Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(N([CH2:17][CH3:18])CC)C>CN(C=O)C>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:6]([CH2:5][C:4]2[CH:3]=[CH:2][CH:10]=[CH:9][C:17]=2[CH3:18])=[O:7])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.9 %

Procedure:
19.56 g (116 mmol) of (2-methylphneyl)acetic acid chloride are added, over 1 hour, to a mixture of 20 g (116 mmol) of 4-amino-2-chlorobenzoic acid, 12.9 g (127 mmol) of triethylamine and 150 ml of DMF dried over a molecular sieve. After stirring for 16 h at room temperature, the DMF is removed by evaporation under vacuum. The residue is washed with water and with dichloromethane to give, after drying, 19 g of an off-white powder (Yield=53%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16](=[O:24])[CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[C:4]=2[CH:3]=1.O.C([O-])(O)=[O:27].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16](=[O:24])[CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[C:4]=2[CH:3]=1
Reactant: O=C(CCn1ccnc1)N1c2ccccc2Sc2ccc(Cl)cc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A solution of 14 g of SO2Cl2 in 65 ml of CH2Cl2 is added dropwise over the course of 1 hour and at 10° to a mixture of 35.6 g of 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine, 8.2 g of silica gel, 8.2 ml of water and 850 ml of CH2Cl2. Stirring is continued for 2 hours at 10°; 100 ml of water is added dropwise and the mixture is rendered alkaline by adding NaHCO3. Working up in the customary manner gives 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, melting point 148°-149°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15].[Br:18]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]([OH:17])([CH3:15])[CH3:16])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Br:18]
Reactant: BrBr
Reactant: COC(=O)c1ccc(N)c(NCC(C)(C)O)c1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(N)c(NCC(C)(C)O)c1
Yield: 26.9 %

Procedure:
To a solution of methy 4-amino-3-[(2-hydroxy-2-methylpropyl)amino]benzoate (1.5 g, 6.30 mmol) in DCM (12.59 mL) added bromine (0.324 mL, 6.30 mmol) drop-wise. The reaction was complete upon total addition of bromine. Reaction mixture was quenched with sodium sulfite and diluted with EtOAc. The aqueous layer was washed with EtOAc (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (0.538 g): LC-MS [M]=317.2.
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5]([CH2:9]O)([CH2:7]O)[CH2:4][C:3]=1[Br:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH2:6][C:5]([CH2:9][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])([CH2:7][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH2:4][C:3]=1[Br:11]
Reactant: OCC1(CO)CC(Br)=C(Br)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(Br)=C(Br)C2)cc1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Under nitrogen, a stirred solution of 5.7 g (19.9 mmol) of 1,2-dibromo-4,4-di(hydroxymethyl)cyclopentene (Step 5) in 50 mL of pyridine at ambient temperature was treated with 19 g (99.7 mmol) of p-toluenesulfonyl chloride. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved ethyl acetate and washed twice with 3% hydrochloric acid followed by brine. The solution was dried (Na2SO4) and concentrated in vacuo to give 5.2 g (44%) of 1,2-dibromo-4,4-di(tosylmethyl)cyclopentene (14 (in Synthetic Scheme V) as a colorless semisolid: NMR (CDCl3) δ2.42 (s, 4H), 2.47 (s, 6H), 3.90 (s, 4H), 7.37 (d, J=8 Hz, 4H), 7.74 (d, J=8 Hz, 4H ).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][F:19].O=O>>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:16][CH2:17][CH2:18][F:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: FCCCBr
Agent: O=O
Product: CC(=O)c1cc(OCCCF)cc(C(C)(C)C)c1

Procedure:
1-(3-tert-Butyl-5-hydroxyphenyl)ethanone (O3.106; 500 mg) was reacted with 1-bromo-3-fluoropropane (239 μl) and worked up analogously to O2.105. 630 mg of the title compound were obtained. LC-MS rt: 1.16 min [M+H]+: 253.2 (met. b)
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5](F)[CH:4]=1.[CH3:15][O-:16].[Na+]>>[CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:16][CH3:15])[CH:4]=1
Reactant: C[O-]
Reactant: CN(C)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Product: COc1cc(N(C)C)c(F)cc1[N+](=O)[O-]

Procedure:
2.0 g (10 mmol) of 4-dimethylamino-2,5-difluoronitrobenzene (18) is treated with sodium methoxide according to general method F to give Compound 19 after chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:11][C:12]1[O:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:17]([C:15]2[O:16][C:12]([CH3:11])=[CH:13][CH:14]=2)(=[O:19])=[O:18])[CH:7]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)o1
Yield: 61.2 %

Procedure:
Following General Procedure B, the title compound (212 mg, 48%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 5-methyl-furan-2-sulfonyl chloride (250 mg, 1.38 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:4]2[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=2)[CH2:13][CH2:14]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1nc(C)cnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine using N-(benzyloxycarbonyloxy)succinimide (Sigma-Aldrich). M.S.(M+1): 371.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([O:16][CH3:17])[C:13]([OH:15])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13](=[O:15])[CH:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[O:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: COC(C(=O)O)c1ccc(C(F)(F)F)cc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(C(F)(F)F)cc1F

Procedure:
(RS)-(2-Fluoro-4-trifluoromethyl-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-trifluoromethyl-phenyl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: COC(=O)c1ccc(CNC2CCN(C)CC2)cc1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), methyl 4-(aminomethyl)benzoate hydrochloride (2.0 g, 1.0 eq.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([N+:20]#[C-])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([NH2:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: [C-]#[N+]C(Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reaction time: 0.05 h
Yield: 96.8 %

Procedure:
To a solution of 1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene (20 mg, 0.052 mmol) in MeOH (0.4 mL) was added 4 N HCl in dioxane (0.3 mL) and the reaction mixture was stirred for 3 minutes. The reaction solvent was evaporated under a stream of nitrogen. The residue was diluted with 1 N NaOH (5 mL) and the aqueous portion was extracted with Et2O (3×5 mL). The combined organic fractions were washed with sat. NaCl (5 mL), dried over Na2SO4, filtered and evaporated under vacuum to yield 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (19 mg, 97% yield) as a clear glass.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C:30]1[NH:34][N:33]=[N:32][N:31]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:9]1=2.CO.[C:46]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:39][C:38]([F:41])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:42])([F:1])[F:43])[CH:37]=1)[CH2:6][N:7]([C:30]1[N:31]=[N:32][N:33]([CH3:46])[N:34]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:9]1=2
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (87 mg, 0.139 mmol), methanol (0.564 mL, 13.9 mmol), triphenyl phosphine (73 mg, 0.278 mmol) in dry dichloromethane (3.4 mL) at 0° C., under nitrogen, add diethyl azodicarboxylate (0.128 mL, 0.278 mmol). Stir the reaction mixture at room temperature for 3 h. Remove the solvents under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate to afford the title compound (47 mg, 53%). MS (ES+): 639 (M+H).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.N1CCCCC1>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])c(O)c2)S1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a solution of 2,4-thiazolidinedione (3.50 g, 30.0 mmol) in ethanol (120 mL) was added 3-hydroxy-4-nitrobenzaldehyde (5.00 g, 30.0 mmol) and piperidine (0.44 mL, 4.50 mmol). The mixture was stirred at reflux for 15 hours and then cooled to 0° C. The resulting precipitate was collected and washed with cold ethanol to afford 3.53 g of the desired compound as a brown solid. Further concentration and precipitation of the mother liquor afforded an additional 3.1 g of the product. This was used without further purification in the next reaction. 1H NMR (CDCl3)·8.20 (1H, d, J=8.8 Hz), 7.75 (1H, s), 7.26 (1H, s), 7.12 (1H, d, J=8.8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>C(O)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Temperature: 25 °C

Procedure:
4-Chloro-6-iodoquinazoline (5.7 g, 19.7 mmol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (4.9 g, 19.7 mmol) was refluxed in isopropanol (150 mL) overnight. The mixture was cooled to room temperature. The solid product was precipitated, filtrated and dried in vacuum. The product 1405-174 was pure enough and used without further purification. (7.4 g, 74.2%): LC-MS: 506 [M+1]+, 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.18 (m, 1H), 7.33 (m, 3H), 7.48 (m, 1H), 7.66 (m, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.94 (s, 1H), 9.29 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[CH2:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2.[H-].[K+].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:8][C:5]1[C:4]([Si:22]([CH3:24])([CH3:23])[CH3:21])=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C)C(C)=C(c2cccc3cccnc23)C1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3cccnc23)=C1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.87 g (3.7 mmol) of 2,3,4-trimethyl-1-(8-quinolyl)cyclopentadiene in 20 ml of tetrahydrofuran was added to a suspension of 0.15 g (3.7 mmol) of potassium hydride in 30 ml of tetrahydrofuran and the mixture was subsequently stirred at room temperature for 6 hours. 0.402 g (3.7 mmol) of trimethylsilyl chloride was added while stirring and the mixture was stirred at room temperature for a further 12 hours. The volatile constituents were distilled off and the residue obtained in this way was distilled. At 126-136° C. and 2×10−2 mbar, 3,4,5-trimethyl-1-(8-quinolyl)-2-trimethylsilylcyclopentadiene distilled over in a yield of 0.455 g (1.5 mmol, 40%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(c1ccccc1CN)S(C)(=O)=O
Product: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.74 g, 3.2 mmol) and N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamide (0.76 g, 3.5 mmol) in a manner analogous to Example 2d. Product isolated as a white foam (0.847 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.87 (d, J=6.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.40-7.28 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.38 (t, J=5.4 Hz, 1H), 4.73 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.00 (s, 3H). MS=366 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Reactant: CCOC1OC(=O)C=C1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 4-amino-5-ethoxy-5H-furan-2-one (0.05 g, 0.35 mmol) and 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.09 g, 0.42 mmol) in tetrahydrofuran (5 mL) at room temperature under nitrogen was added sodium tert-butoxide(0.05 g, 0.49 mmol). The reaction was stirred 3 h at reflux. After cooling, the mixture was diluted with ethyl acetate, was washed with 10% potassium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 4:6 ethyl acetate:hexanes afforded (R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.075 g, 63% yield). Also recovered was starting 4-amino-5-ethoxy-5H-furan-2-one (0.016 g, 32% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][C:15]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:31])=[N:14][C:15]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:27])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)c1nc2cc(OCc3ccccc3)ccc2c(=O)[nH]1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Temperature: 56 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
To phosphorous oxychloride (10 mL) cooled to 5° C. was added portionwise 7-(benzyloxy)-2-(4-fluorobenzoyl)quinazolin-4(3H)-one (500 mg, 1.34 mmol) followed by the addition of DMF (4 drops). The mixture was warmed to 56° C. over 10 min and held at this temperature for 2 min, then the heating bath was removed. The mixture was concentrated, and the residue was diluted with EtOAc, then the solution was and washed with cold water, saturated sodium bicarbonate (aq), brine, and dried over sodium sulfate. The solution was concentrated to afford (7-(benzyloxy)-4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone as an off-white solid (380 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.40 (s, 2 H) 7.37-7.45 (m, 5 H) 7.52-7.55 (m, 2 H) 7.66-7.71 (m, 2 H) 8.09-8.14 (m, 2 H) 8.31 (d, J=9.04 Hz, 1 H). LC-MS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-hydroxybenzoate (22-1) (9.72 g, 64.36 mmol) in 100 mL of DMF was added 24.8 g (76.0 mmol) of Cs2CO3 followed by 5.0 mL (58.5 mmol) of allyl bromide. The resulting solution was then heated at 50° C. for 5 h. The solvent was distilled under reduced pressure and the residue was taken up in 200 mL of EtOAc. The organic phase was extracted with 1N NaOH (2×50 mL), water (5×50 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 22-2 as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:20][CH2:19][CH2:18][N:9]2[CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine (27 mg, 0.1 mmol) obtained in Example 1-f), 4-cyanobenzylbromide (20 mg, 0.1 mmol), and potassium carbonate (17 mg, 0.12 mmol) were dissolved in 1 mL of acetonitrile, followed by stirring at 60° C. for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 14 mg (yield 36.7%) of a title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([I:13])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6]([I:13])=[CH:5]2
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc2ccc(Br)cc2cc1I
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Temperature: 130 °C

Procedure:
6-Bromo-2-chloro-3-iodoquinoline (1.0 g, 2.7 mmol) and neat 4-methoxybenzylamine (3.6 mL, 27.1 mmol) was combined in a microwave vial and heated in a microwave at 130° C. for 15 min. The reaction mixture was purified by silica flash chromatography (0-30% EtOAc/Hex) to give 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[O-]CC.[Na+]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: NCCCN
Reactant: Clc1nc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1nc[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-1,2,4-triazole (10.3 g., 0.1 m.) and 1,3-diaminopropane (7.4 g., 0.1 m.) in ethanol containing sodium ethoxide is allowed to stand overnight. The solvent is removed to give 3-(3-aminopropylamino)-1,2,4-triazole. This intermediate is reacted with methyl isothiocyanate give N-methyl-N'-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:18]#[N:19].[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].CCN(CC)CC>ClCCl>[F:26][C:27]1[C:32]([O:33][S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([C:18]#[N:19])[CH:10]=2)(=[O:16])=[O:15])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55, 500 mg, 1.35 mmol) in dichloromethane (5 ml) was added slowly to pentafluorophenol (249 mg, 1.35 mmol) and Et3N (137 mg, 1.35 mmol) in dichloromethane (5 ml) and stirring continued overnight at ambient temperature. The reaction was concentrated in vacuo and purified using silica gel column chromatography (dichloromethane/heptane 40/60, then 60/40, then 80/20, then dichloromethane) to furnish the title compound. LCMS Rt=1.92 minutes 1H NMR (400 MHz; CDCl3) δ (ppm): 6.69 (d, J=8.98 Hz, 1H) 7.21-7.30 (m, 2H) 7.31-7.38 (m, 2H) 7.43-7.53 (m, 4H) 7.53-7.58 (m, 1H) 7.79 (dd, J=8.98, 2.34 Hz, 1H) 8.06 (d, J=2.34 Hz, 1H) 19F NMR (376 MHz, CDCl3) δ (ppm): 160.82 (t, J=19.50 Hz)-154.87 (t, J=21.80 Hz)-151.09 (d, J=17.21 Hz)