Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:25]2[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:7]=1)[CH3:2]
Reactant: N#Cc1cccnc1Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncccc2C#N)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.672 g, 2.1 mmol), 2-chloro-3-pyridinecarbonitrile (0.274 g, 2.0 mmol), and potassium carbonate (0.966 g, 7.0 mmol) were combined in deoxygenated 2:1 DME:H2O (21 mL). Tetrakis(triphenylphosphine)palladium(0) (0.115, 0.1 mmol) was added, and the reaction was stirred at 70° C. for 1 hour. Once no starting material was seen by analytical LCMS and tlc, the mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26].[H][H]>CO.C1COCC1.[Ni]>[NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
2.17 g of the compound obtained in EXAMPLE 16 in 30 ml of MeOH and 30 ml of THF are reduced with hydrogen under a pressure of 40 bar for 4 hours at RT, in the presence of 1 g of Raney nickel. The mixture is vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=1.3 g. M.p.=198° C.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: CSc1cccc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CSc1cccc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=373.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-6-trifluoromethyl-benzoic acid (intermediate Z).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]([C:11]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:10])C(Cl)(Cl)Cl.C([O-])(=O)C.[NH4+:32]>C(O)C>[F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:11]2[C:12](=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:32][C:5]1=[O:10]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N(CC(F)(F)F)C(=O)C(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F

Procedure:
To a solution of 2.8 g of 2-[N-(2,2,2-trifluoroethyl)-trichloroacetamido]-5-chlorobenzophenone in 50 ml. of ethanol was added 4.6 g of ammonium acetate. The mixture was stirred and heated under reflux for 10 hours. Then the solvent was removed under reduced pressure. The residue was triturated with ether, filtered, washed with water and dried to give 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone. Recrystallization from ethanol gave pale yellow crystals, m.p. 185.0°-186° C.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)N1CCC(Oc2ccc(O)cc2)CC1
Yield: 83.5 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30](=[O:31])[CH2:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a mixture of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.164 g, 0.56 mmol) and 2-phenylacetyl chloride (0.96 mL, 0.724 mmol) was added 1,2-dichloroethane (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the desired product, 1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as a brown oil (0.230 g, 100%). LCMS [M+H]: 413.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([S:35][C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1>ClCCl.CO>[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[C:33]([S:35]([C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)=[O:6])[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Sc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(S(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
Under a nitrogen atmosphere 28 mg (0.11 mmol) 3-chloroperoxybenzoic acid (70%) in 5 mL dichloromethane was added dropwise to 60 mg (0.11 mmol) 7-methoxy-3-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylsulphanyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 5 mL dichloromethane and 1 mL methanol. After the reaction had ended the reaction mixture was evaporated down, dissolved in MeOH/DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14]>>[C:1]1([CH:7]([CH3:11])[C:8]([NH:12][C@H:13]([C:15]([N:17]2[C:23](=[O:24])[CH:22]([CH3:25])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[C:19]3[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]2=3)=[O:16])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CC(C(=O)O)c1ccccc1
Product: CC(C(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21)c1ccccc1

Procedure:
Following General Procedure C-P above using 2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 442 (M+H).
Reaction SMILES: [OH2:1].[OH:2][C@H:3]1[CH2:12][C@H:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]2[C:5]([CH:6]=[CH:7][C@H:8]([CH3:31])[C@@H:9]2[CH2:21][CH2:22][C@H:23]2[O:28][C:27](=[O:29])[CH2:26][C@H:25]([OH:30])[CH2:24]2)=[CH:4]1.[OH-].[Na+:33]>O1CCOCC1>[OH:30][C@H:25]([CH2:24][C@H:23]([OH:1])[CH2:22][CH2:21][C@@H:9]1[C@@H:10]2[C:5](=[CH:4][C@@H:3]([OH:2])[CH2:12][C@@H:11]2[O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH:6]=[CH:7][C@@H:8]1[CH3:31])[CH2:26][C:27]([O-:28])=[O:29].[Na+:33]
Reactant: O
Reactant: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 ml of water was added to a solution of 32 mg (0.076 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-hydroxy-8-(3,3-dimethylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-pyran-2-one [prepared as described in Example 28, above], in 1 ml of dioxane, after which 0.8 ml (0.08 mmol) of a 0.1N aqueous solution of sodium hydroxide was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was lyophilized to give 35 mg of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:18]2[N:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Clc1ncc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1c2ccc(Br)c(Oc3ncc4ccccc4n3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.025 g, 0.088 mmol), 2-chloroquinazoline (0.017 g, 0.106 mmol), and potassium carbonate (0.024 g, 0.176 mmol) in N,N-dimethylformamide (1.0 mL) was stirred in the microwave at 100° C. for 4 h. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.023 g, 63%). MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:4].I[C@@:21]1([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24](O)[C@H:22]1O>>[F:1][C:2]([F:18])([F:19])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:36]1[C:34](=[O:35])[NH:33][C:31](=[O:32])[N:30]([CH:37]=1)[C@@H:21]1[O:29][C@H:26]([CH2:27][OH:28])[CH2:24][CH2:22]1)=[O:4]
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C#CCCCCCCCCCCNC(=O)C(F)(F)F
Product: O=C(NCCCCCCCCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Protected alkynylamine 63 was coupled for 24 h to 5-iodo-2',3'-dideoxyuridine (47, 676.2 mg, 2.00 mmol, prepared as described in Example 2A) following the general procedure described in EXAMPLE 1C. Chromatography on silica gel (100 g) eluting with a 0-5% methanol in dichloromethane gradient afforded a dark red foam. The red impurity was removed by chromatography on a reverse phase column (100 g, octadecylsilane on 40 micrometer silica gel, Baker) with 40% water in methanol. The appropriate fractions were combined, concentrated, and co-evaporated twice with absolute ethanol to afford 731 mg of alkynylamino nucleoside 60 as a clear oil. This material was homogeneous by TLC and NMR except for the presence of residual ethanol (25 mole %, corrected yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1.[Sn](Cl)Cl.Cl.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cc(C)no1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Step H (2): 5-(2-Methoxy-4-nitrophenyl)-3-methylisoxazole (750 mg, 3.2 mmol) was added portionwise (exotherm observed) to a stirred mixture of tin(II) chloride (3.0 g), concentrated hydrochloric acid (3.0 mL), methanol (3.8 mL), and THF (15 mL). The resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo. The residue diluted with water and extracted with MTBE. The aqueous layer was basified with 10% NaOH solution to pH 13. The basic solution was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 3-methoxy-4-(3-methylisoxazol-5-yl)aniline (550 mg, 84% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][N:8]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Solvent: CCO
Solvent: CCNCC
Product: CCN(CC)CCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 135.8 %

Procedure:
20 mg of 4-(benzylamino)-6-({4-[4-(2-methylsulfonyloxyethyl)piperidino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 58) was dissolved in 1 mL of ethanol, to which 0.5 mL of diethylamine was added, and stirred in a sealed tube at 100° C. for 3 hours. After cooling, the solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 13 mg (68%) of the title compound as a slight brown crystalline powder.
Reaction SMILES: [C:1]([N:4]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][CH:20]=[CH:21][C:6]1=2)(=[O:3])[CH3:2].C([N:41](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(N)C=CC1=2)(=O)C>>[C:1]([N:4]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([NH2:41])=[CH:19][CH:20]=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(N)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-9-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 26, Steps 1-2 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 532 (M+H).
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:47])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][S:16][C@H:17]1[C:21](=[O:22])[CH2:20][C@@H:19]([O:23][Si](C(C)(C)C)(C)C)[C@@H:18]1/[CH:31]=[CH:32]/[C@@H:33]([O:39][Si](C(C)(C)C)(C)C)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CC#N>[CH3:8][O:9][C:10](=[O:47])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][S:16][C@H:17]1[C:21](=[O:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]1/[CH:31]=[CH:32]/[C@@H:33]([OH:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1SCCCSCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Hydrogen fluoride-pyridine (220 μL) was added to a solution of bis-TBDMS ether 7 (70 mg, 0.11 mmol) in CH3CN (2.0 mL) at 0° C. The reaction was warmed to room temperature, stirred 1 h, and recooled to 0° C. The reaction was quenched with saturated aqueous NaHCO3 until gas evolution ceased. The mixture was extracted with CH2Cl2 (4×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% CH2Cl2 followed by 30:1 CH2Cl2:MeOH) provided 40 mg (90%) of the above titled compound.
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a two-liter round bottomed flask was placed dimethyl sulfoxide (500 mL), 3-pentadecyl phenol (100.0 g, 0.33 mol) and sodium hydroxide (73.55 g, 1.31 mol). To this mixture methyl iodide (93.5 g, 0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for further 6 h. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous liquid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to obtain 3-pentadecyl anisole Yield 104.6 g (97%), MP 27-28° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH2:10]([O:12][C:13](OCC)(OCC)[C:14](OCC)=[O:15])C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:9]=[C:13]([O:12][CH3:10])[C:14](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc(Cl)c1N
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: COc1nc2c(Cl)ncnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
To a 50 mL round bottom flask at room temperature with a Teflon stir bar was added 6-chloropyrimidine-4,5-diamine (25 g, 172.9 mmol, 1 equiv), and anhydrous acetonitrile (300 mL). Ethyl 2,2,2-triethoxyacetate (36.87 g, 224.8 mmol, 36.9 mL, 1.3 equiv) followed by a catalytic quantity of 10-camphorsulfonic acid (3 g, 12.97 mmol, 0.075 equiv) were then added. The stirred reaction mixture was then heated to reflux for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to approximately 100 mL on a rotary evaporator and poured into 500 mL of vigorously stirring ice water. The resulting slurry was rapidly stirred for 20 minutes, and the resulting tan solid was then filtered through a medium porosity glass fritted funnel and was dried on the vacuum line to give the title compound as a brown solid (25.7 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.32 (broad s, 1H), 8.62 (s, 1H), 3.99 (s, 3H). MS (EI) for C7H5ClN4O2: 213 (MH+).