Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[C:11]=1[CH3:12].[H][H]>C(O)C.[Pd]>[NH2:13][C:3]1[C:2]([F:1])=[C:11]([CH3:12])[C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: Cc1c(F)c([N+](=O)[O-])cc2oc(=O)[nH]c12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)c(N)cc2oc(=O)[nH]c12
Yield: 67.2 %

Procedure:
A mixture of 1.80 g (8.50 mmoles) of 5-fluoro-4-methyl-6-nitro-2-benzoxazolone (Example 1) and 180 mg of 5% Pd/c in ethanol was shaken in a Parr shaker under one atmosphere of hydrogen gas at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate evaporated to solids. Crude product was recrystallized from methanol to yield 1.04 g of the title compound as pale brown solids: m.p. 209°-212° C. (dec).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cc(F)cnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 55 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a tetrahydrofuran (10 mL) mixture of 3-ethynyl-5-fluoro-pyridin-2-ylamine (129 mg, 0.95 mmol) described in Manufacturing Example 173-1-2 and 4-benzyloxy-phenyl-acetohydroximoyl chloride (314 mg, 1.14 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (264 μL, 1.90 mmol) at room temperature, which was stirred for 1 hour at 55° C., and then for another hour at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (212 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](SC)=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:26]1COCC1.O.O[O:33][S:34]([O-:36])=O.[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:34]([CH3:26])(=[O:36])=[O:33])=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CSc1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)cc1C
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
105 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylthio)-phenyl}-3(2H)-furanone (Example 381) was dissolved in 50 ml methanol, 30 ml THF and 50 ml water, to which was added 513 mg of OXONE. The reaction mixture was stirred at room temperature for 4 hours. Then the mixture was concentrated in vacuo, and was extracted with water 50 ml and dichloromethane (30 ml×3). Concentration of the organic layer under reduced pressure was followed by column chromatography (hexane/ethylacetate=3:2) to give 97 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ1.57 (s, 6H), 2.71 (s, 3H), 3.05 (s, 3H), 6.82 (m, 1H), 7.12 (m, 1H), 7.59 (m, 1H), 7.63 (m, 1H), 7.92 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]#[N:19])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:37][C:38]1[CH:39]=[C:40]([C:44]2[N:45]([CH3:49])[CH2:46][CH2:47][N:48]=2)[CH:41]=[CH:42][CH:43]=1>CS(C)=O>[CH3:49][N:45]1[CH2:46][CH2:47][N:48]=[C:44]1[C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[O:37][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]#[N:19])[CH:3]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN=C1c1cccc(Oc2cc(Oc3cc(C#N)ccc3OCc3ccccc3)nc(-c3ccccc3)n2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
To 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile (1.0 g, 2.4 mmol) in DMSO (12 mL) was added Cs2CO3 (0.8 g, 2.5 mmol) and 2-(3-hydroxyphenyl)-1-methylimidazoline (0.44 g, 2.5 mmol). After stirring in an oil bath at 50° C. for 24 hours, the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CH2CL2 /MeOH/NH4OH (120/5/1) to give 0.5 g of 3-[(6-[3-(1-methylimidazolin-2-yl)phenoxy]-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 4-ethoxycarbonylphenylboronic acid were reacted to provide 4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-carboxylic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=2[F:42])=[O:33])=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:20](O)=[O:21])=[O:17])[CH:12]=2)[CH:6]=1.Cl.C[N:45](C)[CH2:46][CH2:47]CN=C=NCC.[CH2:55]([NH2:57])[CH3:56].C1COCC1>CN(C=O)C.O>[CH2:55]([NH:57][C:20](=[O:21])[CH:19]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:28]=[C:29]([C:32]([NH:34][C:35]4[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=4[F:42])=[O:33])[CH:30]=[CH:31][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[CH2:23][CH2:24][C:25]([NH:45][CH2:46][CH3:47])=[O:27])[CH3:56]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)c2)c1
Reactant: CCN
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)NCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioic acid (100 mg, 0.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 83 mg, 0.43 mmol) in 10 ml of anhydrous DMF was added 2M ethylamine solution in THF (0.43 ml, 0.86 mmol). The mixture was stirred at room temperature for overnight and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5-8% of methanol in chloroform to afford N,N′-diethyl-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanediamide as white solid. Yield: 76 mg, 69%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OC/C=C(\C)CCC=C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-6-methoxybenzaldehyde (4.72 g, 30.43 mmol) in dry DMF (50 ml) was added geranyl bromide (7.5 g, 33.50 mmol) followed by solid potassium carbonate (5.5 g, 39.86 mmol). The mixture was stirred at room temperature for 48 h. The suspension was filtered through a layer of dry sodium sulfate (top) and silica gel (bottom), washed with 200 ml ethyl acetate and decanted into a separatory funnel. The mixture was washed sequentially with aqueous ammonium chloride, water (twice), brine, and the organic phase was dried over Na2SO4. The solution was concentrated in vacuo on a rotovap. The brown gel material was then purified by chromatography via silica gel using 8:2 hexanes:ethyl acetate eluent to provide 2-((E)-3,7-dimethylocta-2,6-dienyloxy)-6-methoxybenzaldehyde as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[C:17]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:25]1[CH2:24][CH2:23][N:22]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][CH2:26]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Product: CCOC(=O)N1CCN(C=C2C(=O)Nc3cc(OC)c(OC)cc32)CC1

Procedure:
4.0 g. of 5,6-dimethoxy-3-hydroxymethylene oxindole was reacted with N-carbethoxy piperazine as described in Example 2, except that 0.10 g. toluene sulfone acid was added as a catalyst. Yield, 3.05 g. of product, m.p. 172°-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CO
Agent: [K]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methanol (1.6 g, 4.2 mmol) in toluene (30 ml) was added thionyl chloride (0.61 ml, 8.4 mmol), and the mixture was heated under reflux for 30 min. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.2 g, 6.3 mmol) was added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The extract and the organic layer were combined and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and then saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and toluene (20 ml)-ethyl acetate (10 ml) was added to the residue. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, yield 82%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[O:47]COC)=[O:39])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[OH:47])=[O:39])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccc4OCOC)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccc4O)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 46.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.69 g) was dissolved in methanol (13.8 ml), 4N hydrochloric acid/ethyl acetate (3.45 ml) was added to the mixture at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-hydroxybenzyl)sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 221) (0.30 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([CH3:27])[NH:22]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:22]3[C@H:23]([CH3:27])[CH2:24][CH2:25][CH2:26][C@@H:21]3[CH3:20])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3[C@H](C)CCC[C@@H]3C)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), (2S,6R)-2,6-dimethyl-piperidine (100 μL, 0.72 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethanone (23): HPLC retention time=1.31 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 379.9, found, 380.0.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:12]2[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)c1cccc(O)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(Oc2ncc([N+](=O)[O-])cn2)c1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 3-(1-methylethyl)phenol (680 mg, 5 mmol, Aldrich) in acetonitrile (50 mL) were added 2-chloro-5-nitropyrimidine (800 mg, 5 mmol) and triethylamine (1.01 g, 10 mmol) and the resulting mixture was heated at reflux and stirred for 3 hours. The reaction mixture was concentrated under vacuum and water was added to the residue (80 mL). It was extracted with ethyl acetate (3 times 50 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=0˜20%) to afford the title compound (900 mg).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:48])=[CH:30][CH:29]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH2:58])[CH:52]=1>>[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45]([NH:58][CH2:57][C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:48])=[CH:30][CH:29]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 15% yield: mp 48-50° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60-8.54 (m, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.31-7.25 (m, 3H), 7.04-6.99 (m, 2H), 6.05-6.01 (m, 1H), 4.59-4.57 (m, 4H), 4.17 (t, J=5.8 Hz, 2H), 3.32 (t, J=5.8 Hz, 2H), 2.62 (s, 3H), 2.11-2.04 (m, 2H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:49])[C:19]([CH3:48])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:33]([O:42][CH3:43])[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:49])[C:19]([CH3:48])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:33]([O:42][CH3:43])[CH2:34][C:35]([OH:37])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirring solution of #127 (4.2 g, 6.1 mmol, 1.0 eq.) in 21 mL of dichloromethane under nitrogen, (7 mL, 90 mmol, 10 eq.) of TFA was added. The reaction was allowed to stir at room temperature for −4 hours. Reaction was concentrated in vacuo, azeotroped once with heptane, and then placed underneath high vacuum yielding #128 as a white slight yellow solid (3.8 g, quant.). LC-MS (Protocol Q): m/z 624.2 [M+H+] retention time=2.01 minutes.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][C:6]=12>S(=O)(=O)(O)O>[N+:1]([C:14]1[CH:13]=[CH:12][C:11]2[C:7]3[C:6](=[N:5][CH:10]=[CH:9][CH:8]=3)[CH2:17][C:16]=2[CH:15]=1)([O-:4])=[O:2]
Reactant: c1ccc2c(c1)Cc1ncccc1-2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)Cc1ncccc1-2
Reaction time: 1 h

Procedure:
A ca. 10° C.-cold mixture of nitric acid (65%, 1.1 mL) and sulfuric acid (96%, 1.6 mL) is added dropwise to a solution of 9H-indeno[2,1-b]pyridine (2.44 g) in sulfuric acid (96%, 3 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 1 h and poured then onto crushed ice. The precipitate formed is separated by filtration and the filtrate is neutralized using 4 M aqueous NaOH solution. The precipitate formed is separated by filtration and combined with the precipitate separated before. The precipitate is triturated with acetone and dried to give the title compound as a solid. Yield: 2.64 g (85% of theory); LC (method 1): tR=2.93 min; Mass spectrum (ESI+): m/z=213 [M+H]+.
Reaction SMILES: C(O)(=O)C.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)=[O:8].[N+:28]([O-])([OH:30])=[O:29]>O>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([N+:28]([O-:30])=[O:29])=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=1)=[O:8]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)ccc1Oc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Temperature: 90 °C
Yield: 59 %

Procedure:
To 71 ml of an acetic acid solution containing 14.0 g of N-(5-chloroacetylamino-2-phenoxyphenyl)methanesulfonamide was added 4.4 g of 60% nitric acid with heating at 90° C. with stirring, followed by stirring for 20 minutes. Water was added to the reaction solution of which temperature was allowed to return to room temperature. The precipitate was collected by filtration and recrystallized from ethanol-n-hexane to give 9.3 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide as yellow needles.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:28])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:28])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cncc(C)c3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cncc(Cc2cn3c4cc(Br)ccc4c4cc(O)cc(c2=O)c43)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
9-bromo-2-methoxy-5-(5-methyl-3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (302 mg) produced in Example 123 was suspended in anhydrous methylene chloride (80 ml), and boron tribromide (0.33 ml) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water (100 ml) and saturated aqueous solution of sodium hydrogencarbonate was added thereto until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (227 mg, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.O>CN(C=O)C>[NH2:19][C:17]([C:16]1[CH:20]=[CH:21][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1)=[O:18]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(C(N)=O)cn1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
A mixture of 1.00 g (4.29 mM) of the phenyl carbamate 8 and 0.59 g (4.29 mM) of 6-aminonicotinamide in 4 ml of anhydrous DMF was stirred at 65° C. for 1.5 hr., cooled and poured into water. The resulting precipitate was collected, washed with acetone and air dried to give 0.85 g of the above urea as a pale yellow solid, m.p. 240°-243° C. (dec.).