Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([O:20][P:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19]>C1COCC1>[CH2:18]([O:20][P:21](=[O:25])([O:22][CH2:23][CH3:24])[O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:7]=1[C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:19]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 mL) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g, 169.6 mmol) in THF (150 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and then phosphorochloridic acid diethyl ester (30.15 g, 174.7 mmol) was added dropwise at 0° C. After addition, the mixture was stirred at this temperature for 15 min. The reaction was quenched with sat. NH4Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with Et2O (350 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give crude phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester as a yellow oil (51 g, contaminated with some mineral oil), which was used directly in the next step.
Reaction SMILES: ClC1N=C(NC(C2C=CC3C(=CC=CC=3)C=2)C)N=C(N)N=1.NC(CC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:49][CH:50]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:66]=[C:65]([NH2:67])[N:64]=[C:63]([NH:68][CH:69]([C:71]3[CH:80]=[CH:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[CH:72]=3)[CH3:70])[N:62]=2)=[CH:57][N:56]=1)[C:51]([OH:53])=[O:52]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[NH2:49][C@@H:50]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:66]=[C:65]([NH2:67])[N:64]=[C:63]([NH:68][C@@H:69]([C:71]3[CH:80]=[CH:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[CH:72]=3)[CH3:70])[N:62]=2)=[CH:57][N:56]=1)[C:51]([OH:53])=[O:52]
Reactant: CC(Nc1nc(N)nc(-c2ccc(CC(N)C(=O)O)nc2)n1)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(Nc1nc(N)nc(Cl)n1)c1ccc2ccccc2c1
Agent: CC1(C)OB(c2ccc(CC(N)C(=O)O)nc2)OC1(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H](Nc1nc(N)nc(-c2ccc(C[C@H](N)C(=O)O)nc2)n1)c1ccc2ccccc2c1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 6-chloro-N-[1-naphthalen-2yl-ethyl]-[1,3,5]triazine-2,4-diamine (30 mg, 0.1 mmol), 2-boc protected-amino-3-{5-[4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin2-yl-]-propionic acid (50 mg, 0.15 mmol) 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml; 1N) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and was then purified by Prep-LC to give 7 mg of boc protected 2-amino-3-{5-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2-yl]-pyridin-2-yl}proionic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C>[Br:18][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[CH2:2][Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: CN(C)C=O
Product: O=c1[nH]c(CCl)c(Br)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a solution of 6-(chloromethyl)uracil (2.0 g, 12.5 mmol) in DMF (15 mL) at 0° C. was added NBS (recrystallized, 2.44 g, 13.7 mmol). The mixture was stirred at 0° C. for 1.5 h, and then quenched by ice water. The precipitate was collected by filtration and washed with AcOH and water to give the title compound (2.35 g, 69%) as a white solid. 1H NMR (DMSO, 500 MHz) δ 1.66 (s, 1H), δ 11.61 (s, 1H), δ 4.47 (s, 2H). MS (Multimode, M+H+) C5H5BrClN2O2, calcd. 238.9. found 238.9.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].C([O-])=[O:14].[Na+].Cl.[Na].[Cl-]>C(O)=O.O>[OH:14][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: O=C[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A 1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 50.5 g of 4-chloroacetyl-catechol of a purity of ca. 99%, 500 ml of water, 28 g of sodium formate and 15.5 ml (˜19 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 22 hours. The solution was cooled to about 25° C. and acidified by addition of 36.6 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. The mixture was extracted with ethyl acetate, once with 1 l then 3 times with 0.5 l each. The organic extracts have been back washed 3 times with 300 ml 10% brine. The combined organic phases were dried with sodium sulfate, filtered and evaporated at reduced pressure at 40° C. and dried at 45° C. at ˜0.5 mbar. This resulted in a light tan solid crystalline product of 44.63 g of 96.4% purity corresponding to a yield of 95.9%. Analyses showed this material to have a contamination of 0.12% sodium ions and 0.03% chloride ions.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[N:44]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Product: COc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl(6-methoxy-2-pyridyl)tin (see Gros, Philippe; Fort, Yves. Synthesis (1999), 754-756) were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 478/480 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12](I)=[C:11]([NH2:20])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:27]#[N:28])#[CH:23].C(NC(C)C)(C)C.CN(C)C=O>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:20][C:11]1[N:10]=[C:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12]=1[C:23]#[C:22][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[C:26]([C:27]#[N:28])[CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)c1nc(N)c(I)c2c1ncn2C
Reactant: C#Cc1cc(F)cc(C#N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1nc(N)c(C#Cc2cc(F)cc(C#N)c2)c2c1ncn2C
Temperature: 90 °C

Procedure:
A1.12 tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate (3.2 g, 7.9 mmol), dichlorobis(triphenylphosphine)palladium (270 mg, 0.38 mmol), 3-ethynyl-5-fluorobenzonitrile (C1.2) (1.5 g, 10 mmol), CuI (75 mg, 0.39 mmol), diisopropylamine (15 mL) were added to N,N-dimethylformamide (15 mL). The reaction mixture was heated at 90° C. (in preheated oil bath) for 60 min. Additional 3-ethynyl-5-fluorobenzonitrile (C1.2) (0.5 g, 3.4 mmol) was added to the reaction mixture and heated for another 60 min. The reaction was cooled and diluted with ethyl acetate and washed several times with water. The solvent removed under reduced pressure and the residue was purified by silica gel column chromatography (50%-70% ethyl acetate/hexane) to give 3.0 g (90%) of C1.3. LCMS B: Ret time 2.98 min, (M+H)+=421.31, 1H NMR, 400 MHz, CDCl3: 7.62 (s, 1H), 7.57 (s, 1H), 7.42 (dm, 1H), 7.35 (dm, 1H), 5.00 (bs, 2H), 4.05 (s, 3H), 3.39 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:22])[C:8](=[O:23])[C@H:7]2[CH2:24][CH3:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N+:19]([O-:34])=[CH:18][CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:22])[C:8](=[O:23])[C@H:7]2[CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3)nc2N1C1CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3cc[n+]([O-])cc3)nc2N1C1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(pyridin-4-yl)-7,8-dihydropteridin-6(5H)-one (Example 5, 300 mg, 0.89 mmol) in 25 mL of DCM at 0° C., mCPBA (306 mg, 1.79 mmol) was added and the mixture was stirred at 0° C. for 3 hr, then at rt for another 3 hr. Saturated Na2S2O4 was added and stirred at r.t. for 30 min. The mixture was extracted with DCM, washed with saturated NaHCO3, concentrated and purified by preparative HPLC to give the title compound as a yellow oil (20 mg, 6.4%). 1H NMR (CDCl3) δ: 8.47 (d, 2H), 8.38 (d, 2H) 8.06 (s, 1H), 4.51 (m, 1H), 4.38 (m, 1H), 3.42 (s, 3H), 2.2-1.7 (m, 10H) and 0.89 ppm (t, 3H); LCMS: 354.2 m/z (M+H)+; ret. Time: 1.79 min (Analytical Method E).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(Cl)cc2)cc1
Yield: 83.26 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (11.7 g, 78 mmol) and 4-chloroaniline (10 g, 78 mmol) by following the procedure described in preparation 10 (18.06 g, yield 83.26%, purity 98.9% by HPLC). MS m/z:277.1/278.7 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[Br:27][CH2:28][CH2:29]Br>CN(C=O)C>[Br:27][CH2:28][CH2:29][N:23]1[CH:24]=[C:20]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])[CH:7]=2)[CH:21]=[N:22]1
Reactant: BrCCBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCBr)c2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.0 g; 2.93 mmol) in DMF (50 mL) was added NaH (176 mg; 4.4 mmol; 60%) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour, added 1,2-dibromoethane (0.83 g; 4.4 mmol), warmed to r.t. and stirred overnight. The mixture was poured into ice-water (50 mL) and extracted by EtOAc (50 mL×3). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=2/1) to afford 0.48 g (37%) of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 120 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (9.75 g), phenol (7.10 g), and of Cs2CO3 (41.0 g) were dissolved in 100 mL of DMF and heated to 120° C. overnight. The reaction mixture was taken up in EtOAc and washed with water and brine, and dried over Na2SO4. The solution was concentrated to provide 2-methyl-4-nitro-1-phenoxybenzene as an oil, which was used in Step B without further purification.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(N3CCN(C(OC(C)(C)C)=O)C(C4C=C5C(=CC=4)N(C)N=C5)C3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:50]([O:54][C@@H:55]([C:61]1[C:88]([CH3:89])=[CH:87][C:64]2[N:65]=[C:66]([N:68]3[CH2:73][CH2:72][N:71]([CH:74]([CH3:76])[CH3:75])[CH:70]([C:77]4[CH:78]=[C:79]5[C:83](=[CH:84][CH:85]=4)[N:82]([CH3:86])[N:81]=[CH:80]5)[CH2:69]3)[S:67][C:63]=2[C:62]=1[C:90]1[CH:95]=[CH:94][C:93]([Cl:96])=[CH:92][CH:91]=1)[C:56]([O:58]CC)=[O:57])([CH3:53])([CH3:52])[CH3:51]>>[C:50]([O:54][C@@H:55]([C:61]1[C:88]([CH3:89])=[CH:87][C:64]2[N:65]=[C:66]([N:68]3[CH2:73][CH2:72][N:71]([CH:74]([CH3:75])[CH3:76])[CH:70]([C:77]4[CH:78]=[C:79]5[C:83](=[CH:84][CH:85]=4)[N:82]([CH3:86])[N:81]=[CH:80]5)[CH2:69]3)[S:67][C:63]=2[C:62]=1[C:90]1[CH:91]=[CH:92][C:93]([Cl:96])=[CH:94][CH:95]=1)[C:56]([OH:58])=[O:57])([CH3:52])([CH3:53])[CH3:51]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(N3CCN(C(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-isopropyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (3.7 mg) was prepared in a similar manner as compound (2S)-2-tert-butoxy-2-(2-(4-(tert-butoxycarbonyl)-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-isopropyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetate instead of tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate. LCMS-ESI+: calc'd for C35H41ClN5O3S: 646.3 (M+H+); Found: 646.3 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 8.11 (m, 1H), 8.04 (m, 1H), 7.76 (m, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.36 (s, 1H), 5.15 (s, 1H), 4.37 (m, 2H), 4.11 (s, 3H), 4.1-3.7 (m, 3H), 3.4 (m, 3H), 2.49 (s, 3H), 1.32 (d, J=6.2 Hz, 3H), 1.24 (d, J=6.7 Hz, 3H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C@@H:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C@@:4]1(C)[OH:5]>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C@@H:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C@H:4]1[OH:5]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 3 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L of methylene chloride that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL of methylene chloride while stirring. After maintaining the solution at about 3° C. for approximately 27 hours, another 5.031 mL of stannous chloride (SnCl4) (0.04282 mol) was added and the solution was kept at about 3° C. overnight. After a total reaction time of approximately 43 hours, the reaction was quenched by carefully adding the solution to 1.9 L of a saturated NaHCO3 solution. Tin salts were removed via filtration through Celite after which the organic phase was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g. The crude oil was used directly in the next step without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:20])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH3:19])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCOC(C)=O.O>C(O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:8]2[CH:9]=[C:4]([N:1]3[CH:24]=[C:23]([CH2:22][CH2:21][OH:25])[N:3]=[N:2]3)[CH:5]=[CH:6][C:7]=2[CH3:20])=[O:11])=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(N=[N+]=[N-])ccc1C
Reactant: C#CCCO
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound 451 (170 mg, 0.51 mmol) in ethanol (2 mL) was added but-3-yn-1-ol (39 μL, 0.51 mmol). A freshly prepared solution of copper(II) sulphate pentahydrate (5.0 mg, 0.020 mmol) and sodium ascorbate (20 mg, 0.10 mmol) in water (0.5 mL) was added to the reaction mixture. The flask was closed and stirred for 24 h at RT under argon. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 40:60 to 95:5 as the eluent to afford the title compound as white syrup.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)=[C:4]([NH:7][C:27](=[O:28])[CH2:26][N:17]2[C:18]3[C:23](=[N:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH2:25][C:16]2=[O:15])[S:5][CH:6]=1
Reactant: CCc1n[nH]c(-c2c(Cl)csc2N)n1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: CCc1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (18 mg, 78.7 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (20 mg, 97.0 umol) using protocol A. The residue was purified by HPLC to yield N-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Method [8] Retention time 4.47 min by HPLC (M+=417 and 419) and (M+Na=439 and 441). 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J=5.4 and 1.2 Hz, 1H), 7.67 (dd, J=8.1 and 1.2 Hz, 1H), 7.49 (dd, J=8.1 and 5.4 Hz, 1H), 6.85 (s, 1H), 4.93 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.84 (q, J=7.8 Hz, 2H), 1.39 (t, J=7.8 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8]>C1(C)C=CC=CC=1>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:9]
Reactant: CC(=O)CCCCC=O
Solvent: Cc1ccccc1
Product: CC(=O)CCCCCO
Temperature: 90 °C

Procedure:
6-oxoheptanal (12.8 g, 0.1 mol.), toluene (76.8 g, 600 wt. %) and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium (bispivalate) (9.6 mg, 0.0125 mmol, 0.0125 mol.%) were loaded altogether in a 200 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times to 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 20 bars hydrogen. It was then heated to 90° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 94% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 7-hydroxyheptan-2-one was obtained in 90% yield.
Reaction SMILES: CN([CH2:4][CH:5]([CH2:18][CH2:19][CH2:20][Cl:21])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:9]=1[Cl:17])=[O:7])C.S(=O)(=O)(O)O>>[Cl:21][CH2:20][CH2:19][CH2:18][CH:5]1[CH2:4][C:13]2[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:6]1=[O:7]
Reactant: COc1ccc(C(=O)C(CCCCl)CN(C)C)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Dimethylaminomethyl)-5-chloro-1-(2,3-dichloro-4-methoxyphenyl)-1-pentanone (6.1 g, 0.019 mole) was added in portions to well-stirred concentrated sulfuric acid (25 ml). The temperature rose to 39° C. after which the mixture was stirred at ambient temperature for an additional two hours. The mixture was poured into crushed ice and the resulting precipitate removed by filtration, washed with water, dried and then recrystallized from a mixture of tetrahydrofuran and ether to give 2-(3-chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one, 5 g, m.p. 130°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH3:26]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH2:26])=[O:20]
Reactant: N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: C1CCOC1
Product: NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol) and tetrahydrofuran (20 ml) as a solvent were placed into a round bottom flask (50 cc), and an excess amount of 25% aqueous ammonia was poured into the mixture, followed by stirring for one hour at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.400 g, 38.2% yield).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:19])[C:6]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[O:11]C)[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl>[CH2:1]([C:4]1[C:5](=[O:19])[C:6]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[OH:11])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCc1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a solution of 4-allyl-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.159 g) in dichloromethane (10 mL) was added boron tribromide (1M in dichloromethane, 1.8 mL). After 1.5 hours, the reaction mixture was quenched with 50 mL of saturated aqueous sodium bicarbonate. Dichloromethane (30 mL) was added and the mixture was adjusted to pH 3 using 2.4N hydrochloric acid. The organic portion was separated, washed (water, brine), dried and evaporated. The resulting yellowish solid was triturated with hexanes to afford the title compound (0.074 g); mp 172°-174° C.; NHR: 11.73 (s,1), 10.39 (s,1), 7.93 (d,1, J=8.6), 7.48 (s,1), 7.30 (dd,1, J=8.8, 2.1), 5.86-5.73 (m,1), 5.01-4.91 (m,2), 3.35 (m,2). Analysis for C13H10ClNO3.0.25 H2O: Calculated: C, 58.22; H, 3.95; N, 5.22; Found: C, 58.18; H, 3.91; N, 5.13.