Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:25]=[N:26][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:28][CH:29]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Ic1cnc(N2CCOCC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cnc(N3CCOCC3)nc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-(5-iodopyrimidin-2-yl)morpholine (Intermediate-5, 0.139 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.035 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.67 (br s, 4H), 3.76 (br s, 4H), 7.47-7.71 (m, 5H), 7.98 (d, J=9.0 Hz, 2H), 8.58 (s, 2H), 12.69 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:37])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M168) (236 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (72 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([OH:17])=O)=[N:9]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([Cl:26])=[O:17])=[N:9]1
Reactant: COc1cc(C(=O)O)nn1-c1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)nn1-c1ccccc1F
Temperature: 0 °C

Procedure:
A suspension of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid (39.1 g, 167 mmol) in 2-methyltetrahydrofuran (300 ml) was cooled to 0° C. and DMF (293 μl, 3.81 mmol) was added. Oxalyl chloride (23.1 g, 182 mmol) was added dropwise. After 16 h at room temperature ca. 100 ml of the solvent were removed by distillation. The resulting suspension of the title compound was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.CS(CCO)(=O)=[O:13].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:13])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol) in DMF (20 mL) was added 2-(methylsulfonyl)ethanol (3.7 g, 30 mmol) and then NaH (2.4 g, 60% in mineral, 60 mmol) in portions at 0° C. The mixture was then warmed to rt. and quenched with 1N HCl, and extracted by EtOAc. The organic layers were washed with brine and dried over sodium sulfate, concentrated to give 4-bromo-2-hydroxybenzonitrile. 1H-NMR (400 MHz, DMSO) δ 7.55-7.57 (d, J=8.61 Hz, 1H), 7.16 (s, 1H), 7.11-7.13 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].I[CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][CH:29]([CH3:32])[CH2:30][CH3:31])[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC[C@H](C)CI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)CC)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 73.6 %

Procedure:
A solution of (benzhydrylidene-amino)-acetic acid ethyl ester (5.48 g, 20.5 mmol) in tetrahydrofuran (40 mL) was treated with potassium t-butoxide (2.83 g, 25.26 mmol) and stirred at 0° C. for 35 min. At this time a solution of (S)-1-iodo-2-methyl-butane (5.00 g, 25.25 mmol) in tetrahydrofuran (20 mL) was added via syringe and the resulting solution stirred at 0° C. for 10 min and then room temperature overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid. The layers were separated, and the organic layer was washed with brine and concentrated in vacuo. The residue was purified by ISCO flash chromatography (RediSep silica 120 g, 0% to 10% ethyl acetate/hexanes) which afforded (S)-2-(benzhydrylidene-amino)-4-methyl-hexanoic acid ethyl ester (5.09 g, 74%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].F[B-](F)(F)F.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].CCN(CC)CC>CN(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.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[C:3]([CH2:9][C:10]([NH2:12])=[O:11])[CH:4]=1
Reactant: NC(=O)Cc1cc(F)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(F)cc1CC(N)=O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Under inert conditions a suspension of 2-(2-bromo-5-fluorophenyl)acetamide (A33) (0.242 g, 1.04 mmol), PdCl2(PPh3)2 (0.037 g, 0.052 mmol), t-Bu3PH.BF4 (0.015 g, 0.052 mmol), CuI (0.010 g, 0.052 mmol) and (trimethylsilyl)acetylene (0.177 mL, 1.25 mmol) in anhydrous DMF (9 mL) was degassed with nitrogen for 10 minutes. Et3N (3 mL) was added and the resulting mixture was stirred at 65° C. under nitrogen for 16 hours. The volatiles were removed under reduced pressure, then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A34 as a tan coloured solid (0.242 g, 93%); 1H NMR (400 MHz, d6-DMSO) δ 7.46 (dd, J=8.6, 5.9 Hz, 1H), 7.38 (s, 1H), 7.15 (dd, J=10.0, 2.7 Hz, 1H), 7.08 (td, J=8.6, 2.7 Hz, 1H), 6.99 (s, 1H), 3.60 (s, 2H), 0.23 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[K+].Cl[C:35]([O:37][CH2:38][Cl:39])=[O:36]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([O:22][C:35]([O:37][CH2:38][Cl:39])=[O:36])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)OCCl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.6 %

Procedure:
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (5.8 mmol) was added to a suspension of potassium hydride (7 mmol) in THF at 0C and was allowed to stir for 0.5 hours. Choromethyl chloroformate (5.8 mmol, in 2mL THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hours. The crude reaction was diluted with EtOAc, and was sequentially washed with H2O, 0.1N HCl, H2O, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 3.43 g of the subtitled product as a pale yellow solid. 1H NMR (DMSO) δ 8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1.[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O.CCOC(C)=O>[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:2]2[O:6][C:5]([C:7]3[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=3)=[CH:4][C:3]=2[C:18]2[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=2)[CH2:34]1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Reactant: CN(C)C1CCCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(N3CCCC(N(C)C)C3)o2)c(C)cn1
Temperature: 120 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of N-{-4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.38 mmol) in DMSO (3 mL) was added N,N-dimethylpiperidin-3-amine (0.25 g, 1.9 mmol). The mixture was allowed to stir at 120° C. for 48 h. The reaction mixture was diluted with EtOAc and washed with water. The organic solution was separated, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[3-(dimethylamino)piperidin-1-yl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.15 g, 72%). LCMS (FA): m/z=540.7 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[Br:20][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(F)(F)F)cn1
Solvent: CC#N
Product: COc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a stirred solution of 2-methoxy 5-(trifluoromethyl) pyridine (4 g, 22.58 mmol) was dissolved in acetonitrile (50 ml) was added NBS (6 g, 33.87 mmol) portion wise at 0° C. The reaction mixture was stirred for overnight at RT. The solvent was removed under vacuum, quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (12) as a pale yellow liquid (2 g, 34.7%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[F:7][C:8]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(O)C.[OH-].[K+]>O>[F:7][C:8]1[CH:16]=[C:15]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][F:6])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: FCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCCCF)cc1F
Temperature: 80 °C
Reaction time: 17 h
Yield: 39.1 %

Procedure:
1-Bromo-4-fluorobutane (3.57 g, 23.1 mmol) was added dropwise to a mixture of 2-fluoro-4-hydroxybenzoic acid (3.00 g, 19.2 mmol), ethanol (11.5 ml) and water (2.3 ml), potassium hydroxide (2.37 g, 42.3 mmol) at 80° C., and the mixture was stirred at 80° C. for 17 hrs. The solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was acidified by adding 1N hydrochloric acid. The insoluble materials were filtered off and dried to give the title compound (1.73 g) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41]C)=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Br)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)O)cc2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 50c(0.8 g, 1.2 mmol) in tetrahydrofuran (20 mL) was added an aqueous solution (1 M) of NaOH (10 mL, 10 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 18 h, then acidified to “pH” 2 with concentrated aqueous HCl solution. The mixture was concentrated, partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.6 g, 74%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48]O>C(Cl)Cl>[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48][O:32][C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(COC(=O)CNC(=O)OC(C)(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), N-t-butoxycarbonylglycine(27.8 mg, 0.158 mmol) and triethylamine(23.9 μl 0.171 mmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol) in anhydrous methylene chloride(1 ml). The reaction mixture was stirred for 1 day at room temperature, washed with water. The separated organic layer was concentrated and the residual oil was purified by a silica gel column chromatography (dichloromethane/methanol 20/1) to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[O:7]=[C:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1>CCOCC>[OH:7][C:8]1([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Brc1ccsc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2)C1
Temperature: -65 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 3-bromothiophene (10 g, 61.8 mmol) in dry ether (200 mL) at −65° C. under N2 was added n-BiLi dropwise. After stirring at −65° C. for 1 h, tert-butyl 3-oxopyrrolidine-1-carboxylate (13.7 g, 74.2 mmol) in dry ether (80 mL) was added dropwise. After addition, the reaction mixture was warmed to 0° C. and stirred for 3 h. The reacton was quenched with water and extracted with ether. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.8 g, 59%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>CC(C)=O>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Oc1cc(NC(=O)OCc2ccccc2)c(F)cc1Cl
Yield: 91.1 %

Procedure:
2-Fluoro-4-chloro-5-methoxycarbonyloxyaniline (2.00 g, 6.86 mmol), potassium carbonate (1.42 g, 10.3 mmol), benzyl chloroformate (1.17 g, 6.86 mmol) and acetone (20 ml) as a solvent were charged into a 100 cc two-necked flask, and heated for 2 hours while refluxing. After completion of the reaction, the mixture was added to 1H hydrochloric acid (50 ml), and extracted with ethyl acetate (50 ml×3). After drying, the organic layer was concentrated to obtain substantially pure benzyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate as a solid (2.21 g, 91.1% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: O=C(CCCCCl)c1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:26][C:27]1[O:31][C:30]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:28]=1>C(#N)C>[C:17]([C:9]1[C:10]([C:13]([F:15])([F:16])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:26][C:27]1[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12]2)#[N:18]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.500 g, 1.98 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (6.50 g, 20.0 mmol) along with ethyl 5-(chloromethyl)-2-furancarboxylate (0.561 g, 3.00 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was mixed with 1.0N LiOH (25 mL) and anhydrous 1,4-dioxane (2 5 mL) and the mixture was stirred at rt for 17 h. The mixture was diluted with water and extracted with Et2O. The organics were separated and the aqueous mixture was made acidic using 1.0N HCl. The aqueous mixture was extracted with EtOAc, dried (MgSO4) and concentrated to dryness to give a crude solid (0.579 g, 78%). This solid was used without further purification.
Reaction SMILES: Cl.C([N:6]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N+:25]([O-:27])=[O:26])[C:17]1=[O:28])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])(C)(C)C.CCOCC>C(Cl)Cl>[O:28]=[C:17]1[C:18]2[C:23](=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:20][CH:19]=2)[CH2:24][N:16]1[NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11]
Reactant: CC(C)(C)N([C@@H](CCC(N)=O)C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)CC[C@H](NN1Cc2c(cccc2[N+](=O)[O-])C1=O)C(=O)O
Temperature: 25 °C
Yield: 103.4 %

Procedure:
Hydrogen chloride gas was bubbled into a stirred 5° C. solution of t-butyl N-(1-oxo-4-nitro-isoindolin-2-yl)-L-glutamine (3.6 g, 9.9 mmol) in methylene chloride (60 mL) for 1 hour. The mixture was then stirred at room temperature for another hour. Ether (40 mL) was added and the resulting mixture was stirred for 30 minutes. The slurry was filtered, washed with ether and dried to afford 3.3 g of the product: 1H NMR (DMSO-d6) δ 8.45(d, J=8.1 Hz, 1H), 8.15(d, J=7.5 Hz, 1H), 7.83(t, J=7.9 Hz, 1H), 7.24(s, 1H), 6.76(s, 1H), 4.93(s, 2H), 4.84-4.78(dd, J=4.8 amd 10.4 Hz, 1H), 2.34-2.10(m, 4H); 13C NMR (DMSO-d6) δ 173.03, 171.88, 165.96, 143.35, 137.49, 134.77, 130.10, 129.61, 126.95, 53.65, 48.13, 31.50, 24.69; Anal. Calcd for C13H13N3O6: C, 50.82; H, 4.26; N, 13.68. Found: C, 50.53; H, 4.37; N, 13.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:39]=[CH:38][C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.NN>C(O)C>[NH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:14]3[N:15]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCCN5C(=O)c6ccccc6C5=O)cc4)nn23)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCCN)cc4)nn23)cc1

Procedure:
To a solution of 2-(3-{4-[5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-propyl)-isoindole-1,3-dione (XX-039) (0.1 g, 0.192 mmol) in ethanol (2 mL), hydrazine hydrate (0.05 mL, 0.192 mmol) was added and the solution was refluxed overnight. After removal of the volatiles under reduced pressure, the crude product was purified by preparatory HPLC. LCMS Method: 2: RT: 2.62 min, MI: 390 [M+1].
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=2)[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 23, using 5-bromo-N-(trans-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide and 4-trifluoromethoxyphenylboronic acid (commercially available) as starting materials. MS (m/e): 455.3 (MH+).