Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(CO)nc1C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.23 g of 1-(hydroxymethyl)-3-(trifluoromethyl)-4-ethyoxycarbonyl-1H-pyrazole was dissolved to 30 ml of dichloromethane. 1.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 2.38 g of 1-(chloromethyl)-3-(trifluoromethyl)-4-ethoxycarbonyl-1H-pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Cl
Yield: 47.1 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g, 47%). EI-MS m/z 308(M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]([NH:34][NH2:35])=O.C(O)CCC>ClCCl>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[C:32]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[N:34][N:35]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Reactant: NNC(=O)c1nccs1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1c(Cl)cccc1C(=O)N1CCn2c(nnc2-c2nccs2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(3-Chloro-2-methylphenyl)carbonyl]-2-piperazinone (I134) (185 mg, 0.732 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (137 mg, 0.879 mmol) and stirring for 16 hours at RT, under argon before adding 1,3-thiazole-2-carbohydrazide (I51) (157 mg, 1.098 mmol) and stirring for a further 4 hours. 1-Butanol (3.00 mL) was added then DCM was removed by evaporation and the residue was heated at 110° C. for 3 hours. The reaction was cooled to RT overnight and then worked up by diluting with DCM (50 ml), washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), the combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford an orange gum, of crude material which was purified by MDAP. The desired fractions were isolated, combined and evaporated to afford a white solid, 125 mg. This was dried over the weekend at 40° C. and then dried overnight in a vacuum oven at 40° C. to afford the white solid of desired product in 115 mg.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([CH3:10])([O-:9])[CH3:8].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>O>[C:7]([O:9][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:6]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.9 %

Procedure:
A tetrahydrofuran (THF) solution (20 ml) of potassium tert-butoxide (3.55 g, 31.6 mmol) was cooled in an methanol-ice bath, and 4.2 g of 2,5-difluoronitrobenzene (26.4 mmol) was further added. The mixture was heated to room temperature, stirred for 96 hours, and further stirred at 60° C. for 1 hour. Water (2 ml) and 2N-hydrochloric acid (2 ml) were added to the reaction mixture while cooling with an ice water bath, and subsequently water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=19:1). The purified product was concentrated under reduced pressure to thereby obtain 4.5 g of oily orange 1-tert-butoxy-4-fluoro-2-nitrobenzene (yield: 80%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCc1cc(OCc2ccc(C(=O)OC)cc2)c2c(n1)CCCC2
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 1, but starting from 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone and methyl 4-(bromomethyl)benzoate and purifying the product by flash chromatography eluting with methane/dichloromethane (1:49 v/v), there was obtained in 67% yield methyl 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy)methyl]benzoate (B), m.p. 79°-80° C.; NMR (CDCl3): 1.3(t,3H), 1.75-1.95(m,4H), 2.65-2.8(m,4H), 2.85-2.95(m,4H), 3.9(s,3H), 5.2(s,2H), 6.5(s,1H), 7.5(d,2H), 8.1(d,2H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]1[CH2:45][CH2:44][CH:43](Br)[C:42]1=[O:47].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:43]2[CH2:44][CH2:45][N:41]([CH3:40])[C:42]2=[O:47])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(Br)C1=O
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2hydroxyiminoacetate are dissolved in 12 ml of dimethylsulfoxide, and 1.0 g of anhydrous potassium carbonate is added thereto under nitrogen gas atmosphere. The mixture is stirred at room temperature for 10 minutes. 1.2 g of 1-methyl-3-bromo-2-pyrrolidone are added to the mixture, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into 100 ml of water, and crystalline precipitates are collected by filtration. The crystals are dissolved in ethyl acetate, and the solution is washed with water and then dried. The solution is concentrated under reduced pressure to remove solvent. Then, the residue is crystallized with isopropyl ether and collected by filtration. 2.1 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[C:9]1([C:8]2[O:20][C:18](=[O:19])[C:17](=[CH:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: O=Cc1cccs1
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccccc2)=CC1=Cc1cccs1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Thiophene-2-carboxaldehyde (27.4 cc), 3-benzoylpropionic acid (44.5 g), acetic anhydride (71 cc) and fused potassium acetate (20.5 g) are heated overnight at 80° C. The mixture is cooled to 40° C., chloroform is added and then poured onto crushed ice. Extraction is carried out with chloroform, the organic phase is washed with a decinormal sodium hydroxide solution, it is dried over magnesium sulfate and evaporated under reduced pressure. The residue is stirred for 45 minutes in 40°-60° petroleum spirit, filtered and dried. 5-Phenyl-3-(2-thienylmethylene)-2-furanone (45.3 g), m.p. 141° C., is thereby isolated.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=[O:13].[Na+].NC(N)=O>OS(O)(=O)=O>[Cl:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2SO4 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaNO2 (2.5 M, 25 mL) was added dropwise such that the internal temperature remained at 5° C. Urea was added to the mixture for after stirring for 15 minutes to destroy excess NaNO2 (monitored by starch iodine test). CuSO4 (100-200 mg) was added and the mixture was heated to 90° C. until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3×). The combined organic fractions were extracted with 3N NaOH (3×). The combined aqueous layer was acidified with conc. HCl and the product was extracted with ethyl ether (3×). The organic fractions were washed with water, brine, and dried over MgSO4. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1/1) to afford 2-chloro-4-hydroxybenzoic acid.
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1[N+]([O-])=O.ON1C(=O)CCC1=O.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:32]1([NH:31][C:30](=[O:2])[NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1.97 g (10 mmoles) of 4-methoxy-3-nitrobenzoic acid was dissolved in 50 ml of acetonitrile. 1.15 g (10 mmoles) N-hydroxysuccinimide was added with agitation. Finally 2.063 g (10 mmoles) of N,N′-dicyclohexylcarbodiimide were added and the mixture agitated. After 2 hours at approx. 20° C. a precipitate of dicyclohexyl-urea had formed. The solution was filtered through a Gooch 3G funnel. The formation of ester was determined by t.l.c. of the filtrate (CHCl3/MeOH=9:1, v/v). Observation under U.V. revealed the ester as a dark spot of Rf approx. 0.9. After evaporation of the acetonitrile a whitish-yellow powder remained in the flask. The powder was redissolved in 50 ml of hot isopropanol. Approximately 2 spatula-tips activated charcoal were added and the solution was boiled in a boiling water-bath for about 5 minutes. The boiling solution was quickly poured through a sintered glass filter (G4, previously heated by a passage of hot isopropanol) into a hot flask. The solution was allowed to cool down overnight. White, needle-like crystals were formed (m.p. approx. 145–152° C.) having the expected t.l.c. properties.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH:29]([C:35]([O-])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:1]([O:8][N:9]([C:35](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Reactant: CCOC(=O)c1cccnc1NOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of the product of Example 157A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) in dichloromethane (25 mL) was treated dropwise with ethyl chloromalonate (0.73 g, 4.8 mmol), stirred for 2 hr and partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to provide the title compound (1.1 g, 65%). MS (DCI) m/z 387 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:18]=[CH:17][O:16][CH:15]=1)=[O:13].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[C:3]([C:12]([C:14]3[CH:18]=[CH:17][O:16][CH:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Ex. 19 from 3-amino-6-chloro-2-(3-furoyl)indole (Example 79) and isovaleryl chloride. m.p.: 202-203° C. (recrystallized from ethyl acetate) 1H-NMR (CDCl3) δ: 10.10 (1 H, br s), 8.28 (1 H, d, J=8.8 Hz), 8.23 (1 H, br s), 8.11 (1 H, dd, J=0.7, 1.5 Hz), 7.59 (1 H, dd, J=1.5, 1.8 Hz), 7.31 (1 H, d, J=1.8 Hz), 7.10 (1 H, dd, J=1.8, 8.8 Hz), 6.89 (1 H, dd, J=0.7, 1.8 Hz), 2.39-2.22 (3 H, m), 1.06 (6 H, d, J=6.6 Hz).
Reaction SMILES: [CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.C[O:23][C:24](=[O:31])[CH2:25][CH2:26][CH:27](N)[CH2:28][CH3:29].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.[NH2:33][CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:24]([OH:23])=[O:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(N)CCC(=O)OC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Coumarin 343 (5 mmol, Aldrich No. 393029) and each 5.5 mmol of 4-aminohexanoic acid methyl ester and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) as well as 11 mmol triethylamine were dissolved in 100 ml DMF and stirred for 1.5 h at room temperature. The solvent is removed by evaporation on a rotary evaporator and the residuum is dissolved in trichloromethane. Residual HBTU is removed by extraction with water with 0.5 mol/l hydrochloric acid. The organic solvent is separated and evaporated to dryness in a rotary evaporator. The crude product (2.37 g) is purified by flash chromatography (silica gel 60, Merck, No: 11452134001) with a mobile phase consisting of trichloromethane:ethyl acetate 2:1 (v/v) (yield: 1.03 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([S:20][CH:21](O)[CH3:22])[CH3:19]>>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([O:16][CH2:19][CH2:18][S:20][CH2:21][CH3:22])=[O:15])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(=O)Nc1nc(-c2ccccc2)cs1
Reactant: CCSC(C)O
Product: CCSCCOC(=O)C(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
Using a method similar to Example 12, 6.2 g of N-(4-phenyl-thiazol-2-yl)-oxamic acid and 6.6 g of ethylthioethanol give, after crystallization of the product from ethanol, 3.4 g of the compound of the formula I, with R1 =C6H5 and R2 =CH2CH2SC2H5, of melting point 148°-149° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:35])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:23])[CH3:24])=[O:35])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)cc3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccc(F)cc2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(4-fluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 50, 90 mg, 0.18 mmol) in EtOH (6 ml) was added NaOH (39 mg, 0.90 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 80 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=C[C:46]([O:49]C)=CC=3)C=2N=1)(C)(C)C.Cl.OC[C@H]1[C@@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:24][CH2:25][C@H:27]([OH:26])[C@@H:28]2[CH2:46][OH:49])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Agent: OC[C@@H]1NCC[C@@H]1O
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)[C@@H]4CO)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol hydrochloride and isolated as light-yellow gum. MS (m/e): 413.4 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5].[Mg].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:23])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1.[Cl-].[NH4+]>CCOCC.ClCCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]([OH:23])([CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1
Reactant: COC(C)CCBr
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COC(C)CCC1(O)C2=NCCCN2c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-bromo-3-methoxybutane (2.0 g) in dry ether (20 ml) was added dropwise under a nitrogen atmosphere to magnesium turnings (0.3 g) at such a rate as to maintain gentle reflux. After 0.5 hour the reaction mixture was cooled and a solution of 7-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (1.0 g) in dry 1,2-dichloroethane (50 ml) was added dropwise. After stirring the reaction mixture for one hour at room temperature it was cooled and excess saturated ammonium chloride solution was added dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform. The extracts were combined with the organic phase, dried (MgSO4) and the solution evaporated in vacuo to leave an oil which was triturated with ether to give a solid. Recrystallisation from ethyl acetate gave the title compound as crystals m.p. 146.5°-148°. A solution of these crystals in warm propan-2-ol was treated with ethereal hydrogen chloride. Evaporation in vacuo followed by recrystallisation from propan-2-ol gave the title compound as the hydrochloride, colourless needles, m.p. 226°-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([NH:15][C:16]2[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:28])=O)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:23][C:22](=[N:24][CH:25]([CH3:26])[CH3:27])[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:28])[C:16]=3[N:15]=2)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1
Reactant: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c(=NC(C)C)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Yield: 58 %

Procedure:
To the title compound of Step D (1.2 g, 2.7 mmol) dissolved in 8 mL of dichloromethane, 5 mL of thionyl chloride was added and the solution heated at reflux for 8 hours. The solvent was removed in vacuo and remaining residue partitioned between 70 mL of ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a crude oily solid residue. Purification by flash chromatography on silica gel (2:1 hexane/ethyl acetate) and filtering from hexane afforded 700 mg of the title compound, a compound of the invention, isolated as a white solid melting at 133-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2c1OCC1CC21
Yield: 76.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (0.559 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.40 g) in DCM (12 mL) and pyridine (4 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in DCM and washed with 2N HCl, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give methyl (1aRS,7bSR)-5-(2-bromo-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.612 g) as a solid.