Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=[N:16]O)[C:7]1=[C:6]2[CH3:18]>C(O)C.[OH-].[Na+].[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[C:7]1=[C:6]2[CH3:18]
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1=NO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c(C)c1n2CCCC1N
Temperature: 40 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
Raney alloy (10.2 g) was added portionwise (over 40 minutes) to a solution of 6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one oxime (6.2 g, 25.4 mmol) in ethanol (200 mL) and 10% aqueous sodium hydroxide (100 mL) at ~35° C. The reaction mixture was stirred at 40° C. for 12 hours, cooled to 25° C., and then poured into icy, saturated brine solution (500 mL). The product was extracted with ether (2×200 mL), and the combined extracts were washed with 5% hydrochloric acid (200 mL). Upon cooling the separated aqueous layer was rendered basic with 50% aqueous sodium hydroxide, and extracted with ether (3×150 mL). The ethereal extracts were dried over MgSO4, filtered, and evaporated to afford 5.8 g (99%) of the title amine as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH:9]1[O:14]CCCO1.[Li][CH2:16]CCC.CI>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:16])[C:3]=1[CH:9]=[O:14]
Reactant: [Li]CCCC
Reactant: Brc1cccc(Br)c1C1OCCCO1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc(Br)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1H NMR (500 MHz, CDCl3) δ [ppm] 7.55 (d, 3J=8.0 Hz 2H, ar), 7.00 (t, 3J=8.0 Hz 1H, ar), 6.19 (s, 1H, CH), 4.33-4.29 (m, 2H, CH2), 4.02-3.97 (m, 2H, CH2), 2.44-2.34 (m, 1H, CH2), 1.44-1.40 (m, 1H, CH2); 13C{1H} NMR (125.77 MHz, CDCl3) δ [ppm] 133.9, 132.5, 129.8, 122.9, 101.6, 66.7, 24.1. The acetal (10.1 g, 31.25 mmol) was dissolved in THF, abs. (200 ml). At −78° C. n-BuLi (15.1 ml, 2.5 M in hexane, 37.8 mmol) was added within 25 min, followed by 90 min additional stirring at that temperature. Then the reaction mixture was treated with methyliodide (5.99 g, 42.2 mmol) and stirred for 25 min at −78° C. Next the reaction mixture was allowed to warm to ambient temperature within 1.5 h. The resulting solution was quenched with HCl (290 ml of a 5 N solution) and stirred for 1.5 h at ambient temperature. The complete deprotection of the aldehyde was checked via GC analysis. Then the reaction mixture was subsequently extracted with diethylether (4×100 ml), the combined organic layers were washed with a 10% solution of sodium thiosulfate (100 ml), water (100 ml), dried over MgSO4, filtered and the volatiles removed in vacuo. The resulting slightly yellow solid was purified via Kugelrohr distillation to afford 50 (5.97 g, 96%) as white crystals. Rf 0.56 (cyclohexane:ethylacetate 10:1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCS(=O)(=O)CC1
Yield: 22.1 %

Procedure:
The title compound was prepared as described in Example 57B by using compound I-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea from Example 16C (200 mg, 0.39 mmol), thiomorpholine 1,1-dioxide (158 mg, 1.17 mmol), tetrabutylammonium iodide (144 mg, 0.39 mmol) and N,N′-diisopropylethylamine (139 μL, 0.78 mmol) in N,N′-dimethylformamide (2 mL) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea (52.75 mg, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.56 (s, 1H), 7.61 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d, 1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.10-3.03 (m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 611 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3 g, 9.76 mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl acetate was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2 hrs. The reaction mixture was filtered through a plug of Celite and evaporated under reduced pressure to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the in the next step without further purification.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]=[CH:11][CH2:12][CH2:13][CH3:14].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:17]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][CH2:11][CH2:12][CH:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: C=CCCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Solvent: C1COCCO1
Product: CCCC(C)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
To a solution of 9-BBN (0.5 M in THF) (90.0 ml, 45.0 mmol) at 23° C., 1-pentene (4.93 ml, 45.0 mmol) was added. After 12 h, the solution was diluted with anhydrous dioxane (150 ml) and then 4-bromoacetophenone (5.97 g, 30.0 mmol) K3PO4 (9.55 g, 45.0 mmol), Pd(PPh3)4 (0.867 g, 0.750 mmol) were added. After deoxygenating the solution with N2 for 20 min, the solution was refluxed for 12 h. After cooling to ambient temperature, 3N NaOH (40 ml) and 30% H2O2 (40 ml) were added dropwise followed by dilution with hexanes (200 ml). After separation of layers, the organic layer was washed with brine (200 ml), dried, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes, to afford 4.09 g of 11 as an oil (72%). 1H NMR (CDCl3) δ 0.88 (t, J=6.9 Hz, 3H), 1.23-1.36 (m, 4H), 1.55-1.69 (m, 2H), 2.58 (s, 3 H), 2.66 (t, J=7.7 Hz, 2H), 7.25 (d, J=1.9 Hz, 2H), 7.86 (d, J=1.9 Hz, 2H); 13C NMR (CDCl3) δ 14.09, 22.58, 26.65, 30.89, 31.51, 36.04, 128.55, 128.68, 134.97, 148.92, 197.98.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].C([NH2:15])=O>O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:15][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NC=O
Solvent: O
Product: O=C1NC(=O)c2c(Cl)cccc21
Temperature: 125 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 3-chlorophthalic acid anhydride (9 g, 49.2 mmol) and formamide (100 mL) was heated to 125 ° C. and stirred for 3 h. Water (300 mL) was then added and the mixture was cooled to room temperature. The mixture was filtered and the resulting white solid was washed with water and dried to give 4-chloro-1H-isoindole-1,3(2H)-dione (7.7 g, 86% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH:32]1([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:32]1([CH2:38][NH:39][C:16](=[O:18])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:20][CH2:19][C:5]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NCC2CCCCC2)CCN(C)C1
Reaction time: 16 h

Procedure:
3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid was mixed with EDCI and cyclohexylmethanamine in dichloromethane and the reaction mixture was stirred for 16 h to obtain N-(cyclohexylmethyl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.[NH2:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1>C1(C)C=CC=CC=1>[CH3:32][C:30]1[O:29][N:28]=[C:27]([NH:26][CH2:24][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:6]=3[C:2]=2[CH3:1])[CH:31]=1
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1
Product: Cc1cc(NCc2oc3cccc(OCCCN(C)Cc4cccnc4)c3c2C)no1
Yield: 67.3 %

Procedure:
A solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (55 mg) and 3-amino-5-methylisooxazole (160 mg) in toluene (4 ml) was refluxed overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography developed by ethyl acetate and methanol to give the titled compound as a pale yellow oil (46 mg). ESI-MS: m/z 419 (MH+); 1H-NMR (CDCl3): δ 2.00-2.09 (2H, m), 2.29 (3H, s), 2.44 (3H, s), 2.48 (2H, s), 2.68 (2H, t, J=10.2 Hz), 3.53 (2H, s), 4.14 (2H, t, J=5.9 Hz), 6.16 (1H, s), 6.62 (1H, d, J=7.9 Hz), 7.05-7.17 (2H, m), 7.32 (1H, s), J=7.9 Hz), 7.59-7.63 (1H, m), 8.41 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.51 (1H, d, J=2.0 Hz), 8.82 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[CH3:11][NH:12][C:13]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])=[O:14]
Reactant: CN=C=O
Reactant: CC1Cc2ccccc2N1
Solvent: Cc1ccccc1
Product: CNC(=O)N1c2ccccc2CC1C
Reaction time: 24 h

Procedure:
1 mole of 2-methylindoline is dissolved in 300 ml of toluene and 1 mole of methyl isocyanate is added, the temperature not rising above 25° C. The mixture is left to stand for 1 day and the resulting precipitate is then filtered off. N-Methylaminocarbonyl-2-methylindoline with a melting point of 158°-160° C. is obtained.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of toluene (20 ml), diphenyl phosphite (2.07 g, 6.7 mmole), imidazole (1.09 g, 16 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (A) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was washed with a 5% aqueous potassium hydroxide solution (20 ml). The toluene layer was separated, washed with water, dried and evaporated to give a crystalline mass. Recrystallization from acetonitrile gave 2.57 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 74.5%. M.P., 142°-143° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(N)C=CC1=2)(=O)C>>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([CH3:37])[C:34]([NH2:42])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(N)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 26, Steps 1-2 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine 1-carboxylate. CI MS 546 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClC(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)([O-:10])=[O:9]
Reactant: NCc1ccc(CO)o1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1NCc1ccc(CO)o1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 15.9 parts of 4-chloro-3-nitropyridine, 12.7 parts of 5-(aminomethyl)-2-furanmethanol, 13.3 parts of N,N-diethylethanamine and 745 parts of trichloromethane was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was washed with K2CO3 (aq.), dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 17.76 parts (71.3%) of 5-[[(3-nitro-4-pyridinyl)amino]methyl]-2-furanmethanol; mp. 134.9° C. (interm. 19).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.C(O)(=O)C.[O-:27][C:28]#[N:29].[K+]>O>[CH2:17]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([NH2:29])=[O:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[CH2:15][CH3:16])[CH3:18]
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(NC(N)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
The compound (200 mg, 0.6 mmol) of example 42 was suspended in a mixed solution of water (5 ml) and acetic acid (5 ml), added with potassium cyanate (81 mg, 1 mmol), and heated to reflux and stirred for 2 h. The cooled reaction mixture was poured into water to generate a white solid, which was washed with water (10 ml×3) and dried to give the title compound (210 mg, yield: 91%). 1H NMR (DMSO-d6) δ: 11.76 (1H, br), 8.56 (1H, br), 7.76 (1H, d), 7.59 (1H, dd), 7.06 (1H, d), 5.78 (1H, br), 4.00 (2H, t), 2.56 (2H, q), 2.46 (2H, q), 1.74 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.97 (3H, t).
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][CH3:20].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:21][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([CH3:20])=[O:30]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(C)=O)c1C

Procedure:
Prepared from product of Example 1 (5.75 g, 17.5 mmol) and MCPBA (3.4 g of an 85% mixture with MCBA; 17.5 mmol) as described above. Recrystallization (ether) afforded the product as a white solid (5.23 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH:23][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:22])=[CH:17][CH:16]=1
Reactant: NC(=O)NCc1ccc(Cl)cc1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: N#CCC(=O)NC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
68.7 g of 98% cyanoacetic acid and 155 ml of acetic anhydride were kept at 65° C. for 30 minutes. 4-chlorobenzylurea (132.9 g) was added in portions over 10 minutes. After 2 hrs. at 70-75° C., further acetic anhydride (25 ml) was added. After a further 15 minutes,90 ml of toluene was added, cooled to room temperature, the solid collected and washed with toluene to give the title compound (155.60 g) as a white-solid mp 203-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[C:32]1([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[NH:14][C:15]([C:17]2[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4′-amino-3-cyclohex-1-enyl-biphenyl-4-yl)-amide (as prepared in the Example 28, step (a), 28.1 mg, 0.0547 mmol) in 0.5 mL of DCM was added pyridine (113 μL, 0.16 mmol) followed by methanesulfonyl chloride (5.1 μL, 0.066 mmol). After stirring at RT for 16 h under Ar, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2-4% EtOAc/DCM) to afford 31 mg (95%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.6 Hz), 7.48 (dd, 1H, J=8.6, 2.3 Hz), 7.37 (s, 1H), 7.29 (d, 2H, J=8.6 Hz), 6.64 (s, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.68 (t, 2H, J=8.2 Hz), 3.05 (s, 3H), 2.24-2.38 (m, 4H), 1.75-1.93 (m, 4H), 0.99 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C30H37N5O4SSi, 592.2 (M+H), found 591.6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2].[OH:20]O>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:8](=[O:20])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2]
Reactant: OO
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1S2
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1S2=O
Reaction time: 8 h

Procedure:
3-Carboxythianthrene-5,5-dioxide ((60 mg), acetic acid acid (2.0 ml) and 30% hydrogen peroxide (0.10 ml) were boiled under reflux for 10 mins., filtered and allowed to stand overnight at 0° C. 3-Carboxythianthrene-5,5,10-trioxide crystallised out, was filtered off and dried at 156° C. at 2mm. Hg, m.p. 340°-343° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[OH2:11]>>[OH:11][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: O
Reactant: O=C(O)c1cnccc1Cl
Product: O=C(O)c1cnccc1O
Yield: 80 %

Procedure:
Compound 3 is heated in water (see ROSS, J. Chem. Soc. (C), p. 1816-1821, 1966) to obtain 4-hydroxypyridine-3-carboxylic acid 5 as a colorless solid (>80%).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(Br)ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol), 1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol), bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO3 (0.83 g, 9.9 mmol) in DME (4 mL) and H2O (4 mL) was heated to 80° C. under N2 for 72 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.13 g, 13%). 1H NMR (CDCl3): δ 7.33-7.41 (m, 4H), 7.57 (m, 1H), 7.72 (s, 1H), 1.80-7.86 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of benzotriazole (12 g) in DMF (150 mL) at r.t. was added a solution of 10N NaOH (11 mL). After stirring for 30 min., 4-fluorobenzyl bromide (3.9 mL) was added. The mixture was further stirred for 3 hrs, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed water (2×), dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=O)=[CH:36][CH:35]=1>O1CCCC1>[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:36][CH:35]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 69.4 %

Procedure:
The reaction was performed as in Example 87 using sodium hydride (56% dispersion in oil; 9.5 g) dimethylsulfoxide (100 mL), (3-carboxypropyl)triphenylphosphonium chloride (35 g), 4,4'-difluorobenzophenone (23.8 g) and tetrahydrofuran (100 mL). After the usual work up, the crude product was crystallized from ether-hexane to furnish 18.2 g of 5,5-bis(4-fluorophenyl)-4-pentenoic acid, mp 100°-100° C. Anal. Calculated for C17H14F2O2 : C, 70.82; H, 4.89. Found: C, 70.77; H, 5.00.