Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].O.O.[N+]([O-])(O)=O.[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][C:16](=[O:21])[CH2:17]2)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][CH:17]2[C:16]([OH:21])=[O:1])(=[O:10])[CH3:9]
Reactant: CC(=O)OC1CCC2CC(=O)CCC21
Reactant: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)OC1CCC2C(C(=O)O)CCC12
Yield: 12.2 %

Procedure:
Thallic nitrate trihydrate (133 g) was added to a stirred solution of 7-acetoxybicyclo[4,3,0]nonan-3-one (57 g; prepared as described in Reference Example 4) in glacial acetic acid (290 ml). After 30 minutes the resulting solid was filtered off and the filtrate was heated at reflux for 30 minutes. The acetic acid was distilled off under reduced pressure and the residue was neutralised by treatment with aqueous sodium hydroxide solution to pH 5 and then with aqueous sodium bicarbonate solution to neutral. The resulting solution was washed with diethyl ether, and then it was acidified by treatment with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were washed with saturated aqueous sodium chloride solution, then dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate, hexane, and acetic acid (45:55:1 by volume), to give 6-acetoxy-2-carboxybicyclo[3,3,0]octane (7.55 g), predominantly in the 2β-configuration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=O)[CH2:14]Br)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].C(O)C>O>[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:14]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
1.0 g (11 mmol) of 2-aminopyridine, 3.0 g (11 mmol) of 4-bromophenacyl bromide, and 1.9 g (14 mmol) of sodium hydrogen carbonate were put in a 50 mL three-neck flask, and the air in the flask was replaced with nitrogen. This mixture was added with 10 mL of ethanol, and then heated and stirred at 80° C. for six hours. After the stirring, the mixture was added with water and subjected to suction filtration to give a solid. The obtained solid was washed with water and methanol in this order, whereby 2.3 g of the target white solid was obtained in a yield of 76%.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[S:30])OC.[Cl-].[NH4+]>COC(C)(C)C>[F:17][CH2:16][C:4]1([CH2:18][F:19])[CH:3]=[C:2]([C:27](=[S:30])[O:26][CH3:25])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Reactant: COC(=S)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: COC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
An amount (65 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.11 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 10 minutes. Then, dimethoxycarbon sulfide (39 mg) was slowly added dropwise to the reaction mixture, which was stirred for 30 minutes at −70° C. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (3/1). The resulting organic layers were washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give the titled compound (36 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>>[O:8]=[C:5]1[NH:6][C:7]2[CH:10]=[CH:11][C:12]([CH3:13])=[N:1][C:2]=2[C:3](=[O:9])[NH:4]1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Reactant: C/C=C/C=O
Product: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Reaction time: 0.17 h
Yield: 248.1 %

Procedure:
20 g of 5-aminouracil (40 mmol), 80 ml of 20% HCI and 4 ml of crotonaldehyde (50 mmol) were heated together under reflux for 1 hour. The solution was evaporated to dryness under rotarary evaporation. Water was added to the residue so as to make the mixture just stirrable and then it was triturated with ammonium hydroxide with strong stirring until the pH increased to 10-11. Stirring was continued for another 10 minutes. The precipitate was filtered and was washed with minimal methanol and then chloroform and dried to give 17.58 g (63%) of 1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[F:1][C:2]([F:15])([F:16])[C:3]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: OC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-phenylpropan-2-ol (6.1 g, 25 mmol) was dissolved in concentrated H2SO4 (15 mL) and cooled to −10° C. HNO3 (90%, 5 mL, 100 mmol) was added dropwise and the temperature was maintained below −5° C. The mixture was stirred at −5° C. for 10 min and was poured into ice. The precipitate was collected via filtration, washed with ice water until pH˜6, and was dried to yield 1,1,1,3,3,3-hexafluoro-2-(3-nitrophenyl)propan-2-ol (6.3 g) that was used in next step without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[Br:20]Br>ClCCl>[Br:20][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: BrBr
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1

Procedure:
To a 0.01 mole sample of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of dichloromethane is added 0.01 mole of bromine. After standing, the mixture is worked up as for Example 15 to give the product as crystals, m.p. 138°-140° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[C:27]([I:29])[CH:28]=1>C(Cl)Cl>[Br:20][CH2:30][C:25]1[CH:26]=[C:27]([I:29])[CH:28]=[C:23]([Cl:22])[CH:24]=1
Reactant: BrBr
Reactant: OCc1cc(Cl)cc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(I)cc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred ice-cooled solution of triphenylphosphine in 10 mL of CH2Cl2 was added dropwise a solution of bromine in 5 ml of CH2Cl2. After the reaction mixture was stirred at room temperature for 30 min and cooled at ice bath temperature, a solution of the above (3-chloro-5-iodo-phenyl)-methanol in 15 ml of CH2Cl2 was added dropwise. The reaction mixture was stirred 0° C. for another 1 h and concentrated. The residue was washed with hexane several times and the combined hexane layer was concentrated to give 1-bromomethyl-3-chloro-5-iodo-benzene (1.2 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(6-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 13 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (0.347 mL, 1.99 mmol) in dioxane (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then crystallised from acetonitrile affording 118 as a white solid (35 mg, 24%). LCMS: RT 3.15 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.17-8.07 (2H, m), 7.88-7.78 (1H, m), 7.64-7.45 (6H, m), 7.06 (1H, d, J=8.26 Hz), 6.86 (1H, s), 5.50 (1H, br), 2.35 (3H, s), 1.54 (3H, d, J=6.82 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]>[Ni].C1COCC1>[NH2:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.7 %

Procedure:
To a Parr apparatus was added 4 (0.78 g, 3.67 mmol), Raney nickel (1.2 g), and THF (50 mL). The vessel was sealed under a hydrogen atmosphere and shaken under pressure at room temperature for 15 h. The vessel was then depressurized and the solids filtered off, washing with THF. The filtrate was concentrated under reduced pressure to give impure 5 (0.66 g, 100%). MS: APCI (AP+): 183.1 (M)+, (AP−): 181.0 (M)−.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([OH:26])[C:24]#[CH:25]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:25]#[C:24][CH2:23][OH:26])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g) and Pd(PPh3)2Cl2 (0.032 g) followed by addition of propargyl alcohol (0.16 mL). The reaction is stirred at rt for 3 d. The reaction mixture is partitioned between H2O (100 mL) and ethyl acetate (100 mL). The organic layer is removed, and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are washed with a saturated aqueous NH4Cl solution, dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale orange solid which is recrystallized from CH2Cl2/CH3OH to yield 0.165 g (20%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])(C)[C:9]#N.CCO.C([O-])([O-])=O.[K+].[K+].OO.CC#[N:26]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:26])([CH3:12])[CH3:9]
Reactant: CC#N
Reactant: CC(C)(C#N)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(N)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-(2-Chlorophenyl)-2-methylpropanenitrile (5.0 g, 0.028 mol) along with 50 mL of EtOH was added into a 250 mL round-bottomed flask. To this was added 50 mL of saturated aqueous K2CO3. This mixture was cooled to 0° C. then 85 mL of 30% aqueous H2O2 was slowly added. The reaction mixture was allowed to warm to room temperature, and then it was stirred at that temperature for 12 h. The mixture was extracted with CH2Cl2 (3×150 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a viscous oil. To this oil was added 40 mL of CH3CN, 40 mL H2O, and 13.2 g (0.031 mol) of PhI(O2CCF3)2. This mixture was stirred at r.t. for 12 h, diluted with 300 mL of H2O, and then stirred for an additional 4 h at room temperature. The aqueous phase was extracted using MTBE (1×200 mL) follow by diethyl ether (2×100 mL). The aqueous layer was basified with 1N NaOH (pH=13) and then extracted with CH2Cl2 (3×100 mL). The organic extracts were dried and concentrated in vacuo to give the desired product as a colorless oil that was used in subsequent steps without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[N:5][N:4]([CH:8]2[N:12]([CH2:13][C:14]#[C:15][I:16])[C:11](=[O:17])[CH2:10][CH2:9]2)[N:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH2:23][N:24]=[N+:25]=[N-:26]>>[Br:7][C:6]1[C:2]([Br:1])=[N:3][N:4]([CH:8]2[N:12]([CH2:13][C:14]3[N:26]=[N:25][N:24]([CH2:23][C:22]4[CH:27]=[CH:28][CH:29]=[C:20]([C:19]([F:18])([F:31])[F:30])[CH:21]=4)[C:15]=3[I:16])[C:11](=[O:17])[CH2:10][CH2:9]2)[N:5]=1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(n2nc(Br)c(Br)n2)N1CC#CI
Product: O=C1CCC(n2nc(Br)c(Br)n2)N1Cc1nnn(Cc2cccc(C(F)(F)F)c2)c1I

Procedure:
Synthesized from 5-(4,5-dibromo-2H-1,2,3-triazol-2-yl)-1-(3-iodoprop-2-ynyl)pyrrolidin-2-one and 3-trifluoromethyl-benzylazide using general procedure; 0.663 g, 0.982 mmol, 93%; mp=105-110° C. (dec.); IR (υ[cm−1]) 3002, 2104, 1696, 1415, 1327, 1166, 1123, 1074, 921, 829, 753, 702; 1H NMR (600 MHz, CDCl3) δ=7.59 (d, J=7.8, 1H), 7.56 (s, 1H), 7.48 (t, J=7.7, 1H), 7.40 (d, J=7.7, 1H), 6.16 (d, J=7.6, 1H), 5.59 (d, J=3.3, 2H), 4.88 (d, J=15.7, 1H), 3.92 (d, J=15.7, 1H), 2.95-2.86 (m, 1H), 2.65-2.56 (m, 1H), 2.49 (dd, J=17.1, 9.9, 1H), 2.43-2.36 (m, 1H); 13C NMR (151 MHz, CDCl3) δ=175.0, 147.0, 135.1, 131.6 (m), 131.5, 129.9, 126.1, 125.8 (m), 125.1 (m), 123.9 (m), 79.6, 78.3, 53.9, 36.4, 28.6, 25.6; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C17H14Br2F3IN7O, 673.8618; found 673.8613.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]=1[NH2:24].[C:25](OCC)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:16]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCCC(CCC)Nc1ncnc(-c2ccc(OC)cc2Cl)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CCCC(CCC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3Cl)ncnc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
6-(2-Chloro-4-methoxy-phenyl)-N4-(1-propyl-butyl)-pyrimidine-4,5-diamine (0.29 g, 0.83 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.92 ml, 8.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 13.5 mg of 4-(2-chloro-4-methoxy-phenyl)-6-methyl-8-(1-propyl-butyl)-8H-pteridin-7-one (Example 563). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.42 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.42, 2.56 Hz, 1 H), 3.86 (s, 3 H), 4.40 (m, 1H), 2.48 (m, 2 H), 2.31 (m, 2 H), 1.89 (m, 2 H), 1.19 (m, 5 H), 0.88 (t, J=7.32 Hz, 6 H). MS (AP) 321.2 [(M+H)+, 100]. MS (AP) 401.3 [(M+H)+, 100].
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:58](=[NH:60])[NH2:59])[CH:54]=2)[CH:49]=1)(=O)=O>C(OCC)C>[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[C:53]([C:58](=[NH:59])[NH2:60])[CH:54]=3)[CH:49]=2)=[O:24])=[CH:26][CH:27]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)cc3)ccc2c1
Yield: 46.9 %

Procedure:
To 50 ml of dried pyridine, were added 5.1 g of 4-benzyloxycarbonylaminomethylbenzoic acid and 4.4 g of DCC. The mixture was stirred under cooling in ice for 30 minutes, admixed with 5.0 g of 6-amidino-2-naphthol methanesulfonate and stirred for one hour under cooling in ice, then overnight at room temperature. The reaction mixture was filtered* and the filtrate was mixed with ethyl ether. The precipitate which was formed was collected by filtration and recrystallized from a DMF-ethanol mixture to obtain 3.8 g of a white powder of a white powder of 6-amidino-2-naphthyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24]>C(Cl)Cl>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1 g aminodiphenylmethane, 2 mL triethylamine in 20 mL CH2Cl2. The reaction was cooled to 0° C. and 1 g of methyl 3-chlorosulfonyl-2(R)-methylpropionate was slowly added. The reaction was stirred 1 hour then concentrated in vacuo. The residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried, and concentrated in vacuo. Trituration from Et2O/hexanes gave 1.15 g of methyl 3-[N-(diphenylmethyl) aminosulfonyl]-2(R)-methylpropionate as a white solid. HRMS (M+Li): calcd. 354.1351, obs 354.1569.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-chloro-phenyl)-amide as a white solid. (Yield 32 mg, 46%).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17])=O)C1C=CC=CC=1.Cl[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:45]([O:44][CH2:43][O:17][CH2:16][C@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][NH2:11])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: ClCOCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@H](CCCN)COCOCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (2R)-5-(benzyloxycarbonylamino)-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (Section 1.1.2.) (2.05 g; 3.60 mmol.) in anhydrous CH2Cl2 (40 ml) at room temperature and under argon flow, there are added in succession BOMC1 (benzyl chloromethyl ether) (reagent grade 60%, 1.25 ml; 5.41 mmol; 1.5 eq.) and diisopropylethylamine (942 μl; 5.41 mmol.; 1.5 eq.). The reaction mixture is then stirred overnight at room temperature and evaporated thereafter to dryness. By running a flash chromatography purification on a silica gel (2/1 petroleum ether/EtOAc eluent), there is recovered the O-benzyloxymethyl derivative (2.28 g; 92%) as a white crystalline solid. (Rf=0.70 in 1/3 petroleum ether/EtOAc mixture, phosphomolybdinium acid and UV color developer) m.p.=97-100° C. A solution of this product (2.00 g; 2.90 mmol.) in HPLC-grade EtOH (220 ml) containing Et3N (4 ml) is hydrogenated in presence of 20% Pd(OH)2 on carbon (200 mg) at room temperature and under atmospheric pressure hydrogen for a period of 3 hours. The catalyst is filtered off. The filtrate is evaporated to dryness and the residue is then dried by suction from a vacuum pump to obtain the free amine (1.58 g; 98%) as an amorphous solid. [α]D=1° (c=1.20; CHCl3) 1H-NMR (250 MHz, CDCl3), δ in ppm: 7.45-7.21 (m, 10H, Ar), 6.52 (d, 1H, NH), 4.80-4.45 (m, 6H, 2×CH2-ph, O—CH2—O), 4.10 (m, 1H, H−3′), 3.83 (m, 1H, H−2), 3.62 (dd, 1H, H−1), 3.47 (dd, 1H, H−1), 2.65 (t, 2×H−5), 2.40 (m, 2H, 2×H−2′), 1.80-1.40 (m, 8H, 2×H−4, 2×H−3, 2×H−4′, NH2), 1.40-1.20 (m, 18H, 9×CH2), 0.88 (t, 3H, CH3); 13C-NMR (62.89 MHz, CDCl3), δ in ppm: 170.78; 138.24; 137.63; 128.38; 128.32; 127.66; 127.62; 94.82; 76.70; 71.26; 69.63; 69.44; 48.48; 41.82; 41.47; 33.83; 31.84; 29.88; 29.58; 29.56; 29.51; 29.27; 29.04; 25.11; 22.62; 14.06.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20](O)=[O:21]>>[CH3:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: CC(C)(C)CC(=O)O
Product: CC(C)(C)CC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 3,3-dimethylbutanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.43-8.46 (m, 1H), 8.13-8.16 (m, 1H), 8.03-8.09 (m, 2H), 2.23 (s, 2H), 1.07 (s, 9H); MS (ESI−) M/Z 326 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br>CCOC(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: Brc1ccccc1Br
Reactant: CC(=O)c1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2Br)cc1

Procedure:
Prepared according to the general procedure Coupling-1 using 4-acetylbenzeneboronic acid and 1,2-dibromobenzene as starting material. Flash chromatography (Hex:EtOAc; 95:5) afforded the title compound.