Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C)C=O>[C-]#N.[C-]#N.[Zn+2].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>[C:14]([C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: COC(=O)c1cc(I)c(C)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C)cc1C
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2, 9.2 g, 31.71 mmol, 1.00 equiv), Zn(CN)2 (4.46 g, 38.12 mmol, 1.20 equiv), and Pd(PPh3)4 (2.93 g, 2.54 mmol, 0.08 equiv) in N,N-dimethylformamide (120 mL) was stirred under a nitrogen atmosphere at 100° C. overnight. After cooling to room temperature, the reaction was then quenched by careful addition of 100 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 6.2 g (93%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 5-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-aminophenyl)(4-chlorophenyl)methanone (86.6 g, 370.1 mmol), DCM (2.61 L), and Et3N (70.3 mL, 499.6 mmol). After the solution was cooled to 5° C. in an ice-bath, ethyl 3-chloro-3-oxopropanoate (64.5 mL, 407.1 mmol) was added dropwise over 60 min. The resulting mixture was stirred at 0° C. for 1 h. Additional ethyl 3-chloro-3-oxopropanoate (12.9 mL) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. The reaction was cooled to 0° C. and ice-water (2 L) was added, followed by solid K2CO3 (60 g) until the solution was basic (pH=9-10). After phase separation, the organic layer was concentrated at 40° C. (to remove DCM) and then at 60° C. (to remove ex Et3N) to yield ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate as a slightly yellowish solid, which was used in the next step without further purification. (ES, m/z) 346, 348 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:18]1([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:22]=[N:21][CH:20]=[N:19]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH:22]=[N:21][CH:20]=[N:19]4)=[CH:31][CH:30]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Product: O=C(c1ccc(-n2cncn2)cc1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.86 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[C:10]([OH:12])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:26][C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:30]([C:27]1([NH:26][C:10](=[O:12])[CH:9]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[CH2:8][S:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)(=[O:7])=[O:6])[CH2:29][CH2:28]1)#[N:31]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(CS(=O)(=O)CC2CC2)NC(c2ccc(F)cc2)C(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 3-cyclopropylmethylsulfonyl-2(R)-[2,2,-difluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid (0.95 g), 1-aminocyclopropanecarbonitrile HCl salt (400 mg) in DMF (5 mL) at room temperature was added HATU (1.28 g), followed by diisopropylethylamine (1.68 g/2.26 mL). After being stirred at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and brine. The combined organic extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure, and the residue was purified by recrystallization from 2-propanol to yield N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2-[2,2-difluoro-1-(4-fluorophenyl)ethylamino]-propionamide as colorless crystals (250 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+].[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:3][C:2]([F:13])([F:12])[F:1])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCN(CC(F)(F)F)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.42 g, 1.8 mmol) was dissolved in a mixture of 1.5 mL of EtOAc and 1.5 mL of H2O containing 0.95 g of NaHCO3 (7.5 mmol). The resulting suspension was warmed to 50 C. A solution of racemic piperidin-3-yl-carbamic acid tert-butyl ester (0.30 g, 1.5 mmol) in 1 mL of EtOAc was added dropwise over a 30 minute period. The reaction mixture was left stirring at 50° C. for one hour before being cooled to RT. The organic phase was separated and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give 0.38 g of racemic [1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-carbamic acid tert-butyl ester as a colorless oil which was used in the next step without purification.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([O:10][CH3:11])[O:4]1)[CH3:2].[OH:12]O>CO>[CH3:11][O:10][CH:5]1[O:4][CH:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]2[O:12][CH:6]12
Reactant: CCC1OC(OC)C=CC1=O
Reactant: OO
Solvent: CO
Product: CCC1OC(OC)C2OC2C1=O
Yield: 86.3 %

Procedure:
A 15.6 g quantity of 2-ethyl-6-methoxy-3-oxo-3,6-dihydro-2H-pyran, 15 g of 30% aqueous solution of hydrogen peroxide and 100 ml of methanol are cooled to a temperature of about 10° C with full stirring. The same procedure as in Example 6 is thereafter followed to obtain a concentrate, which is then distilled at a reduced pressure of 3 mm Hg to give 14.8 g of 6-methoxy-4,5-epoxy-3-oxo-2-ethyltetrahydropyran as a colorless liquid fraction at 83° to 88° C in a yield of 86.3%.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([O:13]CC)=[O:12].C(O)(=O)C.O>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@H](CCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NCCCCCC[C@H](N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution of 3(R)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0.16 g) obtained in Example 72 in 1N sodium hydroxide (4 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml) and water (5 ml), the mixture is submitted to Amberlite XAD-2 column chromatography eluting with methanol-water (1:1). The eluate is concentrated under reduced pressure and lyophilized to yield 3(R)-[7-amino-1(S)-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.11 g) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=4)[C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13]3)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=4)[C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13]3)[CH2:4][CH2:3]1
Reactant: CN1CCC(OC2c3cccc(-c4cccc([N+](=O)[O-])c4)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CN1CCC(OC2c3cccc(-c4cccc(N)c4)c3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(1-methylpiperidin-4-yloxy)-8-(3-nitrophenyl)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 242 B) (0.6 mmole), tin(II) chloride dihydrate (2.83 g) in ethanol (15 mL) is refluxed for 2 hours. The mixture is then cooled to room temperature and extracted twice with chloroform. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 14% (B) to 24% (B) in 10 minutes) to afford 3-[4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-8-yl]-phenylamine melting at 120° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:23]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:47]([NH2:50])[CH2:48][NH2:49]>>[NH2:49][CH2:48][CH2:47][NH:50][C:2]1[N:3]=[C:4]([N:23]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:36])([CH3:37])[CH2:29]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:21])([CH3:22])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=1
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCN(c1nc(NCCN)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h

Procedure:
53.6 g of 2-chloro-4,6-bis-(2,2,6,6-tetramethyl-4-piperidyl-butylamino)-1,3,5-triazine in 200 ml of ethylenediamine are refluxed for 24 hours. 200 ml of toluene and 100 ml of 30% sodium hydroxide solution are added to the reaction mixture and the resulting mixture is stirred vigorously for 30 minutes. The aqueous solution is separated off and the toluene solution is washed with twice 200 ml of water, dried over sodium sulfate and evaporated. The 2-(2-aminoethylamino)-4,6-bis-(2,2,6,6-tetramethyl-4-piperidyl-butylamino)-1,3,5-triazine thus obtained is dissolved in 200 ml of xylene and the resulting solution is cooled to 5°. 6.1 g of cyanuric chloride are introduced at this temperature and the reaction mixture is stirred at 5°-10° for 1 hour. After adding 1.4 g of finely powdered sodium hydroxide, the temperature is raised to 35°-40° and the mixture is stirred for 2 hours at this temperature. After adding a fresh portion of 1.4 g of sodium hydroxide, the mixture is heated slowly to the reflux temperature. After refluxing for 3 hours, a final portion of 1.4 g of sodium hydroxide is added and the reaction mixture is then stirred under reflux for 18 hours. After cooling, 200 ml of water are added, the mixture is stirred well for 10 minutes, the aqueous solution is separated off and the xylene solution is washed with 3 times 100 ml of water. The xylene solution is evaporated in vacuo and the residue is then dried under a high vacuum (130°/0.001 mm Hg). The resulting glassy, yellowish mass can be comminuted to a virtually colourless powder. The light stabiliser having the above structural formula melts at about 140°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[F:16][C:17]([F:44])([F:43])[C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[CH2:25][CH2:26][CH2:27]I>CS(C)=O>[F:29][C:24]([F:30])([C:23]([F:31])([F:32])[C:22]([F:33])([F:34])[C:21]([F:35])([F:36])[C:20]([F:37])([F:38])[C:19]([F:39])([F:40])[C:18]([F:42])([F:41])[C:17]([F:44])([F:43])[F:16])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc(OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
(E)-Methyl 3-(4-hydroxyphenyl)acrylate (166 mg, 0.93 mmol) was added to dry DMSO (10 mL) and stirred under nitrogen in a round bottom flask. Crushed sodium hydroxide (44 mg, 1.1 mmol) was added. After 30 minutes, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-11-iodoundecane (500 mg, 0.85 mmol) was added. The reaction was allowed to stir overnight. Washed with water and extracted with dichloromethane to yield an oil. This crude product was purified on a silica column using hexanes with increasing amounts of ethyl acetate as the eluent. A white solid was isolated (418 mg, 77% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.65 (d, J=16.0 Hz), 7.48 (d, J=8.75 Hz, 2H), 6.90 (d, J=8.75 Hz, 2H), 6.32 (d, J=16.0 Hz), 4.07 (t, J=5.90 Hz, 2H), 3.80 (3H), 2.40-2.20 (m, 2H), 2.18-2.05 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[NH:3]1>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[CH:7][CH2:8]2)[NH:3]1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccccc1

Procedure:
2,2-dimethyl-7-methoxy-4-phenyl dihydroquinoline (contaminated with 2,2,4-trimethyl compound) [60 g] was hydrogenated with 10% Pd/C (1.4 g) in ethanol-acetic acid (200 ml). The reaction mixture was filtered through `Mgflo` and the solvent removed under reduced pressure to give the title compound slightly contaminated with the trimethyl isomer (5 g).
Reaction SMILES: [CH3:1][C:2]([CH:16]([CH3:22])[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:25])C>>[O:25]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH2:17][CH:16]([CH3:22])[C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: CC(C)=CCC(C)C(C)=CCOc1ccc2c(c1)OCCC2
Product: CC(=CCOc1ccc2c(c1)OCCC2)C(C)CC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3,4,7-trimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,4,7-trimethyl-2-octenyloxy)-chromane, nD20 = 1.5311.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)c(F)cc2OC)c(N)n1
Product: COc1cc(F)c(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting with (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone, Example 99, and 1-methanesulfonyl-piperidin-4-ylamine (compound with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+: 442.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(#N)C.[C:14](ON1C(=O)CCC1=O)(=[O:25])[C:15]1[C:16](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:17](OC)=[O:18]>O>[OH:4][CH2:3][C@@H:2]([N:1]1[C:17](=[O:18])[C:16]2[C:15](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (3 g, 21.87 mmol) in water (26.5 mL), and acetonitrile (46.4 mL) was added 2,5-dioxopyrrolidin-1-yl methyl phthalate (5.76 g, 20.78 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. After acetonitrile was removed in vacuo, the reaction mixture was then extracted with EtOAc. The organic was washed by water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (2.2 g, 40%). LCMS (m/z): 268 (MH+), 0.79 min.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:13]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](OC(OCC)OCC)[CH3:31]>>[CH2:20]([N:19]1[C:14]2[CH:13]=[C:12]([C:11]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[N:9][C:10]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:17]=[CH:16][C:15]=2[N:18]=[C:30]1[CH3:31])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Reactant: CCOC(OCC)OCC
Product: Cc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2n1CC(C)C
Temperature: 25 °C
Yield: 45 %

Procedure:
Heat a mixture of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (103 mg, 0.26 mmol) and 3 mL triethylorthoformate at 120° C. for 3 hours. Cool to room temperature and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 2:1 ethyl acetate:hexanes to provide the title compound (45%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[F:28]C1C=C(C=CC=1OCC1C=CC2C(=CC=CC=2)N=1)C(N(OC)C)=O>>[F:28][C:14]1[CH:15]=[C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][C:13]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 3-Fluoro-N-methoxyl-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=373.1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:12]=2[NH:20][C:21](=[O:35])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1>>[N:29]1([CH2:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:12]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=3)=[CH:7][CH:6]=2)=[O:10])=[O:35])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(O)cc1)CCCC2)c1cccc(CN2CCOCC2)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN5CCOCC5)c4)sc4c3CCCC4)cc2)cc1
Yield: 87.8 %

Procedure:
By using 169 mg of N-(4-hydroxyphenyl)-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 95 mg of methyl 4-(bromomethyl)benzoate, 193 mg of methyl 4-[(4-{[(2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenoxy)methyl]benzoate was obtained by the method similar to Preparation Example 30.
Reaction SMILES: [OH:1][CH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.CO>[OH:1][CH:2]1[C:6]2=[N+:7]([O-:30])[CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2cccnc2C(O)N1c1cnn(CC(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2ccc[n+]([O-])c2C(O)N1c1cnn(CC(F)(F)F)c1
Reaction time: 24 h
Yield: 54.3 %

Procedure:
As shown in step 18-i of Scheme 18, to 7-hydroxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2055, 4.35 g, 14.6 mmol) in CHCl3 (80 mL) and MeOH (40 mL) was added mCPBA (5.39 g, 21.9 mmol). After stirring for 24 hours, additional mCPBA (1.26 g, 7.30 mmol) was added. After stirring an additional 16 hours, the resulting precipitate was collected by filtration and washed with DCM (10 mL) and Et2O (20 mL) to give 7-hydroxy-5-oxo-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 1-oxide (Compound 2059, 2.49 g) as a white solid: ESMS (M+H) 315.25; 1H NMR (DMSO-d6, 300 MHz) δ 8.44 (d, J=6 Hz, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.65 (m, 2H), 7.43 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.20 (q, J=9 Hz, 2H).