Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=[CH:20]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>O.C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=[CH:20]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)c1cccc2cc(N)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cccc2cc(Nc3ncnc4cc(OC)c(OC)cc34)ccc12
Temperature: 90 °C

Procedure:
The following reagents were combined in a flask and placed in a RT oil bath that was then heated to 90° C.: 4-Chloro-6,7-dimethoxyquinazoline (954 mg, 4.24 mmol), methyl 6-amino-1-naphthoate (857 mg, 4.24 mmol), TFA (098 mL, 12.7 mmol), and isopropanol (12 mL). The reaction was done before the bath reached the desired temperature. The mixture was diluted with water and made pH basic with 6N NaOH. The solid was filtered and rinsed with water and Et2O. The title compound was obtained as a pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:33]([O:35][CH3:36])=[O:34])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Reactant: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.53 g, 1.53 mmol) and triethylamine (0.25 ml, 1.80 mmol) in dichloromethane (10 ml) at room temperature was added methyl chloroformate (0.14 ml, 1.80 mmol). The solution was stirred for 2 hours and then water added. The organic layer was separated, dried and evaporated to give a crude product, which was crystallized from ether. The crystalline material was then purified by chromatography on silica gel, eluting with acetone/dichloromethane (20/80) to give 0.33 g of 6-nitro-2,2-dimethyl-3-(methoxycarbonylamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 199° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][CH3:24])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNC1CCCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Reaction time: 12 h
Yield: 32.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (2.95 g), 3-methylaminopiperidine dihydrochloride (6.69 g) and triethylamine (10 g) in acetonitrile (50 ml) was refluxed with stirring for 12 hours. The reaction mixture was concentrated in vacuum, and the residue was extracted with chloroform. The extract was washed with a saturated NaCl solution and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol:ammoniumhydroxide=15:5:1) to give 1.28 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid, which was recrystallized from acetonitrile-water, colorless needles. m.p. 134°-135° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]\CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 ml of dichloromethane at -30° C. under argon was added 0.18 ml (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of (E,E)-3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 ml of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:pet ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13]=2[N:14]=1)[CH3:3].C(N(CC)CC)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[CH2:2]([C@@H:4]1[CH2:8][N:7]([C:42]([C:33]2[CH:34]=[N:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]=2)=[O:43])[CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]=2[N:14]=1)[CH3:3]
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1CN(C(=O)c2cnc3ccccc3n2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (73 mg) in dicloromethane (2 mL) was added triethylamine (62 mg) and 2-quinoxaloylchloride (40 mg) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via CombiFlash flash chromatography eluting with 24% MeOH/methylene chloride provided the title compound. 400 MHz 1H NMR (CDCl3) δ 12.78-12.62 (m, 1H), 9.41 (d, J=7.5, Hz, 1H), 8.18-8.00 (m, 3H), 7.87-7.73 (m, 2H), 4.84-4.81 (m, 1H), 4.55-3.86 (m, 6H), 3.61-3.53 (m, 2H), 3.38-3.31 (m, 1H), 2.75 (m, 1H), 2.39-2.34 (m, 2H), 1.93-1.89 (m, 2H), 1.58-1.56 (m, 1H), 1.63-1.50 (m, 1H), 1.01-0.88 (m, 3H). MS: (M+H m/z 474.2).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:50]=[CH:49][N:48]=[C:47]([C:51]([OH:53])=O)[C:46]2=[O:54])=[CH:41][CH:40]=1>>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[C:46](=[O:54])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=3)[CH:50]=[CH:49][N:48]=2)=[O:53])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][CH2:22]3)[C:8]=12
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: CC(C)N1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 64 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy) N-(1-isopropylpiperidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in Example 101, Step A except using 1-isopropylpiperidin-4-amine) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (Example 125, Step E) according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 4.6 mg (64%) of the desired product. The desired product was treated with 2N HCl (Et2O solution) in a solution of MeOH and EtOAc to afford HCl salt compound. LRMS (APCIpos) m/e 601.3 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.17 (d, 1H), 8.06 (dd, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.55 (m, 2H), 7.49 (d, 1H), 7.34 (t, 3H), 6.14 (d, 1H), 3.93 (m, 1H), 3.52 (m, 2H), 3.17 (m, 2H), 2.47 (m, 2H), 1.96 (m, 2H), 1.40 (d, 6H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −111.0, −127.6.
Reaction SMILES: [CH2:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[NH2:13]N.O.NN>>[NH2:13][CH:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: NN
Reactant: c1ccc2c(c1)=NC1CCCC=21
Solvent: O
Product: NC1CCC2N=c3ccccc3=C12

Procedure:
In Scheme 1, Step C, the phthalimide group of the tetrahydrocyclopenta[b]indole of formula (2) is cleaved with hydrazine or hydrazine hydrate to provide an aminotetrahydrocyclopenta[b]indole of formula (3). Preferred conditions use tetrahydrofuran/ethanol in a mixture of about 20/1 by volume at a temperature of about 40 to 70° C., for 1 to 12 hours. The resulting phthalhydrazide is removed by filtration and the product isolated by concentration of the filtrate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:36])[CH:19]([NH:23][C:24](=[O:35])[CH:25]([NH:27]C(OC(C)(C)C)=O)[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:36])[CH:19]([NH:23][C:24](=[O:35])[CH:25]([NH2:27])[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)C(C)N)C(C)C
Reaction time: 2.5 h
Yield: 42.4 %

Procedure:
To a solution of 51 (160 mg, 0.28 mmol) in DCM (10 mL) was added TFA (2 mL) at ambient temperature. After 2.5 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. A portion (˜50%) of the crude material was purified by reverse-phase HPLC (C18, 10-100% ACN/water containing 0.1% HOAc) to afford 56 mg of 52 as a white solid. 1H NMR (DMSO, 300 MHz) 58.03 (d, J=8.7 Hz, 1H), 7.77 (m, 1H), 7.43-7.41 (m, 1H), 7.21 (m, 2H), 4.37 (app t, J=8.1 Hz, 1H), 4.19 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.65 (m, 1H), 3.56 (app d, J=6.6 Hz, 1H), 3.28 (m, 1H), 3.06-3.01 (m, 3H), 2.68 (app t, J=7.2 Hz, 2H), 2.07-1.96 (m, 1H), 1.63 (m, 1H), 1.54 (m, 1H), 1.13-1.09 (m, 6H), 0.90 (d, J=6.3 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H) ppm. Mass spectrum: m/z 472 [M+H]+; and, 494 [M+Na]+.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Br)c1F
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2F)CC1

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid was synthesised following the procedure in Example 162 (Step ii) using 3-bromo-2-fluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:10])[C@@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.[Cl:11][C:12]1[C:13]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:14][C:15]([NH:18][C:19]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22](F)=[CH:21][C:20]=2[O:29][CH3:30])=[N:16][CH:17]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:11][C:12]1[C:13]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:14][C:15]([NH:18][C:19]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([N:7]3[CH2:8][CH2:9][C@@H:5]([N:4]([CH3:10])[CH3:3])[CH2:6]3)=[CH:21][C:20]=2[O:29][CH3:30])=[N:16][CH:17]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 61 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine dihydrochloride (90 mg, 0.48 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 200 mg, 0.48 mmol) and DIPEA (0.250 mL, 1.45 mmol) in DMA (3 mL). This mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column, washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (149 mg, 61%) as an orange foam; 1H NMR: 1.76-1.89 (1H, m), 2.14-2.25 (7H, m), 2.69-2.84 (1H, m), 3.12-3.27 (3H, m), 3.41-3.53 (1H, m), 3.89 (3H, s), 6.56 (1H, s), 7.13 (1H, td), 7.26-7.38 (1H, m), 8.06 (1H, s), 8.40-8.43 (2H, m), 8.73 (1H, s), 8.85 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.5.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N+:22]([O-])=O)[C:14]1=[O:25].[Cl-].[NH4+]>CO.O.[Zn]>[NH2:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][N:13]([CH2:12][CH2:11][N:2]1[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]1)[C:14]2=[O:25]
Reactant: O=C1c2cccc([N+](=O)[O-])c2CN1CCN1CCc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1cccc2c1CN(CCN1CCc3ccccc3C1)C2=O
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 37 (0.38 g, 1.1 mmol) in methanol (6 mL) was added a solution of ammonium chloride (0.13 g, 2.42 mmol) in water (1.5 mL). Zinc powder (0.49 g, 7.4 mmol) was then added portionwise and the resulting mixture was stirred for 2 hours. The solids were filtered and washed with methanol, the filtrate was basified with saturated sodium bicarbonate (aq.), and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 38 (0.31 g, 88%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:43][C:40]2[CH:39]=[CH:38][C:37]([CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (43.8 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 15% (0.021 g, 0.067 mmol) of the title compound.
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=1)[O:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:44][CH:43]=1>O1CCOCC1>[NH2:41][C:37]1[N:38]=[CH:39][N:40]=[C:35]([O:34][C:33]2[CH:32]=[C:31]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:57]=[CH:56][CH:55]=2)[C:36]=1[C:42]1[CH:43]=[CH:44][C:45]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:46][CH:47]=1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Reactant: C=CC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Into a 20 mL reaction vial was added acrylic acid (0.01 ml; 0.12 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42.04 mg; 0.17 mmol), and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at rt for 1 h. 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08 mmol) was then added. The reaction mixture was stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was then purified using preparative HPLC eluting from 35-45% CH3CN in 0.1% TFA in H2O. fractions containing the desired product were combined and lyophilized overnight to afford N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide as a white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264 min. MS: m/z=425 [M+H]+, RT=2.14 min. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]3[CH2:16][CH2:15][CH2:14][S:13]3)[C:6]=2[NH:5][C:4]2=[CH:17][C:18]([C:20](O)=[O:21])=[N:19][N:3]12.CO.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]3[CH2:16][CH2:15][CH2:14][S:13]3)[C:6]=2[NH:5][C:4]2=[CH:17][C:18]([C:20]([NH:38][C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[O:21])=[N:19][N:3]12
Reactant: O=C(O)c1cc2[nH]c3c(C4CCCS4)cccc3c(=O)n2n1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cc2[nH]c3c(C4CCCS4)cccc3c(=O)n2n1

Procedure:
From 4,9-dihydro-9-oxo-5-(tetrahydro-2-thienyl)pyrazolo[5,1-b]quinazoline-2-carboxylic acid, compound with methanol (1:1) (0.40 g; 1.3 mmole), DMF (20 ml); 1,1' carbonyl-diimidazole (0.5 g; 3.1 mmole) and 5-amino-1H-tetrazole, monohydrate (0.131 g; 1.3 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-9-oxo-5-(tetrahydro-2-thienyl)-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide (70 mg); mp>230° (d).
Reaction SMILES: [CH3:1][Br:2].[CH:3]([N:6]([CH:24]([CH3:26])[CH3:25])[CH2:7][CH2:8][C@@H:9]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[OH:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH3:4]>CC(C)=O>[Br-:2].[OH:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][CH2:7][N+:6]([CH:3]([CH3:5])[CH3:4])([CH:24]([CH3:26])[CH3:25])[CH3:1]
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: CBr
Solvent: CC(C)=O
Product: Cc1ccc(O)c([C@H](CC[N+](C)(C(C)C)C(C)C)c2ccccc2)c1
Product: [Br-]
Temperature: 22.5 °C
Reaction time: 96 h

Procedure:
A sealed mixture of methyl bromide (100 g) and 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (14 g) in acetone (100 ml) is stirred at 20-25° C. for 4 days. The mixture is cooled to −10° C. and the precipitate is filtered off and washed with ether and dried to give the title compound, mp 189-191° C. (dec). Anal Calcd for C23H34BrNO: C, 65.71; H, 8.15; Br, 19.00; N, 3.33. Found: C, 65.61; H, 8.34, Br, 19.12; N, 3.32. [α]D (c=1, MeOH) +25° C. 1H NMR [(CD3)2SO] δ 1.25, 2.18, 2.48, 2.81, 3.05, 3.89, 4.22, 6.70, 6.83, 7.08, 7.19, 7.33, and 9.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=[C:25]([F:27])[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-amino-5-fluorobenzotrifluoride were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.75 (s, 1H), 9.32 (d, 1H, J=1.2 Hz), 8.13 (d, 1H, J=3.6 Hz), 7.99 (d, 1H, J=12.3 Hz), 7.77 (s, 1H), 7.21 (d, 1H, J=2.4 Hz), 7.13 (dd, 1H, J=2.1 and 8.7 Hz), 7.03 (d, 1H, J=9.0 Hz), 6.80 (d, 1H, J=8.7 Hz), 4.21 (s, 4H); LCMS: purity: 97%; MS (m/e): 425 (MH+).