Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH3:24][S:25][C:26]1[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:32]([C:29]1[CH:28]=[N:27][C:26]([S:25][CH3:24])=[N:31][CH:30]=1)=[O:33])[CH3:2]
Reactant: CSc1ncc(C(=O)O)cn1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Product: CCOC(=O)C(C(=O)c1cnc(SC)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (0.7 g, 32%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 2-methylsulfanyl-pyrimidine-5-carboxylic acid (Arukwe, J.; Undheim, K. Acta Chem. Scand. Ser. B; 1986; 764-767). MS: 484.2 (MH+).
Reaction SMILES: O[N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])C(=O)[O-].[C:13]([O-:16])([O-])=[O:14].[K+].[K+].S([O:24][CH3:25])(OC)(=O)=O>C(Cl)Cl>[CH3:25][O:24][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:13](=[O:14])[O:16][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1N(O)C(=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: ClCCl
Product: CON(C(=O)Oc1ccccc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.4 %

Procedure:
A mixture of 407 g (1.6 mol) of N-hydroxy-N-(2-methylphenyl)carbamate (Example 2a) and 277 g (2.0 mol) of K2CO3 in 700 ml of CH2Cl2 is treated dropwise with 211 g (1.67 mol) of dimethyl sulfate. The reaction mixture warms to about 40° C. during the course of this. The reaction mixture is stirred overnight at room temperature and then filtered through kieselguhr. The filtrate is washed with NH3 soln. and water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with hexane. 324 g (75%) of the title compound are obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32].O>CN(C=O)C>[OH:32][CH2:31][CH:30]([NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][OH:34]
Reactant: NC(CO)CO
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC(CO)CO)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
In DMF (3ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the mixture was added 2-amino-1,3-propanediol (106mg). The mixture was stirred at room temperature for 72 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[(1,3-dihydroxy-2-propyl)aminomethyl]phenyl]-7-(4-methyl-phenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 48) (60mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Sb](Cl)(Cl)(Cl)(Cl)[Cl:12].II>>[Cl:12][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cl[Sb](Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: II
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 99 %

Procedure:
141 G of 4-fluoronitrobenzene, 7 g of antimony pentachloride and 0.5 g of iodine were charged. The same succeeding procedures as in Example 1 were repeated to obtain 173 g (yield: 99%) of 3-chloro-4-fluoronitrobenzene. Analytical value thereof by gas chromatography was as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([NH:14][C:15](=[O:16])[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CN(C)CCCO
Reactant: O=C=NC1CCCCC1
Product: CN(C)CCCOC(=O)NC1CCCCC1

Procedure:
77.3 g of 3-dimethylamino-1-propanol are reacted with 94 g of cyclohexyl isocyanate in accordance with Example 13. Distillation of the reaction product yields 153.4 g (92.8%) of analytically pure product (analysis by gas chromatography) with a boiling point of 105° C./0.015 torr. IR spectrum: 3320 cm-1NH, 1700 cm-1C=O, no bands between 2000 and 2500 cm-1.
Reaction SMILES: [Cl-].[Cl-].[CH:3]1([Ti+2:8][CH:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[CH:28]([N-:31][CH:32]([CH3:34])C)([CH3:30])C.[Li+]>>[CH:9]1([Ti:8]([CH:3]2[CH:4]=[CH:5][CH:6]=[CH:7]2)([C:20]2[C:19]([F:21])=[CH:18][CH:17]=[C:16]([CH2:22][N:31]3[CH:28]=[CH:30][CH:34]=[CH:32]3)[C:15]=2[F:14])[C:20]2[C:19]([F:21])=[CH:18][CH:17]=[C:16]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)[C:15]=2[F:14])[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: C1=CC([Ti+2]C2C=CC=C2)C=C1
Reactant: Fc1ccc(Cn2cccc2)c(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Product: Fc1ccc(Cn2cccc2)c(F)c1[Ti](c1c(F)ccc(Cn2cccc2)c1F)(C1C=CC=C1)C1C=CC=C1
Yield: 55.1 %

Procedure:
Analogously to Example 19,2.5 g (0.010 mol)of bis(cyclopentadienyl)titanium dichloride and 4.25 g (0.022 mol) of 1-[(2,4-difluorophenyl)methyl]-1H-pyrrole are reacted with 0.022 mol of lithium diisopropylamide solution. 3.1 g of orange crystals melting point 192°-194° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:34]1([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH:38]=[CH:37][N:36]=[CH:35]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[N:34]1([C:39]2[CH:40]=[CH:41][C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH2:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH2:20][CH2:19]5)[CH2:14][C:15]#[N:16])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:44][CH:45]=2)[CH2:38][CH2:37][N:36]=[CH:35]1
Reactant: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)n1cc(-c2ccnc(Nc3ccc(N4C=NCC4)cc3)n2)cn1

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(1-(2,4-difluorobenzoyl)piperidin-4-yl)butanenitrile (30 mg, 0.06 mmol), 4-(1H-imidazol-1-yl)aniline (15.2 mg, 0.0956 mmol), and p-toluenesulfonic acid (9.3 mg, 0.054 mmol) in dry 1,4-dioxane (0.5 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (25 mg, 71%). LCMS (M+H) 594.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]1[O:28][CH2:27]1)=[CH:11][CH:10]=3)[CH3:2].C(O)=[O:30]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][OH:30])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Reactant: O=CO
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC(O)CO)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (0.53 g) and formic acid (10 ml) were stirred at room temperature overnight. The excess formic acid was removed in vacuo and then methanol (75 ml) and triethylamine (10 ml) were added and the mixture was stirred for four hours. The reaction mixture was evaporated, ether was added and the product which crystallized was recrystallized from CH2Cl2 /Et2O and then purified by column chromatography on silca eluting with CH2Cl2 /THF (1/1) to afford 1-ethyl-6-(2,3-dihydroxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 197°-199° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10].[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]>CN(C)C=O>[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]
Reactant: CCCN=C=O
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Triethylamine (43 μL, 0.31 mmol) and propyl isocyanate (17 μL, 0.18 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 40 mg, 0.15 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (29 mg) as a pale blue solid (Yield 54%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:2]=1.S(Cl)([Cl:20])=O>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Cl:20])[CH:2]=1
Reactant: OCCCCCCc1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCCCCCc1cnc2ccccc2c1
Yield: 98.5 %

Procedure:
A solution of 7.8 g of 3-quinolinehexanol in 35 ml of dry dichloromethane was treated dropwise with a solution of 6.07 g of thionyl chloride in 15 ml of dichloromethane. The reaction mixture was heated to reflux for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane, washed successively with water, saturated sodium bicarbonate solution and brine, dried over potassium carbonate and evaporated to give 8.3 g of crude 6-(3-quinolinyl)hexylchloride. A suspension of 8.3 g of 6-(3-quinolinyl)hexylchloride, 12.6 g of potassium phthalimide, and 0.50 g of potassium iodide in 60 ml of dimethylformamide was heated to a bath temperature of 130° C. for one hour. The cooled mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and evaporated. The crude solid was crystallized from ethyl acetate-hexane to give 9.9 g (82%) of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 90°-91° C. An analytical sample was obtained from toluene, mp 95.5°-96.5° C.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:2].O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:9](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([O:8][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:7])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: C/C=C(/C=C/C(=O)O)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: C/C=C(/C=C/C(=O)ON1C(=O)CCC1=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of (E,E)-4-ethyl-2,4-hexadienoic acid (7 g) and N-hydroxysuccinimide (5.75 g) in dioxane (100 ml) was added dicyclohexylcarbodiimide (10.8 g). The mixture was stirred at ambient temperature overnight and then filtered. The filtrate was concentrated under reduced pressure to give a residue which was recrystallized from a mixture of ether and petroleum ether to give N-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (10.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)cc1Sc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Sc1ccccc1)c1ccccc1
Yield: 95.6 %

Procedure:
5-Bromo-3-(phenylthio)pyridin-2-amine (17 g, 60.5 mmol), benzoyl isothiocyanate (9.79 mL, 72.6 mmol), and THF (300 mL) were stirred at 40° C. overnight. The THF was concentrated to ˜1/2 volume and 9:1 hexanes:EtOAc (500 mL) added and precipitate filtered to afford the title compound (25.7 g, 95.7% yield).
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:22])([F:21])[C:9]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:11][S:12][CH2:13][C:14]#[N:15].S([O-])([O-])=O.[Na+].[Na+].[OH2:29]>CO>[F:19][C:16]([F:17])([F:18])[C:9]([F:20])([C:8]([F:7])([F:21])[F:22])[CH2:10][CH2:11][S:12]([CH2:13][C:14]#[N:15])(=[O:1])=[O:29]
Reactant: N#CCSCCC(F)(C(F)(F)F)C(F)(F)F
Reactant: O
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: N#CCS(=O)(=O)CCC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a suspension of 16.14 g of a double salt of 2 KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 50 ml of water was added dropwise a solution of 4.77 g of (3-(trifluoromethyl)-3,4,4,4-tetrafluorobutylthio)acetonitrile in 50 ml of methanol at room temperature over 60 minutes under a nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction mixture was added 50 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 50 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 4.00 g of (3-(trifluoromethyl)-3,4,4,4-tetrafluorobutylsulfonyl)acetonitrile represented by the formula:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15](=[S:21])[CH:16]=[CH:17][N:18](C)C)[CH:14]=1)=[O:8])[CH3:5].C(O)C.CO.OOS(N)(=O)=O>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[S:21][N:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(C(=S)C=CN(C)C)cc(-c2ccc(C)cc2)c1
Agent: NS(=O)(=O)OO
Solvent: CCO
Solvent: CO
Solvent: c1ccncc1
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2ccns2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a 0° C. solution of 5-(3-dimethylamino-thioacryloyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (200 mg, 0.505 mmol) in a mixture of pyridine (80 uL), ethanol (3 mL) and MeOH (1 mL) was added hydroxyl-amine-O-sulfonic acid (0.76 mmol, 85.7 mg) in one portion. The reaction mixture was stirred for two hours, during which time the mixture was allowed to warm to room temperature. Solvent was removed in vacuo, and the residue was subjected to Preparative HPLC for separation to give 92 mg (50%) of 5-isothiazol-5-yl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, MS (M+H)=367.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:26]O.C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([C:18]#[N:26])[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: NO
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: N#Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde in MeOH (20 mL), aq. NH2OH (1 mmol) was added. The resulting mixture was stirred at RT for 2 hr. The reaction mixture was concentrated and water (20 mL) was added. The precipitate formed was then collected by suction filtration and dried in vacuo. Above oxime (365 mg, 1 mmol) was dissolved in pyridine (10 mL) and acetic anhydride (0.3 mL, 2 mmol) was added. The resulting mixture was stirred overnight and concentrated. The residue obtained was purified with (30% EtOAc:Hexane) to obtain the title compound. Yield 67%.
Reaction SMILES: [F:1][C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-:9].[Cl-:10].[Cl-:11].ClCl.[Cl:14][CH2:15][CH2:16][Cl:17]>>[F:1][C:2]1[C:15]([Cl:14])=[C:16]([Cl:17])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: ClCCCl
Reactant: Fc1ccccc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Product: Fc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
A solution of 400 g (4.17 mol) of fluorobenzene in 2 l of 1,2-dichlorethane was admixed with 53.2 g (0.417 mol) of powdered AlCl3. 1394 g of chlorine gas were subsequently passed into the solution at 0-5° C. After the end of the reaction, the HCl formed was driven out at about 20-25° C. by means of a stream of nitrogen. The reaction solution was admixed with 200 ml of water while stirring vigorously, and the phases were then separated at 50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCCC1.CN(C)C=O.CCOCC>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)N1CCCC1=O

Procedure:
3-(4-Nitro-phenyl)-5-[(2-oxo-pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylic acid amide (10.2 g,) and 10% palladium on carbon (2 g) in tetrahydrofuran (300 mL) and dimethylformamide (50 mL) was hydrogenated at 80 psi over 24 hr in metal bomb. The catalyst was removed by filtration through celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give an off white solid, which was stirred in ether (150 mL) and filtered to give the title compound as a off white solid (8.7 g, 94%).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CN1CCCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCN(C)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), 1-methyl-1,4-diazepane (100.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 126.6 mg (77%) of methyl 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:12]([C:22]([OH:24])=O)[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:19])([F:18])[F:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:24])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylic acid (32 mg, 0.095 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (50 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (300 μL, 1.72 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:28]1([CH2:38][NH2:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([NH:39][CH2:38][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:18])(=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: N#CC=C1C[C@@H](C(=O)NCc2cccc3ccccc23)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 1-naphthylmethylamine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=396.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:18].[C:19](OC)(OC)(OC)[CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCl
Yield: 60.5 %

Procedure:
Using the general method of Example 1 Part D, N4-(5-chloropentyl)quinolin-3,4-diamine (˜20.4 mmol) was cyclized using trimethyl orthobutyrate (3.6 g, 24.5 mmol) in the presence of pyridine hydrochloride (˜0.1 g). The crude product was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.9 g of 1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light green solid.