Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)(=O)C>[N:13]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: CC1Cc2cc(F)ccc2C1=O
Solvent: CCOC(C)=O
Product: CC1Cc2cc(-n3ccnc3)ccc2C1=O
Temperature: 175 °C

Procedure:
A stirred melt of 5-fluoro-2-methyl-1-indanone (4.9 g) and imidazole (9.8 g) was heated under nitrogen at 175° C. for 2 hours. The warm melt was diluted with ethyl acetate (100 ml), the resulting solution extracted with dilute hydrochloric acid, and the acidic extract treated with potassium carbonate to pH 6. Extraction of the mixture with ethyl acetate with dichloromethane failed to dissolve all of the solids and the mixture was filtered to remove a solid by-product, 5-(1H-imidazol-1-yl)-2-methyl-1H-inden-1-one, 0.92 g, m.p. 215°-217° C. (from toluene). The combined aqueous and organic solutions were evaporated to leave an aqueous mixture which deposited a sticky solid; further product was obtained by ethyl acetate extraction. The combined crude product (5.36 g) was purified by medium pressure column chromatography (silica gel, chloroform) to give 5-(1H-imidazol-1-yl)-2-methyl-1-indanone, 3 g (47%), m.p. 103°-106° C., which was used directly in the next stage.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:10])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:10]
Reactant: COC(=O)c1cccc(C(C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(C(C)N)c1
Yield: 100.7 %

Procedure:
A solution of methyl 3-{1-[(tert-butoxycarbonyl)amino]ethyl}benzoate (200 mg, 0.72 mmol) in 20% trifluoroacetic acid in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours. After this time the mixture was concentrated under reduced pressure and the residue was dissolved in water and basified to pH 11 with aqueous ammonia. The mixture was extracted with ethyl acetate (2×15 mL) and the extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give methyl 3-(1-aminoethyl)benzoate (130 mg, 100%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].S(=O)(=O)(O)O.[Cl:15][CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20]>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:19](=[O:20])[CH:18]=[C:17]2[CH2:16][Cl:15]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 936.1 mg (4.953 mmol) 4-bromoresorcinol, concentrated sulfuric acid (5 mL) and ethyl 4-chloroacetoacetate (1 mL, 7.4 mmol) was stirred for 6 days at room temperature. The reaction mixture was poured into ice-water and stirred for 2 hours to give a fine precipitate. The precipitate was collected by filtration, washed with cold water and dried under vacuum over P2O5 to yield 847.6 mg (2.928 mmol, 59.1% yield) of compound 11 as a solid. 1H NMR (CD3OD) δ 7.96 (1H, s), 6.86 (1H, s), 6.43 (1H, s), 4.83 (2H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: NCCCCO
Product: O=C1N[C@H](C(=O)NCCCCO)CS1
Yield: 41.3 %

Procedure:
Following a procedure similar to that described in Example 16(a), but using 1.2 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.23 g of N-(4-hydroxybutyl)amine, 0.735 g of the title compound was obtained as colorless crystals, melting at 81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11](F)=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[N:7]=[C:6]2[N:19]([CH3:22])[N:20]=[CH:21][C:5]=12>C(O)CCC>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:12]3[C:11]=2[NH:2][N:1]=[C:13]3[NH2:14])[N:7]=[C:6]2[N:19]([CH3:22])[N:20]=[CH:21][C:5]=12
Reactant: NN
Reactant: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Solvent: CCCCO
Product: Cn1ncc2c(Cl)cc(-c3cccc4c(N)n[nH]c34)nc21
Temperature: 90 °C

Procedure:
Hydrazine (0.34 mL, 1.04 mmol) was added to a solution of 3-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzonitrile 15 (0.030 g, 0.1046 mmol) in n-butanol and the reaction mixture was heated at 90° C. for 1 hour. The solvent was removed and diluted with ethylacetate, washed with saturated bicarbonate solution followed by brine. Drying and concentration gave 16.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:9]=1)=[O:7])(C)(C)C.C(OC1C(C(O)=O)=NC(CC2C=CC=CC=2C2C=CC=CC=2)=NC=1O)C1C=CC=CC=1>>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 67.5 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (7-02) (3 g, 67.53%) was synthesized as a white solid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-02) (5 g, 9.94 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01).
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(CC)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH2:41]([C:43]1[CH:44]=[C:45]([CH3:79])[C:46]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:78])=[N:61][CH:62]=3)=[O:56])[CH2:51][CH2:50]2)=[N:47][CH:48]=1)[CH3:42]>>[CH2:41]([C:43]1[CH:44]=[C:45]([CH3:79])[C:46]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][NH:65][C:64]4=[O:78])=[N:61][CH:62]=3)=[O:56])[CH2:51][CH2:50]2)=[N:47][CH:48]=1)[CH3:42]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(Cc5ccc(OC)cc5)CC4C)nc3)CC2)c(C)c1
Agent: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 145 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (88 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 505, the title compound (110 mg) was obtained via 3-{5-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [CH:1](=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH:1](=[N:8][C:9]1[N:10]=[CH:11][N:12]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(N=Cc2ccccc2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
12.8 g (60 mmol) of 4-benzylideneamino-5-imidazole carboxamide which is an intermediate material obtained in the Reference Example 1 was suspended in a mixed solvent of 240 ml dimethylformamide and 30 ml distilled water, and 16.6 g (120 mmol) of potassium carbonate was added to the suspension. 13.8 ml of benzyl chloride was added dropwise to the solution over 45 minutes at 80° C. After the addition, the mixture was stirred for one hour. The solvent was evaporated under vacuum, the residue was dissolved in chloroform, and the chloroform layer was washed with distilled water. Crude crystals obtained after evaporation of solvent was recrystallized from ethanol to obtain 14.4 g of 4-benzylideneamino-1-benzyl-5-imidazole carboxamide (yield 79%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[N+]([O-])=O.[BrH:15]>>[Br:15][C:7]1[CH:6]=[C:5]([CH3:11])[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(C(=O)O)n1
Reactant: Br
Product: Cc1cc(Br)c(C)c(C(=O)O)n1

Procedure:
The title compound, was prepared by treatment of 3,6-Dimethyl-4-nitro-pyridine-2-carboxylic acid with 49% hydrobrornic acid at 101° C. in accordance with the general method of example 1, step 3 to yield the title compound as an amorphous yellow solid, which is directly used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]=1[NH2:21])([O-])=O>C(O)C.[Pd]>[CH:18]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:15]([CH3:17])[CH3:16])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:21])([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Oc1cccc([N+](=O)[O-])c1N)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[Si](Oc1cccc(N)c1N)(C(C)C)C(C)C
Yield: 98.2 %

Procedure:
A solution of (a) (91 g) in ethanol (500 ml) was hydrogenated over 10% palladium on charcoal (8.5 g) for 3 days then filtered and evaporated to give an oil (80.7 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1>>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: OCCN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(CCO)CC4)sc3n2)cn1

Procedure:
2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol (175 mg) was utilized in a Suzuki coupling with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine according to General Procedure Suzuki to provide 385 (20 mg) after reverse phase HPLC purification. MS (Q1) 457 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:20][C:21]([CH:23]2[CH2:32][C:31]3[CH:30]=[C:29]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40](OC)=[O:41])[CH:35]=4)[CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([O:33][C:29]2[CH:30]=[C:31]3[C:26]([CH2:25][CH2:24][CH:23]([C:21]([NH:20][C:12]4[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=4)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:32]3)=[CH:27][CH:28]=2)[CH:39]=[CH:38][N:37]=1
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)CC3)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(CO)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-{[7-({[3-{[(tert-butoxycarbonyl)amino]methyl}-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (1.03 g, 1.72 mmol) in MeOH (17 mL) at 0° C., was added sodium borohydride (0.39 g, 13.3 mmol) in small portions. The reaction mixture was allowed to warm slowly to rt and then allowed to stir for 18 h. Water was added and the precipitate which formed was filtered, washed with water and hexane and dried under vacuum to give tert-butyl [3-{[(7-{[2-(hydroxymethyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (913 mg, 93.0%) as a white solid. LCMS: (FA) ES+ 572.3, ES− 570.4.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=O)C1C=CC=CC=1>CC(O)=O.Br>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][NH:11]1)[CH3:34]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.03 g, 2.15 mmol, 1.0 eq.) in AcOH (30 mL), 33% hydrobromic acid in acetic acid (7.5 mL) was added. The mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to AcOEt with 10% of NEt3) to yield the title amine.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:44])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32]C(OCC4C=CC=CC=4)=O)=[CH:28][C:27]=3[F:43])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]1([O:7][C:8](=[O:44])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:43])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)c(F)c1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.4 %

Procedure:
To a solution of a crude product of {4-[4-(benzyloxycarbonylamino)-2-fluorophenoxy]pyridin-2-yl}-N-(phenoxycarbonyl)carbamic acid phenyl ester (1.945 g) in tetrahydrofuran (100 ml) was added 20% palladium hydroxide on carbon (792 mg), followed by stirring under a hydrogen atmosphere at room temperature for 3 hr. The catalyst was removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide a crude product of the titled compound as a brown oil (1.617 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([F:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([F:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 52.6 %

Procedure:
Prepared in 52.6% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethyl-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.17-8.10 (m, 1H), 7.99 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.23-7.13 (m, 3H), 6.00 (br. s., 1H), 4.61 (br. s., 1H), 3.83 (t, J=11.7 Hz, 1H), 3.63 (t, J=10.8 Hz, 1H), 3.44 (d, J=7.3 Hz, 2H), 3.12 (d, J=8.4 Hz, 1H), 3.07-2.97 (m, 2H), 2.64 (d, J=8.1 Hz, 1H), 2.33 (s, 3H), 1.90-1.59 (m, 9H), 1.52 (br. s., 1H), 1.19 (d, J=2.9 Hz, 5H), 1.16 (s, 9H), 1.07 (d, J=6.2 Hz, 3H); LCMS (ESI, M+1): 690.4.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1>C(Cl)Cl>[CH:14]12[O:9][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)=[O:19])[CH2:13]2
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccc2ccccc2c1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of mCPBA (13.02 g, 58.13 mmol) dissolved in methylene chloride (50 mL) was added dropwise to a cooled (0° C.) solution of naphthalen-2-ylmethyl 5,6-dihydropyridine-1(2H)-carboxylate (11 g, 41.5 mmol) dissolved in methylene chloride (33 mL). The solution was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with 5% K2CO3 and then the layers were separated. The organic phase was washed with 5% K2CO3, saturated NaCl, dried over Na2SO4and concentrated in vacuo (9.5 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCCC1>>[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][N:20]([C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCNc1ccccc1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-methylamino-3-nitro-benzoic acid chloride (23.3 mmol) and 3-phenylamino-propionic acid methyl ester (23.3 mmol) in 80 mL dry tetrahydrofuran (THF) triethylamine (50.2 mmol) was added dropwise under stirring at room temperature. After three hours the reaction mixture was evaporated to dryness, the remaining solid triturated with water and the solid product isolated through filtration.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]([CH2:19][C:20](Cl)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:19][C:20]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 53.7 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (1.1 g, 6.0 mmol), t-butylacetyl chloride (0.93 mL, 6.6 mmol), and triethylamine (2.6 mL, 18 mmol) in tetrahydrofuran (11 mL) provided 3,3-dimethyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-butyramide (0.92 g). Mp 164-165° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.62; H, 8.18; N, 5.00.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.Cl.[CH:16]1([O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([NH2:24])=[NH:23])[CH2:18][CH2:17]1.[CH2:29](N(CC)CC)C>>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:24][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19][CH2:16][CH:18]3[CH2:17][CH2:29]3)=[N:23][C:7]=2[N:8]=1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1ccccc1OC1CC1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Agent: Cl
Product: CSc1nnc2c(=O)[nH]c(-c3ccccc3OCC3CC3)nc2n1
Yield: 59.8 %

Procedure:
In a similar manner to Example 85 reaction of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g) with 2-cyclopropoxybenzamidine hydrochloride (2.35 g) and triethylamine (1.75 g) afforded a yellow solid (1.31 g) which was recrystallized from acetonitrile and then from acetonitrile/ethanol (50%) to afford the title compound, 0.70 g, m.p. 235-236° C.