Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].Br[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:30]#[N:31]>>[C:30]([C:29]1[CH:28]=[C:27]([NH:1][CH:2]([C:4]2[CH:5]=[C:6]([C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]3=[O:20])[CH3:3])[CH:34]=[C:33]([F:35])[CH:32]=1)#[N:31]
Reactant: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: N#Cc1cc(F)cc(Br)c1
Product: CC(Nc1cc(F)cc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 81.7 %

Procedure:
8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (300 mg, 0.87 mmol, [α]D20°: +35° in acetonitrile) was reacted with 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) using a procedure similar to the one described in Example 8.00. Purification was done by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM followed by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (330 mg, 82%) as a clear white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C@@H:13]1[C@H:20]([O:21][C:22](=[O:28])[NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH2:19][CH2:18][C@@:15]2([O:17][CH2:16]2)[C@@:14]1([OH:33])[C:29]([CH3:32])=[CH:30][CH3:31]>ClCCl>[Br:12][C@@H:13]1[C@H:20]([O:21][C:22](=[O:28])[NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH2:19][CH2:18][C@@:15]2([O:17][CH2:16]2)[C@@:14]1([OH:33])[C:29]1([CH3:32])[CH:30]([CH3:31])[O:9]1
Reactant: CC=C(C)[C@@]1(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]12CO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1OC1(C)[C@@]1(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]12CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.5 %

Procedure:
1.12 g (4.74 mmol) of 72% 3-chloroperbenzoic acid are added to a solution of 0.46 g (1.16 mmol) of the compound obtained in Example 1 in 30 ml of dichloromethane. The reaction mixture is stirred at room temperature for 5 hours. The solid formed during the course of the reaction is filtered off. After conventional treatment of the organic phase and purification by chromatography on silica gel twice (eluant: hexane/ethyl acetate, 3:2), 0.146 mg (0.354 mmol) of the expected compound is obtained in the form of a mousse.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:24])=[C:14]([C:16]2([CH3:23])[CH2:21][O:20][CH2:19][C:18]([NH2:22])=[N:17]2)[CH:15]=1>>[NH2:22][C:18]1[CH2:19][O:20][CH2:21][C:16]([C:14]2[CH:15]=[C:10]([NH:9][C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH:11]=[CH:12][C:13]=2[F:24])([CH3:23])[N:17]=1
Reactant: CC1(c2cc(N)ccc2F)COCC(N)=N1
Reactant: O=C(O)CC(F)(F)F
Product: CC1(c2cc(NC(=O)CC(F)(F)F)ccc2F)COCC(N)=N1

Procedure:
In a manner analogous to that described in example E1 (method E), the condensation of 3,3,3-trifluoro-propionic acid with Building block P, (RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine, yielded the title compound as a yellow oil. Mass (calculated) C14H15F4N3O2 [33.283]; (found) [M+H]+=334.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 12 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.94 mmol) followed by the addition of benzoyl chloride (35 mg, 0.24 mmol). The reaction mixture was stirred at RT for 2 hr. The solution was washed with H2O (5 mL) and the organic layer dried (Na2SO4), and concentrated to provide a tan solid. This solid was then purified by chromatography (silica, 1:4 ethyl acetate/hexanes) to provide 19 as a white solid (80 mg, 67%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 1.47 (s, 9H), 2.40 (q, 2H), 6.50 (d, J=16 Hz, 1H), 6.89 (d, J=8 Hz, 2H), 6.95 (d, J=8 Hz, 2H), 7.12-7.16 (m, 3H), 7.17-7.22 (m, 4H), 7.53 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.62-7.72 (m, 3H), 8.01 (d, J=8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:29])([F:31])[F:30])[C:9]=3[CH:17]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccccc1Cl
Product: O=C(NCc1ccccc1Cl)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([NH:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]2)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (5 g) was dissolved in dimethylformamide (50 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (3.9 g) and 1-hydroxybenzotriazole (3.2 g) were added. The mixture was stirred at 0° C. for 15 min and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.5 g) was added, followed by stirring at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, and aqueous potassium carbonate solution was added to the residue. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 3.4 g of 4-amino-N-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].[C-:15]#[N:16].[Na+]>>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([CH3:3])[C:15]#[N:16])=[CH:5][CH:6]=1)[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: [C-]#N
Reactant: CC(C)=CCc1ccc(C(C)Cl)cc1
Agent: [Na+]
Product: CC(C)=CCc1ccc(C(C)C#N)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 81.8 %

Procedure:
A mixture of 21.0 g of 1-chloro-1-(p-prenylphenyl)ethane, 11.3 g of sodium cyanide and 140 ml of dimethylsufoxide was stirred at 60°-65° C. for 7 hours. After cooling, 400 g of ice-water was added and the resulting solution was extracted with n-hexane. The extract was washed with water, concentrated and distilled to give 16.4 g of 2-(p-prenylphenyl)propionitrile, b.p. 108-110 °C/0.28 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH2:22]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:16])([C:19](=[O:21])[NH:30][CH2:29][CH2:28][O:27][CH3:26])[CH2:24][CH3:25])[CH3:23]
Reactant: COCCN
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NCCOC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 2-methoxyethanamine (CAN 109-85-3) as starting materials. MS (EI): m/e=404.4 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:59]1)[NH2:55]>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
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: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (11.3 g, 49.8 mmol) in CH2Cl2 (360 mL). The mixture was allowed to warm to rt then the mixture was stirred at rt for 12 hrs. The mixture was then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride(2×), dried and concentrated. The residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[C:24]([CH:32]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:17]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN(C)C
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1CCCN(C)C
Yield: 40.5 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (113 mg, 0.5 mmol) was condensed with 4-(3-dimethylamino-propyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (133 mg) to give 96 mg (40%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]2[C:3]([CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)=[N:4][N:5]=[N:6]2)=[CH:9][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 575 mg, 2.00 mmol) in acetonitrile (10 mL) was added triethylamine (0.558 mL, 4.00 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (410 mg, 2.20 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor. The crude product was purified by silica chromatography (Biotage SP4, 40+S), eluting with 30% ethyl acetate in hexane (2 column volumes) then a gradient from 30-60% ethyl acetate in hexane (10 CV) then 60% ethyl acetate in hexane (2 column volumes). The relevant fractions were evaporated under vacuum to leave a white solid, 1,1-dimethylethyl 4-({1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (532 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:13])[N:9]([CH2:17][C:18]3[CH:28]=[CH:27][C:21]4[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=4[CH:19]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Cn1cc(-c2ncc[nH]c2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3ccnc(-c4cnn(C)c4)c3=O)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
To 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one (139 mg, 0.78 mmol) from Step 2 of this Example in DMF (3 mL) was added NaH (60% in mineral oil, 32 mg, 0.78 mmol) and the mixture was stirred at rt for 10 min. 6-(Chloromethyl)-2-(methylthio)benzo[d]thiazole (180 mg, 0.78 mmol) from Step 4 of Example 36 was then added. The mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% MeOH/DCM to afford impure 3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one (80 mg, 27%) which was used without further purification. LCMS (ESI) m/z 370 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: OCCCn1cncn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)-[1,2,4]-triazole (119 mg, 0.93 mmol), (EP0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 g, 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 3 hours at ambient temperature. The mixture was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/32/8). The purified product was triturated with a mixture of pentane and ether, collected by filtration and dried under vacuum to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation. The solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)quinazoline hydrochloride (121 mg, 39%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.44(t, 2H); 4.0(s, 3H); 4.3(t, 2H); 4.5(t, 2H); 7.32(s, 1H); 7.47(dd, 1H); 7.62(t, 1H); 7.70(dd, 1H); 8.08(s, 1H); 8.41(s, 1H); 887(s,1H); 9.10(s, 1H) MS-ESI: 429 [MH]+
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:23].C(N(CC)CC)C>C(O)(C)C>[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[N:6]3[CH3:11])[CH2:36][CH2:37]1)=[O:23]
Reactant: Cc1cccc(C(=O)NCc2ccccc2N2CCNCC2)c1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cccc(C(=O)NCc2ccccc2N2CCN(c3ncnc4c3nc(-c3cnn(C)c3)n4C)CC2)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 3-methyl-N-(2-(piperazin-1-yl)benzyl)benzamide (46.4 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 31.5 mg (50% yield) of the title compound.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:22])[NH:12][CH:13]([C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7].[I:23]I>C1COCC1>[C:6]([O:10][C:11](=[O:22])[NH:12][CH:13]([C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][C:20]=1[I:23])[CH3:14])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
Add tert-butyllithium (35 mL, 59.6 mmol) to a solution of [1-(6-chloro-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (5.1 g, 19.87 mmol) in THF (60 mL) under N2 at −78° C. After 30 min, add iodine (7.6 g, 29.8 mmol) in THF (20 mL) over 30 min at −78° C. Stir for 1 hour and then warm up to room temperature. Quench with water, extract in ethyl acetate with saturated aqueous sodium chloride, dry over Na2SO4. Purify on column chromatography 5% to 20% ethyl acetate in hexanes to obtain product (1 g). MS (ES) m/z 383 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:21]#[N:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[CH2:52]([O:54][C:55](=[O:58])[CH:56]=[CH2:57])[CH3:53]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:21]([C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:57]=[CH:56]/[C:55]([O:54][CH2:52][CH3:53])=[O:58])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Br)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 96 %

Procedure:
Tert-butyl 4-(2-bromophenyl)-4-cyanopiperidine-1-carboxylate (20, 100 mg, 0.28 mmol) and Pd(OAc)2 (7.0 mg, 0.030 mmol) were added to a vial, followed by tri(o-tolyl)phosphine (14 mg, 0.047 mmol). The reaction vial was purged with Ar (3×). Dry CH3CN (1.4 mL) and Et3N (103 μL, 0.74 mmol) were added, followed by ethylacrylate (36 μL, 0.33 mmol). The reaction mixture was heated at 85° C. overnight. The reaction was concentrated. Et2O (2 mL) was added to the mixture and was then filtered through Celite. The crude residue was purified by silica gel chromatography (gradient, 10% to 20% EtOAc/hexanes) to yield (E)-tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxoprop-1-enyl)phenyl)piperidine-1-carboxylate as a pale yellow oil (21, 102 mg, 96% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1H), 7.58 (dd, 1H), 7.41 (td, 1H), 7.38-7.34 (m, 1H), 6.31 (d, 1H), 4.29 (q, 1H), 3.29 (bt, 2H), 2.35-2.31 (m, 2H), 1.90 (dt, 2H), 1.47 (s, 9H), 1.35 (t, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[NH2:28]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:28][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:19]=3[CH3:18])[NH:25][N:24]=[CH:23]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc2[nH]ncc2cc1N
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cc3cn[nH]c3cc2C)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and 6-methyl-1H-indazol-5-yl-amine (Bionet), the title compound was obtained as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=C(N1C=CN=C1)[N:29]1C=CN=C1.N>ClCCl.O>[NH2:29][C:22]([C:21]1[CH:20]=[CH:19][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:26][CH:25]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Ammonia (0.88M, 35 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D36). MS (ES+) m/e 301 [M-tBu]+.