Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([Cl:9])[CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CO>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:1]
Reactant: Nc1ccc(S)c(Cl)c1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2cccnc2)c(Cl)c1
Yield: 44 %

Procedure:
4-amino-2-chlorobenzenethiol (1.2 g) was dissolved in methanol (24 ml), and to this solution was added 3N aqueous solution of sodium hydroxide (7.5 ml) and then, 3-(chloromethyl)pyridine hydrochloride (1.48 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 3-chloro-4-[(3-pyridinylmethyl)sulfanyl]aniline (0.83 g).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[C:18]([F:19])=[C:17]([F:20])[C:8]([CH2:9][O:10]C2CCCCO2)=[C:7]([F:21])[C:6]=1[F:22].Cl>CO.O>[Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[C:6]([F:22])=[C:7]([F:21])[C:8]([CH2:9][OH:10])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Agent: Cl
Solvent: CO
Solvent: O
Product: OCc1c(F)c(F)c(C/C=C\Cl)c(F)c1F
Reaction time: 2 h

Procedure:
The tetrahydropyranyl ether prepared in stage (ii) was dissolved in methanol (30 cm3), and to the stirred solution was added a catalytic amount of concentrated hydrochloric acid. After stirring for two hours, the reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed and dried, and the solvent evaporated under reduced pressure to give Z-4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.6 g) as a colourless oil, which solidified on standing.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:10][CH2:9]1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.[I-].[Na+].[OH-].[Na+]>CS(C)=O>[CH:8]1([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:9]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
A mixture of potassium carbonate (450 mg), bromocyclopropane (394 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (3 mL) was stirred at 130° C. overnight. Then bromocyclopropane (788 mg) and sodium iodide (488 mg) were added and the mixture was stirred at 150° C. for 5 hr. The mixture was poured into 1N NaOH aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give 50.9 mg of yellow solid. The solid was purified by preparative HPLC (C18, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with sat.NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (26.8 mg) as a white solid.
Reaction SMILES: [C-]#N.[Na+].[C:4](O)(=[O:6])C.[I:8][C:9]1[N:10]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1>CO.[O-2].[O-2].[Mn+4]>[I:8][C:9]1[N:10]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:11]=[C:12]([C:14]([O:6][CH3:4])=[O:15])[N:13]=1
Reactant: CC(=O)O
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a mixture of activated manganese dioxide (5.66 g, 65 mmol), sodium cyanide (833 mg, 17 mmol), and glacial acetic acid (300 mg) in methanol (70 mL) was added 2-iodo-4-formyl-1-triphenylmethylimidazole (2.33 g, 5.0 mmol) in one portion. The mixture was stirred for 1 hour at room temperature and then filtered through Celite. The filtrate was concentrated and the residue was partitioned into methylene chloride and water. The organic phase was dried (magnesium sulfate) and concentrated in vacuo to give a white foamy solid. Purification by column chromatography using ethyl acetate:hexanes (1:2) afforded 2-iodo-4-(methoxycarbonyl)-1-triphenylmethylimidazole (2.26 g, 92%) as a white solid, mp 192-194° C. 1H NMR (CDCl3) δ 7.55 (s, 1H), 7.37-7.29 (m, 9H), 7.18-7.09 (m, 6H), 3.84 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:37])[CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[Cl:8][C:7]1[C:2]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=2)=[CH:3][C:4]([CH2:9][NH:10][C:11](=[O:37])[CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])=[O:14])=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Yield: 68.1 %

Procedure:
A mixture of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (1.06 g, 1.791 mmol), (3-formylphenyl)boronic acid (0.330 g, 2.2 mmol), tetrakis (triphenylphosphine) palladium (0) (0.092 g, 0.08 mmol), sodium carbonate (0.212 g, 2.0 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was microwaved at 140° C. for 30 min. The reaction mixture was diluted with water and EtOAc; layers were separated. The aqueous phase was re-extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to a residue. This residue was purified on the Chromatotron on silica gel (2000u) eluting with CH2Cl2 (3-6% MeOH) to give N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (752.4 mg, 68.1%) as a glassy solid. LC-MS m/z 617.3 (M+H)+, 0.86 min (ret time).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)S1
Yield: 62.9 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 1.77 g of 5-{4-[2-(indol-3-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 11), 53 ml of methylene chloride and 0.3 ml of trifluoroacetic acid were used, to give 0.67 g of the title compound, melting at 42.6-44.5° C.
Reaction SMILES: C[N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)=[N:3]1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1B(O)O)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1[C:13]1[CH:14]=[C:9]([NH:8][C:4]2[CH:5]=[C:6]([CH3:7])[NH:2][N:3]=2)[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 38 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 218a (201 mg, 0.71 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (282 mg, 0.71 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol), K3PO4 (301 mg, 1.42 mmol), sodium acetate (116 mg, 1.42 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 260a as a red solid (150 mg, 38%). MS-ESI: [M+H]+ 556.3
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29]>>[C:23]([O:22][C:20]([NH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:3]3[CH:4]=[CH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:31])[CH:18]=[CH:17][CH:16]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3ccccc3c2N)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Yield: 41 %

Procedure:
1-Amino-2-(3-tertbutoxycarbonylaminophenyl)aminonaphthalene (1.05 g, 3 mmol) and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound (0.50 g, yield 41%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:14]=1[C:15](Cl)=[O:16]>C1C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:15](=[O:16])[C:14]2[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH3:11])[NH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: c1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1cc(C(C)(C)C)n[nH]1
Yield: 18.2 %

Procedure:
To a stirred solution of 1.39 g of 3-tert.-butyl-5-amino-1H-pyrazole in 50 ml of benzene were added in one portion 2.01 g of 2,6-dimethoxybenzoyl chloride. The reaction mixture was heated at reflux for sixteen hours. The reaction mixture was then cooled, filtered, and the solvent was removed from the filtrate by evaporation. The residue was crystallized from ethyl acetate to provide 550 mg of N-[3-(1,1-dimethylethyl)-1H-pyrazol-5-yl]-2,6-dimethoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3cccc(F)c3F)cccn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 500 mg of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 0.35 ml of 2,3-difluorobenzylbromide, and 650 mg of potassium carbonate in 8.6 ml of N,N-dimethylformamide (DMF) was stirred at 60° C. for 1 hour. The reaction mixture was left to be cooled to room temperature and water was then added thereto. The resulting solid was collected by filtration and washed with water. The solid was washed with diisopropyl ether to obtain 650 mg of ethyl 8-[(2,3-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3ccc(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)ccc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M151) (245 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (101 mg, 52%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([Cl:13])[CH:10]([CH2:14][N:15]=[N+]=[N-])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].C(O)C>[NH2:15][CH2:14][CH:10]1[CH:11]([Cl:13])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1Cl
Agent: [Pd]
Solvent: CCO
Product: NCC1CN(Cc2ccccc2)CC1Cl
Yield: 110.1 %

Procedure:
To 1-benzyl-3-azidomethyl-4-chloropyrrolidine (3.0 g) are added ethanol (50 ml) and 10 % palladium carbon (0.5 g), and catalytic reduction is carried out under a hydrogen pressure of from 3 to 4 atm. at 50° C. After removing the catalyst from the mixture by a filteration, the resultant is concentrated to give 3-aminomethyl -1-benzyl-4-chloropyrrolidine (2.96g) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[O:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+].Cl>O.CCO>[NH2:17][C:13]1[N:12]=[C:11]([C:9]2[O:8][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)oc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3ccccc3)o2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ester 59 (221 mg, 0.71 mmol) in 1:1 H2O/EtOH (9 mL), 4M aq NaOH (10 eq) was added and the reaction mixture was stirred at 100° C. for 1 h. After cooling to rt, the solution was acidified with 2M HCl yielding 5-(2-amino-pyrimidin-4-yl)-2-phenyl-furan-3-carboxylic acid as a white solid which was filtered, washed with water and dried under reduced pressure (quant.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:42][C:43]1[CH:50]=[C:49]([CH2:51]Br)[CH:48]=[CH:47][C:44]=1[C:45]#[N:46]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([O:38][CH2:51][C:49]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Br:42])[CH:50]=4)[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reactant: N#Cc1ccc(CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(C#N)c(Br)c2)c1
Temperature: 0 °C
Yield: 34.5 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (100 mg, 0.18 mmol) in DMF (3 mL) was added sodium hydride (8 mg, 60% 0.2 mmol). The solution was cooled to 0° C. and 2-bromo-4-(bromomethyl)benzonitrile (55 mg, 0.2 mmol) while stirring. The mixture was warmed to room temperature and quenched by addition of water and ethyl acetate after 45 minutes. Phases were separated and the water phase was extracted with ethyl acetate. Combined organic extracts were concentrated in vacuum and the residue was purified by preparative HPLC to yield 46 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-{5-[(3-bromo-4-cyanobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (36 mg, 0.18 mmol) in dry DMF (1 ml) DIPEA (52 μl, 0.3 mmol) and then HATU (65 mg, 0.17 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 158, 40 mg, 0.15 mmol) was then added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (57 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:3]=1[C:4](O)([C:16]([F:19])([F:18])[F:17])[CH2:5][C:6](=[O:15])[N:7]3[CH2:8][CH2:9][O:10]2.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:3]=1[C:4]([C:16]([F:19])([F:18])[F:17])=[CH:5][C:6](=[O:15])[N:7]3[CH2:8][CH2:9][O:10]2
Reactant: Nc1ccc2c3c1C(O)(C(F)(F)F)CC(=O)N3CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc2c3c1c(C(F)(F)F)cc(=O)n3CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Impure 7-amino-6-hydroxy-6-trifluoromethyl-2,3,5,6-tetrahydro-1-oxa-3a-aza-phenalen-4-one (0.2 g) was heated to 140° C. for 1.5 hours then stirred at room temperature overnight. The reaction mixture was poured onto ice, made basic with 1M sodium carbonate, extracted three times with ethyl acetate, dried the organic extracts over magnesium sulfate, filtered, evaporated to a yellow solid. The yellow solid (crude material) was purified using the Biotage 40S system eluting with 30% ethyl acetate/hexane to yield 7-amino-6-trifluoromethyl-2,3-dihydro-1-oxa-3a-aza-phenalen-4-one
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([O-:9])=[O:8])[S:5][CH:6]=1.[CH3:11][N-:12][CH3:13].[CH3:14][O:15][C:16]1[C:17](=O)[C:18](=[O:22])[C:19]=1[O:20]C>CO>[OH:10][C:3]1[C:2]([NH:1][C:17]2[C:18](=[O:22])[C:19](=[O:20])[C:16]=2[O:15][CH3:14])=[CH:6][S:5][C:4]=1[C:7]([O-:9])=[O:8].[CH3:11][N-:12][CH3:13]
Reactant: Nc1csc(C(=O)[O-])c1O
Reactant: COc1c(OC)c(=O)c1=O
Agent: C[N-]C
Solvent: CO
Product: COc1c(Nc2csc(C(=O)[O-])c2O)c(=O)c1=O
Temperature: 50 °C
Yield: 84.6 %

Procedure:
A mixture of 5.20 g (27.92 mmol, 1.0 eq) of dimethylamide 4-amino-3-hydroxythiophene-2-carboxylate and 5.95 g (41.88 mmol, 1.5 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 52 ml of methanol was heated at 50° C. for 16 hours. The insoluble material was filtered off and oven-dried under vacuum at 45° C. 7.38 g of dimethylamide 3-hydroxy-4-(2-methoxy-3,4-dioxocyclobut-1-enylamino)thiophene-2-carboxylate were obtained. Yield=89%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2[C@H](O)C[N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C@H:19]([OH:27])[CH2:20][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl(trans)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.49–7.11, 5.97, 5.17, 4.78, 4.67, 4.33–4.26, 4.16–3.96, 3.46, 2.69, 2.49, 1.46–1.24, 1.14; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1606.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:27]([CH3:41])[CH2:28][CH2:29][N:30]1C(=O)C2C(=CC=CC=2)C1=O>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:19][CH2:20][N:21]([CH:27]([CH3:41])[CH2:28][CH2:29][NH2:30])[CH2:22][CH2:23]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3ccccc3O2)CC1
Yield: 69.2 %

Procedure:
Using general procedure B with the above amine (115 mg, 0.330 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (143 mg, 0.660 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (96 mg, 69% over 2 steps) as a colorless oil.