Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:11](#[N:14])[CH:12]=[CH2:13].N(C1C=NC=CC=1)N>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:3]2[CH2:13][CH2:12][C:11]([NH2:14])=[N:4]2)[CH:6]=1
Reactant: NNc1cccnc1
Reactant: C=CC#N
Agent: Cl
Product: NC1=NN(c2cccnc2)CC1

Procedure:
In a typical reaction, 3-hydrazinopyridine.dihydrochloride and an anhydrous alcohol are introduced into a reaction vessel and the alkoxide base is gradually added. The mixture is stirred and the acrylonitrile is added. The mixture is stirred at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH:16]([F:18])[F:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH:16]([F:18])[F:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: FC(F)CNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2-difluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 70:30) for the chromatographic purification. Light brown solid (0.053 g; 11%). MS (ESI): m/z=509.07 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[N:20]([NH2:21])[CH:19]=[N:18][N:17]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:11]=[N:21][N:20]3[CH:19]=[N:18][N:17]=[C:16]3[N:15]=2)[CH:4]=1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1nncn1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cnn3cnnc3n2)c1

Procedure:
A solution of 12.5 g. of m-trifluoromethylphenylglyoxal, 7.69 g. of 3,4-diamino-4H-1,2,4-triazole and 4.67 g. of sodium acetate in 120 ml. of 67% acetic acid is reacted as described in Example 4, giving the desired product as a yellow solid, m.p. 288°-290° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.Br[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=Cc1ccc(Br)s1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cnc3ccc(Cl)nn23)s1
Yield: 60.1 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.55 g, 10.1 mmol, 1.0 equiv) in toluene (10.0 mL) was added 5-bromothiophene-2-carbaldehyde (1.80 mL, 15.1 mmol, 1.5 equiv), potassium carbonate (2.79 g, 20.2 mmol, 2.0 equiv), triphenyl phosphine (529 mg, 2.02 mmol, 0.2 equiv) and potassium acetate (227 mg, 1.01 mmol, 0.1 equiv). The reaction mixture was heated to reflux for 24 h then diluted with water and extracted with ethyl acetate. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 1.60 g of the white solid, 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2oc(-c3cccs3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
Step A - 15.4 g of 4-nitro-o-aminophenol and 11.2 g of thiophenecarboxaldehyde are dissolved in glacial acetic acid (450 ml) and heated to 85°. 44.4 g of lead tetraacetate is dissolved in 400 ml glacial acetic acid by warming and added to the above solution. Heating is continued for 0.5 hr and the solution is cooled to room temperature, diluted with an equal volume of water and the dark precipitate is collected and washed with additional water. The crude product is dissolved in CH2Cl2 (800 ml) and heated with 2.0 g of "Darco" G-60, followed by evaporation of the CH2Cl2. The resulting material is recrystallized from ethanol-chloroform (3:1) to yield 12.4 g of 5-nitro-2-(2-thienyl)benzoxazol, mp 186°-188°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]([OH:15])=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:13]([C:5]3[O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH2:3][O:2][CH3:1])=[O:15])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: COCc1c(C(=O)O)oc2ccccc12
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3oc4ccccc4c3COC)cc2)C1

Procedure:
With a procedure similar to the example above, 3-{4-[(3-methoxymethyl-benzofuran-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 3-methoxymethyl-benzofuran-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C24H26N2O6 (m/e) 438, obsd 439 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]1([F:24])[CH2:20][NH:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.O.C(O)C>[F:15][C:16]1([F:24])[CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 88.2 %

Procedure:
To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (416 mg, 2 mmol), (S)-4,4-difluoropyrrolidine-2-carboxylic acid (301 mg, 2 mmol), and sodium carbonate (633 mg, 574 μL, 6.0 mmol) was added 1:1 water/Ethanol (8 mL) and the reaction mixture was heated at 90° C. for 72 h. The reaction mixture was diluted with water (50 mL) then acidified with 1 N HCl and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield (S)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid as a brown oil (600 mg, 89%), which was used directly in the next reaction. LC/MS: m/z 341.00 (M+H)+ at 1.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:17]=1)=[O:15])[CH2:11][CH3:12]>ClCCl>[CH3:12][CH2:11][CH:10]([NH:13][C:14]([C:16]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:17]=1)=[O:15])[CH2:9][CH3:8]
Reactant: CCC(CC)NC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)NC(=O)C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred solution of compound (F1) (0.60 g, 1.50 mmol) in dichloromethane (10 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide N-(pentan-3-yl)spiro[indene-1,4′-piperidine]-3-carboxamide (F2) as an oil (0.62 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 299 (M+1) Rt 1.9 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[F:20])[CH:3]=1.[CH3:21][O-:22].[Na+].O>CN(C=O)C>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][C:4]1[CH:3]=[C:2]([O:22][CH3:21])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C[O-]
Reactant: COc1cccc(F)c1Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Oc2c(F)cccc2OC)c1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
A mixture of 4-fluoro-2-(2-fluoro-6-methoxyphenoxy)-1-nitrobenzene (1.33 g, 5 mmol) and sodium methoxide (035 g, 6 mmol) in DMF (10 ml) was heated at 80° C. for 2 h. The mixture was poured into water and was extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water, brine and dried (Na2SO4). The solution was concentrated under reduced pressure to obtain 2-(2-fluoro-6-methoxyphenoxy)-4-methoxy-1-nitrobenzene (1.02 g, 70%). This compound was reduced to 2-(2-fluoro-6-methoxyphenoxy)-4-methoxyaniline (0.62 g, 73%) following the general procedure C. N-[2-(2-Fluoro-6-methoxyphenoxy)-4-methoxyphenyl]-N′-(thiazol-2-yl)urea (136 mg, 70%) was prepared from 2-(2-methoxy-6-fluorophenoxy)-4-methoxyaniline (132 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>CC(N(C)C)=O.CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:23][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([C:34]([F:33])([F:44])[F:45])[CH:36]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCOCC1
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.07 g, 0.2215 mmol) in 2.0 mL of DMA was added DIEA (0.057 g, 0.443 mmol), followed by m-trifluoromethyl benzoyl chloride (0.056 g, 0.266 mmol), and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and purified by RP-HPLC. The proper fractions were collected and lyophilized to afford N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide as an off-white semisolid in 87% yield. LCMS m/z (%)=489 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.5 (bs, 1H), 8.29 (s, 1H), 8.26 (d, J=7.94 Hz, 1H), 7.98 (d, J=7.83 Hz, 1H), 7.89 (dd, J=8.93 and 2.55 Hz, 1H), 7.79 (t, J=7.82 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=9.14 Hz, 1H), 6.31 (d, J=1.79 Hz, 1H), 4.29-4.43 (m, 2H), 3.69 (s, 3H), 3.55-3.64 (m, 5H), 3.01-3.18 (m, 5H), 1.8-2.1 (m, 2H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21](O)[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Br)([Br:45])=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:45][CH:21]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCCCCCCCCCCCCCCCCC
Reactant: O=S(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(Br)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
To a solution of 11.0 g of 1,3-dioctadecyloxy-2-propanol in 400 ml of dry dimethylformamide 20 g of thionyl bromide were added dropwise, while stirring well and boiling, after which the reaction mixture was heated at 100° C for 5 hours. After cooling down said mixture was slowly poured out into 400 ml of 5% sodium bicarbonate solution. The aqueous solution was extracted with 4 × 150 ml of hexane, after which the hexane extract was consecutively washed with water, 5% sodium bicarbonate solution, and water. After drying on sodium sulphate 0 aq the solvent was removed under vacuum. The resulting coarse product was purified by means of column chromatography. After evaporation and drying in vacuum (P = 0.001 mm Hg, t = 40° C) 8 gram were obtained, melting point 47.9° - 48.7° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[S:11](=[O:14])([OH:13])[O-:12].[Na+].S(=O)(O)[O-]>>[S:11]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7])([OH:14])(=[O:13])=[O:12]
Reactant: O=S([O-])O
Reactant: CCCC=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CC(=O)O)S(=O)(=O)O

Procedure:
114 g. of 2-hexenoic acid is neutralized with aqueous sodium hydroxide and reacted with 204 g. of a 50% wt. aqueous solution of sodium bisulfite at 25° C. Complete addition of bisulfite to the double bond requires several hours. The product is concentrated to approximately 50% wt. solids and then treated with a strong acid ion exchange resin to obtain an aqueous solution of 3-sulfohexanoic acid. This is dried by vacuum stripping and converted into 3-propyl-1,2-oxathiolane-5-one-2,2-dioixde with refluxing thionyl chloride at 80° C. for 3 hours. Equivalent weight is 93.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[CH:26]=1>CN(C)C=O.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[CH:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Yield: 50.5 %

Procedure:
In the same manner as in Example 7-4 and using 1-methyl-1H-pyrazole-5-carboxylic acid (73.6 mg, 0.584 mmol), oxalyl chloride (102 μL, 1.17 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop) and N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.195 mmol) as starting materials, the title compound (41.0 mg, 50%) was obtained as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, light brown solid (79 mg, 66%), MS (ISP) m/z=481.3 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and p-toluenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20]O.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:22]([CH:19]1[CH2:20][N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18]1)[CH2:23][CH3:24]
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCCC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCC1CN2N=C(c3cccc(C(F)(F)F)c3)C=CC2=N1
Temperature: 130 °C

Procedure:
A mixture of 5.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 10 g of 2-amino-1-pentanol is heated at 130° C. for 24 hours, cooled, poured into water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-2-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to obtain the desired product.
Reaction SMILES: C=CC1C=CC=CC=1.[N+](=CC(OCC)=O)=[N-].[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)CCC(C(C)C)C(O)C1.C1([C@@H]2C[C@H]2C([O-])=O)C=CC=CC=1>ClCCl>[C:17]1([CH:23]2[CH2:25][CH:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccccc1

Procedure:
To a mixture of styrene (2.15g, 20.7 mmol) and Rh2 (4S-BNOX)4 (0.0113 g, 0.0131 mmol) in 5.0 mL of anhydrous dichloromethane was added, by syringe at room temperature, ethyl diazoacetate (0298 g, 2.62 mmol) in 3.0 mL of dichloromethane under nitrogen and at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina to separate the catalyst, and solvent and excess styrene were removed under reduced pressure Gas chromatographic separation of the trans-isomer produced a material whose specific rotation was -6.4° which corresponded to an enantiomeric excess of the ethyl (1R,2R)-2-phenylcyclopropanecarboxylate. Conversion of the ethyl esters to the 1-menthyl esters by base hydrolysis, acid chloride formation, and esterification with (-)-menthol provided a gas chromatographically separable mixture that showed 25% enantiomeric excess for the (1R,2R)-enantiomer of the trans-2-phenylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][NH:11][CH:12]=O)[C:5]=1[Cl:14].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][N:7]2[CH:12]=[N:11][CH:10]=[C:6]2[C:5]=1[Cl:14])=[O:15]
Reactant: COC(=O)c1ccnc(CNC=O)c1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccn2cncc2c1Cl
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A mixture of 3-chloro-2-formylaminomethyl-isonicotinic acid methyl ester (1.5 g, 6.6 mmol) and phosphorous oxychloride (1.3 mL, 14.2 mmol) in toluene (80 mL) was stirred at 90° C. for 15 minutes, then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The organic layer was separated and washed with water and brine, dried (Na2SO4), filtered and concentrated to give the title compound as a pale yellow solid (1.3 g, 93%). LCMS (method B): RT=2.38 min, [M+H]+=211.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[CH:16]=[CH:15][C:14]=2[CH:21]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>C(O)(=O)C>[CH3:8][O:9][C:10]1[C:11]([N+:22]([O-:24])=[O:23])=[CH:12][C:13]2[O:18][C:17]([CH3:19])([CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)C=CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixed solution of acetic acid (6.2 mL) and acetic anhydride (6.2 mL) containing 6-methoxy-2,2-dimethyl-2H-1-benzopyran (3.1 g, 16.4 mmol) was cooled with ice, nitric acid (1.37 mL, 18.0 mmol) was added dropwise and then the mixture was stirred at 0° C. for 1 hour. Upon the completion of the reaction, an aqueous solution of 1 mol/L sodium hydroxide was added to the reaction solution, the resulting solution was extracted with ethyl acetate (150 mL). The organic phase was washed twice with 1 mol/L sodium hydroxide aqueous solution and once with saturated sodium chloride solution. Then, the organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/1) and the aimed product was obtained as yellow crystal (yield: 79%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:23][CH2:22][N:21](C)[CH2:20][CH2:19]3)[N:8]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:19][CH2:20][N:21]([C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:22][CH2:23]3)[N:8]=2)=[CH:25][CH:26]=1
Reactant: CN1CCC(n2nc(Cc3ccc(F)cc3)c3ccccc3c2=O)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(n2nc(Cc3ccc(F)cc3)c3ccccc3c2=O)CC1
Reaction time: 4 h

Procedure:
366.5 g (1.043 mol) 4-(4-Fluorobenzyl)-2-(N-methyl-piperidin-4-yl)-1-(2H)-phtalazinone are dissolved in 1100 ml toluene which had been dried over K2CO3. Any water present in azeotropically distilled off using a water separator. 390 g (3.59 mol) ethylchloroformate are added dropwise over 11/2 hours and the mixture stirred for 4 hours under reflux. A precipitate separated out and is suction filtered. The filtrate is evaporated on a rotary evaporator, the residue is taken up in 400 ml ether, stirred briefly and suction filtered. After washing with ether, the substance is dried in a drying cupboard. (M.p. 151°-152° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:10]#[N:11])=[C:4]([Cl:18])[CH:3]=1.[NH4+].[OH-:20]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:10]([NH2:11])=[O:20])=[C:4]([Cl:18])[CH:3]=1
Reactant: [OH-]
Reactant: N#CC(c1ccccn1)c1c(Cl)cc(N)cc1Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C(c1ccccn1)c1c(Cl)cc(N)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of (±)-α-(4-amino-2,6-dichlorophenyl)-2-pyridineacetonitrile (0.324 mol) in H2SO4 90% (900 ml) was stirred at 90° C. for 2 hours, then poured out on ice and basified with a concentrated NH4OH solution. The precipitate was filtered off, washed with H2O and centrifuged. The residue was dried, yielding 86.0 g (90%) of (±)-α-(4-amino-2,6-dichlorophenyl)-2-pyridineacetamide (interm. 43).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[N:3][CH:4]=1
Reactant: Clc1ccncn1
Reactant: C#CCCc1nc2ccccc2o1
Product: C(#Cc1ccncn1)CCc1nc2ccccc2o1
Yield: 17.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-chloropyrimidine (85 mg, 0.74 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (127 mg, 0.74 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 32 mg (128 μmol, 17%) of 2-(4(pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a white solid.