]2[CH:29]=[N:28][CH:27]=[N:32][CH:31]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 120.6 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromo-6-chloropyridine (500 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (50 mg, 1%) and tributyl(pyrimidinyl)tin (0.64 g, 1.72 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:3) to afford an oil (500 mg, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.26-2.42 (m, 2H), 3.84-3.92 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.31 (d, 1H, J=3.0 Hz), 8.22 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([C:13]([O:15]CC)=[O:14])[O:12][C:7]=2[CH:6]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: CCOC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Ethyl 7-(2-chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate (Compound 7) (1.1 g) was dissolved in methanol (10 ml), 1N sodium hydroxide (3 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. Then 1N hydrochloric acid (5 ml) was added, the solvent was evaporated under a reduced pressure, and the residue was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure to give 0.9 g of the title compound (colorless oil).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([CH:25]=3)[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[N:5]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([CH:25]=3)[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3noc(C)n3)nc2)ccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Oc3ccc([N+](=O)[O-])c(C(=O)O)c3)cn2)no1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
1.96 ml of aqueous 5 N sodium hydroxide solution was added to a solution of 700 mg of methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrobenzoate in 5 ml of methanol and 5 ml of tetrahydrofuran, and stirred at room temperature for 2.5 hours. Aqueous 10% citric acid solution was added to neutralize it, then extracted with ethyl acetate, and the organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 399 mg of 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrobenzoic acid as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:13](O)(=[O:15])C>[C-]#N.[Na+].O=[Mn]=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:15][CH3:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccc2cnccc2c1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
290 mg of isoquinoline-6-carbaldehyde are dissolved in 40 ml of MeON, and firstly 450 mg of NaCN, then 210 μl of glacial acetic acid, and finally 3.5 g of MnO2 are added. The mixture is stirred at RT for 3 days, and the precipitate is filtered off and the filtrate is poured into a solution of 15 g of FeSO4 in 150 ml of water. Subsequently, the pH of the mixture is adjusted to 9 with Na2CO3 solution, the precipitate is filtered off, and the filtrate is extracted 3× with 150 ml of EA. Drying takes place over Na2SO4, and the solvent is removed in vacuo. 190 mg are obtained of a colorless oil, which in reacted without any further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(Cl)CCl>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:34][S:35]([NH:38][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([CH2:15][N:5]([C@@H:6]3[CH2:8][C@H:7]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3](=[O:4])[C:2]([F:32])([F:1])[F:33])[CH2:21][CH2:20]2)=[CH:31][CH:30]=1)(=[O:37])=[O:36]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
To a solution of 4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoic acid (150 mg, 0.326 mmol) in N,N-dimethylformamide (DMF) (2 mL) were added methanesulfonamide (37.2 mg, 0.391 mmol), EDC (74.9 mg, 0.391 mmol) and DMAP (39.8 mg, 0.326 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% NH4Cl aqueous solution and extracted with EtOAc(3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexaens) to give 82 mg of product as off-white solid. MS: (M+H)+=538.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.38-1.74 (m, 4H), 1.91-2.22 (m, 3H), 2.47 (m, 1H), 2.98-3.11 (m, 2H), 3.21 (d, J=6.82 Hz, 1H), 3.37-3.66 (m, 7H), 4.39 (s, 2H), 7.04-7.38 (m, 5H), 7.67 (d, J=8.34 Hz, 2H), 8.03 (d, J=8.08 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=2)=[C:34]([CH3:41])[CH:33]=1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CCCCCCC(Oc1ccc(-c2ccc(F)cc2C)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step D. MS (ES): 492.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1ccc(-n2ccc(Nc3ccc(OC)cc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2ccn(-c3ccc(OCC(=O)O)cc3)n2)cc1
Yield: 92 %

Procedure:
Ethyl 4-[3-(4-methoxyphenylamino)-1H-pyrazol-1-yl]phenoxyacetate (1.0 g) in ethanol (200 ml) and 10% sodium hydroxide (5 ml) was heated to reflux for 1 hour. Upon cooling, the resultant pink solid was filtered off and treated with a little 10% hydrochloric acid to give a violet solid which was filtered off, rinsed with water and dried to give the title compound (0.85 g), mp 163°-165°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:24]([C:26]1[S:27][C:28]([O:31][CH2:32][CH3:33])=[N:29][N:30]=1)[CH3:25]>O.CN(C)C=O>[CH2:32]([O:31][C:28]1[S:27][C:26]([CH:24]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:9][CH:10]=2)[CH3:25])=[N:30][N:29]=1)[CH3:33]
Reactant: CCOc1nnc(C(C)Br)s1
Reactant: Oc1ccc(Oc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccccn3)cc2)s1
Yield: 61.1 %

Procedure:
To a mixture of 4-(2-pyridyloxy)phenol (0.75 g), anhydrous potassium carbonate (0.67 g), potassium iodide (0.07 g), cupuric oxide (0.02 g) and 7 ml of dimethyl formamide, was added 2-(1-bromoethyl)-5-ethoxy-1,3,4-thiadiazole (0.95 g) under stirring, and further stirred at 80° C. for one hour. After cooling and pouring water, the resulting solution was extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under a reduced pressure and the residue was purified on column chromatography to obtain 0.84 g of the compound (No. 1) described in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]([O:16]CC)=O)[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:19]1([C@@H:25]([NH:27][C:14]([C:12]2[S:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:13]=2)=[O:16])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)ns1
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2nsc(C(=O)N[C@@H](C)c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 117.9 %

Procedure:
A mixture of (S)-1-phenylethyl)amine (1.21 g, 10 mmol) and ethyl 3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylate (1.32 g, 5 mmol) is stirred at 80° C. for 2 hours. A further portion of (S)-1-phenyl-ethylamine (0.5 g, 4 mmol) is added and the mixture is stirred for at 80° C. for a further 1.5 hours. The mixture is then cooled and dissolved in dichloromethane. The solution is washed with dilute sulphuric acid followed by water, and the organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo to give (S)-3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylic acid (1-phenylethyl)-amide (1.6 g, 94%) as colourless crystals, m.p. 143°-145° C.
Reaction SMILES: [C:1](O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.O>C1(C)C=CC=CC=1>[CH3:19][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[O:18][C:1](=[O:10])[CH2:2][CH:3]2[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2
Temperature: 60 °C

Procedure:
Cinnamic acid (100 gms) and p-cresol (76.6 gms) were charged to a clean and dry flask under nitrogen and stirred. Concentrated sulphuric acid was slowly charged and the reaction mixture heated to 125° C.-130° C. for 6 hours. After completion of reaction the mixture was cooled to about 60° C. and about 50 ml water and about 300 ml toluene were charged under stirring. The layers were separated. The toluene layer was washed with aqueous saturated solution of sodium bicarbonate and water. The organic layer was dried over sodium sulfate and concentrated under vacuum, at a temperature below 50° C. The residue was stripped with 2×100 ml IPA. The residue was dissolved in 200 ml isopropanol, chilled to 5° C. and stirred for 2 hours. The solids obtained were filtered and dried at about 60° C. for 4-5 hours to give about 135 to 137 gms of the title product.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:31])[CH3:30]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:26][N:31]=[C:29]([CH3:30])[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 21.9 mg (0.269 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 41.6 mg (32% of theory).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (345 mg, 1.0 mmol) in ethyl acetate (100 mL) was treated with 10% palladium on activated carbon (34.5 mg). The reaction mixture was stirred under 60 psi hydrogen gas at 25° C. for 6 h. The catalyst was then removed by filtration through a pad of celite and was washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg, 91.4%) as a yellow solid: mp 102-107° C.; EI-HRMS m/e calcd for C17H21N3OS (M+) 315.1405, found 315.1401.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Si]([C:19]#[N:20])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].CS(O)(=O)=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11]([OH:14])([C:19]#[N:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ncccc2Cl)CC1
Reactant: C[Si](C)(C)C#N
Agent: CS(=O)(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(O)CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
A solution of N-(3-chloro-2-pyridyl)-4-piperidone (compound 21) (13 g, 62 mmol), TMS-CN (6.2 g, 62 mmol) and AlCl3 (0.1 g) in toluene (100 ml) was heated to 60° C., and stirred overnight. Then 0.1 equivalent of methanesulfonic acid was added, and the reaction mixture was heated to reflux for half an hour. After the reaction was completed, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (8 g, 55%)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(C(C)C)C(C)C)C.O1CCCC1>[Cu]I>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:16][C:14]([C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([C:6]=1[OH:22])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
In a sealed tube was combined methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.75 g, 2.0 mmol), Dichlorobis(triphenylphosphine) palladium(II) (0.14 g, 0.20 mmol), copper(I) iodide (0.077 g, 0.41 mmol), ethynyltrimethylsilane (1.4 ml, 10 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16 mmol) in tetrahydrofuran (20.0 ml, 2.0 mmol). The tube was flushed with Ar, sealed, and placed in an oil bath at 100° C. for 5 hours. The dark mixture was cooled to rt, filtered and washed with ethyl acetate (2×30 mL). The crude mixture was concentrated, adsorbed onto silica and purified by flash chromatography (15% to 40% EtOAc:Hex gradient) to afford the product as a solid (0.59 g, 75% yield).
Reaction SMILES: [BH3:1].[C:2]1([PH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[C:21]1[CH:22]=[C:23]([CH3:29])[C:24]([CH3:28])=[CH:25][C:26]=1[Br:27]>C1COCC1>[BH3:1].[Br:27][C:26]1[CH:25]=[C:24]([CH3:28])[C:23]([CH3:29])=[CH:22][C:21]=1[P:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c(Br)cc1C
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)c(P(c2ccccc2)c2ccccc2)cc1C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of diphenylphosphine borane (V-a) (0.17 g, 0.83 mmol) in dry THF (2 mL) was added dropwise under argon at −78° C. n-BuLi (0.83 mmol). The resulting solution was stirred at this temperature during one hour and 4,5-dibromo-o-xylene (VI-b) (0.31 g, 1.16 mmol) was then added dropwise followed by n-BuLi (0.17 mmol). After one hour at −78° C., the reaction mixture was quenched with water (10 mL) and extracted with methylene chloride (3×10 mL). The organic phases were dried over MgSO4, filtered and the solvent evaporated giving a residue which was purified by column chromatography on silica gel using petroleum ether/methylene chloride 3:1 as eluent. Analytical pure sample can be obtained by recrystallization in methylene chloride/hexane. White solid; yield 56%; Rf 0.45 (petroleum ether/ethyl acetate 3:1); IR (neat) 3050, 2986, 2946, 2917, 2417, 2388, 2357, 1588, 1481, 1471, 1436, 1343, 1136, 1125, 1102, 1062, 1028, 999, 923, 877, 749, 734, 701, 692 cm−1; 1H NMR (300MHz, CDCl3) δ 2.17 (s, 3H, CH3), 2.29 (s, 3H, CH3), 7.21 (d, J=12.3 Hz, Harom), 7.43-7.56 (m, 7H, Harom), 7.65-7.72 (m, 4H, Harom); 13C NMR (75.5 MHz, CDCl3) δ 19.4 (CH3), 19.5 (CH3), 124.7 (d, J=4.4 Hz, Carom), 131.1 (d, J=2.5 Hz, Carom), 133.2 (d, J=9.6 Hz, Carom), 135.9 (d, J=6.1 Hz, Carom), 136.3 (d, J=9.9 Hz, Carom), 137.8 (d, J=11.8 Hz, Carom), 142.6 (d, J=2.2 Hz, Carom); 31P NMR (121 MHz, CDCl3) δ 25.5; HRMS calcd for C20H21PBBrNa (M+Na)+ 405.0553, found 405.0563; Anal calcd for C20H21PBBr: C, 62.71; H, 5.53; found: C, 62.86; H, 5.58.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[C:13](=[O:15])=[O:14]>Cl.C1COCC1>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
In a reactor under an N2-atmosphere, 22.7 g (933 mmol) of magnesium flakes were added and stirred at room temperature for 3 days. Then, 80 ml of THF and an iodine flake were added, a 100 ml THF solution of 150 g (777 mmol) of 1-bromo-3,5-difluorobenzene was slowly added at room temperature, and then the mixture was refluxed for 1 hour. Next, the mixture was cooled to 10° C., slowly added with 75 g (1710 mmol) of dry ice and stirred at room temperature for 1 hour. The reaction solution was poured in 500 ml of 1N HCl(aq) and then subjected to extraction with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate, filtered to remove insoluble substance, and concentrated under a reduced pressure. The residue was washed using n-heptane to obtain 66.3 g of 3,5-difluorobenzoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[CH3:21]I>N1C=CC=CC=1>[CH3:21][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CI
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2NC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl 2'-amino-4-biphenylylglycolate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 2'-methylamino-4-biphenylylglycolate.
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:23][NH2:24]>C(O)C>[CH2:19]([NH:18][C:4]([NH:24][CH3:23])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CN
Reactant: CCCCN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Solvent: CCO
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC
Reaction time: 504 h

Procedure:
A mixture of 2-methyl-3-(n-butyl)-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (4.0 g) and 33% methylamine in absolute ethanol solution (200 ml) was heated initially for 24 hours at 45° and then left at room temperature for 21 days to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine as an oil; a solution of which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether to give 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m.p. 170°-172° C.).