Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH3:38][CH:39]([O:42][C:43]([S:45]Cl)=[O:44])[CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:45][C:43]([O:42][CH:39]([CH3:38])[CH2:40][CH3:41])=[O:44])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCC(C)OC(=O)SCl
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)OC(=O)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) 0.4 g, 0.96 mmol)in 5 ml methylene chloride was added triethylamine (0.12 g) and cooled to 0° C. To this solution was added (1-methylpropoxycarbonyl)sulfenyl chloride (Step A) (0.2 g, 0.0012 mol). The mixture was stirred at room temperature for one hour. At this stage thin layer chromatography indicated only partial conversion, therefor, additional amounts of (1-methylpropoxycarbonyl)sulfenyl chloride (0.2 g) and triethylamine (0.12g) was added and the mixture was let stand over night. The reaction mixturewas subjected to silica gel column chromatography using hexane-ether (7:1) as eluent. The title compound was obtained (0 g) in high purity; m.p.: 125°-126° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7](O)=[O:8])=[O:4].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>C(Cl)Cl.Cl>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:17])=[O:8])=[O:4]
Reactant: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-proline (1.10 g, 4.8 mmol) in CH2Cl2 (24 mL) at −15° C. under nitrogen was added 4-methylmorpholine (0.64 mL, 5.76 mmol), and then isobutyl chloroformate (0.81 mL, 6.24 mmol) over 10 minutes. A white precipitate formed. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of NH3 in dioxane (0.5 M, 29 mL, 14.4 mmol) was added. The reaction mixture was stirred at −15° C. for 30 minutes, warmed to room temperature, and stirred at that temperature for 16 hours. The reaction mixture was diluted with 1M HCl to ˜pH 4 and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (60-75% ethyl acetate/hexane) provided the titled compound. MS (DCI) m/z 229 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)([Br:14])=O>>[Br:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: CC(C)(C)c1cc(=O)cc[nH]1
Reactant: O=P(Br)(Br)Br
Product: CC(C)(C)c1cc(Br)ccn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
A mixture of 2-tert-butyl-1H-pyridin-4-one (Step 1.5) (4.25 g, 28 mmol) and POBr3 (8.88 g, 31 mmol, 1.1 eq) is heated to 120° C., stirred for 15 min, allowed to cool, quenched by addition of a saturated solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 95:5) to afford 5.18 g of the title compound as a yellow oil: ESI-MS: 214.0/216.0 [M+H]+; tR=2.49 min (System 1); TLC: Rf=0.35 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].P([O-])(O)(O)=[O:19].[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1OC1C=CCC1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1C=CCC1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwise with an aqueous solution (150 mL) containing sodium chicrite (80% technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), and left to stand overnight. The resulting mixture is extracted with dichloromethane (2×250 mL), and the combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is recrystallized from ethyl acetate, to give 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of a colorless solid. m.p. 160°-163° C. [Elemental analysis: C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: C(O[C:4](=[O:30])[CH:5]([C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]([NH2:40])[NH:37][N:36]=1)=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]2[NH:40][C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[C:5]([CH2:6][CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:4](=[O:30])[N:37]2[N:36]=1)=[O:34]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: CCOC(=O)C(CCC1CCCCC1)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(CCC3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 10 %

Procedure:
A mixture of 71 mg (0.171 mmol) of 2-(4-benzyloxy-benzoyl)-4-cyclohexyl-butyric acid ethyl ester, 24 mg (0.171 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 7 mg (20 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 3 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) desired 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C29H31N3O4 [M++H]+: 486.23, found: 486.2. This material was then converted to 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (559) via the well known. LiOH saponification protocol (10% yield over 2 steps); LC-MS—calcd for C28H29N3O4 [M++H]+: 472.22, found: 472.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30][N:32]2[CH2:36][CH2:35][C@@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:33]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: FC(F)(F)c1ccc(-c2cc([C@@H]3C[C@H]3NCCCl)ccc2OCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)c(-c3ccc(C(F)(F)F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)-N-(2-chloroethyl)cyclopropanamine (500 mg, 1.12 mmol) in dry DMF (5 mL), (R)-tert-butyl pyrrolidin-3-ylcarbamate (438 mg, 2.3 mmol) was added and stirred at RT for 48 h. After completion, the reaction mixture was poured into ice water (20 mL), extracted with EtOAc (2×20 mL). The combined extracts were washed with water (25 mL), brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH: CHCl3 (4:96) to get tert-butyl(R)-1-(2-((trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg, 60.6%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[OH:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].ClCCl.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1.[O-]Cl.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([C:31]([F:32])([F:33])[F:34])[CH:20]=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O/N=C/c1ccc(Br)c(C(F)(F)F)c1
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(Br)c(C(F)(F)F)c3)=NO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed (E)-N-[[4-bromo-3-(trifluoromethyl)phenyl]methylidene]hydroxylamine (1.5 g, 5.60 mmol, 1.00 equiv), dichloromethane (20 mL), 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.6 g, 5.83 mmol, 1.10 equiv), NaOCl (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 1.7 g (56%) of 3-[4-bromo-3-(trifluoromethyl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5].O.[CH2:12](O)C>>[OH:10][C:9]1[C:3]2[N:2]=[CH:12][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: Nc1c(O)cccc1O
Agent: Cl
Solvent: O
Product: Oc1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Aminoresorcinol hydrochloride (2 g) and triethylchloroformate (4.5 ml) were heated to reflux under nitrogen for 3 h. After cooling to room temperature, the reaction mixture was poured into a mixture of water (70 ml) and ethanol (20 ml). The mixture was stirred vigorously for 30 minutes, then left to stand at room temperature overnight. The beige precipitate which formed was collected by filtration, and dried by azeotroping with toluene to give the title compound as a beige solid (1.2 g).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[CH3:20]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH:18]=[CH2:20]
Reactant: COC(C)(C)C
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.28 g of methyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature within 1 minute with 962 mg of potassium tert.butylate and stirred for 1 hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.5 g of 4-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]butyraldehyde in 20 ml of tert.butyl methyl ether and stirred at 0° C. for a further 45 minutes. Thereafter, the reaction mixture was diluted with 80 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the crude product (2.1 g) on silica gel at 0.5 bar with ethyl acetate/petroleum ether (vol. 2:98) and recrystallization from 20 ml of methanol gave 1.26 g of trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarbonitrile as colorless crystals with m.p. (C-SB) 20.1° C., SB -N 36.9° C., cl.p. (N-I) 54.8° C.
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]([O:9]C)=O.[NH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C>[O:9]=[C:7]1[N:15]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6]1
Reactant: Nc1nccs1
Reactant: COC=C(C=CC(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(-c2nccs2)c1
Temperature: 150 °C
Yield: 43 %

Procedure:
After 2 g (9.9 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioate obtained in Example 1-1 was dissolved in 10 mL of DMF, 1 g (9.9 mmol) of 2-aminothiazole was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 150° C. for 6 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then washed using brine, followed by drying using magnesium sulfate, and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethylacetate=1:3) to obtain a target compound (Actual yield: 1 g, Percent yield: 43%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:27][CH2:26]1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:37]2[CH:36]=[N:35][C:34]([NH:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:39][CH:38]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(NCCN3CCOCC3)nc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and N-(2-morpholinoethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(6-(2-morpholinoethylamino)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [O:1]1[CH2:4][C:3](=[CH:5][C:6]#[N:7])[CH2:2]1.[C:8]1([CH2:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:14]([NH:15][C:3]1([CH2:5][C:6]#[N:7])[CH2:4][O:1][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC=C1COC1
Reactant: NCc1ccccc1
Product: N#CCC1(NCc2ccccc2)COC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
A mixture of oxetan-3-ylidene-acetonitrile (950 mg, 10 mmol) and phenylmethanamine (1.31 ml, 12 mmol) was heated with stirring at 60° C. for 5 hours under nitrogen. The mixture was concentrated in vacuo. The residue was purified by flash column (eluting with 0-50% ethyl acetate in hexane) to afford 1.65 g of 3-(benzylamino)oxetan-3-acetonitrile as a colorless oil (yield was 81.7%).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[NH2:9].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[N:9]=[S:2]([CH3:3])[CH3:1]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CSC
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: CS(C)=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
A solution of 1.1 mL (15 mmol) of dimethyl sulfide in 170 mL of dichloromethane was cooled to -10° C. and 0.90 g (13 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 23.3 g (120 mmol) of 2,4,6-trichloroaniline and then 22 g (170 mmol) of quinoline were added with cooling and stirring. The resulting product was a mixture of the title compound and unreacted 2,4,6-trichloroaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:15]([NH2:21])C(OCC)=O)=[N:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2].CN(C)[CH:29]=[O:30]>>[N+:1]([C:4]1[C:5]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:6][C:7]2[C:8]3[N:9]([C:29](=[O:30])[NH:21][N:15]=3)[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)N(N)c1nc(=O)[nH]c2cc([N+](=O)[O-])c(N3CCCC3)cc12
Reactant: CN(C)C=O
Product: O=c1[nH]nc2c3cc(N4CCCC4)c([N+](=O)[O-])cc3[nH]c(=O)n12
Temperature: 25 °C
Yield: 78 %

Procedure:
500 mg (1.38 mmol) of ethyl (7-nitro-2-oxo-6-pyrrolidin-1-yl-1,2-dihydro-quinazolin-4-yl)-carbazate in 30 ml of dry dimethylformamide were heated at reflux for 3 hrs. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was triturated with a small amount of acetone and the red precipitate was filtered off and dried in a vacuum. 342 mg (78%) of 8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as a red powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].[C:18]1([CH2:24][CH2:25][CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: BrCCCc1ccccc1
Product: COC(=O)Cc1c(C)n(CCCc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using methyl [5-methoxy-2-methyl-indol-3-yl]-acetate and 3-phenylpropyl bromide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.C(C(NC(=O)[C@H](N1C=CC(C2C=CC([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(C)(C)C
Yield: 55 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester was deprotected. The crude amine salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 4(b)) were condensed in wet 1,2-dichloroethane at 90-100° C. to yield 180 mg(55%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester. 1H NMR) δ 7.90 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.7 Hz), 7.60 (dd, 3H, J=8.7, 11.5 Hz), 7.38-7.22 (m, 8H), 7.10 (t, 1H, J=2.2 Hz), 6.82 (t, 1H, J=2.5 Hz), 6.62 (t, 1H, J=3.0 Hz), 6.32 (d, 1H, J=9.0 Hz), 5.63 (d, 1H, J=4.70 Hz), 5.14 (d, 3H, J=3.7 Hz), 4.00 (d, 1H, J=8.7 Hz), 3.48 (dd, J=7.2, 13.1 Hz), 3.39 (d, 1H, J=5.9 Hz), 3.14 (dd, 1H, J=8.7, 16.8 Hz), 2.78 (d, 3H, J=4.7 Hz), 0.92 (s, 9H). IR (KBr): 3356, 2929, 1735, 1657, 1402 cm−1. Anal. Calculated for C35H39N4O5.0.5H2O: C, 69.63; H, 6.51; N, 9.28. Found: C, 69.85, H, 6.46; N, 9.14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.S(=O)(O)[O-].[Na+].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O>O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=Cc1ccccn1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Brc1ccc2[nH]c(-c3ccccn3)nc2c1
Temperature: 90 °C
Yield: 40.5 %

Procedure:
A mixture of 4-bromo-1,2-diaminobenzene (1.00 g, 5.35 mmol), sodium bisulfite (1.02 g) in water (8 mL) and ethanol (80 mL) and 2-pyridine carboxaldehyde (0.63 g, 5.88 mmol) was heated at 90° C. for 15 h. The reaction was cooled to room temperature and concentrated under vacuum. The residue was partitioned between water (60 mL) and chloroform (80 mL) and the aqueous phase was extracted with chloroform (2×50 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated under vacuum to give the crude product (1.36 g). The residue was purified by column chromatography eluting with EtOAc:hexaxes 0 to 50% to afford 594 mg of 5-bromo-2-(pyridin-2-yl)-1H-benzo[d]imidazole (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>N1C=CC=C(C)C=1>[CH:13]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]4)[CH:10]=3)[C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7]2)[CH2:15][CH2:14]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(Cl)cc2c1=O
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 0.30 g (1.0 mmole) of 6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.26 g (2.0 mol) of N-ethyl-3-pyrrolidinemethanamine and 10 ml of 3-picoline was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and the solid filtered off and washed with acetonitrile to give 0.33 g of the title compound, mp >310° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([CH3:19])[C:11]=1[O:20][CH3:21])[CH2:4][CH3:5])[CH3:2].[H][H]>[Pt]=O.CO>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([CH3:19])[C:11]=1[O:20][CH3:21])[CH2:4][CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CCN(CC)CCNC(=O)c1cc([N+](=O)[O-])cc(C)c1OC
Agent: O=[Pt]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1cc(N)cc(C)c1OC
Yield: 62 %

Procedure:
A mixture of N-(diethylaminoethyl)-2-methoxy-3-methyl-5-nitrobenzamide (4.25 g), platinum oxide (425 mg) and methanol (85 ml) is shaken in a hydrogen stream. After absorption of hydrogen stops, the reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under vacuum and the residue is chromatographed on a column of alumina, which is eluated with methylene chloride to methylene chloride-2% methanol. The eluate is concentrated under vacuum and the residue is washed with isopropyl ether to give N-(diethylaminoethyl)-5-amino-2-methoxy-3-methylbenzamide (2.38 g) as crystals melting at 56° to 57° C.