Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:9]=1[O:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (226 μL, 2.83 mmol) was added to a stirring solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 0.94 mmol) and triethylamine (390 μL, 2.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt overnight. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.80 (m, 1H), 7.77–7.74 (m, 1H), 7.71 (s, 1H), 7.56–7.50 (m, 2H), 7.35–7.30 (m, 2H), 3.94 (s, 3H), 3.71 (s, 2H), 2.59 (s, 4H), 1.81–1.78 (m, 4H). MS (ESI) 309 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9]([O:12][Si](C)(C)C)=[CH:8][CH2:7]1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)([O-])O.[Na+].O>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]([F:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@H]1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H]1CCC(=O)[C@@H](F)C1
Reaction time: 1.25 h
Yield: 37.5 %

Procedure:
Silyl enol ether (a) (3.5 g) in acetonitrile (40 mL) at 0° C. was treated portionwise with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), (Selectfluor™), (6.16 g). After 75 min, saturated sodium hydrogen carbonate (50 mL) and water (50 mL) were added and the mixture extracted with ethyl acetate. The organic soluble material was purified by careful chromatography on silica gel eluting with 5-60% diethyl ether in hexane to give an oil (1.02 g).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[S:7])[CH:2]([CH3:4])[CH3:3].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1>C(Cl)Cl>[CH2:1]([NH:5][C:6]([NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH2:15])[CH:9]=1)=[S:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1cccc(N)c1
Reactant: CC(C)CN=C=S
Solvent: ClCCl
Product: CC(C)CNC(=S)Nc1cccc(N)c1

Procedure:
Isobutyl isothiocyanate (16 g.) is added dropwise with stirring to a solution of m-phenylenediamine (17 g.) in methylene chloride (500 ml.) at room temperature. After 16 hours the solution is concentrated until crystallization begins. The mixture is diluted with benzene, and the product is filtered off, washed with benzene and dried. The 1-isobutyl-3-m-aminophenylthiourea thus obtained (23 g.) is dissolved in ethanol (250 ml.) saturated with ammonia gas, and stirred for 48 hours at room temperature with yellow mercuric oxide (28.2 g.). The mixture is filtered, the solids washed thoroughly with boiling ethanol and the combined filtrate and washings are evaporated to dryness. The residue is dissolved in a little methanol, treated with excess saturated ethereal hydrogen chloride and a large volume of dry ether. A red oil separates, which is triturated with fresh ether until solid, and the solid is filtered off and crystallized from methanol/ethyl acetate, to give 1-isobutyl-3-m-aminophenylguanidine dihydrochloride, m.p. 215° C.
Reaction SMILES: CO[CH2:3][CH2:4]OC.C(S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)C.[CH2:23]([CH:26]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[CH2:27]1)[CH2:24][CH3:25].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:37](/[CH:34]1[CH2:35][CH2:36][CH:31]([CH:28]2[CH2:29][CH2:30][CH:26]([CH2:23][CH2:24][CH3:25])[CH2:27]2)[CH2:32][CH2:33]1)=[CH:3]\[CH3:4]
Reactant: COCCOC
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Agent: CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C/C1CCC(C2CCC(CCC)C2)CC1
Temperature: -70 °C

Procedure:
DME (1,2-dimethoxyethane; 80 ml) and 5-(ethylsulfonyl)-1-phenyl-1H-tetrazole (4.62 g) were added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (3.29 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −70° C., and then KHMDS (Potassium Hexamethyldisilazide; 20%, in a THF solution) (23.9 ml) was added dropwise. The reaction solution was warmed to room temperature, and was extracted with diethyl ether after the addition of water (50 ml). The resulting organic layer was washed with water and dried over anhydrous sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) and then purified by means of a preparative HPLC system, Model PLC-561 made by GL Sciences Inc. to give (E)-1-(prop-1-enyl)-4-(3-propylcyclopentyl)cyclohexane (2.0 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:37]=[CH:38][C:39]([CH:40]=[CH:1][C:2]4[O:3][C:4]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=4)=[CH:42][CH:43]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 4, 0.4 g (1.7 mmol) of 2-(2-methyl-6phenyl-pyran-4-ylidene)-malononitrile and 0.55 g (1.7 mmol) of 4-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde} were added into 40 ml of ethanol, and 0.17 g (2.0 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=3)[CH2:3]2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: O=C=Nc1ccccc1
Product: O=C1CCC(c2ccc3c(c2)CC(NC(=O)Nc2ccccc2)C3)=NN1

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and phenyl isocyanate were treated in the same manner as in Example 29 to obtain 2-(phenylcarbamoyl)amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[B]1OC2C(=CC=CC=2)O1.[CH2:25]([O:27][C:28]#[CH:29])[CH3:26]>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])[C:2](/[CH:26]=[CH:25]/[O:27][CH2:28][CH3:29])=[CH:7][N:6]=1
Reactant: C#COCC
Reactant: COCC(C)(C)Nc1nc(Cl)ncc1Br
Agent: [B]1Oc2ccccc2O1
Product: CCO/C=C/c1cnc(Cl)nc1NC(C)(C)COC

Procedure:
The title compound was prepared according to the method described for Preparation 61 using (5-Bromo-2-chloro-pyrimidin-4-yl)-(2-methoxy-1,1-dimethyl-ethyl)-amine (Preparation 256), catechol borane and ethoxyacetylene (40% in hexane) to afford the title compound as light brown gum in 44% yield, 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].CI.[C:15](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:15])[C:7]=12
Reactant: CC(=O)O
Reactant: Clc1nccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250 mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of MeI (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1 (M+H) (found).
Reaction SMILES: C(OC([Cl:6])=O)C.[CH2:7]([NH:9][C:10]([CH:12]1[CH2:15][C:14]([F:29])([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]N3CCCC3)=[C:18]([F:28])[CH:17]=2)[CH2:13]1)=[O:11])[CH3:8]>ClCCCl>[CH2:7]([NH:9][C:10]([CH:12]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][Cl:6])=[C:18]([F:28])[CH:17]=2)([F:29])[CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)C1CC(F)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: ClCCCl
Product: CCNC(=O)C1CC(F)(c2ccc(CCl)c(F)c2)C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Ethylchloroformate (0.505 ml, 5.28 mmol) was added to a solution of Example 16, 3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanecarboxylic acid ethylamide (1.7 g, 5.28 mmol) in DCE (50 ml) After 1 hr stirring at rt. the reaction was quenched with saturated aq. NaHCO3 (150 ml) and extracted with CH2Cl2 (3×100 ml) to recover a residual oil. This was purified by flash column chromatography using a 120 g ISCO™ cartridge and 35% and 40% EtOAc/hexanes to obtain an intermediate 3-(4-chloromethyl-3-fluoro-phenyl)-3-fluoro-cyclobutanecarboxylic acid ethylamide (1.1 g, 75% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[N:25]=2)=[O:22])=[CH:13]1)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[N:25]=2)=[O:22])=[CH:13]1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3cn(Cc4ccccc4)c4ccccc34)n2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c[nH]c4ccccc34)n2)CC1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Add aluminum trichloride (106 mg, 0.795 mmol) to a suspension of 1-benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide (180 mg, 0.398 mmol) in benzene (6 mL) and heat the mixture at reflux for 1.25 hr. Then add another 2 equivalents of aluminum trichloride (108 mg) and continue heating at reflux for an additional 5.5 hr. Cool the reaction mixture to room temperature. Then pour the reaction into ice cold H2O (50 mL) and then dilute with ethyl acetate. Adjusted the pH of the solution to 11 with saturated Na2CO3, separate the layers and extract the aqueous layer with ethyl acetate (3×50 mL). Combined the organic fractions, dry with Na2SO4, filter and concentrate in vacuo. Purify the intermediate by flash chromatography on a silica gel column, eluting with CHCl3/methanol/NH4OH (93:7:1) to obtain the sub-title compound (96 mg, 67%). 1H NMR (CD3OD) 8.45 (d, J=8 Hz, 1H), 8.25 (s, 1H), 8.21 (m, 1H), 7.96 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.48 (m, 1H), 7.18-7.27 (m, 2H), 3.90 (m, 1H), 2.94-3.01 (m, 2H), 2.31 (s, 3H), 2.19-2.28 (m, 2H), 1.92-2.02 (m, 2H), 1.71-1.84 (m, 2H). CIMS (Methane) m/z 363 [C21H22N4O2]+.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Br:24][CH:25](Br)[CH3:26].O>C(COC)OC>[Br:24][CH2:25][CH2:26][C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCBr)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Diethyl 2-(4,4,5,5,5-pentafluoropentyl)propane-1,3-dioate (51 0 mg, 1.592 mmol) was dissolved in anhydrous dimethoxyethane (5 ml). Sodium hydride (60%. 88 mg, 2.2 mmol) was added to the solution and then stirred at room temperature for 1 h under nitrogen atmosphere. Dibromoethane (0.82 ml, 9.55 mmol) was added to the mixture and then stirred at 70° C. for 5 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:dichloromethane=3:1) to obtain 489 mg (yield: 72° C.) of the title compound as a colorless oil.
Reaction SMILES: [Cs+].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O-:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:33])=[O:32]>CO.CN(C=O)C>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:32])=[O:33])=[O:6]
Reactant: O=C([O-])c1c(Cl)cccc1Cl
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid cesium salt (prepared from 0.42 g of the acid and cesium carbonate (0.36 g) in methanol followed by removal of methanol and drying in vacuo) and 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) in DMF was allowed to react at 90°-100° C. for 2 hours, and then cooled. The mixture was diluted with ice/water, extracted with ether/ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography to afford 0.64 g (80%) of 2-(2,6-dichloro-phenylcarbonyloxymethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=O.C(O)(=O)C>C(O)C>[NH:30]1[C:31]2[C:27](=[C:26]([CH:24]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: CC(=O)O
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (15 mg, 0.048 mM) in absolute ethanol (2.0 mL), there were added 4-formyl-indole (11 mg, 0.076 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off and then washed with ethanol to thus give the title compound (12 mg, yield: 58%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=2[CH:13]=O)[CH2:9][CH2:8]1.P(=O)(OC=[N+]=[N-])OC(=O)C>CO>[CH:7]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=2[C:13]#[CH:1])[CH2:9][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Agent: CC(=O)O[PH](=O)OC=[N+]=[N-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
Potassium carbonate (6.15 g, 44 mmol) was added to a stirred solution of 2-cyclopropyloxy-5-trifluoromethoxybenzaldehyde (Description 3; 4.4 g, 17.8 mmol), and acetyl diazomethyl phosphonate (6.15 g, 32 mmol) in dry methanol (50 ml) at +5° C. The reaction mixture was stirred at +5° C. for 30 minutes and at room temperature for 3.5 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted into hexane (3×30 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%) to give the title compound (4.2 g, 94%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]([CH2:16][CH2:17][CH3:18])([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)[CH3:7].[N-:19]=[N+]=[N-].[Na+].[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[CH2:6]([C:8]([NH2:19])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7]
Reactant: CCCCC(CC)(CCC)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCC(N)(CC)CCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a condenser, were introduced 70 ml of chloroform, 18 ml of concentrated sulphuric acid (d = 1.83) and 11 g (0.06 mol) of 2-ethyl-2-n-propyl-hexanoic acid prepared as described above. The mixture was heated to 50° C. and while stirring 7.5 g of sodium azide in powder form were added. The operation of addition lasted 90 minutes after which the reaction mixture was heated to 50° C. for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide previously cooled to 0° C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided 1-ethyl-1-n-propyl-n-pentylamine in free base form.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.BrC1C2C(=CC=CC=2)C=C(NC(C2(C3C=CC4OC(F)(F)OC=4C=3)CC2)=O)N=1.[CH3:62][C:63]1[NH:64]C2C([CH:71]=1)=CC(B(O)O)=CC=2>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]6[C:30](=[CH:31][CH:32]=5)[NH:64][C:63]([CH3:71])=[CH:62]6)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Nc1cc2ccccc2c(-c2ccccc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cc2cc(B(O)O)ccc2[nH]1
Agent: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Product: Cc1cc2cc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)ccc2[nH]1

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl-N-(1-phenylisoquinolin-3-yl)cyclopropanecarboxamide was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 2-methyl-1H-indol-5-ylboronic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].Cl[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].Cl.C(N(CC)CC)C>ClCCl.C(N(CC)CC)C>[CH3:10][C:11]1([CH3:16])[CH2:15][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:12]1=[O:13]
Reactant: NNc1ccccn1
Reactant: CC(C)(CCl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccccn2)NC1=O
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
2-Pyridylhydrazine (10.9 g) in dichloromethane (120 ml) and dry triethylamine (28 ml) were chilled in an ice bath. -chloropivaloyl chloride (15.5 g) in dichloromethane (20 ml) was added dropwise with stirring for 15 minutes and the mixture was refluxed for 3 hours. When cool the triethylamine hydrochloride was filtered off and the filtrate evaporated to dryness and rinsed four times with the minimum quantity of ether to give the title compound (13.6 g) after recrystallisation from cyclohexane mp 141°-144°.
Reaction SMILES: C1(C2SC(NC3C=CC(OCCN4CCCC4)=CC=3)=NC=2)C=CC=CC=1.[S:27]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([CH2:38][CH:39]=O)[CH:35]=[CH:36][CH:37]=2)=[CH:28]1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH2:57])=[S:56])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>>[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:55]3[S:56][C:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:29]5[CH:30]=[CH:31][S:27][CH:28]=5)[CH:33]=4)=[CH:39][N:57]=3)=[CH:52][CH:53]=2)[CH2:44][CH2:43]1
Reactant: O=CCc1cccc(-c2ccsc2)c1
Reactant: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Agent: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Product: CN1CCN(c2ccc(Nc3ncc(-c4cccc(-c5ccsc5)c4)s3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (3-thiophen-3-yl-phenyl)-acetaldehyde and [4-(4-methyl-piperazin-1-yl)-phenyl]-thiourea (Example 5). MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 435.0 [M+3]+; single peak at tR=3.09 min (System 2); Rf=0.25 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]2[N:19]=[CH:20][CH:21]=[C:7]2[N:6]=1)[CH2:2][CH:3]=[CH2:4].C1C(=O)N([Br:29])C(=O)C1.O>C(COC)OC.O>[Br:29][C:21]1[CH:20]=[N:19][N:8]2[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])=[N:6][C:7]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Solvent: COCCOC
Solvent: O
Product: C=CCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound of Example 1), 500 mg, was dissolved in 10 ml of dimethoxyethane-water (3:1). The solution was cooled to 0° C. and 380 mg of NBS was added. The mixture was stirred at 0° C. for 1 hour and further stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crystals precipitated were collected by filtration. The crude crystals were recrystallized from dichloromethane-n-hexane to provide 440 mg of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.