Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S=[C:2]([CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)[C:3](=[O:5])[OH:4].BrC(O)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOCCOC>[OH:5][C:3]([CH2:2][CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)=[O:4]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCC(=S)C(=O)O)N1
Agent: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 0.1 %

Procedure:
A diglyme solution (3 ml) containing dl-thioxobiotin (255 mg. 0.981 mol) and bromoethanol (140 μl, 1.98 mmol) was allowed to reflux (150°) for 2.5 hours. The solution was cooled, dilute sodium carbonate (50 ml) was added, and the solution was extracted with hexane (50 ml). The pH of the aqueous phase was adjusted to 1.5 with 6N HCL and extracted with ethyl acetate (4×100 ml). The ethyl acetate extract was dried over magnesium sulfate, filtered and concentrated in vacuo to give 148 mg (62%) of crude biotin, mp 220°-223° C. which was recrystallized from water IR (KBr) 3279, 2899, 1724; NMR (d, DMSO) 0.76-1.95 (6H, m, C--CH2), 2.00-2.40 (2H, t, CH2 --CO), 2.70-2.98 (1H, m, CH2S) 3.00-3.54 (2H, m, CH2S, CHS) 4.00-4.44 (2H, m, CHN), 6.44 (1H, bs, NH), 6.55 (1H, bs, NH), 11.8-12.4 (1H, bs, OH). Analysis calculated for C10H16O3N2S: C, 49.18; H, 6.56; N, 11.48; Found: C, 49.30; H, 6.23; N, 11.37. Mass spectrum: calculated: 244.0880, found: 244.0925.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][OH:45].[H-].[Na+].O>CN(C)C=O>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][O:45][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: CN(C)CCO
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOCc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 60.5 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 120 (1) was dissolved in 20 mL of dimethylformamide at 0° C., 0.28 mL (2.75 mmol) of 2-dimethylaminoethanol and 220 mg (5.20 mmol) of sodium hydride (60% oil dispersion) were added, and the mixture was stirred at room temperature for 80 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give 477 mg of 7-(2-dimethylaminoethoxymethyl)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 60%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:15]N>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:15]1
Reactant: CN(C)/C=C\C(=O)c1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]n2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
Compound 16a (1 g, 6.2 mmol) obtained from the aforesaid process and hydrazine hydrate (2 mL) were dissolved in ethanol (3.3 mL), and reacted at 60° C. for 0.5 hour. Then, the mixture was cooled to room temperature, and then the solvent was removed in vacuum to afford the product 17a (874.7 mg) as a faint yellow solid, with a yield of 97.3%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[CH:30][C:31]([CH3:32])=[C:26]4[N:25]=[C:24]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:33]([C:24]1[N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][CH:18]=2)[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:34]
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of Compound 164 (1.44 g, 3.04 mmol) in chloroform (15 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (7.0 mL) followed by stirring at room temperature for 2 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 165 (1.03 g, 2.84 mmol, 93%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24](=[S:26])[NH2:25])[N:6]2[CH2:21][O:22][CH3:23].Br[CH2:28][CH:29](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]1[S:26][CH:28]=[CH:29][N:25]=1)[N:6]2[CH2:21][O:22][CH3:23]
Reactant: CCOC(CBr)OCC
Reactant: COCn1c(C(N)=S)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCn1c(-c2nccs2)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Yield: 62 %

Procedure:
A mixed solution of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.25 g), 1-bromo-2,2-diethoxyethane (0.24 mL) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85-30:70) to give the title compound (165 mg, yield 62%) as colorless needle crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:6]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:11]=1[N+:18]([O-:20])=O)[CH:7]1[CH2:9][CH2:8]1)=[O:5].C(OCC)(=O)C>CO>[Cl:16][C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][C:13]=1[F:17])[N:18]([OH:20])[C:3](=[O:2])[C:4](=[O:5])[N:6]2[CH:7]1[CH2:9][CH2:8]1
Reactant: COC(=O)C(=O)N(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c(=O)n(C2CC2)c2cc(Cl)c(F)cc2n1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.2 g (3.789 mmol) N-(5-chloro-4-fluoro-2-nitro-phenyl)-N-cyclopropyl-oxalamic acid methyl ester in 15 mL MeOH was added 120 mg Pd(C) 10% on charcoal. The reaction mixture was stirred for 2 hours under hydrogen atmosphere at 1.2 bar at room temperature. 30 mL ethyl acetate was added and the reaction mixture was filtered over Dicalite® speed plus (Acros) speed plus (Acros) and concentrated under vacuum. Light yellow solid (68%). MS (ESI): m/z=269.014 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13](OC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:14])[NH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)C2(C)C)cc1OC
Temperature: 25 °C

Procedure:
192 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) is dissolved in 600 ml of ethanol, 145 ml hydrazine hydrate is added and the mixture is heated under reflux for 17 h. The mixture is concentrated in vacuo, resuspended in 400 ml of ethanol and concentrated again. The solids are refluxed for 60 min in 400 ml of ethanol, cooled to RT and filtered. The product is washed with 50 ml of ethanol followed by 100 ml of diethyl ether and dried in vacuo at 50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[CH2:11]O.[Li+].[Cl-].S(Cl)([Cl:17])=O.O>CN(C)C=O>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([S:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(SC)cc1CO
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SC)cc1CCl
Reaction time: 0.25 h

Procedure:
To a solution of Example 170B (1.23 g, 6.69 mmol) in 15 mL of N,N-dimethylformamide was added LiCl (567 mg, 13.4 mmol), then 2 mL (27 mmol) of thionyl chloride. The solution warmed spontaneously on addition of the thionyl chloride. After 15 min, 50 mL of water was added, then the aqueous suspension was extracted with diethyl ether (3×15 mL). The combined organic layers were back extracted with water (1×15 mL), saturated NaHCO3(aq.) (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to 1.24 g (92%) of an oil. This was used in the next step on the same day and without further purification.
Reaction SMILES: C(O[CH2:5][CH:6]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]([C:34](=[O:36])[CH3:35])[C:31](=[O:33])[CH3:32])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:30]([C:34](=[O:36])[CH3:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6](=[CH2:5])[C:7]([O:9][CH3:10])=[O:8])(=[O:33])[CH3:32]
Reactant: COC(=O)C(COC(C)=O)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g (1.97 mmol) of methyl 3-acetoxy-2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N2O7S: Calc'd: C,57.4; H,5.3; N,6.1; S,7.0; Found: C,56.2; H,5.5; N,5.6; S,7.2.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.[Cl:46][C:47]1[N:52]=[C:51]([NH:53][NH2:54])[CH:50]=[CH:49][CH:48]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:51]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:46])[N:52]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cccc(Cl)n1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccc(Cl)n2)n1

Procedure:
1.10 g (2.40 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 518 mg (3.61 mmol) of 6-chloropyridin-2-yl-hydrazine. After hydrolysis, 737 mg (66% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][O:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:48]=1[C:59]([NH2:61])=[O:60]>C(Cl)Cl>[C:59]([C:48]1[C:47]([NH:46][C:8]([C:5]2([CH3:11])[CH2:4][O:3][C:2]([CH3:1])([CH3:12])[O:7][CH2:6]2)=[O:10])=[CH:52][CH:51]=[CH:50][C:49]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:60])[NH2:61]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCC(C)(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a solution of the commercially available 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid (0.6 g, 4 mmol) in DCM (30 mL) was added HATU (1.8 g, 4.7 mmol) and DIPEA (1.6 mL, 23.5 mmol). The reaction mixture was stirred at room temperature for 1 h. After this time, 3-aminobiphenyl-2-carboxamide (0.6 g, 2.35 mmol) was added and the resulting solution was stirred for 16 h. At the conclusion of this period, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (25% ethyl acetate in hexanes) to yield N-(2-carbamoylbiphenyl-3-yl)-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (0.25 g, 24% yield) as a white solid. LCMS Method Y: retention time 1.69 min; [M+1]=367.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[Cl:23]CC(Cl)=O>C1C=CC=CC=1>[Cl:23][CH2:8][C:2]([NH:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])=[O:1]
Reactant: O=C(Cl)CCl
Reactant: O=C1COC(c2ccccc2C(F)(F)F)c2ccccc2N1
Solvent: c1ccccc1
Product: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1C(F)(F)F

Procedure:
To a solution of 2-amino-2'-trifluoromethylbenzophenone 1 [L. H. Sternbach et al. Helv. Chim. Acta., 45, 2226 (1962)] (8 g) in benzene (80 ml) is added chloroacetyl chloride (29 ml), and the mixture is refluxed under heating for 30 minutes. Benzene is evaporated under reduced pressure, and the residue is washed with n-hexane to give crystalline 2-(2-chloroacetyl)amino-2'-trifluoromethylbenzophenone (10.05 g), which is recrystallized from benzene-n-hexane to give the pure crystals, mp. 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester 1 (5 g, 21.5 mmol) and triethylamine (4.56 g, 45.0 mmol) in dichloromethane (100 ml) was added 2,4-dichlorobenzoyl chloride (3.90 g, 19.4 mmol). The reaction mixture was stirred for 30 min a 0° C. and 16 h at room temperature. Then, the reaction mixture was partitioned between 25 ml of H2O, 50 ml sat. NaHCO3 and 50 ml of CH2Cl2. The organic layer was separated and the aqueous phase was washed twice with CH2Cl2 (2×50 mL). The combined dichloromethane layer was dried (MgSO4), concentrated and the residue was purified by recrystallization in CH2Cl2 to obtain 5.832 g (74%) as a white solid of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 8.30 ppm (s, 1H, Haro); 7.74-7.66 ppm (m, 3H, Haro); 7.51 ppm (d, 1H, Haro); 7.46-7.34 ppm (m, 4H, Haro); 3.91 ppm (s, 3H).
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.[F-:19].[K+].[CH:21]1([CH2:24][N:25]2[C:31]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=3[C:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:28][CH:27](OS(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[O:54])[CH2:23][CH2:22]1>C(#N)C>[CH:21]1([CH2:24][N:25]2[C:31]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=3[C:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:28][CH:27]([F:19])[C:26]2=[O:54])[CH2:23][CH2:22]1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OC2N=C(c3ccccc3)c3cc(Cl)ccc3N(CC3CC3)C2=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=C1C(F)N=C(c2ccccc2)c2cc(Cl)ccc2N1CC1CC1
Reaction time: 0.5 h

Procedure:
To 5.4 g. of 1,4,7,10,13,16-hexaoxacyclooctadecane dissolved in 50 ml. of dry acetonitrile is added, with stirring, 1.4 g. of anhydrous KF. After 30 minutes, 4.95 g. of 1-cyclopropylmethyl-3-p-toluenesulfonyloxy-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, obtainable by tosylation of the 3-hydroxy compound, in 50 ml. of dry acetonitrile are added. The mixture is stirred for 2 hours more and is worked up in the customary manner to give 1-cyclopropylmethyl-3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:34]([N:36]([CH2:42][CH3:43])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:35]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH2:42][CH3:43])[CH2:34][CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(CC)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-diethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 3H), 0.83 (d, 3H). m/z: 474 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([OH:19])=O)[C:3]=12.[C:21]1([C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:28]([C:31]#[N:32])[C:29]#[N:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([N:36]3[CH2:35][CH2:34][N:33]([C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:28]([C:31]#[N:32])[C:29]#[N:30])[CH2:38][CH2:37]3)=[O:19])[C:3]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Reactant: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3c(-n4ccnn4)ncc(F)c23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (70 mg), 2-(phenyl(piperazin-1-yl)methylene)malononitrile (55 mg), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (200 mg) and Hunig's Base (0.1 ml) were combined in 1.5 ml of DMF. The mixture was stirred at room temperature for 16 hours. Then, DMF was removed via evaporation at reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer washed saturated NaHCO3 solution (3×100 ml), and brine (10 ml). The organic phase was dried over anhydrous MgSO4-Concentration in vacuo provided a crude product, which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH2:23]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[N:6]=[CH:5][CH:4]=[C:3]2[NH:23][C:22]1[CH:24]=[C:25]([OH:29])[C:26]([CH3:28])=[CH:27][C:21]=1[F:20])#[N:14]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1C#N
Yield: 67.6 %

Procedure:
4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol) in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the precipitated product collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline hydrochloride (273 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]Br)=[CH:4][CH:3]=1.[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1)OC
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A suspension of 3,3-bis(4-fluorophenyl)-1-bromo-2-(tetrazol-1-yl)-2-propene (108 mg, 0.29 mmol) and trimethylphosphite (4 mL, 34 mmol) was heated to reflux under an inert atmosphere for five minutes. After cooling to room temperature, excess trimethylphosphite was evaporated under reduced pressure to give a pale crystalline material. The crude product was crystallized from a 10:1 mixture of hexanes: ethyl acetate to give 98 mg (83%) of the title compound as rhombic, colorless crystals; m.p.=132.8-133.7° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]2[CH2:24][CH2:25][C:26](=[O:27])[C:11]=2[CH:10]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[NH:9]1.Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39].O>CN(C)C=O>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([CH:10]2[N:9]([CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[C:8](=[O:7])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:12]3[CH2:24][CH2:25][C:26](=[O:27])[C:11]2=3)=[CH:35][CH:34]=1)#[N:33]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
Cesium carbonate (737 mg, 2.26 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 300 mg, 0.76 mmol) and methyl 2-bromopropionate (252 mg, 1.51 mmol) in N,N-dimethylformamide (10.0 mL), and the mixture is stirred at 50° C. over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is washed twice with water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 160 mg; ESI mass spectrum: [M+H]+=484; Retention time HPLC: 0.85 min (Z018_S04).