Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C[Sn](C)C.C[Sn](C)C.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:38]1[N:43]=[N:42][C:41]([N:44]([CH2:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)([CH3:55])[CH3:54])[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:40][CH:39]=1>[F-].[K+].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.CN(C=O)C.O1CCOCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:38]2[N:43]=[N:42][C:41]([N:44]([CH2:52][C:53]([C:56]3[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=3)([CH3:54])[CH3:55])[C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[CH:40][CH:39]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(Br)nn1
Reactant: N#Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(-c2ccc(C#N)cn2)nn1
Temperature: 80 °C

Procedure:
To a 20 dram vial was added 2-bromo-5-cyanopyridine (182 mg, 1.0 mmol, 1.0 equiv), hexamethylditin (639 mg, 1.1 mmol, 1.1 equiv), Cl2Pd(Ph3P)2 (91 mg, 0.13 mmol, 0.13 equiv), triphenylarsine (34 mg, 0.11 mmol, 0.11 equiv), and dioxane (7 mL). The reaction mixture was stirred and heated to 80° C. for 12 h. The reaction was then concentrated, followed by the addition of tert-butyl 6-bromopyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate (423 mg, 1.0 mmol, 1.0 equiv), Pd(Ph3P)4 (172 mg, 0.15 mmol, 0.15 equiv), and DMF (3.3 mL). The reaction was stirred and heated to 100° C. for 3 h. After cooling to room temperature, the reaction was diluted with aqueous potassium fluoride (5 mL), extracted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated to give crude tert-butyl 6-(5-cyanopyridin-2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]([C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:18]2)[N:13]=1)([CH3:11])[CH3:10])(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C:9]([C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:18]2)[N:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(N)c1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.12 ml (0.50 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 29 mg (about 0.05 mmol) of the compound from Example 86A in 0.2 ml of dioxane. The reaction mixture was stirred at room temperature for 20 hours. The mixture was then concentrated to dryness under reduced pressure and dried until the weight remained constant. Yield: 24 mg (96% of theory).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([OH:18])[CH:9]=1.O>C1COCC1>[OH:13][CH2:12][C:11]1[CH:16]=[CH:17][C:8]([Cl:7])=[CH:9][C:10]=1[OH:18]
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of lithium aluminum hydride (1.1 g) in THF (50 ml), methyl 4-chloro-2-hydroxybenzoate (5.38 g; prepared in Reference Example 46.) in THF (50 ml) was added dropwise in a stream of argon at 0° C. After the solution was warmed to at room temperature, the solution was stirred for 30 minutes. To the reaction mixture, water was added. The mixture was extracted with mixture solution of ether-AcOEt, washed, dried over and concentrated under the reduced pressure. The residue was recrystallized from mixture solution of hexane-AcOEt to give the title compound (3.92 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nnc2n1-c1ccc(NO)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.55 g (0.01 m) of 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, 200 ml of tetrahydrofuran, 100 ml of methanol, 13.6 g of sodium acetate trihydrate and 12 g of stannous chloride dihydrate was stirred at room temperature for 1 hr under nitrogen atmosphere. After addition of 5 ml of conc. aqueous ammonia the inorganic material was separated by filtration over celite. The filter cake was washed with 500 ml of methylene chloride containing 20% of ethanol. The filtrate was evaporated and the residue was stirred with 100 ml of water and 30 ml of methylene chloride. The crystalline material was collected and washed successively with water, ethanol and ether to yield the above-named product. For analysis it was recrystallized from tetrahydrofuran/methanol, mp. 276°-278° dec.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:19])[CH3:18])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[C:20]1([N:16]([CH2:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[C:17](=[O:19])[CH3:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(=O)N(CC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methanolic hydrogen chloride (4M, 20 mL) was added to a stirred, cooled (0° C.) solution of N-[(1-t-butoxycarbonylpiperidin-4-yl)methyl]-N-phenylacetamide (2.72 g, 8.2 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give the title compound as a tan foam (2.17 g, 99%), δH (250 MHz, d6 -DMSO) 9.12-8.70 (2H, br m), 7.50-7.33 (5H, m), 3.57 (2H, d, J 7.1 Hz), 3.19 (2H, m), 2.75 (2H, m), 1.73 (6H, m), and 1.37 (2H, m).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O>C(#N)C>[Cl:28][C:20]1[S:19][C:18]([NH:17][C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[O:27])=[N:22][C:21]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Solvent: CC#N
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)c(Cl)s2)c(C(=O)C2CCCC2)c1
Reaction time: 2 h
Yield: 23.5 %

Procedure:
To a suspension of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (0.50 g, 1.29 mmol) in 20 ml of acetonitrile was added N-chlorosuccinimide (0.19 g, 1.42 mmol). The reaction mixture was stirred under nitrogen, in a pressure bottle excluded from light, for 2 h at 80° C. The mixture was concentrated under reduced pressure, dissolved in DMSO and purified by preparative HPLC to afford the title compound (0.128 g, 24%).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[C:21](=[N:26]\[O:27][CH3:28])/[C:22]([NH:24][CH3:25])=[O:23])[CH:10]=[CH:9][CH:8]=1.Cl>O>[CH3:1][O:2][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[C:21](=[N:26]\[O:27][CH3:28])/[C:22]([NH:24][CH3:25])=[O:23])[CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(OC)n1
Reaction time: 4 h

Procedure:
28% sodium methoxide--methanol solution (1.16 g) was added to (E)-2-[2-(6-chloropyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (400 mg), and the mixture was heated under reflux with stirring for 4 hours. The mixture was neutralized with 1N hydrochloric acid, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (61 mg). mp. 81°-82° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.FC(F)(F)C(O)=O.[O:40]=[C:41]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:42][CH2:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[O:40]=[C:41]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:42][CH2:43][CH:44]1[CH2:45][CH2:46][N:47]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:48][CH2:49]1
Reactant: O=C(CCC1CCNCC1)c1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCC(=O)c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
Molecular sieve pellets (3 Å) were added to a solution of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (30 mg, 0.069 mmol, Aldehyde 5), 4-(3-oxo-3-phenylpropyl)piperidine trifluoroacetate (25 mg. 0.075 mmol, from Step D), and DIEA (0.013 mL, 10 mg, 0.075 mmol) in 1,2-dichloroethane (0.70 mL). The mixture was stirred for 15 min at rt before the addition of sodium triacetoxyborohydride (17 mg, 0.080 mmol). After 2.5 h, the mixture was diluted with EtOAc (20 mL) and washed with sat'd NaHCO3 (10 mL) followed by sat'd NaCl (10 mL). The organic layer was dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 15-20% EtOAc/0.5% CH3OH/CH2Cl2 gave 30 mg of the title compound as a colorless viscous oil. ESI-MS: 637 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:16]([F:19])=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6].[CH3:21][O:22][C:23]1[C:24](=O)[C:25](=[O:29])[C:26]=1[O:27]C>CO>[F:20][C:3]1[C:2]([NH:1][C:24]2[C:25](=[O:29])[C:26](=[O:27])[C:23]=2[O:22][CH3:21])=[CH:18][CH:17]=[C:16]([F:19])[C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(N)c1F
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(Nc2c(OC)c(=O)c2=O)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A mixture of methyl (S)-1-(3-amino-2,6-difluorobenzoyl)pyrrolidine-2-carboxylate (prepared above) and 4.20 g (29.55 mmol) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in solution in 50 ml of methanol was heated at 60° C. for one hour and then stirred at ambient temperature for 4 hours. The reaction medium was concentrated and the residue (6.29 g) was chromatographed on silica gel (300 g prepacked column, eluted with heptane/ethyl acetate, from 70% to 100% of ethyl acetate). 2.30 g of methyl (S)-1-[2,6-difluoro-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]-pyrrolidine-2-carboxylate were obtained. Yield=79%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[I-].[Li+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C.C(Cl)Cl.CO.N>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: ClCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Agent: N
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2[nH]c(-c3ccc(OCCCN4CCOCC4)cc3)nc2c1

Procedure:
A solution of 6-bromo-2-[4-(3-chloropropoxy)phenyl]-3H-imidazo[4,5-b]pyridine (50 mg, 0.14 mmol), lithium iodide (20 mg, 0.15 mmol) and morpholine (0.1 ml, 1.15 mmol) in DMF (5 ml) was heated at 100° C. for 6 h. Column chromatography on silica using methylene chloride/methanol/ammonia as eluent afforded the title compound in almost quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH2:34][CH2:35][CH2:36]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Reactant: CN(C)CCCCl
Product: COc1cc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 141° C., NMR, IR, MS 553, 555.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Subject 6.5 g. of adamantane carboxylic acid chloride, 4.0 g. of m-anisidine and 10.0 ml. of triethylamine to the process of Example 14 and obtain thereby the title product, m.p. 172°-174° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:29])[N:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH:15]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:29])[N:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH:15]=1
Reactant: CC(=O)Nc1ccccc1-c1cn(C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1-c1cn(C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1

Procedure:
A mixture of 3.0 g (7.68 mmol) of 4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one, 50 ml of 5 N sodium hydroxide solution and 25 ml of ethanol was refluxed for 3 hours. After cooling the organic phase was separated off, dried over sodium sulphate and evaporated down in vacuo. A colourless amorphous substance was obtained in a quantitative yield, Rf=0.53 (eluant: dichloromethane/methanol 9/1 v/v).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([N:18]=C=O)(=[O:17])=[O:16].C1(CC#N)C=CC=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][S:15](=[O:17])(=[O:16])[NH2:18])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: N#CCc1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 69 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 17.0 g (0.1 mole) of 4-phenylphenol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 17.2 g (69%) of white crystals, mp 166°-168° C. (benzene-acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6](N)=[CH:5]2.[FH:13].N1C=CC=CC=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:13])=[CH:5]2
Reactant: F
Reactant: Nc1cc2cc(Br)ccc2cn1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1cc2cc(Br)ccc2cn1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
To a mixture of 6-bromoisoquinolin-3-amine (0.71 g, 3.18 mmol) in pyridine hydrofluoride (10 mL, 3.18 mmol) at −78° C. was carefully added sodium nitrite (0.26 g, 3.82 mmol). The reaction mixture was stirred at −78° C. for 5 minutes. The reaction mixture was then warmed to room temperature over 40 minutes. The mixture was poured into an ice bath and the pH was adjusted to >9 with Na2CO3. The mixture was filtered to recover a yellow-purple solid. The solid was dissolved in EtOAc and water with stirring. The mixture was extracted with EtOAc (3×200 mL). The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in DCM-MeOH and adsorbed onto silica gel. Purification by chromatography on silica gel eluting with EtOAc 0-7% in hexanes provided the product (500 mg, 70%). LCMS (API-ES) m/z: 226, 228 (M+H+).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O-:35][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2c[n+]([O-])c3ccccc3c21
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CH2Cl2 was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 4.60 g of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10])(C)(C)C.Cl[CH2:20]Cl>FC(F)(F)C(O)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]2[O:10][CH2:20][CH2:6][NH:7][CH2:8]2)=[CH:12][CH:13]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of [2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (90 mg) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous potassium carbonate (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in dry tetrahydrofuran (3 mL) and triethylamine (54 μL). Chloroacetyl chloride (31 μL) in dry tetrahydrofuran (1 mL) was added dropwise at 0° C. After 30 minutes the reaction was diluted with ethyl acetate (10 mL) and washed with water/brine (1:1.3×10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in tert-butanol (5 mL). Potassium tert-butoxide (79 mg) was added and the reaction stirred at 25° C. for 1.5 hour. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and co-evaporated with toluene (2×5 mL). The residue was dissolved in dry toluene (5 mL) under argon and treated with sodium bis(2-methoxyethoxy)aluminium hydride (70% in toluene, 205 μL) dropwise and stirred at 25° C. for 5 hours. The reaction was quenched at 0° C. with 10% aqueous sodium hydroxide (5 mL), and the mixture was extracted with diethyl ether (2×15 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to furnish 60 mg (94%) of the title compound as a colorless oil. LC-MS (m/z) 182 (MH+); tR=1.06, (UV, ELSD) 78%, 98%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 84 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4-fluoroaniline (1 M in DMF) instead of methylamine, to the title compound (109 mg, 84%) which was obtained as a white solid. MS: m/e=404.4 [M+H]+.
Reaction SMILES: C([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH4+:8].[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[NH:8][S:9]2(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)NC2=O

Procedure:
A mixture of 2-benzyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (2.05 g), methanol (75-100 mL), ammonium formate (1.10 g) and palladium on carbon (10%, 1.0 g) was heated under reflux for 40 minutes, allowed to cool and filtered. The filtrate was stripped of volatiles affording 6-[2-(2-methoxyethoxy)-ethoxy]saccharin ammonium salt, a mixture of which with chloromethyl phenyl sulfide (0.79 g) and dimethylformamide was heated for eight hours at 100° C., stirred overnight at room temperature, and poured into ice-water (600 mL). The resulting mixture was extracted with dichloromethane. The dichloromethane extract was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and stripped of dichloromethane. Column chromatography of the residue (1.70 g) on silica gel using dichloromethane-acetone (98:2) as eluant and again using dichloromethane-acetone (99:1) as eluant afforded 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.96 g, 45% yield).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:11].[Na+].[Na+].[OH2:16]>>[O-:16][OH:11].[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Product: [O-]O

Procedure:
Cumene was air-oxidized at 100°-110° C. in the presence of an aqueous solution of sodium carbonate. After the reaction, oil-water separation was conducted, and the oily product was concentrated to provide a solution of cumene hydroperoxide (CHP) of which composition is indicated in Table 1.