Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>C(#N)C>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[C:3]([NH2:21])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCc1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see intermediate 18, 2.5 g,) and (2-pyridinylmethyl)amine (1.41 g) in acetonitrile (30 ml) were heated at 80° C. for 2 h. The mixture was extracted with DCM and the organic washed with a saturated solution of sodium hydrogen carbonate, dried over Na2SO4, filtered and concentrated to dryness. The residue was taken-up in diethyl ether, filtered and dried under vacuum. The residue was dissolved in ethanol (20 ml) and HCl (3.8 ml, conc.). Tin (II) chloride dihydrate (5.6 g) was then added in four portions and the reaction mixture was stirred for 1 h at 40° C. The mixture was hydrolysed using sodium hydroxide (1N), extracted with DCM and the organic were dried over Na2SO4. The mixture was filtered through Celite and concentrated to dryness. The crude product was purified by chromatography on silica gel eluting with DCM/methanol (56.5/3.5) to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (500 mg) as a clear brown foam.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:21][C:22]5[C:28]([C:29]([O:31]C)=O)=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[NH4+:33]>CO>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:21][C:22]5[C:28]([C:29]([NH2:33])=[O:31])=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(C(=O)N4CCN(C(=O)C5CC5)CC4)c3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(C(=O)N4CCN(C(=O)C5CC5)CC4)c3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
Methyl 2-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxylate (130 mg, 0.33 mmol) was added to ammonium in methanol (10 mL) in a sealing tube and stirred at 25° C. for 3 days. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxamide (30 mg, yield 22%). 1H-NMR (400 MHz, CD3OD) δ: 0.85-0.92 (m, 4H), 1.29 (m, 1H), 3.20-3.99 (m, 8H), 7.52-7.56 (t, J=8.0 Hz, 1H), 7.74-7.75 (m, 2H), 7.92-7.97 (m, 2H), 8.43-8.47 (m, 2H); LC-MS (ESI) m/z: 419 (M+1)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][CH:16]3[NH:19][CH2:20][CH2:21][CH:15]3[CH2:14]2)=[CH:11][C:10]([C:22]#[N:23])=[CH:9][C:8]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:8]([NH:24][C:25]2[N:30]=[C:29]([N:31]([CH:41]3[CH2:42][CH2:43]3)[CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[C:28]3=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]3[N:26]=2)=[CH:9][C:10]([C:22]#[N:23])=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]2[N:19]([C:2]([O:4][CH3:5])=[O:3])[CH2:20][CH2:21][CH:15]2[CH2:14]1
Reactant: COC(=O)Cl
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Methyl chloroformate (5.66 μl, 0.073 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 443F, 29 mg, 0.049 mmol) and triethylamine (0.020 ml, 0.146 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature overnight. Solvent was evaporated in vacuo and the crude intermediate was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-4% 2 N ammonia in methanol/dichloromethane) to give 28 mg of methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([F:18])[CH:9]=2)[CH:7]=1.Cl>>[ClH:1].[Cl:1][C:2]1[C:3]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([F:18])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)c(F)c3)cc2Cl)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2cc(Cl)c(OC3CCNCC3)cc2=O)cc1F
Reaction time: 0.25 h
Yield: 199.3 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (300 mg, 0.599 mmol) and hydrogen chloride (37% in H2O, 5 mL) was stirred for 15 min and then concentrated in vacuo to yield 261 mg of the desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (br s, 2H) 8.11 (s, 1H) 7.97 (t, J=8.16 Hz, 1H) 7.78 (dd, J=10.92, 1.88 Hz, 1H) 7.57 (dd, J=8.28, 1.76 Hz, 1H) 6.30 (s, 1H) 4.80-491 (m, 1H) 3.39 (s, 3H) 3.05-3.26 (m, 4H) 2.10-2.20 (m, 2H) 1.85-1.98 (m, 2H). MS (ESI) 401 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH:19]3[CH2:20][CH2:21][CH:15]2[CH2:16][O:17][CH2:18]3)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:22]3[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH:19]3[CH2:20][CH2:21][CH:15]2[CH2:16][O:17][CH2:18]3)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3C4CCC3COC4)nc(Cl)nc21
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine-8-carbaldehyde (500 mg, 1.63 mmol), 2-piperidin-4-ylpropan-2-ol (256 mg, 1.79 mmol) and 4 Å powdered molecular sieves (500 mg) in DCE (11 mL) was stirred for 4 h before the addition of sodium triacetoxyborohydride (690 mg, 3.26 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow solid (577 mg, 82%). LCMS (method H): RT 0.30 and 2.00 min [M+H]+ 435.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:21]Cl.C[Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of the 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.22 g, 0.81 mmol) in methanol (5 mL), THF (5 mL), and dichloromethane (5 mL) was added (trimethylsilyl)diazomethane solution (2M in diethyl ether, 1 mL, 2 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 hr and carefully quenched by the slow addition of acetic acid. Concentration under reduced pressure and titration with methanol gave methyl 1-(4-fluorophenyl)-1H-indazole-5-carboxylate (0.16 g, 0.59 mmol, 73% yield) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.S([O-])([O-])(=O)=O.[Mg+2].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and magnesium sulfate (47.32 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (88.0 g).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:11][C@H:9]1[CH2:10][N:6]([CH3:4])[C@H:7]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:8]1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(OC)cc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(OCC[C@@H]2C[C@@H](O)CN2C)c(CCc2ccccc2)c1
Yield: 37.4 %

Procedure:
448 mg of (2R,4R)-1-ethoxycarbonyl-4-hydroxy-2-{2-[4-methoxy-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in step (a) above], 10 ml of tetrahydrofuran and 120 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 144 mg (yield 37%) of the title compound as a colorless solid substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>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>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: C[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 4-chloro-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (500 mg, 2.19 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.397 g, 2.4 mmol) in 1,4-dioxane (10 mL). Saturated aqueous NaHCO3 (5 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.126 g, 0.11 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 95° C. overnight. The reaction was cooled to room temperature, solids and other insoluble impurities formed during the reaction were filtered, and the orange filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in CH2Cl2 and purified by flash chromatography on SiO2 (gradient: 100% CH2Cl2 to 15% of 90/10/1 CH2Cl2/CH3OH/NH4OH). Fractions were evaporated, and the solids were triturated with Et2O and filtered to afford the title compound (403 mg) as a yellow solid. LC-MS (ES) m/z=314 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 620.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br>ClC(Cl)Cl>[Br:13][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6]1
Reactant: BrBr
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Br)C1

Procedure:
To a stirred mixture of 17.1 parts of ethyl 4-oxo-1-piperidinecarboxylate and 225 parts of trichloromethane was added dropwise a solution of 16 parts of bromine in 75 parts of trichloromethane at -5°-0° C. The trichloromethane-phase was washed with ice-water, dried, filtered and evaporated, yielding 25 parts of ethyl 3-bromo-4-oxo-1-piperidinecarboxylate as an oily residue (intermediate 62).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (2.45 g, 6.84 mmol) and ethyl acetate (280 mL, 0.024M) was treated with 10% palladium on carbon (0.24 g, 10% weight of starting material used). The flask was fitted with a hydrogen balloon, and the reaction stirred at 25° C. overnight. At this time, the reaction was filtered through a pad of Celite®, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 80 g silica gel column, 1-20% ethyl acetate/hexanes) afforded 4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (2.00 g, 81%) as an orange solid.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[CH3:19][C:18]1[N:1]([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A stirred suspension of N-aminophthalimide (19.75 g), acetonylacetone (14.3 ml), p-toluenesulfonic acid (5 mg), and toluene (406 ml) was heated at reflux for 1 hour and cooled to room temperature. The reaction mixture was combined with another reaction mixture and the entire mixture decolorized with activated charcoal. Filtration through a bed of celite gave a solution which upon partial concentration resulted in crystallization of the desired product as a solid (11.0 g), m.p. 182.5°-183.5° C.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:34]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2)=[N+:35]=[N-:36]
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2O)C(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step B, 11.2 g, 37.9 mmol, 1.0 eq) in THF (150 mL) at RT was added DPPA (Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq). The resulting mixture was cooled to 0° C. and then DBU (Aldrich, 7.7 mL, 51.6 mmol, 1.36 eq) was added slowly through a syringe. The reaction was warmed to RT and stirred over the weekend. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL), washed with saturated NH4Cl (twice), H2O, and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by flash chromatography (5% EtOAc-hexane) to provide the title compound.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
Biphenyl-3-carboxylic acid (217.0 mg, 1.09 mmol) in THF was added to LiAlH4 (1.0 M in THF) (1.64 ml) at 0° C. under N2 during 15 min. The mixture was then stirred at r.t. for 2.5 h. H2O was carefully added to the mixture at 0° C. NaOH (1.0 M) was added. The product was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated yielding the title compound as a yellow oil (95%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
4-Aminobenzoic acid (0.94 g, 6.85 mmol) was dissolved in 5 mL of pyridine and dodecanoyl chloride (1.58 mL, 6.85 mmol) was added. The mixture was stirred for 4 h at room temperature. The product was precipitated by dilution with water (50 mL), filtered, and dried to provide 1.96 g of the title compound.
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]#[N:13])[CH2:5][CH2:4][CH2:3]1.[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH2:14]([O:16][C:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[O:2][CH2:3][CH2:4][CH2:5]2)=[NH:13])[CH3:15]
Reactant: CCO
Reactant: N#Cc1cccc2c1OCCC2
Agent: Cl
Product: CCOC(=N)c1cccc2c1OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Hydrogen chloride gas was passed through a solution of chroman-8-carbonitrile (370 mg, 1.736 mmol) in anhydrous ethanol (15 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a stopper. After stirring at room temperature for 1 d, the reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was evaporated in vacuo to afford chroman-8-carboximidic acid ethyl ester hydrochloride (491 mg, 88%). It was used without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12])(=[O:4])=[O:3].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(#N)C>[C:20]([O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CS(=O)(=O)NC1CCCCC1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
In a nitrogen atmosphere, a mixture of 108 g of 1,2-epoxycyclohexane, 95.1 g of methanesulfonamide, 11.2 g of t-butoxypotassium, and 1,000 g of tetrahydrofuran was heated under reflux for 100 hours. The reaction solution was neutralized with hydrochloric acid and then subjected to conventional aqueous work-up. Purification by column chromatography yielded an alcohol compound, 2-[(methylsulfonyl)amino]cyclohexanol. In a nitrogen atmosphere, the alcohol compound was combined with 111 g of triethylamine and 2,000 g of acetonitrile, to which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 165 g of 2-[(methylsulfonyl)amino]-cyclohexyl methacrylate. The yield was 63% based on the methanesulfonamide.