Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:69])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:69][N:43]([CH3:42])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester (93 mg, 240 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H33N5O4, 480.25. found 480.4.
Reaction SMILES: NN1CCCC1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=O)[CH:12]=[C:11]2[O:19][CH3:20].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:13]1[CH:12]=[C:11]([O:19][CH3:20])[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([Cl:7])[CH:9]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(=O)[nH]c2ccc(Cl)cc12
Agent: NN1CCCC1
Solvent: CN(C)c1ccccc1
Product: COc1cc(Cl)nc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 10 h

Procedure:
Methyl 5-chloro-2-(2-(triphenyl-λ5-phosphanyliden)-acetylamino)benzoate (3.8 g) was heated at 180° C. for 1 h. The reactant was suspended in chloroform and diisopropyl ether. Solids were collected by filtration and dried to obtain 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g). (3) A mixture of 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g), N,N-dimethylaniline (1 mL), and phosphorus oxychloride (4 mL) was stirred at 80° C. to 90° C. for 10 h. The reaction solution was added dropwise to ice water and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, followed by addition of silica gel. The desiccant and silica gel were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 2,6-dichloro-4-methoxyquinoline (1.2 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:15]([Cl:16])=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[K+]>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:15]([Cl:16])=[CH:14][C:11]([CH2:12][N:20]=[N+:21]=[N-:22])=[CH:10][C:9]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Yield: 100.9 %

Procedure:
A suspension of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (3.2 g, 8.5 mmol) and potassium azide (1.3 g, 16 mmol) in ethanol (32 ml) was refluxed 5 hours, cooled, and filtered. The precipitate was washed once with ethanol and the combined filtrate and wash were evaporated under vacuum. The residue was triturated with diethyl ether (50 ml) and filtered. The filtrate was evaporated under vacuum to provide 2.92 g (100%) of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl azide, m.p. 50°-55° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Yield: 64.9 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4dihydro-4-oxoquinoline-3-carboxylic acid, 260 mg of 5-chloroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14]>>[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Yield: 59.7 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 12.6 ml (79 mmol) of ethyl 3-bromobenzoate with 15 g (100 mmol) of 4-formylbenzene boronic acid, 12 g (60%) of the expected product are obtained.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=C(Br)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 3-bromobut-3-en-1-ol (ACROS, 15.18 g, 100.53 mmol) in DCM (300 mL) at room temperature was added imidazole (8.90 g, 130.69 mmol), 4-dimethylaminopyridine (2.456 g, 20.11 mmol) and tert-butyldimethylsilyl chloride (16.67 g, 110.58 mmol). The reaction mixture was stirred at room temperature for 3 hours, then filtered to remove solids and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound (24.67 g, 93%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:39])([F:38])[CH2:19][N:20]1[C:24]([CH2:25]O)=[CH:23][C:22]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:21]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:38])([F:17])[F:39])[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])[CH3:2].[NH2:12][C:13]([NH2:15])=[S:14].[NH4+].[OH-]>ClCCl>[CH2:1]([O:3][C:4]([C:5]1[S:14][C:13]([NH2:15])=[N:12][C:6]=1[CH:7]([CH3:9])[CH3:8])=[O:11])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N)nc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (10 g, 63.2 mmol) in dichloromethane (150 mL) at 0° C. is added SO2Cl2 (5.64 mL, 69.5 mmol). The reaction mixture is stirred at ambient temperature for 1 hour. The reaction mixture is extracted with water (30 mL). To the aqueous layer is added 1,4-dioxane (60 mL) followed by thiourea (8.8 g, 63.2 mmol). The mixture is stirred at 80° C. overnight and cooled to room temperature. The reaction mixture is adjusted to pH 12 with conc. NH4OH and filtered. The filter cake is washed with water to give the title compound (12.4 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:24](=[S:25])[N:23]([C:26]3[CH:27]=[C:28]([C:34]([F:37])([F:36])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=3)[C:22](=[O:38])[C:18]32[CH2:21][CH2:20][CH2:19]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N:17]3[C:24](=[S:25])[N:23]([C:26]4[CH:27]=[C:28]([C:34]([F:36])([F:37])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=4)[C:22](=[O:38])[C:18]43[CH2:19][CH2:20][CH2:21]4)=[CH:3][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:41])[CH3:40]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCCN4CCNCC4)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCOc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A mixture of 5-(5-(3-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 174, 50 mg, 0.1 mmol), acetic anhydride (13 μL, 0.14 mmol), and triethylamine (40 μL, 0.27 mmol) in DCM (2 mL) was stirred at room temperature for 2 days. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford 34 mg of 5-(5-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.74 (s, 1H), 7.42 (t, 1H), 7.35 (dd, 1H), 7.22 (m, 1H), 4.28 (t, 2H), 3.42 (m, 4H), 2.80 (t, 2H), 2.65-2.59 (m, 2H), 2.54-2.44 (m, 6H), 1.98 (m, 4H), 1.57 (m, 1H). LCMS [M+1]+ 591.9.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35]Cl)[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1COCC1>[CH:32]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:33]=1[C:34]1[N:22]3[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:9][O:8][CH2:35][C:23]3=[N:24][C:25]=1[CH:26]=[N:27]2
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3cnc4ccccc4c3n21
Temperature: -78 °C
Reaction time: 96 h
Yield: 89.3 %

Procedure:
tert-Butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentylcarbamate (1.28 g, 2.40 mmol) was dissolved in 200 mL of CH2Cl2 and the solution was cooled to −78° C. under N2. A 1.0 M solution of tetrabutylammonium fluoride in THF (2.88 mL) was added and the reaction mixture was allowed to warm to ambient temperature. After 4 days, the reaction mixture was then treated with 50 mL of saturated sodium bicarbonate solution. The layers were separated and the organic portion was washed with H2O (50 mL) and brine (4×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 4% methanol/CHCl3) gave tert-butyl 3-[(11S)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (820 mg) as a light yellow foam.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].N([O-])=O.[Na+].C(#N)C.O.[ClH:28]>O.Cl[Cu]>[Br:9][C:6]1[CH:5]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:2]([Cl:28])[C:7]=1[OH:8]
Reactant: Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H2O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO2 (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO4 and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). 1HNMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:10]=1)#[N:4]>CCO>[F:23][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[N:1][OH:2])[NH2:4])=[CH:10][C:9]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13]
Reactant: NO
Reactant: N#Cc1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Solvent: CCO
Product: NC(=NO)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 70 °C

Procedure:
NH2OH (10 mL, 32.1 mmol) was added in one portion to a stirred suspension of N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70° C. for 3 hours and then the solvent was removed to yield N-(2-fluoro-5-(N′-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (50). 1H NMR (400 MHz, d6-DMSO) δ 10.21 (s, 1H), 9.70 (s, 1H), 9.45 (td, J=1.2, 7.2 Hz, 1H), 8.61 (s, 1H), 7.95 (dd, J=2.4, 7.6 Hz, 1H), 7.79 (td, J=1.2, 8.8 Hz, 1H), 7.51-7.60 (m, 2H), 7.31-7.37 (m, 1H), 7.19 (dt, J=1.2, 6.8, 1H), 5.88 (s, 2H). MS m/z 314.1 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][C:12]([O:40][CH3:41])=[C:13]([O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:43][C:44]([NH:46][CH:47]([CH3:49])[CH3:48])=[O:45].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:47]([NH:46][C:44](=[O:45])[CH2:43][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][C:12]([O:40][CH3:41])=[C:13]([O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:49])[CH3:48]
Reactant: CC(C)NC(=O)CCl
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(O)c3)nc2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Temperature: 80 °C

Procedure:
To a solution of tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.400 g, 0.72 mmol) and 2-chloro-N-isopropylacetamide (0.107 g, 0.79 mmol) in DMF (16 mL) was added K2CO3 (0.297 g, 1.44 mmol). The mixture was heated at 80° C. for 72 h. The mixture was concentrated in vacuo and taken on directly into the next step. HPLC retention time 6.76 mins.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:6]2[CH2:7][C:8]3([CH3:11])[CH2:9][CH2:10][CH:5]2[C:3](=[O:2])[O:12]3)(=[O:14])=[O:15])=[CH:17][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCC(C)(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC12CCC(C(=O)O1)N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid methyl ester (0.047 g, 0.11 mmol), p-toluenesulfonic acid (0.010 g, 0.05 mmol) and toluene (2.0 mL) was heated to 90° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo, giving 0.035 g of 5-(4-Benzyloxy-benzenesulfonyl)-1-methyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless oil:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH:37]=2)=[CH:32][CH:31]=1>N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:41][CH2:40][N:39]([C:18](=[O:20])[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:22][CH:21]=3)[CH2:38][CH:37]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CC=C(c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 3.9 g of 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoic acid and thionyl chloride is allowed to reflux for 41/2 hours. After isolation, the acid chloride is dissolved in 100 ml pyridine and 4.0 g of 4-[4-chlorophenyl]-1,2,5,6-tetrahydropyridine is added. The reaction is stirred overnight and then partitioned between chloroform and aqueous sodium carbonate. The organic phase is dried and concentrated. The residue is crystallized from methylene chloride. The crystals are filtered, washed with ether, and dried to yield 2.99 g (57%) of 4-(4-chlorophenyl)-1,2,5,6-tetrahydro-1-[4-[[7-(trifluoromethyl)-4-quinolinyl]-amino]benzoyl]pyridine, of melting point 225°-226° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:40])[C:26]1[CH:38]=[CH:37][C:36]([OH:39])=[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:27]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCCC.CCOC(C)=O>[CH3:23][O:24][C:25](=[O:40])[C:26]1[CH:38]=[CH:37][C:36]([O:39][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH:27]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Yield: 96.4 %

Procedure:
15-Bromo-pentadecanoic acid tert-butyl ester (598 mg, 1.59 mmol), 4-hydroxy isophthalic acid 3-tert-butyl ester 1-methyl ester (400 mg, 1.59 mmol) and K2CO3 (329 mg, 2.38 mmol) were placed in a flask with acetonitrile (25 ml) and refluxed under N2. The reaction was followed via TLC (4:1 heptane/AcOEt). After 13 h the sample was concentrated under vacuum to near dryness. AcOEt (50 ml) and water (25 ml) were added to the residue. The phases were separated and the organic phase was washed with water and brine (25 ml each), dried over MgSO4 and concentrated to yield an oil (841 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[C:9]#[CH:10])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[C:9]#[CH:10])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: C#CC(O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C#CC(=O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-ol (257 mg, 0.535 mmol) was dissolved in DCM (5 ml) charged with Dess-MartinPeriodinane (341 mg, 0.803 mmol) and allowed to stir for 2 h at rt. The reaction was charged with 5 mL 1N sodium thiosulfate and 5 mL saturated sodium bicarbonate and allowed to stir for 15 minutes. The organic layer was separated and the solvents were concentrated in vacuo. Purification on silica gel, 10-50% EtOAc/hexanes gave 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-one (60B, 137 mg, 0.287 mmol, 53.5% yield). MS: [M+H]+ m/z 478.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1cccc(S(C)(=O)=O)c1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cccc(S(C)(=O)=O)c2)nc2nc(N)sc12

Procedure:
The title compound was prepared from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (16.5 g, 55.3 mmol) and 1-[(1R)-1-chloroethyl]-3-(methylsulfonyl)benzene (12.1 g, 55.3 mmol) according to general method A.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][CH2:4][NH:5][C:6]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([C:23]#[C:24][CH2:25][CH:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]C)=O)[CH2:28][CH2:27]4)[N:20]=[C:21]([NH2:22])[C:16]=3[N:15]=[CH:14]2)[C@H:10]([OH:36])[C@@H:9]1[OH:37])=[O:7]>CO>[CH2:4]([NH:5][C:6]([CH:8]1[CH:9]([OH:37])[CH:10]([OH:36])[CH:11]([N:13]2[CH:14]=[N:15][C:16]3[C:17]2=[N:18][C:19]([C:23]#[C:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]([C:32](=[O:34])[NH:2][CH3:1])[CH2:28][CH2:27]2)=[N:20][C:21]=3[NH2:22])[O:12]1)=[O:7])[CH3:3]
Reactant: CN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CCC4CCC(C(=O)NC)CC4)nc32)C(O)C1O
Temperature: 70 °C
Reaction time: 120 h
Yield: 48 %

Procedure:
To a sealed tube containing 10 mL 2.0 M methylamine in methanol was added 16.5 mg (0.03 mmol) of ATL146e. The flask was sealed and allowed to stir at 70° C. for 120 hours. The vessel was cooled to 0° C., opened, and the solvent was removed in vacuo to yield 8.0 mg (48%) of JR3065 as a white solid after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 486.3 (MH+, 100), 313.4(35).