Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 18.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (47.9 mg, 0.075 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (104 mg, 0226 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk37) (14.6 mg, 19%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13]([O-:15])=O)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[OH:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[NH:59][C:58](=[O:63])[N:57]([CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:56]2.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13]([N:67]2[CH2:66][CH2:65][CH:64]([N:57]3[CH2:56][C:55]4[C:60](=[CH:61][CH:62]=[C:53]([OH:52])[CH:54]=4)[NH:59][C:58]3=[O:63])[CH2:69][CH2:68]2)=[O:15])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22]
Reactant: O=C1Nc2ccc(O)cc2CN1C1CCNCC1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3cc(O)ccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
A solution of 1.37 g (4.04 mmol) 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate, 1.42 g (4.40 mmol) TBTU, 0.63 mL (4.50 mmol) triethylamine and 1.00 g (4.04 mmol) 6-hydroxy-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one in 10 mL DMF was stirred for 3 h at RT. The reaction mixture was poured onto 300 mL saturated NaHCO3 solution, the precipitated substance was suction filtered, washed with 50 mL water and dried at 60° C. in the circulating air dryer.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14](C(OC(C)(C)C)=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:27][O:26]C(C)(C)O3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC1C=C(C=CC=1OC)CN1CCC(NC2C=CC(CC)=CC=2)CC1)C.BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+].Cl.ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC>CN(C=O)C.O1CCOCC1.C(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:27][OH:26])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC3COC(C)(C)O3)cn2)CC1
Agent: BrCCCOC1CCCCO1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: CCOc1cc(CN2CCC(Nc3ccc(CC)cc3)CC2)ccc1OC
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: OCCCOc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for rac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (intermediate B19/step 1) from 4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate B18/step 5) by reaction with rac-2-(3-bromopropoxy)-tetrahydro-2H-pyran (commercially available) and potassium carbonate in DMF at rt, followed by BOC and THP cleavage with 4 M HCl in dioxane and ethanol at 70° C. in analogy to the synthesis of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2). MS (ISP): 252.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1sc(C(=O)CCc2ccc(O)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.3 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (139 mg, 0.385 mmol, Intermediate 6) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (110 mg, 1.16 mmol). The reaction mixture is stirred at rt for 18 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-chloro-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (39 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=417.21.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]([Si:52]([CH3:55])([CH3:54])[CH3:53])#[CH:51]>C1COCC1.C(NCC)C.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:51]#[C:50][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Br)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC(Oc1ccc(C#C[Si](C)(C)C)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 85 °C
Yield: 67.6 %

Procedure:
To a suspension of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-bromo-pyridine (128 mg, 0.253 mmol) and bis(triphenylphosphine) palladium(II) chloride (53 mg, 0.076 mmol) and triphenylphosphine (16.6 mg, 0.0632 mmol) and CuI (11 mg, 0.0578 mmol) in THF (3 mL) and diethylamine (1.5 mL) was added ethynyltrimethylsilane (0.108 mL, 0.759 mmol) under Ar. The mixture was heated at 85° C. over night. The reaction mixture was diluted with ethyl acetate and washed with aq.ammonium chloride solution two times. The separated organic phase was dried over anhydrous sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by silica gel column chromatography (DCM) yielding 89.5 mg (68%) of the titled compound as a light yellow oil. ES-MS m/e: 523.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH:12]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([NH:11][C:19](=[O:20])[CH2:18][CH2:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1nn2cccnc2c1Br
Product: O=C(CCC1CCCC1)Nc1nn2cccnc2c1Br

Procedure:
The product from Example 110A and 3-cyclopentylpropionyl chloride were processed using the method analogous to that described in Example 1D to provide the title compound. MS (APCI) m/z 337/339 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Si:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Product: C[Si](C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 497.4/499.3 (100/48) (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[C:5]=2[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: CCCOc1cc(CO)cc(C2CC2)c1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCOc1cc(C=O)cc(C2CC2)c1-c1ccc(F)cc1
Yield: 74.7 %

Procedure:
Manganese dioxide (60.4 g) was added to a mixture of (2-cyclopropyl-4′-fluoro-6-propoxybiphenyl-4-yl)methanol (29.8 g) and toluene (200 mL), and the resultant mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (22.1 g).
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(OC)(C)(C)C>O>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of p-toluenesulfinic acid sodium salt (30 g) in H2O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HCI (15 mL). After stirring 5 min, the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether. The organic phase was dried (Na2SO4) and concentrated to near dryness. Hexane was added and the resulting precipitate collected to afford p-toluenesulfinic acid; yield 22 g. p-Toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503 mmol) and camphor sulphonic acid (4 g, 17.3 mmol) were combined and stirred at 60° C. 18 h. The resulting solid was broken up and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) then filtered. The solid was resuspended in MeOH/hexanes (1:3, 200 mL) and stirred vigorously to break up the remaining chunks. Filtration afforded the title compound (27 g, 62% yield): 1H NMR (400 MHz, CDCl3) d 8.13 (s, 1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:31])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[C:17]([O:29]C)[C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[C:20]=2[O:23]C)[CH2:15]1)[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH2:1]([NH:3][C:4](=[O:31])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:20](=[O:23])[C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[C:17](=[O:29])[C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNC(=O)OCCCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)OCCCCCCCCC1CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octyl N-ethylcarbamate (1.22 g) in acetonitrile (12 ml) was dropwise added a solution of CAN (3.83 g) in water (12 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=4:1) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (630 mg) as crystals.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:42])[C@@:11]([CH3:41])([N:16]([CH3:40])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][NH:9][C:10](=[O:42])[C@@:11]([CH3:41])([N:16]([CH3:40])[C:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)[C@@](C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@](C)(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Yield: 35.1 %

Procedure:
10% Pd—C (5.0 mg) was added to a methanol (3.0 mL) solution of (2S)-N-(benzyloxy)-N′,2-dimethyl-2-[methyl({4′-[2-(morpholin-4-yl)ethoxy]biphenyl-4-yl}carbonyl)amino]propanediamide (27 mg) as obtained in Example 19-(5), and the mixture was stirred in a hydrogen atmosphere for 6 hours at room temperature. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was subjected to isolation and purification by LC to obtain (2S)-N-hydroxy-N′,2-dimethyl-2-[methyl({4′-[2-(morpholin-4-yl)ethoxy]biphenyl-4-yl}carbonyl)amino]propanediamide (Compound 437, light yellow solid) (8.0 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: NCc1cccc(N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(N)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>C1COCC1>[OH:31][C:29]([CH3:32])([CH3:30])[CH2:28][N:27]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:25]=[CH:26][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:12]([CH3:24])[C:13]=2[CH3:23])[C:16]1=[O:17]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1C=O
Reactant: CC(C)(O)CN
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1C)CN(CC(C)(C)O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.11 g) in THF (4.00 mL) was added 1-amino-2-methylpropan-2-ol (0.03 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (4.0 mL). Sodium triacetoxyborohydride (0.11 g) was added thereto under argon atmosphere, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 46.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=1[F:52]>>[Cl:44][C:45]1[C:46]([F:52])=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Cl)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-chloro-3-fluorophenol, the title compound was obtained (33%): 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 7.52-7.41 (m, 2H), 7.23 (t, 1H), 6.96 (d, 1H), 6.84 (d, 1H), 6.80 (d, 1H), 4.15 (s, 1H), 3.79-3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 346 (M−17), 386 (M+23).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].[Na].Cl([F:23])(=O)(=O)=O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH2:3][CH:4]([F:23])[CH2:5][CH3:6])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(F)CC)C(=O)OCC

Procedure:
To a suspension of sodium hydride (1.08 mol) in 1200 ml of toluene was added dropwise 235 g (1.08 mol) of diethyl n-butylmalonate. To the resulting clear solution of the sodium salt was then bubbled perchloryl fluoride while the the temperature was maintained below 10° C. When the calculated amount of perchoryl fluoride had been added a stream of argon was bubbled through the solution for a short period of time. The mixture was filtered and the toluene removed under reduced pressure. The remaining oil was distilled to give 223 g, b.p. 78° (0.1 mmHg) of diethyl-2-fluoro-n-butylmalonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][P:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([P:11]([CH3:13])([CH3:10])=[O:12])=[CH:20][CH:19]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)ncc2Cl)cc1
Temperature: 110 °C
Yield: 36.2 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (0.15 ml, 1.31 mmol) in 1 mL of DMF was added 4-(dimethylphosphoryl)aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The mixture was heated at 110° C. for 4 h. It was basified with saturated sodium bicarbonate solution. The suspension was filtered and washed with ethyl acetate to give the final product (0.15 g, 36% yield). MS/ES+: m/z=316.