Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.N#N>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].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>[Cl:16][C:10]1[C:9]([CH3:17])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonate (3.00 g, 8.29 mmol) and (3-fluorophenyl)boronic acid (1.74 g, 12.4 mmol) in toluene (80 mL) and saturated NaHCO3 (80 mL) was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.479 g, 0.415 mmol) was added The reaction mixture was bubbled with N2 for 5 minutes more and heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting material was purified on silica gel column, eluting with ethyl acetate/hexane, 0-30%, to give the desired product (2.35 g, 92%). LCMS calculated for C15H12ClFNO3 (M+H)+: m/z=308.0; Found: 308.1.
Reaction SMILES: [O-2].[La+3].[O-2].[O-2].[La+3].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C:12](=[CH:14][CH:15]=O)[CH3:13])[CH3:8].[CH3:17][C:18]([CH3:20])=[O:19]>>[CH3:8][C:7]([CH3:6])=[CH:9][CH2:10][CH2:11]/[C:12](/[CH3:13])=[CH:14]/[CH:15]=[CH:17]/[C:18]([CH3:20])=[O:19]
Reactant: CC(C)=O
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [La+3]
Agent: [O-2]
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
The following examples demonstrate the catalytic effectiveness of unsupported catalysts of pure lanthanum oxide for the aldol reaction of citral and acetone to give pseudoionone.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])/[CH:3]=[CH:4]/B1OC(C)(C)C(C)(C)O1.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[C:24]=2[F:31])[N:20]=[C:19]([C:32]([O:34][CH3:35])=[O:33])[C:18]=1Br.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[C:24]=2[F:31])[N:20]=[C:19]([C:32]([O:34][CH3:35])=[O:33])[C:18]=1/[CH:4]=[CH:3]/[Si:2]([CH3:1])([CH3:14])[CH3:15]
Reactant: CC1(C)OB(/C=C/[Si](C)(C)C)OC1(C)C
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2F)nc(N)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2F)nc(N)c1/C=C/[Si](C)(C)C
Temperature: 150 °C
Yield: 42.9 %

Procedure:
(E)-Trimethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)silane (470 mg, 2.1 mmol, 1.2 equiv) and methyl 6-amino-5-bromo-2-(4-chloro-2,3-difluorophenyl)pyrimidine-4-carboxylate (650 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by cesium fluoride (260 mg, 1.7 mmol, 1.0 equiv), palladium(II) acetate (19 mg, 0.086 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (98 mg, 0.17 mmol, 0.10 equiv). A 3:1 mixture of water:acetonitrile (3.5 mL) was added and the resulting brown mixture was placed in a Biotage microwave and heated to 150° C. for 15 m. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by silica gel column chromatography (17% ethyl acetate in hexane) to afford the title compound as an off-white powder (290 mg, 43% yield): mp 139-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.76 (m, 1H), 7.22 (m, 1H), 6.94 (d, 1H, J=20 Hz), 6.37 (d, 1H, J=20 Hz), 5.38 (br s, 2H), 3.92 (s, 3H), 0.19 (s, 9H); IR (neat film) 3449 (m), 3350 (s), 3242 (m), 3103 (w), 2954 (m), 1728 (s), 1634 (s); ESIMS m/z 398 ([M+H]+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.BrC[C:23]([O:25][CH2:26][CH3:27])=[O:24].[ClH:28].C(O)C>CN(C)C=O>[ClH:28].[N:8]1([CH2:6][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.FC1C=CC=CC=1C(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=2[Cl:75])[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Cl:75][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[O:68][CH:65]1[CH2:64][CH2:63][N:62]([C:60](=[O:61])[CH2:59][NH:58][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[NH:21][N:20]=2)=[O:24])[CH2:67][CH2:66]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Agent: CC(=O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2F)[nH]n1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
DIPEA (110 mg, 0.85 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (50 mg, 0.24 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 2′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (33 mg, 0.24 mmol) and EDCI.HCl (49 mg, 0.25 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (75 mg, 0.24 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. Recrystallisation using 25% EtOAc in hexane afforded 89 mg (80.9% Yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457, 90.38%. 1H NMR (300 MHz, DMSO-d6): 613.8 (s, 1H), 8.2 (bs, 1H), 7.9 (t, 1H), 7.1 (m, 7H), 4.61 (m, 1H), 4.4 (d, 2H), 3.7 (m, 2H), 3.3 (m, 2H), 1.9 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[CH2:6][N:5]2[CH:21]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:21]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=2)[CH2:6]3)=[N:15][CH:16]=1
Reactant: Cc1cnc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1cnc(C23Cn4cc(-c5cccnc5)cc4C(=O)N2CCN3)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a mixture of 7-bromo-10a-(5-methylpyrazin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (20 mg, 0.057 mmol), 3-pyridylboronic acid (9 mg, 0.073 mg) in 1,2-dimethoxyethane (0.5 mL) was added a solution of sodium carbonate (16 mg, 0.19 mmol) in water (0.15 mL) and ethanol (0.1 mL). The mixture was flushed with argon and dichlorobis(triphenylphosphine)palladium(II) (3.5 mg, 5×10−3 mmol) was added. The mixture was further degassed with argon, sealed and heated at 100° C. overnight. The following day an additional batch of 3-pyridylboronic acid (20 mg, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (4 mg, 5.7×10−3 mmol) were added. The mixture was degassed, sealed and heated at 100° C. After 3 hours the reaction was complete. The mixture was then concentrated and purified by flash chromatography (Biotage SP4, gradient 1CV CH2Cl2, 0-10% MeOH in CH2Cl2 and hold 10% MeOH) to give 10a-(5-methylpyrazin-2-yl)-7-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (15 mg, yield: 76%). 1H-NMR (400 MHz, CDCl3): δ 2.53 (s, 3H), 2.99 (dt, 1H, J 7.9 Hz), 3.35 (ddd, 1H, J 10.9, 7.5, 3.7 Hz), 3.77 (ddd, 1H, J 11.2, 7.6, 3.8 Hz), 4.00 (dt, 1H, J 11.1, 7.8 Hz), 4.26 (d, 1H, J 12.0 Hz), 4.87 (d, 1H, J 12.0 Hz), 6.87 (d, 1H, J 1.7 Hz), 7.20-7.25 (m, 2H), 7.66-7.70 (m, 1H), 8.37-8.44 (m, 3H), 8.68 (d, 1H, J 1.8 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:16]1[C:11]([NH:10][CH3:9])=[N:12][CH:13]=[C:14]([C:17]([F:23])([F:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(C(F)(F)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CNc1ncc(C(F)(F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
5.0 g of N-bromosuccinimide was added to a mixture of 4.6 g of methyl-(5-pentafluoroethyl-pyridin-2-yl)-amine and 70 ml of acetonitrile, and the mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 6.3 g of (3-bromo-5-pentafluoroethyl-pyridin-2-yl)-methyl-amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].[OH-].[K+]>CO>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
A mixture of p-hydroxyacetophenone (106 g) and 1-bromo-3-chloropropane (309 mL) in methanol (800 mL) was treated with potassium hydroxide (65.5 g). The mixture was stirred at reflux temperature for 2 hours when an additional portion of potassium hydroxide (65.5 g) was added and the resulting mixture maintained at reflux temperature for 16 hours. The reaction was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and unreacted 1-bromo-3-chloropropane removed ia distillation. The residue was dissolved in ether (500 mL), washed with water (500 mL), dried over magnesium sulfate, filtered and evaporated to yield the title compound (147 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:25][CH2:26][NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (125 mg, 0.541 mmol) was dissolved in DMF(10 mL), followed by addition of potassium tert-butoxide (79 mg, 0.703 mmol). After stirring for 15 minutes, 1,1-dimethylethyl (2-bromoethyl)carbamate (121 mg, 0.541 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 50% EtOAc:Hex). The final product was obtained as 0.114 g (56%). LCMS E-S (M+H)=375.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.14 (m, 4 H), 1.15-1.20 (m, 2 H), 1.27 (s, 7 H), 1.41 (t, J=7.07 Hz, 3 H), 2.36-2.45 (m, 1 H), 3.31-3.41 (m, 3 H), 4.36-4.50 (m, 5 H), 6.84 (t, J=5.81 Hz, 1 H), 7.65 (s, 1 H), 8.24 (s, 3 H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:22]=[C:23]=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].C(N(CC)CC)C.[CH3:32][C:33]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:38][S:39][CH2:40][CH2:41][NH2:42].CO>O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH:42][CH2:41][CH2:40][S:39][CH2:38][C:34]2[N:35]=[CH:36][NH:37][C:33]=2[CH3:32])=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11]
Reactant: N=C(N)Nc1nc(CSCCN=C=S)cs1
Reactant: Cc1[nH]cnc1CSCCN
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: Cc1[nH]cnc1CSCCNC(=S)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-guanidinothiazol-4-ylmethylthio)ethyl isothiocyanate hydrogen maleate (0.778 g), triethylamine (1.0 g), 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazole (0.364 g) and methanol (20 ml) was stirred at room temperature overnight. The mixture was poured into water (60 ml), extracted with ethyl acetate (2×50 ml), the combined extracts washed with water (25 ml), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in acetone (10 ml) and added to a solution of maleic acid (0.28 g) in acetone (10 ml). The precipitate was filtered off and recrystallized from ethanol (charcoal) to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-3-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea maleate as a white solid, m.p. 90°-93° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Br:37][CH2:38][CH2:39]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C=O)C>[Br:37][CH2:38][CH2:39][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)=[CH:3][C:2]=1[Cl:1]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A 100 ml round bottom flask was loaded with 3-(3-chloro-4-hydroxyphenyl)-7-morpholino-9H-carbazole-1-carboxamide (114.9 mg, 0.245 mmol, Example 406), K2CO3 (386 mg, 2.79 mmol), DMF (10 ml) and 1,2-dibromoethane (0.24 ml, 2.79 mmol) and the mixture stirred at room temperature for 4 hours. The reaction mixture was partitioned between 500 ml water+citric acid (0.5 M solution in water) (20 ml, 10.00 mmol) and ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 118.6 mg 3-(4-(2-bromoethoxy)-3-chlorophenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=528/530/532, m/e−=526/528/530 consistent with isotope pattern for 1 Br and 1 Cl. 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.50 (d, 1H, J=1.5), 8.34 (b, 1H), 8.15 (d, 1H, J=1.6), 8.07 (d, 1H, J=8.5), 8.01 (d, 1H, J=2.2), 7.83 (dd, 1H, J=8.6, 2.4), 7.52 (b, 1H), 7.31 (d, 1H, J=8.8), 7.24 (d, 1H, J=2.0), 6.95 (dd, 1H, J=8.8, 2.2), 4.50 (t, 2H, J=5.5),), 3.89 (t, 2H, J=5.5), 3.83-3.79 (m, 4H), 3.22-3.17 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O)([O-])=O>C(O)C>[N:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: O=Cc1nccn1Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: c1ccc2c(c1)Cn1ccnc1CN2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole-2-carboxaldehyde is dissolved in 150 ml of hot ethyl alcohol, cooled to room temperature and filtered. To the filtrate is added 0.5 g of 10% Pd/C and the mixture hydrogenated at 48 psi for 4 hours. An additional 0.5 g of 10% Pd/C is added and hydrogenation continued for 25 hours at 65 psi. The mixture is filtered through diatomaceous earth and the cake washed with ethyl acetate. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, treated with activated carbon, filtered through diatomaceous earth and hexanes added to the filtrate at the boil to give 1.86 g of the desired product as a crystalling solid, m.p. 164°-170° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1COCC1>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[CH:23]=2)[CH:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc[nH]c3c2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
Pd2(dba)3 (30 mg, 0.026 mmol), tert-butyl piperazine-1-carboxylate (570 mg, 3.06 mmol), X-Phos (CAS Number: 564483-18-7, 40 mg, 0.077 mmol) and 6-bromo-1H-indole (500 mg, 2.55 mmol) were added to THF (2 mL) in a sealed reactor. After adding lithium hexamethyldisilazide (LHMDS; 1 M in THF, 5.61 mL, 5.6 mmol) at room temperature, the mixture solution was stirred at 65° C. for 24 hours in a sealed state. After cooling to room temperature, the reaction was terminated with saturated ammonium chloride aqueous solution. After extraction with ethyl acetate, the collected organic layer was washed with saturated sodium bicarbonate aqueous solution and brine and then concentrated by drying with anhydrous sodium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:2). The target compound (334 mg) was obtained as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[N:10]2)[CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C=O)C.C1COCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[N:10]2)[CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)nn2-c2cc(C#N)ccn2)cc1
Temperature: 65 °C
Yield: 41 %

Procedure:
A solution of methyl 1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate (500 mg, 1.57 mmol) in DMF/THF (1:1, 15 mL) was heated to 65° C. and NaOH (628 mg, 15.7 mmol) in water (1 mL) was added. The resulting solution was stirred at 65° C. and monitored by TLC. The reaction was cooled to rt at the point where a second more polar eluting product (relative to the product spot) began to form. The pH of the solution was adjusted to pH=4 with 6 N HCl, and the reaction mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with water (2×50 mL), dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (EtOAc:hexanes=40:60) to give the title compound (196 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:34]#[N:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[OH:37][CH2:38][C:39](=O)[CH3:40].[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@@H:26]([C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1)[NH:33][C:34]1[O:37][CH:38]=[C:39]([CH3:40])[N:35]=1
Reactant: CC(=O)CO
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC#N)c1nc(C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](Nc1nc(C)co1)c1nc(C)no1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 260 mg of (R)-3-[dimethyl -(1,1,2-trimethyl-propyl)-silanyloxy]-2-[2-cyanoamino-2-(3-methyl-1,2,4-oxadiazol-5-yl) -ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester in 50 ml of tetrahydrofuran were added 0.1 ml of 25% aqueous hydroxyacetone and 0.09 ml of 1N sodium hydroxide solution. The suspension was stirred for 12 h at 40° C. After cooling, the mixture was diluted with 100 ml water and subsequently extracted with 200 ml ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, and the purified product was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-3-hydroxy-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol -5-yl)-2-(4-methyl-oxazol-2-ylamino)-ethylsulfanylmethyl]-benzoic acid methyl ester as a white powder.