Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].[N+](C1C=C(B(O)O)C=CC=1)([O-])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][C:6]1=[O:14]
Reactant: CC1(C)CNc2ccc(Br)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)C(=O)Nc2ccccc21
Yield: 95.9 %

Procedure:
Using the standard coupling conditions given in Example 1, the title compound was prepared from 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.25 g, 1.1 mmol), tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) in dimethoxyethane (5 mL) with 3-nitrophenylboronic acid (0.22 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in 5 mL water. The title compound (0.17 g, 60%) was obtained as a brown semi-solid: 1H NMR (CDCl3) δ1.38 (s, 3H), 3.40 (s, 2H), 6.72 (d, J=8.0 Hz, 1H), 7.29-7.34 (m, 2H), 7.54 (dd, J=8.0, 8.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.09 (dd, J=8.0, 1.5 Hz, 1H), 8.40 (dd, J=2.0, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ27.89 (q), 41.93 (s), 62.05 (d), 109.78, 120.87, 121.02, 121.23, 126.87 (d), 129.19 (s), 129.69, 132.52 (d), 139.64, 143.75, 148.94, 151.17 (s); MS (EI) m/z 268 (M)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:22][O:23][CH2:24][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([OH:12])=[O:11]
Reactant: COCCl
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(=O)O)ccc1OC
Yield: 76.5 %

Procedure:
In a similar manner to Step 1 of Example 347, isovanillic acid (5.00 g, 29.7 mmol) was suspended in dichloromethane (100 mL), and the suspension was treated with diisopropylethylamine (22.8 mL, 131 mmol) and chloromethyl methyl ether (4.96 mL, 65.4 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL) and treated with 4 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-methoxymethoxy-4-methoxybenzoic acid (4.82 g, yield 76%).
Reaction SMILES: CCN(C(C)C)C(C)C.C([Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:26][O:25]2)=[CH:18][CH:17]=1)(C)(C)C.Cl.[CH3:30][C:31]1[N:32]=[C:33]([N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C:34]2[CH:39]=[CH:38][S:37][C:35]=2[N:36]=1>CC(O)C.CS(C)=O>[OH:25][CH:24]([CH2:26][NH:46][CH:43]1[CH2:42][CH2:41][N:40]([C:33]2[C:34]3[CH:39]=[CH:38][S:37][C:35]=3[N:36]=[C:31]([CH3:30])[N:32]=2)[CH2:45][CH2:44]1)[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1nc(N2CCC(N)CC2)c2ccsc2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N2CCC(NCC(O)COc3ccc(O)cc3)CC2)c2ccsc2n1
Yield: 22 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 48 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 22% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 3:7:1.5) with 25% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[F:38][C:37]([F:40])([F:39])[CH2:36][NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](N)C3)ccnc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](NCC(F)(F)F)C3)ccnc21
Temperature: 40 °C

Procedure:
A mixture of (S)-4-(3-aminopyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (131 mg, 0.32 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (490 mg, 2.1 mmol), and N,N-diisopropylethylamine (365 uL, 2.1 mmol) in methylene chloride (15 mL) was heated at 40° C. for 4 hours. The cooled reaction mixture was diluted with water (20 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as an oil, which was used in the next step without any further purification (156 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:13]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>O.CS(C)=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NC(=O)c1cccnc1N
Yield: 52.4 %

Procedure:
2-Aminonicotinic acid (5.0 g), WSC (10 g), HOBt (7.3 g), ammonium chloride (5.8 g), diisopropylethylamine (28 g), and DMSO (100 mL) were stirred for 16 hours at room temperature. Water was added and then extraction was performed with ethyl acetate and THF. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate) to obtain the titled compound (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([Br:22])[CH:24]=3)[C:27]2=[O:28])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(Br)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
To a suspension of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (6.78 mmol, 1.99 g) in dichloromethane (90 mL) was added a solution of 4-bromophthalic anhydride (6.78 mmol, 1.54 g) in dichloromethane (30 mL) and 1,1′-carbonyldiimidazole (6.78 mmol, 1.1 g) at room temperature. The resulting solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water (100 mL) and layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude product which was purified by silica gel column chromatography to obtaine 2.4 g (70%) of a white solid: mp 168-170° C. HR MS C23H23BrN2O6): Obs mass, 525.0656. Calcd mass, 525.0637 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](/[CH:24]=[CH:23]/[C:22](=[O:25])[N:21]([CH3:20])[CH2:26][C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Br)cnc21
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
A solution of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester (494 mg, 1.5 mmol) in propionitrile (12 mL) was treated with N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (685 mg, 3 mmol) and diisopropylethylamine (788 μL, 4.5 mmol) and purged with Argon for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-Tol)3 (92 mg, 0.3 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hours under Argon. Upon cooling, solvent was removed and the residue was purified by Flash chromatography (silica, 1-3% MeOH in CH2Cl2) to afford the title compound (480 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 10.81 and 10.73 (rotamers, 2s, br, 1H), 8.46 and 8.41 (rotamers, 2s, 1H), 7.58 (d, J=15.4 Hz, 1H), 7.51 (m, 3H), 7.23 (d, J=15.4 Hz, 1H), 7.11 (m, 1H), 7.03 (m, 1H), 6.45 and 6.20 (rotamers, 2s, 1H), 5.06 and 4.87 (rotamers, 2s, 2H), 4.32 and 4.28 (rotamers, 2s, 2H), 3.74 and 3.71 (rotamers, 2s, 3H), 3.16 and 3.05 (rotamers, 2s, 3H), 1.44 and 1.42 (rotamers, 2s, 9H). MS (ESI) m/e: 476.2 (M+H)+, 420.2 (M-tert-Bu)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH:7]=1.C[N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([NH2:16])=[O:12])[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)nc2ccc(I)cn12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g) in DMF (15 ml) were added HATU (1.88 g) and triethylamine (1.38 ml) at 0° C. The mixture was allowed to warm to room temperature for 30 min, and then NH4Cl (725 mg) was added thereto. The resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3 solution, water and brine. The DCM layer was then dried over Na2SO4 and concentrated in vacuo to give the title compound (600 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[CH3:23][N:24]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1COCC1.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][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: Cn1cc(B(O)O)cn1
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2cnn(C)c2)c1
Temperature: 130 °C
Yield: 55.9 %

Procedure:
A mixture solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (85.9 mg, 0.2100 mmol), 1-methyl-pyrazol-4-boronic acid (31.28 mg, 0.2300 mmol), Cs2CO3 (0.23 mL, 1 N, 0.23 mmol) and Pd(Ph3P)4 (17.0 mg, 0.0146 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred under microwave heating for 30 minutes at 130° C. After reaction mixture was cooled to room temperature, the solvent was removed under vacuum and the residue was purified by preparative HPLC to afford 4′-methyl-5-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (42.68 mg, 56%). MS (M+H)=364.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(COC)OC.[Br-:21].[Li+]>CCOCC>[Br:21]/[CH:2]=[CH:3]/[C:4](=[O:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: [Br-]
Reactant: CC(C)(C(=O)/C=C/Cl)c1ccccc1
Agent: [Li+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C(=O)/C=C/Br)c1ccccc1

Procedure:
A solution of 14 g. of 1-chloro-4-methyl-4- phenyl-1-trans-1-penten-3-one in 90 ml. of dimethoxyethane was treated with 24 g. of lithium bromide and refluxed for 24 hours. The mixture was diluted at 0° C. with ether, washed with brine, dried with MgSO4 and evaporated to dryness. The residue was redissolved in dimethoxyethane, treated with lithium bromide and refluxed for an additional 24 hours. After the exact same process was repeated thrice and the crude product was chromatographed on silica gel. Elution with 5% ethyl acetate in hexane afforded 8.9 g. of the title produce as a yellow oil, λmaxfilm 3.4, 5.88, 6.32, 6.66, 6.78, 6.88, 7.70, 9.25, 9.48, 9.98, 10.64, 12.80, 13.10 and 14.25 μ.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:13]([OH:35])[CH2:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@H:13]([OH:35])[CH2:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]([NH:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29]
Reactant: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 104.7 %

Procedure:
A solution of 150 mg of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1 -carboxamide (isomer A) in 5 ml of ethanol was hydrogenate d under a pressure of 3.4 atmospheres over 10% palladium-on-charcoal at 20° C. for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 120 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide (isomer A); MS: m/e 435 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
9.3 g (50 mmol) of 3-chloro-4-hydroxylphenylacetic acid was dissolved in 100 ml of N,N-dimethylformamide, and 15.2 g (110 mmol) of potassium carbonate was added thereto. The mixture was stirred at 100° C. for one hour. Then, 10.9 g (60 mmol) of 2-chloro-5-trifluoromethylpyridine was added thereto, and the mixture was stirred for 8 hours at 120° C. After cooling, the reaction solution was poured into water and washed twice with ethyl acetate. The obtained aqueous layer was adjusted to pH 4 with citric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 8.3 g of the desired product as a white powder (melting point: 138° to 139° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]#[N:40]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:32][C:31]=1[C:39]#[N:40]
Reactant: N#Cc1cc(B(O)O)ccc1Cl
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2ccc(Cl)c(C#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 4-chloro-3-cyanophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=551.1 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[I:16]I.[OH-].[K+]>CN(C=O)C.CCOC(C)=O.OS([O-])=O.[Na+]>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:13])=[O:14])=[CH:9][CH:10]=2)[C:5]([I:16])=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2cc(S(N)(=O)=O)ccc21
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(I)c2cc(S(N)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
To a solution of 1-ethyl-1H-indole-5-sulfonamide (Intermediate 56, 175 mg, 0.78 mmol) in DMF (5.0 mL) was added a solution of iodine (218 mg, 0.86 mmol) in DMF (5.0 mL). KOH (109 mg, 1.95 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with EtOAc and sat. aq. NaHSO3 solution. The organic layer was washed with sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (95 mg, 35%) as a pale yellow solid after lyophilization. 1H NMR (DMSO-d6) δ 7.86-7.76 (m, 2H), 7.74-7.61 (m, 2H), 7.21 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 351.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]=1[C:10]([O:12]C)=[O:11].[OH-].[Na+]>>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH2:4][C:3]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C1=C(C)CC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C(=O)O)CCC(C)(C)C1
Yield: 65 %

Procedure:
Methyl 2,4,4-trimethyl-1-cyclohexene-1-carboxylate (0.5 g; 2.75 m. moles) was added to 8% aqueous sodium hydroxide solution (5 ml) and the mixture was heated under reflux for a period of 24 hours. The solution was washed with light petroleum (b.p. 60°-80° C.), acidified with dilute hydrochloric acid and extracted three times with ether. The combined extracts were dried (MgSO4) and evaporated to give a crystalline product (0.373 g; 82%) which was recrystallized from aqueous methanol to give 2,4,4-trimethyl-1-cyclohexene-1-carboxylic acid (0.3 g; 66%), m.p. 108°-110° C., (N.M.R.: δ0.92 (s,6,CH3 --C--CH3), 2.05 (b,3,C=C--CH3)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:7]([CH2:8][NH:13][CH2:11][CH3:12])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(C)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-methyl-pyridine-3-carbaldehyde (0.22 g, 1.41 mmol), ethylamine (2M in THF; 1.06 mL, 2.12 mmol), and sodium cyanoborohydride (0.133 g, 2.12 mmol) were combined in MeOH (2.52 mL). Acetic acid (0.12 mL, 2.12 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, concentrated, and purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:14]I.S(=O)(O)[O-].[Na+]>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (1 g, 7.048 mmol) in DMF (10 mL) was added KOH pellets (1.15 g, 21.14 mmol), followed by I2 (3.57 g, 14.08 mmol) portionwise. The reaction was stirred for 1 h at RT. 10% aq sodium bisulphite solution (10 mL) was added to the mixture and an off-white solid precipitate was formed. The suspension was filtered and the solid was washed with H2O (10 mL) and dried under vacuum to give 3-iodo-1H-indole-5-carbonitrile (1.7 g, 94.5%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.18 (brs, 1H), 7.78 (s, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.59 (dd, J=8.4, 0.4 Hz, 1H), 7.52 (dd, J=8.4, 1.6 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:12][CH2:13][OH:14])[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH2:3]([N:10]([CH2:12][CH2:13][O:14][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN(C)Cc1ccccc1
Reaction time: 1 h
Yield: 102 %

Procedure:
Sodium hydride (60% (by weight) in oil, 8 g) was stirred in dry tetrahydrofuran (THF) (100 ml) under nitrogen while 2-(N-benzyl-N-methylamino)ethanol (17 g) was added slowly. The warm mixture was stirred for 1 hour, then kept cool on a water bath at room temperature (20°) while a solution of ethyl 4-chloroacetoacetate (16.5 g) in dry THF (100 ml) was added dropwise over 3.5 hours. The mixture was stirred overnight at room temperature under nitrogen, then quenched with a little ethanol and poured onto ice (100 g) and concentrated hydrochloric acid (30 ml). The THF was removed by evaporation, and the residue washed with light petroleum (b.p. 60°-80°) to remove mineral oil. The residue was basified with solid sodium carbonate and extracted with ethyl acetate (200 ml and 100 ml). The combined extracts were dried (Na2CO3), filtered and evaporated to give the title compound as an oil (30 g), sufficiently pure for further use. N.m.r. spectrum in CDCl 3, δ values: 7.27 (5H,s); 4.12 (2H,q); 4.06 (2H,s); 3.45-3.70 (6H,m); 2.61 (2H,t); 2.25 (3H,s); 1.23 (3H,t).