Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[S:13](Cl)([Cl:16])(=[O:15])=[O:14].[Sb](Cl)(Cl)(Cl)(Cl)Cl>C(#N)C>[Cl:16][S:13]([NH:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:15])=[O:14]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1(NS(=O)(=O)Cl)CCCCC1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a suspension of methyl 1-aminocyclohexane-1-carboxylate HCl salt (4.06 g, 20.9 mmol) in acetonitrile (37 ml) was added sulfuryl chloride (26.2 ml, 326 mmol) and antimony pentachloride (0.17 ml, 2.4 mmol). The reaction was heated at 80° C. using, a calcium sulfate drying tube overnight. The reaction was concentrated in vacuo to give methyl 1-(chlorosulfonylamino)cyclohexane-1-carboxylate (85%) as a yellow oil that was used without further purification. This material was converted to N-hydroxy-1-[4-(4-chlorophenyl)-piperazine-1-sulfonyl]amino}cyclohexane-1-carboxamide by following Examples 2 and Example 13 except that the reaction was heated at 45° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 375) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.051 g, 18%). Yellow oil. 1H NMR (300 MHz, DMSO d6) δ 0.80 (d, J=5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, 1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22FN3O4S: C, 58.46; H, 5.14; N, 9.74. Found C, 58.16; H, 5.21; N, 9.57.
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=CC=CC=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+]([O-])=O)([O-])=O.C([O-])=[O:24].[Na+].CN1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[OH:33][C:29]1[C:13]2[C:14](=[O:18])[C:15]3[C:6](=[C:5]([OH:24])[CH:4]=[CH:17][CH:16]=3)[C:7](=[O:19])[C:8]=2[CH:32]=[CH:31][CH:30]=1.[OH:33][C:29]1[C:8]2[C:7](=[O:19])[C:6]3[C:15](=[CH:16][CH:17]=[CH:4][C:5]=3[OH:24])[C:14](=[O:18])[C:13]=2[CH:32]=[CH:31][CH:30]=1
Reactant: O=C[O-]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: CN1CCCC1=O
Agent: [Na+]
Product: O=C1c2cccc(O)c2C(=O)c2c(O)cccc21
Product: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21
Yield: 92.5 %
Yield: 7.5 %

Procedure:
Dinitroanthraquinone (same composition as in Example 2, 18.0 g; 0.06 mole), N-methylpyrrolidone (100 ml) and sodium formate (12.2 g; 0.18 mole) were stirred at 110° C. for 16 hours while air was sparged into the reaction mass. Product work-up as in Example 1 gave a cake of 1.9 g (92.5% 1,5-dihydroxyanthraquinone, 7.5% 1,8-dihydroxyanthraquinone) and a filtrate product of 12.0 g (4.0% 1-hydroxyanthraquinone, 88% 1,5- and 1,8-dihydroxyanthraquinone, 2.7% intermediate and 5.3% dinitroanthraquinones).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH-:9].[Na+].[OH2:11].Cl>CCO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:5]([C:4]([OH:11])=[O:9])=[C:6]([CH3:7])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2ccc(Br)cn2c1C(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 2-amino-5-bromopyridine (25.0 g, 144.5 mmol) in EtOH (150 mL), was added methyl 2-chloro-3-acetoacetate (18.6 mL, 144.5 mmol), and the mixture was refluxed at 80° C. for 12 h. Then the reaction mixture was allowed to cool to rt, and then were added 8N aqueous sodium hydroxide solution (60 mL, 480 mmol) and water (30 mL). The mixture was stirred at 80° C. for 12 h, allowed to cool to 0° C., and then neutralized by the addition of 6N hydrochloric acid (300 mL). The resulting precipitate was collected by filtration and sequentially washed with water, EtOH and diethyl ether to give the title compound (11.1 g, 30%) as a brown solid.
Reaction SMILES: [O:1]1[CH:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1>>[B:18]([C:15]1[CH:14]=[N:13][C:12]([N:4]2[CH2:5][CH2:6][CH:7]([C:8]([OH:10])=[O:9])[O:1][CH2:2][CH2:3]2)=[N:17][CH:16]=1)([OH:20])[OH:19]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(O)C1CCNCCO1
Product: O=C(O)C1CCN(c2ncc(B(O)O)cn2)CCO1

Procedure:
The title compound was prepared from 1,4-oxazepane-7-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH2:13]([C:5]1([OH:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 10 g of 5-chloroisatin in 150 ml of THF is cooled to +4° C., 220 ml of a 1M solution of benzylmagnesium chloride in ether are added dropwise and the mixture is stirred for 3 hours at RT. 500 ml of a saturated solution of ammonium chloride are added and the solvents are concentrated under vacuum. The aqueous phase is extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 5.6 g of the expected product after crystallization from a THF/AcOEt mixture. M.p.=204°-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6]2.F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 80 %

Procedure:
6-(Methyloxy)-3-pentyl-2-phenyl-1-naphthalenol (113) (0.41 g, 1.28 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMF at 100° C. to give 0.44 g (80%) of the title compound (114) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=6.8 Hz, 3H), 1.10-1.25 (m, 4H), 1.40-1.55 (m, 2H), 2.47 (t, J=7.9 Hz, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (d, J=2.4 Hz, 1H), 7.19-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 425 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2ccncc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7-isoquinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was partitioned between dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.83 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless solid, mp 144°-145° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]3([CH3:19])[CH:13]4[CH2:17][C:16]([CH3:18])([C:10]3([CH3:20])[C:9]=2[CH:21]=1)[CH2:15][CH2:14]4)=[O:4].[OH:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[I:33])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:18][C:16]12[CH2:17][CH:13]([C:11]3([CH3:19])[C:10]1([CH3:20])[C:9]1[CH:21]=[C:5]([C:3]([CH2:2][O:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=4[I:33])[C:26]([O:28][CH3:29])=[O:27])=[O:4])[CH:6]=[CH:7][C:8]=1[O:12]3)[CH2:14][CH2:15]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)CBr)cc3C21C
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(OCC(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)c1

Procedure:
A solution of 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofur-8-yl bromomethyl ketone (2.5 g, 6.86 mmol), methyl 3-hydroxy-4-iodobenzoate (1.9 g, 6.83 mmol) and potassium carbonate (0.95 g, 6.88 mmol) in methyl ethyl ketone (50 ml) is refluxed for five hours. The reaction medium is filtered, after which 40 ml of water and 40 ml of ethyl ether are added. After stirring and separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (30% ethyl acetate, 70% heptane).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:12]1[N:29]([CH2:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]2)[C:15]2[C:16]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=3)=[N:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=2[N:13]=1)=[CH2:11])(C(C)(C)C)(C)C.[F-].[CH2:39]([N+](CCCC)(CCCC)CCCC)CCC.[H-].[Na+].CI>C1COCC1>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2[C:15]3[N:29]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:12]([C:10]([CH2:9][O:8][CH3:39])=[CH2:11])=[N:13][C:14]=3[CH:19]=[C:18]([C:20]#[N:21])[N:17]=2)[CH:23]=[N:24][CH:25]=1
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C=C(COC)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Steps 5 & 6: A stirred solution of 2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1.2 g, 2.24 mmol) in THF (20 mL) was cooled to 0° C. Tetrabutylammonium fluoride (3.36 mL, 3.36 mmol, 1M solution in THF) was added dropwise over a period of 5 minutes, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was separated, washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude 4-(5-chloropyridin-3-yl)-2-(3-hydroxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (0.9 g, 2.14 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C. NaH (0.123 g, 3.12 mmol, 60% in mineral oil) was added in several portions and stirred for 15 minutes. Methyl iodide (0.16 mL, 2.57 mmol) was added dropwise over a period of 5 minutes, and the reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice and extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 15% ethyl acetate/petroleum ether as eluent to yield 4-(5-chloropyridin-3-yl)-2-(3-methoxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calcd. for C24H26ClN5O [M+H]+ 436. found 436
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[NH:27]1[C:35]2[C:30](=[C:31]([C:36]3[CH:37]=[C:38]([NH2:51])[C:39]4[C:43]([CH:44]=3)=[N:42][N:41](C3CCCCO3)[CH:40]=4)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.CC1C=CC(S(O)(=O)=O)=CC=1.N>C1COCC1.CO>[NH:27]1[C:35]2[C:30](=[C:31]([C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[C:38]([NH:51][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[O:9])[CH:37]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Methyl-3-isoxazolecarboxylic acid (21 mg) was treated with anhydrous THF (2 ml) and then 1-chloro-N,N,2-trimethylpropenylamine (0.026 ml). The reaction was stirred at RT under nitrogen for 2 h. The reaction was then treated with anhydrous DIPEA (0.131 ml) and 2 ml of solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (750 mg) in THF (30 ml). The reaction was then stirred at RT under nitrogen for 69 h. The solvent was blown off under a stream of nitrogen, dissolved in methanol (3 ml) and then the solvent removed under reduced pressure. The crude reaction mixture was dissolved in methanol (5 ml), treated with macroporous tosic acid resin (102 mg; 4.45 mmol/g) stirred at RT for 17 h and then treated with 0.88 ammonia (0.5 ml), stirred for 30 min and then filtered. The solvent was removed under reduced pressure and then purified by mass directed preparative HPLC (Method A) to give the title compound.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>C(O)C>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CC(O)CN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCC(C)O)ncc2c(=O)[nH]1
Yield: 83.4 %

Procedure:
In a similar manner to Example 38 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and 1-amino-2-propanol (0.97 g) in ethanol (15 ml) for 40 hours yielded the title compound 0.37 g, m.p. 212.5-214° C. (recrystallized from methanol).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[Cl:24])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: O=C(Cc1ccccc1Cl)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 6 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-chlorophenylacetic acid, the title compound was obtained as a pink solid (71%), mp 212.0°-14.0° C.; MS(CI): 457 (M+H); NMR (300 MHz,DMSO-d6): 1.38(m, 2H), 1.70(m, 2H), 2.28(m, 2H), 2.46(s, 2H), 2.93(m, 2H), 3.30(m, submerged, 2H), 3.54(m, 3H), 4.31(s, 1H), 6.87-6.96(m, 4H), 7.17-7.41(m, 8H), 7.96(d, 1H, J=7.7 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:20])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24]>>[CH3:20][C:13]1([CH3:21])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:24][CH3:23])[C:12]1=[O:22]
Reactant: CN
Reactant: CC1(C)C(=O)N([C@H](CCCl)c2ccccc2)c2ccccc21
Product: CNCC[C@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Temperature: 125 °C
Yield: 93 %

Procedure:
A mixture of 1-[(1R)-3-chloro-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (220 mg, 0.700 mmol) and ethanolic solution of methylamine (33% in ethanol, 5 mL) was heated at 125° C. for 2 h with stirring in a sealed reaction vessel. Upon cooling, all volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion chromatography (RediSep 4-g silica column, 0-15% methanol/dichloromethane/0.5% triethylamine) gave 200 mg (93%) of 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one as a viscous colorless liquid, which was dissolved dichloromethane (5 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 0.7 mL, 0.7 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one hydrochloride as a white powder. MS (ES) m/z 308.9 ([M+H]+); HRMS: calculated for C20H24N2O+H+, 309.1961; found (ESI, [M+H]+), 309.1953.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([C:14]2[C:23](=[O:24])[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO>[F:3][C:4]1[C:13]([C:14]2[C:23](=[O:24])[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(-c2nc3ccccc3n(COCC[Si](C)(C)C)c2=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(=O)c(-c2cccc(C(=O)O)c2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5N Sodium hydroxide (0.50 ml) was added to the compound (methyl 2-fluoro-3-[3-oxo-4-(2-(trimethylsilyl)ethoxymethyl)-3,4-dihydroquinoxaline-2-yl]benzoate) (283 mg) obtained in Working Example 28-2) in methanol (2 ml). The mixture was stirred at room temperature for 2 hours. After adding the mixture to 5N hydrochloric acid, the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (285 mg) as a crude material, which was served in the subsequent reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[CH:11](O)=O.Cl.[OH-].[NH4+]>O>[CH3:9][C:6]1[C:7]2[NH:8][CH:11]=[N:1][C:2]=2[C:3]([CH3:10])=[CH:4][CH:5]=1
Reactant: Cc1ccc(C)c(N)c1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c2[nH]cnc12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-p-xylene (5.1 g), formic acid (88%, 200 mL) and 12N HCl (20 mL) is heated to reflux for 3 hours. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (100 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×100 mL). The combined extracts are dried over MgSO4 and rotary evaporated to afford 4,7-dimethylbenzimidazole as a yellow solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])/[C:23](=[N:25]/O)/[NH2:24].Cl>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:2]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:17][CH:18]=3)[O:3][N:24]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC(=O)O)cc3)n2)cc1Cl
Temperature: 200 °C
Reaction time: 0.42 h
Yield: 31.5 %

Procedure:
A 25 mL microwave reaction vial was charged with tert-butyl 2-(4-(chlorocarbonyl)phenoxy)acetate (0.815 g, 3.01 mmol) and pyridine (15 mL), (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.459 g, 2.007 mmol) was added. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The mixture was cooled, the reaction mixture was poured into stirring HCl (10%, 100 mL), the resulting suspension was filtered, the solid was washed by HCl (5%, 2×10 mL) and dried to afford grey solid, which was purified by RP-HPLC (A=50 mM ammonium acetate, B=acetonitrile; 30-95% B over 25.0 min (21.0 mL/min flow rate); 21.2×250 mm Thermo Hyperprep C18 column, 8 μm particles) to give 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetic acid (0.246 g, 0.633 mmol, 31.5% yield) as white solid. LC/MS (Table 1, Method f) Rt=2.08 min.; MS m/z: 389.14 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO δ ppm 13.28-13.07 (m, 1H), 8.13 (d, J=9.03 Hz, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.04 Hz, 1H), 7.18 (d, J=9.06 Hz, 2H), 4.85 (s, 3H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)C(F)(F)F)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NC(=O)C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 45 °C

Procedure:
4.1 g (11 mmol) of N-{2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-trifluoroacetamide are cooled to about 10° C. in 20 mL dimethylsulphoxide and 80% NaH (0.33 g, about 11 mmol) are added in batches with stirring. The mixture is heated to 40-50° C. for 0.5 h and then cooled to 30° C. Methyl iodide (0.75 mL, 11.9 mmol) is then added dropwise. The mixture is stirred for 0.5 h at 40-50° C., diluted with 100 mL ethyl acetate, poured onto water and extracted. The organic phase is again washed with water, dried and evaporated down. The residue is chromatographed over silica gel. The methylated trifluoroacetamide is taken up in MeOH, combined with 10 mL of conc. aqueous ammonia solution and stirred for 4 h at 30-40° C. The methanol is distilled off, the residue is taken up in 75 mL of ethyl acetate, washed with water, dried and evaporated down. The product is crystallised from diethylether. Yield: 2.0 g (63%); melting point: 155-158° C.