Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:16]([CH2:23][CH2:24][CH3:25])=[N:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([CH2:23][CH2:24][CH3:25])=[N:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: CCCc1n[nH]c(C(N)=O)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOc1ccccc1C(=O)Nc1c(CCC)n[nH]c1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-n-propoxybenzoyl chloride (57.6 g, 0.291 mol) in dichloromethane (50 ml) was added dropwise to a stirred, ice-cooled suspension of 4-amino-3-propyl-1H-pyrazole-5-Carboxamide (the compound of Preparation 8 of WO 98/49166) (35.0 g, 0.208 mol) in dry pyridine (350 ml) and the resulting mixture stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was azeotroped with toluene (2×100 ml) and the resulting brown solid triturated with ether (100 ml) to give the title compound (83.0 g) as a beige solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[N:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[C:9]=[S:10]>CCOC(C)=O>[NH2:7][C:6]1[S:10][C:9]([NH:8][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: N#CC(N)C(N)=O
Reactant: S=C=Nc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Yield: 78.2 %

Procedure:
To a suspension of 2-amino-2-cyanoacetamide (0.486 g, 2.70 mmol) in EtOAc (15 mL), was added 2-isothiocyanatonaphthalene (0.5 g, 2.70 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 0.6 g (78% yield) of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[SH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Ethyl bromoacetate (21.5 mL, 194 mmol) and potassium carbonate (50.7 g, 367 mmol) were added to a DMF (450 mL) solution of 4-mercaptophenol (23.1 g, 183 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 30.3 g (78%) of the captioned compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[C:4]([C:8]([NH:10][C:11]([NH:13]C2C=CC(Cl)=CC=2)=[O:12])=[O:9])=[C:3](F)[CH:2]=1.C1C=C(F)C(C(NC(NC2C=C(Cl)C(OC3N=CC(C(F)(F)F)=CC=3Cl)=C(Cl)C=2)=O)=O)=C(F)C=1.C1C=C(F)C(C(NC(NC2C=C(Cl)C(OC(F)(F)C(F)F)=C(Cl)C=2)=O)=O)=C(F)C=1.C1C=CC(Cl)=C(C(NC(NC2C=CC(OC(F)(F)F)=CC=2)=O)=O)C=1.C1C=C(F)C(C(NC(NC2C=CC(CO/N=C(\C3CC3)/C3C=CC(Cl)=CC=3)=CC=2)=O)=O)=C(F)C=1.CC(N1C(=O)N(C2C=CC=CC=2)CS/C/1=N\C(C)(C)C)C.CC(OC1C=CC=CN=1)COC1C=CC(OC2C=CC=CC=2)=CC=1.C[C@H](C/C=C/C(/C)=C/C(OC(C)C)=O)CCCC(OC)(C)C.C1OS(=O)OCC2C3(Cl)C(Cl)(Cl)C(Cl)(C12)C(Cl)=C3Cl.CC(C1C(NC(NC(C)(C)C)=S)=C(C(C)C)C=C(OC2C=CC=CC=2)C=1)C.C1C(CN2CCN/C/2=N\[N+]([O-])=O)=CN=C(Cl)C=1.S(O)(O)(=O)=O.N1C=C(C2CCCN2C)C=CC=1.CC([C@@H]1OC2C=CC3C(=O)[C@@H]4[C@@H](COC5C4=CC(OC)=C(OC)C=5)OC=3C=2C1)=C.CC1OC(C)OC(C)OC(C)O1>>[C:8]([NH:10][C:11]([NH2:13])=[O:12])(=[O:9])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Cl)cc1
Agent: C=C(C)[C@H]1Cc2c(ccc3c2O[C@@H]2COc4cc(OC)c(OC)cc4[C@@H]2C3=O)O1
Agent: CC(C)N1C(=O)N(c2ccccc2)CS/C1=N\C(C)(C)C
Agent: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(=S)NC(C)(C)C
Product: NC(=O)NC(=O)c1ccccc1

Procedure:
Diflubenzuron, Chlorfluazuron, Hexaflumuron, Triflumuron, Tetrabenzuron, Fulfenoxuron, Flucycloxuron, Buprofezin, Pyriproxyfen, Methoprene, Benzoepin, Diafenthiuron, Imidacloprid, Fipronyl, Nicotin sulfate, Rotenone, Metaldehyde, Machine oil, Microbial insecticides such as BT and insect-pathogenic viruses, etc.
Reaction SMILES: CN(C)C=O.[C:6]([O:15][CH2:16][CH3:17])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O.C(OCC)(=O)C>[CH2:16]([O:15][C:6](=[O:14])[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[O:9][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH3:17]
Reactant: CCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1C(=O)OCC
Reaction time: 0.5 h

Procedure:
200 ml of N,N-dimethylformamide was added to 18.3 g of ethyl salicylate, and 34.5 g of potassium carbonate and 24.9 g of lauryl bromide were added thereto dropwise over about 30 min with stirring on a steam bath. After the addition the reaction mixture was heated for 2 hours with stirring, then after cooling it was transferred into a separately funnel, and 300 ml of ethyl acetate and 1l of water were added for extraction. The ethyl acetate solution was washed with dilute hydrochloric acid and then with an aqueous sodium hydrogencarbonate solution and was concentrated, to obtain an oil of 2-dodecyloxybenzoic acid ethyl ester. The oil was dissolved in 300 ml of ethanol, and a solution of 12 g of sodium hydroxide in 50 ml of water was added dropwise thereto over about 10 min at room temperature with stirring. After the addition stirring was continued for 1 hour further and 30 ml of concentrated hydrochloric acid diluted with 300 ml of water was added dropwise. The deposited crystals were filtered, washed with water, and dried to obtain 29.1 g of 2-dodecyloxybenzoic acid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][N:18]([C:25]4[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1c[nH]nc1C(F)(F)F
Reactant: Nc1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C(F)(F)F)n2)ncc1F

Procedure:
A solution of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (100 mg, 0.306 mmol), 2-chloro-5-fluoro-pyrimidin-4-ylamine (52 mg, 0.35 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in NMP (1.0 mL) is heated in a microwave reactor at 150° C. for 1 h. The mixture is poured into H2O. The crude product is filtered out, dissolved in 10% MeOH in DCM, and dried over anhydrous Na2SO4. The title compound is purified by PTLC (eluted with 5% MeOH in DCM). 1H NMR (CD3OD): 8.96 (s, 1H), 8.11 (s, 1H), 3.0 (s, 2H), 1.98 (m, 3H), 1.78-1.68 (m, 6H), 1.58 (s, 611). MS (M+1)=439.29; RT=1.34 min. *IC50.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.C(N(CC)CC)C.Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:23]([N:30]1[C:5]2[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12

Procedure:
2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236, 1995) (0.24 g) was treated with triethylamine (0.73 ml)and benzyl hydrazine dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by filtration; m/z (M+1)+ 268.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)C.N1C(O[BH3-])=NN=1.[Na+].C(Cl)Cl>ClCCCl.C(O)(=O)C>[CH2:2]([N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: CC=O
Agent: [BH3-]OC1=NN=N1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Yield: 12 %

Procedure:
To a stirred suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (189 mg, 0.37 mmol) in DCE (3 mL) was added acetic acid (3 drops, catalytic) acetaldehyde (0.023 mL, 0.41 mmol) and sodium triazetoxyborohydride (94 mg, 0.44 mmol). After stirring for 2 h at RT DCM was added and the mixture washed with saturated aqueous sodium hydrogen carbonate, water and then brine before being dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) then freeze dried from methanol/water and triturated in petroleum ether to give 314 as a brown solid (18 mg, 12%). LCMS: RT=2.73 min, [M+H]+=407. 1H NMR 400 MHz (DMSO-d) δ: 8.32 (1 H, d, J=8.29 Hz), 7.90 (2 H, d, J=2.38 Hz), 7.06 (1 H, d, J=8.41 Hz), 6.90 (1 H, s), 5.90-5.89 (1 H, m), 4.49 (4 H, d, J=7.47 Hz), 2.97 (2 H, d, J=10.98 Hz), 2.34 (2 H, q, J=7.20 Hz), 1.95 (2 H, t, J=11.47 Hz), 1.76 (2 H, d, J=12.54 Hz), 1.72-1.54 (3 H, m), 1.48 (6 H, d, J=6.59 Hz), 1.02 (3 H, t, J=7.20 Hz)
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:21][CH2:20]2)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Br[Mg]C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 1-benzhydrylazetidin-3-one dissolved in 3.8 ml of tetrahydrofuran was added to 2 ml of 1M cyclopropyl magnesium bromide/tetrahydrofuran solution under ice water cooling, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction solution was poured into a saturated aqueous solution of sodium carbonate and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 334 mg of the objective compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH3:42])C(OCC)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.Cl>O1CCCC1>[CH2:41]([CH:35]([O:34][C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1)[C:31]([OH:34])([CH3:32])[CH3:30])[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2ncnn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]butanoate (0.20 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. Methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13]>CO>[CH3:13][C:12]1([CH3:14])[S:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:10][C@H:11]1[C:16]([OH:18])=[O:17]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Product: CC1(C)SC(c2ccc(O)cc2)N[C@H]1C(=O)O
Reaction time: 20 h

Procedure:
1.26 g (10 mmoles) of 4-hydroxybenzaldehyde dissolved in 20 ml of 30% aqueous methanol are added to a solution containing 1.49 g (10 mmoles) of D-penicillamine in 30 ml of 30% methanol. After stirring for 20 hours and recrystallization from ethanol containing water, the title acid is obtained in a yield of 2.4 g (94.8%), m.p.: 207°-209° C., [α]D =+91.3° (c=0.2, dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 66.2 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 36 g of 2-amino-2-methylpropan-1-ol in 100 ml of EtOH is refluxed for 36 hours. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 16 g of the expected product, which is used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20]Br.O>CN(C=O)C>[Br:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCCO2
Temperature: 100 °C
Yield: 501.6 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (20.78 g, 95 mmol) in 480 ml DMF was added K2CO3 (52.95 g, 383 mmol) followed by 1,2-dibromoethane (8.7 ml, 101 mmol). The mixture was warmed to 100° C. After 18 additional 1,2 dibromoethane (1.0 mL) was added. After 2 h the mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified via flash chromatography (9:1 hexane/ethyl acetate) to give 8-bromo-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde (115.82 g, 99%) as a white solid.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:42]=[CH:41][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:40])[C@@H:16]3[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:18][N:17]3C(OC(C)(C)C)=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:40])[C@@H:16]3[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:18][NH:17]3)=[CH:10][CH:9]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(Cl)cc3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline 4-(4′-chlorophenoxy)phenylamide (A, 230 mg) in 1,4-dioxane (5 mL) at room temperature. After stirring at room temperature for 1 hr, the reaction mixture was concentrated in vacuo. The residue was washed with ether to give the title compound (112 mg) as colorless crystals: 1H NMR (400 MHz, D2O) δ 2.31 (quintet, J=7.0 Hz, 1 H), 2.59 (m, 1 H), 3.53 (m, 1 H), 3.74 (m, 1 H), 3.88 (s, 2 H), 4.50 br s, 1 H), 4.80 (m, 1 H), 6.65 (d, J=7.8 Hz, 2 H), 6.72 (d, J=7.8 Hz, 2 H), 7.03 (d, J=7.8 Hz, 2 H), and 7.39 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [ClH:1].[C:2]([N-:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH2:6][CH3:7])#[N:3].[Na+]>>[NH2:12][C:11]1[C:8]([C:9]#[N:10])=[C:5]([CH2:6][CH3:7])[N:4]=[C:2]([Cl:1])[N:3]=1
Reactant: CCC([N-]C#N)=C(C#N)C#N
Reactant: Cl
Agent: [Na+]
Product: CCc1nc(Cl)nc(N)c1C#N
Temperature: 0 °C

Procedure:
With stirring, 200 ml of conc. hydrochloric acid are slowly added dropwise to 37.57 g of ca. 80% strength (178.76 mmol) of sodium cyano[1-(dicyanomethylidene)propyl]-azanide such that the reaction temperature does not exceed 30° C. The reaction mixture is then added to ca. 600 ml of ice water and the solid that is formed is isolated by filtering off with suction. After drying, 33.89 g of 4-amino-2-chloro-6-ethylpyrimidine-5-carbonitrile with the melting point 226.5° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]=[N:11]O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[C:3]2[N:4]([N:11]=[CH:10][N:9]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: ON=CNc1nc(Cl)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ccc(Br)c2ncnn12
Temperature: 25 °C
Yield: 49.9 %

Procedure:
N-(3-Bromo-6-chloro-pyridin-2-yl)-N′-hydroxyformamidine (1.62 g, 6.47 mmol) is treated for one hour and 45 minutes with polyphosphoric acid (20 g) at 80° C. After cooling to room temperature, water (200 mL) is added to the reaction mixture. The resulting solution is brought to pH 8 by careful addition of solid NaHCO3 in small portions. The clear solution is extracted three times with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The solid residue (1.44 g) is purified by flash chromatography (silica gel, 4:4:0.7 petroleum ether: dichloromethane: ethyl acetate) to give the title compound (0.75 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)c(C)c1
Yield: 98.7 %

Procedure:
Compound 28 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.[NH2:23][OH:24].Cl.C([O-])(=O)C.[NH4+]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[N:23][OH:24]
Reactant: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To the compound (2,4-difluorophenyl)[1-(phenylmethyl)-3pyrrolidinyl]methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OH.HCl (10.1 g) and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 ml). This was followed by washing with water, brine, and drying over magnesium sulfate. The product was concentrated to an oil and purified by column chromatography to yield 12 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O1CCCC1>CN(C)C=O.O>[CH2:3]([O:10][CH:11]([CH2:12][O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: OCC(CO)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1

Procedure:
To a suspension of about 26.07 g of washed about 50% sodium hydride in about 1000 ml of dimethylformamide was added about 90 g of 2-(benzyloxy)-1,3-propanediol with stirring under argon. An about 187.88 g portion of octadecyl iodide and about 150 ml of tetrahydrofuran were added and the thick mixture was stirred with a glass rod, and then with magnetic stirring for about 3 hours. Water was then added and the mixture was extracted with ether. The ether extract was washed with brine, dried and filtered through a pad of florisil. The solvent was removed and the residue chromatographed on florisil, eluting first with petroleum ether, then with about 10% ether in petroleum ether and finally eluting the product with about 30% ether in petroleum ether, giving about 73.3 g of the desired title compound as a waxy solid.
Reaction SMILES: [CH3:1][As:2]([CH3:7])[CH2:3][CH2:4][CH2:5]Cl.[Mg].[Cl-].[CH3:10][Ga+:11][CH3:12]>C(OCC)C>[CH3:1][As:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Ga:11]([CH3:12])[CH3:10]
Reactant: C[As](C)CCCCl
Reactant: C[Ga+]C
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C[Ga](C)CCC[As](C)C

Procedure:
5.47 g (30 mmol) of (3-dimethylarsinopropyl)chloride are added to 1.44 g (60 mmol) of magnesium chips in 100 ml of diethylether at 20° C., and then the mixture is heated under reflux for two hours. The solution is allowed to come to room temperature, 4.0 g (30 mmol) of dimethylgallium chloride is 50 ml of diethylether are added, and the solution is refluxed again for two hours. The working up is carried out analogously to Example 1. (3-Dimethylarsinopropyl)-dimethylgallium is obtained as a clear liquid with a B.p. of 86° C./0.01 mbar.