Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])\[CH3:5].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1([C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1)[CH3:5]
Reactant: C/C(=C\CCl)c1cccc(C#N)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1

Procedure:
To a solution of 3-[(E)-3-chloro-1-methyl-1-propenyl]benzonitrile (Preparation 34, 13.1 g, 69.6 mmol) in dichloromethane (20 ml) was added rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To the mixture was added dropwise at room temperature over 8 h (via a syringe pump) a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml). The solvent was removed in vacuo and the crude residue was then partially purified by silica column chromatography eluting with dichloromethane:hexane (80:20). This material was then dissolved in dichloromethane (20 ml) containing rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To this mixture was added dropwise a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml) at room temperature over 8 h. The mixture was concentrated in vacuo and the residue purified by silica column chromatography eluting with hexane:dichloromethane (80:20) and then hexane:diethyl ether (80:20) to give the title compound as a colourless oil which solidified on standing (5.82 g, 30%).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15]([C:17]2[C:18]3[CH2:19][CH2:20][C:21]([CH3:31])([CH3:30])[C:22]=3[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[K+].O>CCO>[C:26]([C:24]1[CH:25]=[C:17]([C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:16])[C:18]2[CH2:19][CH2:20][C:21]([CH3:31])([CH3:30])[C:22]=2[CH:23]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)C1(NC(=O)c2cc(C(C)(C)C)cc3c2CCC3(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c2c(c1)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 2-[(6-tert-butyl-1,1-dimethyl-indane-4-carbonyl)-amino]-indan-2-carboxylic acid methyl ester (600 mg, 1.4 mmol) and KOH (1.8 g, 30.8 mmol) is dissolved in EtOH (25 mL) and water (2 mL) under water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is neutralized with 1N HCl and extracted with EtOAc (3×150 mL), the organic washes are combined and concentrated in vacuo. The residue is purified by preparative HPLC (C18 column 10 micron, gradient elution: 20-100% ACN 0.1% TFA in H2O 0.1% TFA). Product crystallizes out of the collected fractions on standing. Filtration and drying gave pure product as white solid (454 mg, 78%).
Reaction SMILES: COC(C1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1)=O.C1COCC1.C[Mg]Cl.Cl.[C:24]([O:28]C)([CH3:27])([CH3:26])[CH3:25]>O>[F:12][C:11]([F:14])([F:13])[C:7]1[N:6]=[C:25]([C:24]([OH:28])([CH3:27])[CH3:26])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(C(F)(F)F)n1
Reactant: COC(C)(C)C
Agent: C[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(C(F)(F)F)n1
Temperature: 0 °C
Yield: 90 %

Procedure:
Add 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (80.0 g, 390 mmol) to a mixture of THF (240 mL) and tert-butylmethyl ether (400 mL). Add the solution slowly to a 3 M methylmagnesium chloride in THF (390 mL, 1.17 moles) and maintain 8° C. to 16° C. Cool the mixture to 0° C. and add a mixture of 5 M hydrochloric acid (257 mL, 1.29 moles) and water (200 mL). Separate the phases and concentrate the organic phase under reduced pressure. Add heptane (160 mL) and cool the mixture to 5° C. Collect the precipitate by vacuum filtration and rinse the solid with heptane (20 mL) followed by pentane (30 mL). Vacuum dry the solid to afford the title compound as a tan solid (72.3 g, 352 mmol, 90%). 1H NMR (400 MHz, DMSO d6) δ 8.04 (t, J=7.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.40 (s, 1H), 1.43 (s, 6H). HRMS (ESI) m/z (M+H)+ calcd for C9H10F3NO: 206.0787, found 206.0787.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[CH:16]([NH2:18])=[O:17]>>[CH3:15][C:2]1[O:17][CH:16]=[N:18][C:3]=1[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Reactant: NC=O
Product: COC(=O)c1cccc(-c2ncoc2C)c1
Temperature: 130 °C

Procedure:
A mixture of methyl 3-(2-bromo-propionyl)-benzoate (5.42 g) and formamide (3.6 ml) was heated to 130° C. for 5 h. The mixture was cooled and partitioned between H2O and AcOEt. The organic layer was dried over Na2SO4 and evaporated and the residue was purified by chromatography on silica gel (AcOEt/hexane 1:4 as eluent) to give 1.8 g methyl 3-[5-methyl-oxazol-4-yl]-benzoate as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Mg]Br.C(OCC)C>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:10]([OH:11])[CH3:27])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: COCOc1c(C=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1c(-c2ccc(C(F)(F)F)nc2)cc(C(C)(C)C)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (1.0 g, 2.72 mmol) in THF (15 mL) at −78° C. under argon was added a 3 M solution of methyl magnesium bromide in diethyl ether (1.0 mL, 3.0 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and then the solution poured onto brine cooled to 0° C. forming a gel. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was separated, dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give 1-(5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-ol (660 mg, 63% yield) as a tan oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([Cl:21])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reaction time: 2 h

Procedure:
To a cooled (ice-bath) suspension of 150 mg (0.63 mmol) of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid in 15 mL of CH2Cl2 were added 0.081 mL (0.956 mmol) of oxalyl chloride, followed by a drop of DMF. The mixture was allowed to reach room temperature with stirring over two hours. Solvents were evaporated in in vacuo, and methylene chloride was added and solvent was removed in vacuo. Methynele chloride (10 mL) was again added and removed in vacuo, and the residue dried in high vacuum for 20 minutes to give (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride, which was dissolved in 8 mL of dry CH3CN and transferred to a sealable tube under Argon atmosphere. DIPEA 0.22 mL (1.26 mmol), DMAP (few crystals) were added, followed by 6-amino-5-ethylquinoline (60 mg 0.348 mmol). The tube was sealed and heated with stirring to 120° C. for 24 hours. The tube contents were cooled to room temperature, saturated aqueous NaHCO3 solution (10 mL) was added and product extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH/NH4OH (100/10/1) to give 30 mg (22.2%) of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-ethyl-quinolin-6-yl)-amide as a pale yellow foam. MS (ESI): m/z 389 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.N1C=CC=CC=1.[C:52]1([S:58](Cl)(=[O:60])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:27][C@H:26]([C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@H:6]1[O:5][CH2:4][C@@H:3]([CH2:2][NH:1][S:58]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:60])=[O:59])[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7]1)=[O:45])[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in DCM (0.1M) were added pyridine (3 eq) and benzene sulfonyl chloride (1.3 eq). The reaction mixture was stirred for 4 hrs at room temperature, diluted with CH2Cl2 and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Li]C(CC)C.CN([CH:19]=[O:20])C>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dichloro-5-methoxybenzene (1.0 g, 5.65 mmol) in THF (15 mL), cooled to −78° C., under N2 protection, was added dropwise sec-BuLi (4.18 ml of a 1.4 M solution in hexane, 5.82 mmol). After 30 minutes, anhydrous DMF (0.65 ml, 8.48 mmol) was added slowly to the solution and the mixture was stirred for at −78° C. 1.5 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (10:1) as eluent to give 2,4-dichloro-6-methoxybenzaldehyde as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])/[CH:27]=[CH:2]/[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Product: CN(C)/C=C/C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Yield: 95.8 %

Procedure:
A solution of N-(2-acetylthiophen-3-yl)-2-(naphthalen-1-yl)acetamide (165 mg, 0.53 mmol) in N,N-dimethylformamide dimethyl acetal (0.2 mL, 1.50 mmol) was heated at 80° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried (sodium sulfate), filtered and concentrated under reduced pressure to give the desired N-(2-(3-(dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (185 mg, 95%) which was used without further purification. Method [4] m/z 387.0 (M+Na); rt=2.199 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:30])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:28][NH2:29])[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:29][CH2:28][C:20]1([C:17]2[CH:16]=[N:15][C:14]([CH:13]([F:30])[F:12])=[N:19][CH:18]=2)[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22][CH2:21]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and (1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=450.1, tR (minutes, Method F)=2.93
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:29]1[C:34]([I:35])=[CH:33][N:32]=[CH:31][N:30]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>>[I:35][C:34]1[C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)=[O:16])[CH:9]=3)=[CH:4][CH:3]=2)=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: Clc1ncncc1I
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(Nc2ncncc2I)cc1
Yield: 44.3 %

Procedure:
4′-Amino-6-methyl-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.26 g, 0.00070 mol) was mixed with 4-chloro-5-iodopyrimidine (0.17 g, 0.00070 mol) in ethanol (3.00 mL, 0.0514 mol) and the mixture was heated to reflux for 2 hours at which time LCMS analysis showed mainly product. To the reaction was added sat. Na2CO3 solution and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 30% EtOAc/hexanes to give the product (178 mg, 44% yield). 1H NMR (CDCl3): δ□ 8.66 (s, 1H), 8.62 (s, 1H), 7.96 (m, 2H), 7.70-7.89 (m, 5H), 7.37-7.50 (m, 5H), 7.20 (s, 1H), 2.38 (s, 3H). MS (EI) m/z=575 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[OH-:37].[K+].O>C(O)C>[NH2:1][C:2]1[C:7]([C:8](=[O:37])[NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C#N)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Temperature: 70 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a stirred suspension of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.619 mmol), which was obtained in the step (1) of Example 1-1, in ethanol (10 mL) was added a solution of potassium hydroxide (0.695 g, 12.381 mmol) in ethanol (20 mL). The reaction mixture was stirred at 70° C. for 60 hrs. After cooled to room temperature, the reaction mixture was poured into water and the resulting solid was filtrated and dried under reduced pressure to give tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylat as a white amorphous. (0.226 g, yield; 73%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:15]=[C:14](Br)[CH:13]=[CH:12][C:11]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([N:33]2[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]2)[CH:13]=[CH:12][C:11]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: CSc1ccc(Oc2ccc(Br)cc2CN(C)C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CSc1ccc(Oc2ccc(N3CCN(C(C)C)CC3)cc2CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 120 °C
Yield: 54.2 %

Procedure:
A mixture of [5-bromo-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester (300 mg, 0.684 mmol) {prepared in an analogous fashion to Example 1, Steps A-C}, isopropyl piperazine (132 mg, 1.02 mmol), XPHOS (39 mg, 0.082 mmol), Pd2(dba)3 (62.6 mg, 0.0684 mmol), and t-BuONa (98.0 mg, 1.02 mmol) in toluene was heated in a sealed tube overnight at 120° C. After cooling to rt, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Purification by FCC gave the desired product (180 mg, 54%). MS (ESI): mass calcd. for C27H39N3O3S, 485.27; m/z found, 486.4 [M+H]+. 1H NMR (CDCl3): 7.22 (d, J=8.5, 2H), 6.86-6.83 (m, 1H), 6.83-6.80 (m, 4H), 4.42-4.35 (m, 2H), 3.19-3.16 (m, 4H), 2.87-2.83 (m, 2H), 2.80-2.75 (m, 1H), 2.75-2.71 (m, 1H), 2.71-2.67 (m, 4H), 2.44 (s, 3H), 1.48-1.40 (m, 9H), 1.10 (d, J=6.5, 6H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[K+].O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:21])[Cl:22])=[O:17])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 g. of ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate in 50 ml. of ethanol is added a solution of 11.2 g. of KOH in a mixture of 30 ml. of water and 150 ml. of ethanol. The whole mixture is stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue is extracted with ethyl acetate. The water layer is made acidic with 10% aq. HCl and the separated solid is collected. Recrystallization of the solid from aq. methanol gives α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonyl-amino)thiazol-4-yl]acetic acid. 4.1 g. Melting point: 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:25])[CH2:24][O:23][CH2:22]2)=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:25])[CH2:24][O:23][CH2:22]2)=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)c(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C1(O)COC1
Temperature: 70 °C
Yield: 17.5 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylate (100 mg, 0.258 mmol) in methanol (3 mL) and sodium hydroxide (1M, 1.0 mL, 1.0 mmol) was heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure and the reaction was acidified with 1M hydrochloric acid aqueous to pH=2 then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate two additional times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure yielding 83 mg of the crude desired product. A portion of the crude material (60 mg) was purified by prep-HPLC (Phenomenex HILIC (Diol) 250×21.2 mm 5 μm; Mobile phase A: heptane; Mobile Phase B: Ethanol, gradient 95% A/5% B hold for 1.5 minutes, linear gradient to 0% A/100% B in 8.5 minutes, Hold at 0% A/100% B for 1 minutes; flow rate: 28 ml/min) to afford the title compound (16.9 mg, 17.5%) as a solid. MS (ES−) 372.0 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.13 (br. s, 1H), 11.96 (br. s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.99 (dd, J=7.6, 1.5 Hz, 1H), 5.89 (s, 1H), 5.02 (d, J=6.8 Hz, 2H), 4.67 (d, J=6.8 Hz, 2H), 3.81 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:13][C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:25][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCN2CCOCC2)c1
Temperature: 80 °C
Yield: 45.6 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (2.5 g, 18.37 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.4 g, 7.35 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 0-50% EtOAc/hexane as eluent gave the product (1.0 g, 47%) as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29]([O:31]C)=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:35])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Yield: 43 %

Procedure:
A solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (100.0 mg, 0.24 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 24 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 41.0 mg (43%) of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.7 (m, 13H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). MS (ES) m/e 407, 409.