Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26]C(OCC)=O)=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[OH-].[NH4+].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(O)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 42.7 %

Procedure:
43.20 g (0.081 Mol) of 6-[((2E)-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate are dissolved in 66 ml (0.815 Mol) of pyridine and 400 ml of acetone at room temperature. 61 ml (0.815 Mol) of ammonium hydroxide solution 25% are added dropwise to the solution at room temperature. After 12 h reaction, the mixture is thrown on water and acidified by the addition of HCl 25% (up to pH=3-4). A paste is obtained which is filtrated and dissolved in ethyl acetate and extracted with water. The organic phase is dried with sodium sulfate, filtrated, concentrated by rotary evaporation. Filtration of the residue over silica gel with tert-Butyl methyl ether as eluant and crystallization of the residue in 200 ml of ethyl acetate and 1200 ml of hexane at 0° C. give 15.84 g of 6-[((2E)-{4-hydroxyphenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][S:10][C:11]1[S:12][C:13]2[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=[O:23])[CH:17]=[CH:16][C:14]=2[N:15]=1.[Cl:24]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:24][CH:21]([CH2:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([S:10][CH3:9])[S:12][C:13]=2[CH:19]=1)[CH:22]=[O:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1nc2ccc(CCC=O)cc2s1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Product: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
L-proline (0.22 g, 1.9 mmol) was added to a solution of 3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (2.3 g, 9.7 mmol) in DCM (40 mL) at 0° C. followed by addition of N-chlorosuccinimide (1.4 g, 10 mmol). The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with 10:1 to 2:1 petroleum ether/EtOAc to afford 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal as a yellow oil (2.1 g, 79%). 1H NMR (300 MHz, CDCl3) δ 9.56 (dd, J=1.2, 2.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63 (d, J=0.6 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 4.44-4.39 (m, 1H), 3.51-3.44 (m, 1H), 3.20-3.13 (m, 1H), 2.78 (s, 3H). LCMS (ESI) m/z 290 (M+18+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:22]([C:23]3[CH2:28][CH2:27][CH:26]([O:29][Si](C(C)(C)C)(C)C)[CH2:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13]1)=[O:11].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([O:16][C:17]2[C:22]([C:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:15]1)=[O:11]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2OC2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2C2=CCC(O)CC2)C1
Reaction time: 24 h
Yield: 28.9 %

Procedure:
To a solution of (1H-benzo[d]imidazol-2-yl)(3-(3-(4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)pyrazin-2-yloxy)azetidin-1-yl)methanone (336 mg, 0.664 mmol) and THF (6 mL) was added 1M TBAF in THF (1.6 mL, 1.600 mmol). After 24 hours, the reaction solution was eluted through a short plug of silica gel. The filtrate was concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 4% MeOH in DCM, to provide (1H-benzo[d]imidazol-2-yl)(3-(3-(4-hydroxycyclohex-1-enyl)pyrazin-2-yloxy)azetidin-1-yl)methanone (75 mg, 28.8% yield), as a light yellow solid. MS (ESI) m/z 392.1 (MH+). IC50 (uM) 0.07168. 1H NMR (CDCl3, 400 MHz) δ (ppm): 1.63-1.67 (m, 1H), 1.77-1.87 (m, 1H), 2.00-2.07 (m, 1H), 2.26-2.35 (m, 1H), 2.60-2.71 (m, 2H), 2.74-2.84 (m, 1H), 4.07-4.13 (m, 1H), 4.33 (dd, 1H, J=11.74 Hz, 4.11 Hz), 4.71 (dd, 1H, J=11.74 Hz, 6.65 Hz), 4.90 (dd, 1H, J=11.93 Hz, 4.11 Hz), 5.31 (dd, 1H, J=11.93 Hz, 6.65 Hz), 5.52-5.58 (m, 1H), 6.76 (br s, 1H), 7.29-7.41 (m, 2H), 7.54 (d, 1H, J=7.82 Hz), 7.82 (d, 1H, J=8.02 Hz), 7.93 (d, 1H, J=2.54 Hz), 8.19 (d, 1H, J=2.54 Hz), 10.59 (s, 1H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24](O)[CH2:25][C:26]2[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:29][N:30]=2)=[CH:20][CH:19]=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([N:55]2[C:51](=[O:61])[C:52]3[C:53](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:54]2=[O:56])[CH2:25][C:26]2[N:27]([C:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:29][N:30]=2)=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Di-tert-butyl azodicarboxylate (0.808 g, 3.51 mmol) was added portionwise to 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanol (Intermediate 86) (1.36 g, 2.92 mmol), phthalimide (0.473 g, 3.22 mmol) and triphenylphosphine (0.921 g, 3.51 mmol) in THF (25 mL) at room temperature over a period of 15 minutes. The resulting solution was stirred at room temperature for 60 minutes then concentrated by evaporation and purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethyl)isoindoline-1,3-dione (1.78 g, 102%) as a colourless foam.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:26]=[CH:25][C:20]5[O:21][CH2:22][CH2:23][O:24][C:19]=5[C:18]=4[O:27][CH2:35]3)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2ccc3c(c2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c2ccc2c1OCCO2

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one was obtained (85%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.22 (m, 12H), 7.10 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 6.99 (dd, J=7.4, 7.4 Hz, 1H), 6.88 (s, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.32 (d, J=8.3 Hz, 1H), 6.04 (d, J=8.3 Hz, 1H), 4.93 (d, J=9.5 Hz, 1H), 4.81 (d, J=9.5 Hz, 1H), 4.27 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 148.8, 144.7, 142.0, 137.6, 137.5, 131.6, 129.3, 128.7, 128.5, 128.3, 128.1, 127.9, 127.7, 127.6, 123.9, 122.9, 122.4, 113.8, 111.0, 109.9, 80.1, 64.1, 63.9, 58.1, 57.1; MS (ES+) m/z 461.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5]O.P(Br)(Br)[Br:17]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5][Br:17]
Reactant: BrP(Br)Br
Reactant: COc1c(C)c(C)c(OC)c(CO)c1C
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CBr)c1C
Yield: 119.9 %

Procedure:
A solution of 16.5 g (78.5 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzylalcohol in 90 ml of tetrahydrofuran was cooled to 0° C., to which 14.2 g (52.5 mmol) of phosphorus tribromide was added with stirring. After stirring at the same temperature for 30 minutes, the reaction mixture was diluted with water and extracted with isopropyl ether. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried, from which the solvent was evaporated off. The residue was crystallized from methanol, to give 17.2 g (80.0%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide. m.p. 71°-72° C.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]2[N:24]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=3)[N:26]=2)[CH:25]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ncc(Br)cn3c2-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
0.15 g (0.5 mM) of 4-[bromo(phenyl)acetyl]benzaldehyde and 2.0 equivalents of 5-bromopyrimidin-2-amine are dissolved in 6 ml DMF. The reaction mixture is heated at 90° C. overnight. The reaction mixture is cooled and water is added. It is then extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.
Reaction SMILES: [OH-:1].[K+].[CH:3]1([N:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=O)=[C:11]([C:26]#[N:27])[C:10]([CH3:28])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.OO>O.CO>[CH:3]1([N:8]2[C:12]3=[N:13][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[C:20]5[C:25]=4[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:27][C:26](=[O:1])[C:11]3=[C:10]([CH3:28])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: Cc1nn(C2CCCC2)c(NC(=O)c2cccc3cccnc23)c1C#N
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1[nH]n(C2CCCC2)c2nc(-c3cccc4cccnc34)nc(=O)c1-2
Temperature: 25 °C
Yield: 19.3 %

Procedure:
To potassium hydroxide (0.2 g, 3.0 mmol) in water (75 ml) cooled in an ice bath was added 1-cyclopentyl-3-methyl-4-cyano-5-(8-quinolinecarboxamido)-1H-pyrazole (2.05 g, 5.9 mmol) in methanol (30 ml) followed by 30% hydrogen peroxide (3.0 ml, 30 mmol). The reaction mixture was slowly warmed to room temperature and then refluxed for 24 hours. Additional potassium hydroxide (3.0 mmol) and 30% hydrogen peroxide (30 mmol) were added and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled in an ice-bath, the precipitated product was collected by filtration through a glass frit and was washed with water, then ether. Recrystallization from ethyl acetate afforded 0.2 g (10%) of 1-cyclopentyl-3-methyl-6-(8-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one as yellow crystals, m.p.242°-244° C. when dried for 24 hours at 120° C. in high vacuum.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH:18]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Solvent: O=CO
Product: CC(CCNC=O)c1ccccc1-c1ccccc1
Reaction time: 8 h

Procedure:
2.25 g of 3-p-biphenyly-butylamine are dissolved in 30 ml of formic acid, 10 ml of acetic anhydride are added dropwise at 60°, while stirring, and the mixture is allowed to stand overnight and worked up in the customary manner to give 1-formamido-3-p-biphenyly-butane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.Cl.[F:17][C:18]1([F:25])[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1([F:25])[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)[CH2:20][CH2:19]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(NC2CCC(F)(F)CC2)c2cccc([N+](=O)[O-])c2n1
Yield: 69.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-15, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 200 mg, 0.896 mmol), 4,4-difluorocyclohexanamine hydrochloride (228 mg, 1.345 mmol), and K2CO3 (370 mg, 2.68 mmol) in CH3CN (4 mL) to afford 200 mg of the title product. MS [M+H]+: 323.23.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[C:9]([NH:21][CH3:22])[CH:8]=2)=[C:4]([F:25])[CH:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2OC1C=CC(N[C:50]([C:52]2([C:55]([NH:57][C:58]3[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=3)=[O:56])[CH2:54][CH2:53]2)=[O:51])=CC=1F>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:50]([C:52]2([C:55]([NH:57][C:58]3[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=3)=[O:56])[CH2:54][CH2:53]2)=[O:51])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([NH:21][CH3:22])[CH:8]=1
Reactant: CNc1cc(Oc2ccc(N)cc2F)c2cc(OC)c(OC)cc2n1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Product: CNc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)c2cc(OC)c(OC)cc2n1

Procedure:
′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was synthesized from [4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-amine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (6.0 mg, 4.0% yield). 1H NMR (DMSO-d6) δ 10.42 (s, 1H), 9.91 (s, 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H), 7.09 (t, 2H), 5.90 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.39 (br s, 1H), 2.92 (s, 3H), 1.41 (dt, 4H). LCMS: m/z 535 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:27](=[O:38])[NH:28][CH2:29][C:30]1[O:31][CH:32]=[C:33]([OH:37])[C:34](=[O:36])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(#N)C>[C:39]([O:37][C:33]1[C:34](=[O:36])[CH:35]=[C:30]([CH2:29][NH:28][C:27]([CH:9]2[CH2:10][N:11]([S:14]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=4)(=[O:16])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:38])[O:31][CH:32]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1C(=O)NCc1cc(=O)c(O)co1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2C(=O)OC(C)(C)C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In acetonitrile (10 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]piperazine (411 mg), followed by the addition of acetic anhydride (0.075 ml) and triethylamine (0.11 ml). The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue. The resulting mixture was washed successively with 0.2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution. The organic layer was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (methylene chloride:methanol=50:5), whereby the title compound (256 mg) was obtained as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:21])[C:11](=[O:22])[C:10]2[C:5](=[CH:6][C:7]([N+]([O-])=O)=[CH:8][CH:9]=2)[N:4]=1)C.BrN1C(=O)CCC1=O.[CH3:34][N:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Pd].[C]>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:1][N:38]1[CH2:39][CH2:40][CH2:41][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH3:21]
Reactant: CCOc1ccccc1-n1c(CC)nc2cc([N+](=O)[O-])ccc2c1=O
Reactant: CN1CCCNCC1
Agent: [Pd]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOc1ccccc1-n1c(CN2CCCN(C)CC2)nc2ccccc2c1=O

Procedure:
Briefly, 2-amino-4-nitrobenzoic acid was acylated with propionyl chloride in triethylamine (TEA) and tetrahydrofuran (THF). The acylated compound was refluxed with 2-ethoxyaniline in phosphorus oxychloride (POCl3) and toluene to produce 2-ethyl-7-nitro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one. The 2-ethyl-7-nitro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one was brominated with N-bromosuccinimide (NBS) in carbon tetrachloride, the product of which was subsequently reacted with N-methylhomopiperazine in THF. The product of this reaction was subjected to hydrogenation conditions using catalytic amounts of Pd/carbon (10% Pd) to afford Compound 10.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: COc1ccc(Nc2cc(-c3cc(Cl)ccc3C)nc(N)n2)cc1
Yield: 52 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-methoxy-phenylamine provided the title compound (52% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 3.74 (s, 3H, CH3), 6.01 (s, 1H, Ar), 6.28 (s, 2H, NH2), 6.87-6.89 (m, 2H, Ar), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.34-7.39 (m, 2H, Ar), 7.60 (d, 2H, J=8.9 Hz, Ar), 9.01 (s, 1H, NH).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][CH2:8][N:9]([C:11](=[O:43])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)[CH3:10])(C)(C)C.[Li+].[OH-].Cl>C1COCC1.O>[CH:21]1([CH2:20][CH:19]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:43])=[CH:13][CH:14]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCC(=O)O)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a mixture of (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid tert-butyl ester (7.4 mg, 0.012 mmol) in THF (0.5 mL) is added LiOH (1 N aqueous, 0.5 mL) and stirred at 70° C. overnight. The reaction mixture is acidified with 1N HCl (1.0 mL), diluted with water, and extracted with EtOAc (3×5 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid (4.6 mg, 68%) as a clear syrup. MS (ES): 554.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[H-].[Na+]>>[CH2:2]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][C:4]1=[O:12])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(=O)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(=O)n(Cc2ccccc2)c2ccccc12
Reaction time: 1 h

Procedure:
4-Methylquinol-2-one (24.0 g.) was added in portions to a stirred suspension of sodium hydride [6.5 g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with petroleum ether (b.p. 40°-60° C.)] in dimethylformamide (150 ml.), at 20°-25° C. After the addition was complete the mixture was stirred at 20°-25° C. for a further 1 hour. Benzyl chloride (23.0 g.) was then added and the subsequent mixture was heated at 95°-100° C. for 20 hours. The mixture, which contained some solid, was then added to water (1 liter) and the resultant mixture was stirred for 1 hour. The solid which formed was separated by filtration, washed with water, and then was resuspended in a mixture of water (300 ml.) and 2 N hydrochloric acid (50 ml.). This mixture was stirred for 15 minutes and then the solid separated by filtration to give 1-benzyl-4-methylquinol-2-one, as a white crystalline solid, 20.0 g., m.p. 109°-111° C. after recrystallisation from cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C)C=O.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichlorormethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted with water and extracted into ethyl acetate and concentrated to provide the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Reaction time: 3 h

Procedure:
2 g of cis-4-hydroxycyclohexanecarboxylic acid (13.87 mmol, 1 eq.) are placed in 50 mL of a 4/1 mixture of toluene/methanol at room temperature. Trimethylsilyl-diazomethane (111 mL, 221.96 mmol, 16 eq.) is poured into the reaction medium with stirring. After 3 hours at room temperature, the reaction medium is evaporated to give 2.6 g of methyl cis-4-hydroxycyclohexanecarboxylate.