Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Yield: 693 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (Preparation 1(b)) (24.46 g, 7.72 mmol), potassium carbonate (32 g, 3 mol equiv) and morpholine (7.34 ml, 1.09 mol equiv) in acetonitrile (200 ml) was heated under reflux for 4 hours. The solution was then cooled to room temperature, water (50 ml) added and the mixture concentrated in vacuo. The residue was then partitioned between ethyl acetate (400 ml) and water (400 ml) and the organic phase washed with water (2×400 ml). The organic phase was dried over MgSO4, and the solvent removed in vacuo. The residue was chromatographed using silica gel eluting with hexane: diethyl ether (1:1) to give the title compound (16.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[N:5]2.[OH:14]O>C(O)=O.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[N:5]2
Reactant: O=Cc1cnc2cc(F)ccc2n1
Reactant: OO
Agent: Cl
Solvent: O=CO
Product: O=C(O)c1cnc2cc(F)ccc2n1
Temperature: 0 °C
Yield: 45 %

Procedure:
Using the method of Dodd (Synthesis, 1993, 295-297), a solution of 6-fluoroquinoxaline-2-carboxaldehyde (71 mg, 0.4 mmol) in formic acid (2 mL) was cooled in an ice bath and treated with hydrogen peroxide (2 mL of 30%). The reaction was stirred in the ice bath for 3 hours. After this time the reaction mixture was diluted with 10% HCl (25 mL) and extracted with dichloromethane (4×25 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to afford 35 mg (45%) of 6-fluoroquinoxaline-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:9]1[C:10]([C:25]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:32][CH:31]=3)=[N:27][N:26]=2)=[N:11][C:12]([C:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[C:49]([O:48][C:46]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([C:25]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:32][CH:31]=3)=[N:27][N:26]=2)=[N:11][C:12]([C:15]2[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:47])([CH3:50])([CH3:51])[CH3:52]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC5(CC4)OCCO5)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(=O)CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (680 mg, 0.94 mmol) in THF (2.0 mL) was added 1M aqueous HCl (1.9 mL of 1 M, 1.9 mmol) and the reaction mixture was heated at 60° C. for 6 h. The reaction was cooled to room temperature and diluted with EtOAc, the layers were separated and the organic layer was washed once with aqueous NaHCO3, then once with brine, dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-oxocyclohexen-1-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (487 mg, 76%) and was used without further purification. LC/MS m/z 677.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:27]([NH:29][NH2:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1.O>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:30][NH:29][C:27]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])=[O:46])=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a mixture of the product of example 15 (807 mg, 1.97 mmol) and sodium carbonate (418 mg, 3.95 mmol) in tetrahydrofuran (25 ml), 4-fluorophenylacetyl chloride (374 mg, 2.17 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature. Then water (25 ml) was added and the mixture was stirred for 1 hour. The resulting solids were collected by filtration, washed with water and PE successively and dried to give the titled product (697 mg, 64.8%).
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 30 mL of water and 7.3 g (100 mmol) n-Butylamine is added dropwise 8.4 g (100 mmol) methyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 96%, purity 96% by GC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([N:38]2[C:42]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:41](=[O:48])[NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:45]4[CH2:44][CH2:43][C:42]5([N:38]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:39][NH:40][C:41]5=[O:48])[CH2:47][CH2:46]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as in General Procedure 10 to give the title compound. LCMS: m/z=661.03 (M+H+); retention time=0.86 minutes.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1>>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: ClCc1nccs1
Product: NCCNCc1nccs1

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 34 gives N-(2-thiazolylmethyl)ethylenediamine. Reacting this intermediate with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:22][CH:21]=[CH2:20])[C:6]=2[CH:13]=1
Reactant: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Yield: 56 %

Procedure:
6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (700 mg, 3.544 mmol) was suspended in dry DMF (20 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (1.614 mg, 11.695 mmol) and allyl iodide (0.43 ml, 4.607 mmol). It was then stirred at rt for 2 h before addition of further allyl iodide (0.86 ml, 9.214 mmol) and then the reaction was heated at 60° C. for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid which was purified by column chromatography on silica with a 0-5% MeOH in DCM gradient to give the desired product as a light brown solid (472 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[CH3:11][C:7]1[C:5]2[S:6][C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])=[C:3]([C:12]#[N:13])[C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c(C#N)c(N)sc12
Reactant: O=[N+]([O-])c1ccccc1F
Product: Cc1cccc2c(C#N)c(Nc3ccccc3[N+](=O)[O-])sc12

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-7-methylbenzo[b]thiophene-3-carbonitrile and 2-fluoronitrobenzene, 7-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile is obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[NH:11][C:10](=[O:15])[N:9]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[N:18]=[C:8]3[C:7]=2[CH2:6]1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[C:32]([N:11]1[C:12]2[CH2:13][CH2:14][N:5]([CH2:4][C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[F:1])[CH2:6][C:7]=2[C:8]2=[N:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:16][N:9]2[C:10]1=[O:15])(=[O:34])[CH3:33]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3nc(-c4ccccc4F)cn3c1=O)CN(Cc1ccccc1F)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (392 mg, 1 mmol) and 50% sodium hydride(144 mg, 3 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. Acetyl chloride (1 mL) was added and stirring was continued for 30 min. The reaction was diluted with ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as the eluent to afford 6-acetyl-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (compound 55) and 5-acetoxy-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2c]pyrido[3,4-e] pyrimidine (compound 56) as white solids.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CSCC[C@@H](N)C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of Example 1C (2.68 g, 12.5 mmol), triethylamine (3.47 ml, 75.0 mmol), and 2-(tert-butyoxycarbonyloxyimino)-2-phenylacetonitrile (3.22 g, 13.0 mmol) in 30% aqueous dioxane was heated to 50° C. for 6 hours, cooled to ambient temperature, and concentrated. The residue was diluted with aqueous sodium hydroxide (0.25M, 50 mL) and extracted twice with ethyl acetate. The aqueous layer was acidified to pH 3 with 1M H3PO4 and extracted five times with chloroform. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product (1.62 g). MS (ESI) m/e 278 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N+:6]([O-:18])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCc1ccc(Br)cn1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in dichloromethane (80 ml) and cooled to 0° C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) in dichloromethane (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O

Procedure:
8-Chloro-1-(2,6-difluoro-phenyl)-3,4-dihydro-benzo[c]azepin-5-one (4aa) (4.2 g, 15 mmol) was dissolved in toluene (100 mL) and N,N-dimethylformamide dimethyl acetal (19 mL) and heated at 80° C. for 2 h. The solution was evaporated in vacuo and the resulting residue was purified by column chromatography (silica gel, 0 to 75% EtOAc/hexanes) to afford 5aa (2.6 g, 78%) as a pale brown solid MS m/z=361 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in the ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 ml dichloromethane are added followed by 9.8 ml triethylamine and 0.5 g dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulphate. After the solvent has been eliminated the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. n-Butylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (88 mg, 70%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=8.01 Hz, 2H), 7.59 (d, J3=7.16 Hz, 2H), 7.51-7.34 (m, 4H), 6.11 (br. s., 1H), 3.51-3.44 (m, 2H), 1.64 (sext., J3=7.59 Hz, 2H), 1.43 (quint., J3=7.98 Hz, 2H), 0.96 (t, J3=7.32 Hz, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[CH:7]=[C:6]([S:5][CH3:4])[NH:3][N:2]=1
Reactant: NN
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Solvent: CCO
Solvent: O
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reaction time: 0.75 h

Procedure:
Hydrazine monohydrate (0.51 ml) was added dropwise to a solution of 3.6 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (17) in 40 ml of ethanol at room temperature, and the mixture was stirred for 45 minutes and then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=2/5) to afford 3.3 g of the desired compound in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].O1CCCC1.[CH3:13][C:14](=O)[CH2:15][C:16](=[O:18])[CH3:17]>O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:14]([CH3:13])=[CH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(CN)OC
Reactant: CC(=O)CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(CNC(C)=CC(C)=O)OC
Reaction time: 8 h

Procedure:
21.0 g of aminoacetaldehyde dimethylacetal (0.2 moles) were dissolved into 100 ml of tetrahydrofuran to which 20.0 g of 2,4-pentanedione (0.2 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH(OMe)2)Me=25.0 g (72% of theoretical).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)([CH3:43])[CH3:42])[CH2:36][CH2:35]3)[O:31][C:28]2=[CH:29][N:30]=1>ClCCl.CO>[F:14][C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([F:11])([CH3:43])[CH3:42])[CH2:38][CH2:39]3)[O:31][C:28]2=[CH:29][N:30]=1
Reactant: CC(C)(O)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(F)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene; 0.27 mL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-furo[2,3-c]pyridine (0.19 g) in dichloromethane (3 mL) chilled in an ice bath. The solution is stirred at room temperature overnight. The solution is diluted with dichloromethane and little methanol and washed with aqueous NaHCO3 solution. The solution is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:2) to give the title compound. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: CCCCCC(=O)Cl
Reactant: O=C1N(CCl)CCC(O)N1c1nnc(C(F)(F)F)s1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OC1CCN(CCl)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hexanoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1nnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C#N)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])nnc3ccc(Br)cc23)cc1
Yield: 99.9 %

Procedure:
A yellow suspension of 6-bromo-4-chloro-3-nitrocinnoline (1.75 g, 6.07 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (1.069 g, 6.67 mmol) and K2CO3 (1.677 g, 12.13 mmol) in MeCN (2 mL) was heated to reflux for 5 min. The workup followed general workup procedures, and the crude was purified on silica gel with PE/EtOAc as eluant to give 2-(4-(6-bromo-3-nitrocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile as yellow solid (2.5 g, yield 100%). MS (m/z): 414 (M+H)+.