Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2C(=O)[C:9]([C:26]3[CH:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:30][CH:31]=3)=[C:10]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:2]=1.[Br:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][C:54]2[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=2)=[CH:48][CH:47]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Br:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:7]([C:3]3[CH:2]=[C:1]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:6]=[CH:5][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]([C:26]3[CH:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:30][CH:31]=3)[C:53]=2[C:54]2[CH:55]=[CH:56][C:57]([Br:60])=[CH:58][CH:59]=2)=[CH:50][CH:51]=1
Reactant: Brc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1cccc(-c2ccccc2)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Brc1ccc(-c2c(-c3ccc(Br)cc3)c(-c3cccc(-c4ccccc4)c3)c(-c3ccccc3)c(-c3ccccc3)c2-c2cccc(-c3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
A degassed solution of 300 mg of 2,5-di([1,1′-biphenyl]-3-yl)-3,4-bis(4-bromophenyl)cyclopenta-2,4-dienone (8a, 0.432 mmol) and 77.0 mg of 4,4′-dibromotolane (0.432 mmol) in 3 ml of diphenyl ether was heated to 230° C. in a microwave reactor at power 300 watts and a maximum pressure of 7 bar for 3×12 h. After cooling to room temperature, the reaction solution was diluted with hexane and purified by column chromatography (silica, hexane with 6% ethyl acetate). After purification by means of recycling GPC and drying under high vacuum, 145 mg of monomer 6a were obtained in the form of colorless crystals (40%, 0.172 mmol). Elemental analysis measured: C 76.7; H 3.1% (calculated for C54H36Br2: C, 76.8; H, 4.3%); 1H NMR (700 MHz, d8-THF) δ=7.30-7.25 (m, 4H, CH), 7.23-7.17 (m, 6H, CH), 7.13 (d, J=1.5 Hz, 1H, CH), 7.12-7.11 (m, 1H, CH), 7.11-7.09 (m, 4H, CH), 7.09-7.06 (m, 2H, CH), 6.95 (s, 1H, CH), 6.94 (br s, 2H, CH), 6.93 (s, 1H, CH), 6.91 (t, J=4.1 Hz, 2H, CH), 6.89 (d, J=8.0 Hz, 2H, CH), 6.85 (d, J=7.0 Hz, 4H, CH), 6.83 (d, J=2.0 Hz, 2H, CH), 6.81 (d, J=1.4 Hz, 1H, CH), 6.79 (d, J=8.3 Hz, 2H, CH), 6.78 (s, 1H, CH); 13C NMR (125 MHz, d2-TCE) δ=141.05, 140.74, 140.20, 140.00, 139.44, 139.03, 138.52, 133.03, 132.92, 131.30, 131.15, 130.26, 129.92, 129.85, 128.42, 127.17, 126.87, 126.62, 126.52, 125.20, 124.15, 120.18, 119.51; MS (MALDI-TOF): m/z (%): 845.1 (100) [M+] (calculated for C54H36Br2: 844.1); Rf (hexane with 6% ethyl acetate)=0.40; m.p. (° C.): decomposition at >400° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[C@H:35]([CH2:36]Br)[CH2:34][CH2:33][C:32]1=[O:38].CCN(C(C)C)C(C)C>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:36][C@H:35]3[NH:31][C:32](=[O:38])[CH2:33][CH2:34]3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C1CC[C@@H](CBr)N1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O[C@H]1CC[C@@H](NC[C@@H]2CCC(=O)N2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoro-methyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(amino)cyclopentane from Example 39 in 0.5 mL of acetonitrile was added 50 mg of (2-pyrrolidon-5-(S)-yl)methylbromide and 0.10 mL of DIPEA. The reaction was heated in a sealed vial at 90° C. for 60 h and then evaporated. The residue was purified on a 2×1 mm preparative silica gel plates eluted with 2% TEA in methanol to afford 50 mg of title compound as a white solid. Mass spec (NH3 /CI): 533 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([S:28][CH3:29])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[C:25]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[C:9]([F:12])([F:11])[F:10])[N:24]=[C:23]([S:28][CH3:29])[N:22]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(O[C@H](c2ccc(Cl)cc2-n2ccc(C)n2)C(F)(F)F)n1
Temperature: 70 °C

Procedure:
To a solution of (R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (5.00 g, 17.2 mmol) and 4,6-dichloro-2-(methylthio)pyrimidine (3.36 g, 17.2 mmol) in dioxane (250 mL) was added Cs2CO3 (16.8 g, 51.6 mmol). The reaction mixture was then heated to 70° C. for 90 h, then cooled to RT. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided 4-chloro-6-[(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfanylpyrimidine as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28](O)([C:30](F)(F)F)=[O:29]>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][C:28](=[O:29])[C:30]4[CH:6]=[CH:7][CH:8]=[CH:3][CH:2]=4)[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(=O)c3ccccc3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91). LCMS (0.05% TFA): 471.3 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 9.03 (bs, 1H), 8.83 (bs, 1H), 8.38 (bs, 1H), 8.03 (bs, 1H), 7.78 (d, 2H, J=9 Hz), 7.50 (t, 1H, J=9.0 Hz), 7.42 (t, 2H, J=9.0 Hz), 5.02 (s, 2H), 4.49 (m, 1H), 4.39 (m, 1H), 3.42 (s, 3H), 2.16-1.68 (m, 10H), 0.91 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:41]Cl.S(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:34]([F:35])=[CH:33][C:32]([I:41])=[CH:31][C:10]=1[CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)cc(F)c1OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 72 h

Procedure:
12.5 g (26.1 mmol) of benzyl 2-(benzyloxy)-N-(tert-butoxycarbonyl)-3-fluoro-L-phenylalaninate are introduced into 200 ml of dichloromethane, and 8.76 g (104 mmol) of sodium bicarbonate are added. 8.46 g (52.4 mmol) of iodine monochloride in 10 ml of dichloromethane are slowly added dropwise. After 72 h, 300 ml of a 5% sodium bisulfite solution are added. The phases are separated and the organic phase is extracted with water. The organic phase is concentrated and the residue is purified on silica gel (cyclohexane:ethyl acetate 6:1).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[O:1]=[C:2]1[O:6][C@H:5]([C:7]([Cl:18])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of (2S)-5-oxotetrahydrofuran-2-carboxylic acid (compound 28a, 70 g, 539 mmol) and a drop of DMF in anhydrous DCM (500 mL) was added oxalyl dichloride (137 g, 1.07 mol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was then concentrated in vacuo to afford 70 g crude product of (2S)-5-oxotetrahydrofuran-2-carbonyl chloride (compound 28b), which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc(F)c(F)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(F)c(F)c1O

Procedure:
A solution of 3,4-difluoro-2-hydroxybenzoic acid (6.45 g, 37.05 mmol) and sulfuric acid (6 ml, 113 mmol) in MeOH (25 ml) was heated at reflux overnight. The mixture was diluted with water and extracted with ether. The ether was washed with aqueous NaHCO3, water and brine. The combined aqueous layers were twice more extracted with ether, which was washed with NaHCO3, water, and brine. The combined ether extracts were dried (MgSO4) and concentrated to give 6.4 g of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoate (60 g, 96.94 mmol, 1.00 equip, 98%), ethanol (15 mL), and sodium hydroxide (3 mL). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated and acidified to pH3-4 with 1N HCl. The solids were collected by filtration. The resulting residue was purified by re-crystallization from methanol to yield 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.[CH2:21]([O:23][C:24]([NH:26][NH2:27])=[O:25])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([NH:26][NH:27][C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)NN
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)NNC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1
Yield: 73 %

Procedure:
A solution of 1.3 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e] [1,4]diazepine-2-thione and 0.5 g of ethoxycarbonylhydrazine in 30 ml of ethanol is refluxed for 5 hours. Then the ethanol is removed under reduced pressure, and the residue is crystallized from ligroin to give 2-ethoxycarbonylhydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e] [1,4]diazepine appearing as orange crystals. The product is recrystallized from ethanol to give the pure substance melting at 207° C, in 73% yield.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CCO.[Cl-].[Na+].O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[CH:5][C:6](/[C:9](/[CH3:16])=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(=C\C(=O)O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 142A (3.5 g, 13.5 mmol) in EtOH (80 mL) was treated with aqueous 1M NaOH (40 mL) and stirred for 16 hours at ambient temperature. The reaction mixture was neutralized with 1N HCl (40 mL), diluted with brine, and extracted with diethyl ether to provide the title compound. NMR (CDCl3) 2.60 (s, 3H), 6.82 (s, 1H), 7.58 (d, 2H), 7.65 (d, 2H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: c1ccc2c(c1)NCCCO2
Product: O=S(=O)(CCCCl)N1CCCOc2ccccc21

Procedure:
2,3,4,5-tetrahydro-1,5-benzoxazepine and 3-chloropropanesulfonyl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=O)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([Cl:16])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reaction time: 3 h

Procedure:
(R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 3.00 g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between chloroform and saturated aqueous sodium carbonate. The layers were separated and the organic layer was washed twice with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 2.88 g (87%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q, 1H), 6.32 (d, 1H), 8.21 (d, 1H); MS (Cl) 201, 203 (MH+); [α]D+27.6 (c, 1.0, MeOH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:44][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][CH2:36][Cl:35])=[CH:47][CH:46]=1)[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Reactant: ClCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reaction time: 0.33 h

Procedure:
A solution consisting of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g, 15.5 mmol) in DMF (60 mL) was cooled to 0° C. and treated with addition of sodium hydride (0.68 g, 17.0 mmol) and stirred for 20 minutes. A solution of 4-(3-chloropropoxy)-benzyl bromide No. 163 in DMF (10 mL) was then added slowly. The reaction was allowed to come to rt and stirred for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried over magnesium sulfate and concentrated. The concentrate was treated with methanol and 5 g of the desired product precipitated as a white solid with a melting point of 130–132° C.
Reaction SMILES: Cl[Si](C)(C)C.ClN1[C:11](=O)[CH2:10][CH2:9][C:8]1=[O:13].Cl[CH2:15][Cl:16]>>[Cl:16][CH:15]([C:8]([CH:9]1[CH2:11][CH2:10]1)=[O:13])[C:8]([CH:9]1[CH2:11][CH2:10]1)=[O:13]
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)Cl
Product: O=C(C1CC1)C(Cl)C(=O)C1CC1
Temperature: 12.5 °C
Reaction time: 0.75 h

Procedure:
The diketone described in Preparation 5 (700 g, 4.6 mol) was dissolved in dichloromethane (7 L) with chlorotrimethylsilane (549 g, 5.08 mol), at room temperature. The solution was stirred for 45 minutes, after which time it was cooled to 10 to 15° C. N-chlorosuccinimide (614 g, 4.6 mol) was then added portion-wise, keeping the temperature between 10 and 15° C. The reaction was then warmed to room temperature and stirred for a further 30 minutes. The reaction slurry was then filtered and the organic solution was washed twice with 2M hydrochloric acid (2×1.8 L), followed by two washes with water (2×4.6 L). The organic layer was then dried over anhydrous magnesium sulphate before being concentrated to an oil under vacuum to provide the title compound as a 2:3 mixture of keto:enol tautomers. (780 g, 91%)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[CH3:31][N:32]([CH3:49])[S:33](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:35])=[O:34]>>[CH3:31][N:32]([CH3:49])[S:33]([C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6])(=[O:35])=[O:34]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) after a reaction time of 65 hours. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system eluting with EtOAc. Light brown foam (19%). MS (ESI): m/z=512.13 [M+H]+.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]2C(=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][C:13]=1[F:14]>C(COC)OC>[F:2][C:3]1[CH:4]=[C:5]([NH2:1])[C:6](=[CH:12][C:13]=1[F:14])[C:7]([OH:9])=[O:8]
Reactant: N
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Solvent: COCCOC
Product: Nc1cc(F)c(F)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Dimethoxyethane (43 parts) was charged to a reactor and ammonia was bubbled in to form a saturated solution. The ammonia addition was maintained while a solution of 1.84 parts of 4,5-difluorophthalic anhydride in 13 parts of dimethoxyethane was added slowly over a period of 0.5 hours. The reaction mixture was stirred for an additional 5 minute period and the dimethoxyethane was removed by vacuum distillation. The remaining white solid (the ammonium salt of 4,5-difluorophthalamic acid) was dissolved in 20 parts of aqueous sodium hydroxide (40% NaOH) and the solution was de-gassed under moderately reduced pressure to remove any remaining ammonia; then heated at atmospheric pressure, to 50° C. and maintained at tha temperature while 14.1 parts of a 5.78% aqueous sodium hypochlorite solution was added. The solution was then heated to 60°-65° C. and maintained at that temperature, with stirring for about 30 minutes; then cooled to about 20°-25° C. and acidified to a pH of 4-6, by addition of concentrated hydrochloric acid. A precipitate formed and the mixture was extracted with chloroform. The acidification procedure was repeated until no additional precipitate formed. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the chloroform removed by vacuum distillation to yield 1.34 parts of solid 4,5-difluoroanthranilic acid having a melting point of 180°-181° C. The chemical structure of the product was confirmed by infra-red analysis.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH:12]1([O:15][C:16]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:14][CH2:13]1>C(OCC)C>[CH:12]1([O:15][C:16]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=2[CH2:18][NH2:19])[CH2:14][CH2:13]1
Reactant: N#Cc1ccc(F)cc1OC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1ccc(F)cc1OC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. suspension of lithium aluminum hydride in THF (1M, 15 mL, 15 mmol) was added 2-cyclopropoxy-4-fluorobenzonitrile in 14 mL diethyl ether dropwise. The reaction solution was stirred for 3 hours, gradually warming to room temperature, at which point it was recooled to 0° C., an additional 8 mL lithium aluminum hydride in THF (1M, 8 mmol) added, and stirred for an additional 90 minutes. The reaction was quenched by sequential addition of 0.9 mL water, 0.9 mL 15% NaOH(aq), and 2.7 mL water. The reaction was filtered through celite with diethyl ether rinses, dried over MgSO4, and concentrated to afford 2-cyclopropoxy-4-fluorobenzylamine of sufficient purity to carry on as crude. 1H-NMR (400 MHz, Chloroform-d) δ 7.17-7.08 (m, 1H), 6.96 (dd, J=10.9, 2.4 Hz, 1H), 6.61 (td, J=8.3, 2.5 Hz, 1H), 3.78-3.66 (m, 3H), 0.89-0.72 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>C1COCC1>[OH:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)cc1O
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)cc1O
Temperature: 60 °C
Yield: 4.3 %

Procedure:
To a mixture of (S)-7-amino-2-(1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (5.86 g, 15.6 mmol) in THF (60 mL), was added cyclopropanecarbonyl chloride (1.5 mL, 16.1 mmol). The mixture was heated to 60° C. for 1 hour then cooled to room temperature. The solvent was removed and the crude residue purified using column chromatography (MeOH/CH2Cl2: 0-5% over 60 minutes) to give 4.7 g of crude, 68% yield. Further purification was then carried out by prep-HPLC to give (S)—N-(2-(1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (0.3 g, 4.3% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 minutes Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 11.84 minutes. 1H-NMR (DMSO-d6): 10.50 (1H, s), 9.11 (1H, s), 8.22-825 (1H, d), 7.48-7.53 (1H, t), 7.18-7.2 (1H, d), 6.84-6.95 (3H, m), 5.80-5.85 (1H, m), 4.60-6.66 (1H, d), 3.90-4.30 (3H, m), 3.75 (3H, s), 3.04 (3H, s), 1.79-1.83 (1H, m), 0.88-0.90 (4H, m); LC-MS ES+ (M+1) 445.