Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH:23]([C:30]1[CH:31]=[C:32]2[C:37](=[O:38])[NH:36][C:34](=O)[C:33]2=[CH:39][C:40]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[NH:23]([C:30]1[CH:31]=[C:32]2[C:37](=[O:38])[NH:36][C:34](=[S:10])[C:33]2=[CH:39][C:40]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Solvent: ClCCl
Product: O=C1NC(=S)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
138 mg (0.36 mmol) of Lawesson reagent [=2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane]are added to a solution of 100 mg (0.3 mmol) of 4,5-bis(anilino)phthalimide (Example 1) in 15 ml of dichloromethane and the mixture is boiled under reflux for 4 hours. The reaction mixture is concentrated by evaporation and chromatographed directly on silica gel with hexane/ethyl acetate 2:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of yellow crystals, FAB-MS: 346 [M+ +H].
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:27])=O.C(=O)([O-])[O-].[K+].[K+]>>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][Cl:27])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CO)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-amino-6-[2-(7-hydroxymethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.5 g) and thionyl chloride (5 ml) was stirred for 40 minutes under ice-cooling. The reaction mixture was poured into ice-water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The aqueous mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and triturated with diethyl ether to give 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.42 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:42](Cl)[O:43][CH3:44]>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][O:43][CH3:44])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added i-Pr2NEt (47 μl, 0.27 mmol) and MOMCl (35 μl, 0.45 mmol). The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11](SN(CCC)CCC)[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:13])=[C:7]([F:33])[CH:6]=1.[CH:42]([N:45]([CH:48]([CH3:50])[CH3:49])[S:46]Cl)([CH3:44])[CH3:43]>>[Cl:1][C:2]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([S:46][N:45]([CH:48]([CH3:50])[CH3:49])[CH:42]([CH3:44])[CH3:43])[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:13])=[C:7]([F:33])[CH:6]=1
Reactant: CC(C)N(SCl)C(C)C
Reactant: CCCN(CCC)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Product: CC(C)N(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(C)C

Procedure:
39 was prepared, as a white solid, m.p.: 147°-149° C. in a similar manner to (38). The intermediate compound, di(isopropyl)aminosulphenyl chloride, boiled at 92°-4° C. at 20 Torr.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
120 g of carbobenzoxy-L-alanine are dissolved in 800 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 70 g of thionyl chloride and stirred for 40 minutes while cooling with ice. There is then rapidly added dropwise thereto a suspension of 100 g (0.38 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 400 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of methylene chloride and treated with ether. There is obtained (S)-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate. A further recrystallisation from methylene chloride/ether yields a product which melts at 158°-160° C. and shows a rotation of [α]25D =-23.4° (in methylene chloride; 1%). The mother liquors are purified on a 600 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4)c3O2)cc1
Yield: 31.7 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with phenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.40 g (32%) of (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C22H20O4S.0.2H2O: C, 68.8; H, 5.35. Found: C, 68.78; H, 5.08.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22]CC2C=CC(OC)=CC=2)[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([OH:22])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@]2(C)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](O)[C@]1(C)O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a stirred solution of 5.08 (7.2 g, 11.6 mmol) in CH2Cl2 (137 mL) and H2O (8 mL) at 0° C. was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.4 g, 15.0 mmol). The reaction mixture was stirred for 1 h then diluted with CH2Cl2 and sequentially washed with saturated aqueous NaHCO3, H2O, and brine. After concentration of the organic phase in vacuo, the crude residue was purified by silica gel chromatography (25% EtOAc/petroleum ether) to afford the title compound (4.5 g, 9.0 mmol, 78%). 1H NMR (500 MHz, CDCl3): δ ppm 7.39-7.32 (m, 4H, PhH), 7.29 (t, J=6.8 Hz, 1H, PhH), 4.95, 4.68 (ABq, J=11.2 Hz, 1H each, OCH2Ph), 4.42 (d, J=7.8 Hz, 1H, H-1), 4.01-3.94 (m, 1H, OCHHCH2SiMe3), 3.90-3.80 (m, 2H, H-6), 3.60 (d, J=9.8 Hz, 1H, H-3), 3.60-3.54 (m, 1H, OCHHCH2SiMe3), 3.51 (br s, 1H, OH), 3.41 (t, J=6.8 Hz, 1H, H-5), 3.16 (dd, J=9.8, 7.8 Hz, 1H, H-3), 2.48 (br s, 1H, OH), 1.25 (s, 3H, Me), 1.05-0.99 (m, 2H, OCH2CH2SiMe3), 0.90 (s, 9H, SiCMe3), 0.11, 0.11 (s, 3H each, SiME2), 0.02 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 138.73, 128.56, 128.03, 127.86, 103.70, 80.62, 78.29, 75.77, 74.63, 73.80, 67.81, 62.57, 25.91, 18.68, 18.21, 15.31, −1.31, −5.39, −5.52; HRMS calcd for C25HSONO6Si2 [M+NH4]+: 516.3177. found 516.3165.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH:25]1C2C(=CC=CC=2C(C2C=CC=CC=2)=CC(NC)=O)C=[CH:26]1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([NH:25][CH3:26])=[O:24])=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ccc12

Procedure:
3-(7-Methoxy-1H-Indol-4-yl)-N-methyl-3-phenyl-propionamide LV was prepared from 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for 3-(1H-indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH3:1][Sn](C)(C)C.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17][C:16]3=[O:35])=[CH:9][C:8]=1[C:36]([O:38][CH3:39])=[O:37]>O1CCOCC1.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>[CH3:39][O:38][C:36]([C:8]1[CH:9]=[C:10]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:17][C:16]3=[O:35])[CH:11]=[N:12][C:7]=1[CH3:1])=[O:37]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cnc1C
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
The mixture of tetramethyltin (1.14 ml), and PdCl2(PPh3)2 (97 mg), tert-butyl 6-[6-chloro-5-(methoxycarbonyl)-3-pyridinyl]-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.35 g) in dioxane (13 ml) was stirred at 180° C. for 15 min under microwave irradiation. The reaction mixture was evaporated, and purified by silica gel chromatography (hexane/ethyl acetate) to give the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[OH:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: C1CCC2OC2C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(C2CCCCC2O)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 100 °C

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, cyclohexene oxide (12 mg, 0.12 mmol) and K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 100° C. for 3 hours. After this time the solution was cool to RT and diluted with ethyl acetate. The resultant solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-hydroxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-(24.1 mg, 48%) as yellow solid. MS M+H=455; 1H NMR (CDCl3) δ 8.17 (1H), 7.33 (6H), 7.08 (2H), 4.26 (1H), 3.98 (1H), 2.17 (1H), 1.99 (1H), 1.82 (3H), 1.50-1.30 (3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.CCN(CC)CC.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 51.2 %

Procedure:
A solution of 2-amino-4-methylthiazole (11.42 g, 0.10 mol) in CH2Cl2 was cooled to 0° C. in an ice bath and treated with Et3N (12.1 g, 0.12 mol). While stirring, the mixture was treated with phenyl chloroformate (15.6 g, 0.10 mol) drop-wise from an addition funnel. After the addition was complete the mixture was stirred for 10 minutes. The reaction mixture was washed with saturated NaHCO3, water, brine and then dried over MgSO4. The solution was filtered and the solvent removed under vacuum in a rotary evaporator and the resulting solid was chromatographed on silica gel (eluting with 40% ethyl acetate/hexane) to give 12 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ δ 12.38 (bs, 1H), 7.47-7.40 (m, 2H), 7.30-7.19 (m, 3H), 6.52 (d, J=1.1 Hz, 1H), 2.41 (d, J=0.8 Hz, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:35])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH:32]([CH3:34])[CH3:33])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:35])[CH:24]=1)([CH3:34])[CH3:33]
Reactant: CC(C)Oc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
4-[6-(2-lsopropoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XIII) (0.32 g, 0.67 mmol) was dissolved in methanol (20 ml) and 10% Pd/C (0.17 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. Then the crude product was triturated with dry diethyl ether (10 mL) and the resulting solid was filtered to obtain piperidine-4-carboxylic acid [6-(2-isopropoxy-phenyl)-pyrimidin-4-yl]-amide (compound #7A) (0.12 g, 52%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH:27][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2)c1
Yield: 96.1 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(3-methoxyphenyl)-ethylamine (361 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 96%). Light yellow solid, MS (ISP) 374.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[C@H:23]12[CH2:29][C@H:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:27]1[CH2:28][C@@H:23]2[CH2:29][C@H:26]1[CH2:25][N:24]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 194.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (400 mg, 1.32 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (665 mg, 3.35 mmol), HATU (1.02 g, 2.68 mmol), and DI PEA (1.2 ml, 6.7 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 72 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product (1.23 g) as brown oil, used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33]C)=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 57.4 %

Procedure:
To a solution of Methyl (1RS,2RS,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane. (2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 48 h, then concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane containing 5% of acetic acid) to afford the title compound (36 mg, 46%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1([CH:16]([CH3:18])[CH3:17])[O:13][C:12](=[O:14])[CH:11]=[C:10]([OH:15])[CH2:9]1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:11]1[C:12](=[O:14])[O:13][C:8]([CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)([CH:16]([CH3:18])[CH3:17])[CH2:9][C:10]=1[OH:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCc2ccco2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccco3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-17; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1 mmol), potassium carbonate (4 mmol) in DMF (5 mL) mp 64-110° C. MS (APCI): 457 (M−H).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH2:10][CH2:11][N:6]([CH3:4])[CH2:7][CH2:8]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid ethyl ester (0.28 g, 0.66 mmol) and lithium aluminum hydride (0.051 g) were suspended in tetrahydrofuran (5 ml) and stirred for 2 hours. The reaction mixture was quenched with addition of water, solvent removed under reduced pressure, the residue was partitioned between ethyl acetate and 2N NaOH. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford the desired product (0.241 g, 99% yield). LC/MS: (PS-B3) Rt 3.78 [M+H]+ 363.95, 365.73,