Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:6][C:7]2[C:17]([N:18]=1)=[CH:16][C:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=1[CH:8]=2)([CH3:4])[CH3:3].[Cl:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:19].[CH3:4][C:2]([C:5]1[O:6][C:7]2[C:17]([N:18]=1)=[CH:16][C:10]1[CH2:11][CH2:12][N:13]([CH2:20][CH2:21][CH2:22][S:23][C:24]3[N:25]([CH3:40])[C:26]([C:29]4[CH:38]=[CH:37][CH:36]=[C:35]5[C:30]=4[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]5)=[N:27][N:28]=3)[CH2:14][CH2:15][C:9]=1[CH:8]=2)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C(C)(C)C)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(1,1-dimethylethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.20 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a yellow slightly hygroscopic solid (59 μmmol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>C(OCC)(=O)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]3[C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Yield: 56.2 %

Procedure:
This compound was prepared according to the method described in Example 6 of U.S. Ser. No. 09/308,954 filed May 8, 1997 as Attorney Docket No. PC9798, starting with 3.0 grams (9.4 mmol) of 6-bromo-3-ethyl-1-(4-fluoro-phenyl)-1H-indazole and 2.0 grams (11.7 mmol) of 4-oxo-cyclohexanecarboxylic acid ethyl ester to give after silica gel flash column chromatography (using 20% ethyl acetate 80% hexane as elutant) 2.17 grams of light yellow semi-solid which was a mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) δ 1.25-1.3 (t, 3H); 1.4-1.5 (t, 3H); 1.6-1.78 (m, 2H); 1.8-2.5 (m, 7H); 2.70 (m, 1H); 3.04 (m, 2H); 4.16 (m, 2H); 7.17-7.28 (m, 3H); 7.61-7.79 (m, 4H); MS, m/z 324.4 (M+H+, base).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].CC([O-])=O.[Na+].[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>Cl.O.CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:19]=[N:18][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=N[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ncn(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.8 %

Procedure:
4-Fluoroaniline (2.8 g, 26 mmol) was dissolved in 10% HCl and cooled to 0° C. To this solution was carefully added NaNO2 (1.8 g, 26 mmol) dissolved in 10 mL water. In a separate flask, NaOAc (13 g, 96 mmol), and water (25 mL) were added to a solution of ethyl isocyanoacetate (2.0 g, 18 mmol) in methanol (80 mL). This solution was cooled to 0° C. and the diazonium salt of 4-fluoroaniline was carefully added over the course of 15 minutes. Stirring was continued at 0° C. for an additional 15 minutes, after which the flask was removed from the ice bath and stirring was continued for an additional 2 hours. The reaction mixture was then added to 500 mL water and the resulting brown precipitate was collected by filtration and dried in vacuo to obtain 3.8 g of the desired ester (90% yield).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([CH3:17])(=O)=O.C(N([CH2:24][CH3:25])CC)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:14][C:17]3[CH:25]=[CH:24][C:7]([OH:8])=[CH:1][CH:2]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1COC(c2ccccc2)=N1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccc(SCC2COC(c3ccccc3)=N2)cc1
Reaction time: 24 h

Procedure:
To a solution of 11.1 g (67mm) of 2-phenyl-2-oxazolin-4-yl methyl alcohol in 150 ml methylene chloride was added 5.25 ml (67 mm) of mesylchloride at 0° C. To this stirred solution under argon was added 9.4 ml (67 mm) of triethylamine over a 30 minute period. The methylene chloride was removed in vacuo. The residue was diluted with 10 ml DMF and pumped on at high vacuum. 8.5 ml (67 mm) of 4-mercaptophenol in 5 ml of DMF was added followed by 9.4 ml (67 mm) of triethyamine. After stirring for 1 day, 0.5 g sodium borohydride was added. After a total of 3 days another 0.5 of sodium borohydride was added followed by a one hour delay. The reaction mixture was poured into 300 ml ethylacetate and washed with 3×150 ml of water, 150 ml 0.1 N, HCl, and brine, then dried over Na2SO4 and concentrated to a yellow oil. Dilution with 50 ml ethyl acetate and seeding gave 4.23 g of a white crystalline solid isolated by filtration mp. 114.5°-165.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:32])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].C(Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:25]3[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([F:22])[CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 46.8 %

Procedure:
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (300 mg) and 3-fluoro-4-nitrophenol (785 mg) were dissolved in chlorobenzene (3 ml), and the solution was stirred at 130° C. for 5 hr. Chloroform and an aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was stirred for one hr. The reaction solution was extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with hexane/ethyl acetate (1/1) to give 197 mg (yield 47%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C=O)C>[ClH:13].[CH3:8][C:7]1[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:3][C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N)cc1Nc1nccc(-c2ccccc2)n1
Product: Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of N-(3-amino-4-methyl-phenyl)acetamide (5 g, 25 mmol) in DMF (5 ml) was added 2-chloro-4-phenyl-pyrimidine (4 g, 35 mmol) and KI (0.5 g, 3 mmol), which was stirred at 100° C. overnight, cooled to 10° C. and added to H2O (100 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL), the combined organic layers dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in conc. HCl (10 mL), stirred at 80° C. for 2 h and concentrated in vacuo to yield 6-methyl-N1-(4-phenylpyrimidin-2-yl)benzene-1,3-diamine hydrochloride (4.5 g, 65%). 1H NMR (CDCl3): 7.96 (m, 2H), 7.50-7.47 (m, 1H), 7.47-7.41 (m, 5H), 7.26 (m, 2H), 2.21(s, 3H); MS (ESI) m/e: 277 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:13].CO[C:17](OC)([N:19](C)C)[CH3:18].C[N:25](C)C=O>CN(C)C(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:17]([CH3:18])[NH:19][N:25]=2)[CH:7]=[CH:6][C:5]=1[Cl:13]
Reactant: COC(C)(OC)N(C)C
Reactant: COC(=O)c1cc(C(C)=O)ccc1Cl
Reactant: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2cc(C)[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-acetyl-2-chloro-benzoic acid methyl ester (1.58 g, 7.5 mmol) and N,N-dimethylacetamide dimethylacetal in N,N-dimethylformamide and N,N-dimethylacetamide was stirred at 90° C. for 3 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethanol (18 mL) and tetrahydrofuran (2 mL). Hydrazine hydrate (0.34 mL) was added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (gradient 0-10% methanol-ethyl acetate) to afford the title compound (1.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][NH:4][C:3]1=[O:7].[CH2:8]=[O:9].[OH-].[Na+].CO>CC(C)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]([CH2:8][OH:9])[C:3]1=[O:7]
Reactant: Cn1cc[nH]c1=O
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: Cn1ccn(CO)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-methyl-4-imidazolin-2-one (4 gms, 0.04 mol), 20 ml of formaldehyde (37% aqueous solution), sodium hydroxide (100 mg), and 20 ml of methanol was stirred at room temperature for 20 hours. After removing the solvent using a rotovap at reduced pressure, a liquid residue was obtained and filtered through a column of silica gel using chloroform as the eluent. The residue solidified after left standing overnight and was dissolved in water and then extracted with chloroform. The aqueous phase was concentrated and chromatographed through a column of silica gel G 60. Removal of the solvent afforded a solid which upon addition of acetone became white suspension. The solid was washed twice with acetone and air-dried (1.0 gm, 22%) and sublimed at reduced pressure, m.p. 101.5°-103.5° C. Found: C, 46.70; H, 6.18: N, 21.80. Calc. for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86%. 1H n.m.r.(CDCl3 ): δ3.15(3H, s, CH3N--); 5.02(2H, s, broad, N-CH2OH); 5.8(1H, s, broad, OH); 6.1 (1H, d, J=3 Hz, HC-CH); 6.3(1H, d, J=3 Hz, HC=CH). νmax (KBr): 3220(OH, broad); 3120, 3100(HC=CH); 1655 cm-1 (C=O). m/e 128, C5H8N2O2 requires 128.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23]>>[CH3:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1ccc(C)c(Br)c1
Product: COC(=O)CCc1ccc(C#Cc2cc(C)ccc2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromo-1,4-dimethylbenzene (0.08 mL, 0.60 mmol) according to the general procedure IF to give 123 mg (84%) of a clear oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rf=0.21 (EtOAc:PE, 1:8); 1H NMR (CDCl3) δ 7.46-7.43 (m, 2H), 7.31 (s, 1H), 7.19-7.17 (m, 2H), 7.11-7.10 (m, 1H), 7.04-7.02 (m, 1H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.45 (s, 3H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 173.5, 140.8, 137.2, 135.2, 132.4, 131.8, 129.5, 129.3, 128.5, 123.0, 121.7, 93.0, 88.4, 51.8, 35.6, 31.0, 20.9, 20.3; ESI-MS m/z 315.1 (M+Na+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH:4]=1)[CH3:2].C=O.[BrH:15].O.[C:17](O)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([C:5]1[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:17][Br:15])[CH3:12]
Reactant: CCc1cc(CC)cc(CC)c1
Reactant: Br
Reactant: CC(=O)O
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(CC)c(CBr)c(CC)c1
Temperature: 45 °C
Yield: 84 %

Procedure:
To a mixture of 3.00 g of 1,3,5-triethylbenzene (purity: 93%) and 5.58 g of acetic acid, 0.82 g of paraformaldehyde and 4.7 mL of a 33% solution of hydrogen bromide in acetic acid were added. This mixture was heated at 45° C. for 7.5 hours under stirring. After the reaction mixture was cooled to room temperature, 16.8 g of water and 16.8 g of toluene were added thereto. The reaction mixture was separated. The organic layer was washed sequentially with 11.2 g of water, a mixture of 5.6 g of an aqueous saturated sodium hydrogen carbonate solution and 5.6 g of water, and 11.2 g of water, dried over anhydrous magnesium sulfate, and then concentrated to obtain 4.72 g of 2,4,6-triethylbenzyl bromide (GC-area: 84%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1.[Cl-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]cc(I)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of C6 (900 mg, 3.2 mmol) in N,N-dimethylformamide (3 mL) and tetrahydrofuran (70 mL) was added sodium hydride (60% in mineral oil, 168 mg, 4.2 mmol). After 5 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (592 mg, 3.55 mmol) was added to the cold mixture. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0° C. and treated with additional sodium hydride (56 mg, 1.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (197 mg, 1.18 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided the product as a yellow oil. Yield: 650 mg, 1.59 mmol, 50%. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=6.0 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 5.44 (s, 2H), 3.44-3.50 (m, 2H), 0.86-0.92 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](=[O:19])[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37].Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[C:6](=[O:19])[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(C)(C)c1ccc(OC)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)C(C)(C)c1ccc(OC)c(Br)c1)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester (Compound K3, 10.3 g, 30.01 mmol) was dissolved in DMF (80 mL), added with cesium carbonate (24.4 g, 2.5 eq.) and 4-chloro-3-nitro-benzonitrile (7.12 g, 1.3 eq.), and then stirred at 45° C. for 4 hr. The reaction solution was added to 1 N aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration, and after concentration under reduced pressure the title compound was obtained as a crude product (yellow oily substance).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)([CH2:28][CH3:29])[CH3:27]>>[CH:26]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:22]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)(=[O:24])=[O:23])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1)([CH2:28][CH3:29])[CH3:27]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)N1CCOCC1
Product: CCC(C)c1ccc(N2CCC3(CCN(S(=O)(=O)N4CCOCC4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 436.22 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), morpholine-4-sulfonyl chloride and 4-sec-butyl-phenylamine.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].Cl>[Cu].ClCCl>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[C:4]([NH:2][CH3:1])[CH:9]=1
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: CN
Agent: [Cu]
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(C)=O
Reaction time: 2 h

Procedure:
A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)-acetophenone as a brown oil which solidified at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:14]2[C:20]([F:21])=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:17][C:15]=2[N:16]=1.CCCCCC.C(OCC)(=O)C.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:14]2[C:20]([F:21])=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(F)cc34)oc2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cn1cc(-c2nc3ccc(CC(=O)O)c(F)c3o2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To methyl (2-(5-fluoro-1-methyl-3-indolyl)-7-fluoro-6-benzoxazolyl)acetate (279 mg, 0.78 mmol) were added THF/methanol (1/1, 20 ml) and 0.25N NaOH (9.4 ml, 2.35 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured in 1N HCl to acidify the mixture therewith, followed by extraction with chloroform/methanol (10/1). The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The crystals thus obtained were collected by filtration under reduced pressure, washed with hexane, and dried under reduced pressure to give (2-(5-fluoro-1-methyl-3-indolyl)-7-fluoro-6-benzoxazolyl)acetic acid (208 mg, 78%) as a brown crystalline powder.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:31])[F:30])[CH:22]=4)=[CH:19][N:20]=3)[N:17]=2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NCC1CCC(F)(F)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC1(F)CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 120 °C
Reaction time: 5 h
Yield: 0.8 %

Procedure:
To the solution of compound (4,4-difluorocyclohexyl)methanamine (100 mg, 6 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (190 mg, 6 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 12 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((4,4-difluorocyclohexyl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (21 mg, 10%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[CH:25]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:23][C:24]2[O:28][N:27]=[C:26]([CH3:29])[CH:25]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Reactant: Cc1cc(N)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(C)=O)C(=O)Nc2cc(C)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a suspension of acetoxy-(4-methoxy-phenyl)-acetic acid (79a) (2.78 g, 12.40 mmol) in CH2Cl2 (50 mL), was added 2.0 M oxalyl chloride in CH2Cl2 (9.30 mL, 18.60 mmol), followed by 10 drops of DMF. The mixture was stirred at ambient temperature for one hour, concentrated and further dried under high vacuum. It was re-dissolved in CH2Cl2 (50 mL); to this solution was added 5-amino-3-methylisoxazole (1.34 g, 13.66 mmol), followed by Et3N (2.60 mL, 18.60 mmol). After stirring at ambient temperature overnight, the mixture was concentrated in vacuo and purified by flash column chromatography eluting with 1:1 EtOAc and hexanes to provide 2.70 g yellow solid as the intermediate 79b. 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.36 (d, 2H, J=8.67 Hz), 6.90 (d, 2H, J=8.67 Hz), 6.24 (s, 1H), 6.17 (s, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H). LCMS (ESI—) [M−H]/z Calc'd 303, found 303.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:17])(=[S:16])[CH2:14][CH3:15]>>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:17]=[C:13]([CH2:14][CH3:15])[S:16][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: CCC(N)=S
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: Br
Product: CCC1=NC2(O)c3ccc(Cl)cc3CC2S1

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-chloroindan-1-one and thiopropionamide; melting point: 230-240° C. (dec.).