Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([C:29](=[O:36])[NH:30][O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([Cl:19])[C:13]2=[N:12][CH:11]=1)C)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH:33]1([CH2:32][O:31][NH:30][C:29]([C:16]2[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([Cl:19])[C:13]3[N:14]([C:10]([CH2:9][NH:7][CH3:6])=[CH:11][N:12]=3)[CH:15]=2)=[O:36])[CH2:35][CH2:34]1
Reactant: CN(Cc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cn12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cn12
Yield: 83 %

Procedure:
A solution of [7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxy-carbamoyl-imidazo[1,2-a]pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (62) in 1:1 dichloromethane/trifluoroacetic acid was stirred for two hours. Solvent was removed under reduced pressure and the residue redissolved into ethyl acetate. The organic solution was washed with saturated aqueous potassium carbonate and brine. The aqueous washes were back-extracted with ethyl acetate. The combined organic extracts are dried over NaSO4, filtered, and concentrated in vacuo to provide the desired product as a yellow solid (8 mg, 83%). MS (APCI+) m/z 512, 514, 516 (M+; Cl, Br pattern) detected. 1H NMR (400 MHz, methanol-d4) δ 8.72 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.25 (d, 1H), 6.55 (d, 1H), 4.23 (s, 2H), 3.67 (d, 2H), 2.51 (s, 3H), 1.13 (m, 1H), 0.50 (d, 2H), 0.24 (d, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)[N:22]=[C:21]4[NH:32][CH:33]=[CH:34][C:20]=34)[CH:18]=2)[CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:31][C:27]1[N:26]=[C:25]([C:23]2[N:22]=[C:21]3[NH:32][CH:33]=[CH:34][C:20]3=[C:19]([C:17]3[CH:18]=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[CH2:6][NH:5][CH2:4][CH2:3][OH:2])[CH:14]=[N:15][CH:16]=3)[CH:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CNCc1cccc(-c2cncc(-c3cc(-c4cccc(C)n4)nc4[nH]ccc34)c2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(-c3cncc(-c4cccc(CNCCO)c4)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-{5-[6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyridin-3-yl}-benzylamino)-acetic acid methyl ester (Example 131) (1 eq, 0.216 mmol, 100 mg) in THF (2.5 ml) at 0° C. is added LAH (1M in THF, 0.8 eq, 0.173 mmol, 0.173 ml). The resulting suspension is allowed to warm to r.t. and then stirred for 1 h at this temperature. After cooling to 0° C. sat. aqueous Na2SO4 solution is added, and the mixture is stirred for additional 30 min. The suspension is filtered and concentrated under reduced pressure. Addition of 4 M aqueous NaOH solution is followed by extraction with EtOAc. The organic layer is dried with MgSO4, filtered, and concentrated under reduced pressure. The crude product is recrystallized using EtOAc/MeCN to give the title compound; [M+H]+=436; 1H-NMR (400 MHz, CD3OD): δ 8.98 (d, 1H), 8.90 (d, 1H), 8.50 (t, 1H), 8.26 (s, 1H), 8.20 (d, 1H), 7.80-7.76 (m, 2H), 7.68 (d, 1H), 7.56 (d, 1H), 7.50 (t, 1H), 7.43 (d, 1H), 7.25 (d, 1H), 6.70 (d, 1H), 3.89 (s, 2H), 3.69 (t, 2H), 2.77 (t, 2H), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 0.295 mMol) in ethanol (3 mL) was added SnCl2 ·2H2O (331 mg, 1.47 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring to 0.5 h, to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 70 mg (97%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 32 mg of pure title compound as bright yellow needles; mp: 342°-5° C. (dec. from 335° C.), changed color from 325° C. IR (KBr, cm-1): 3468, 3362, 3193, 1693, 1631, 1493, 1375; NMR (1H, DMSO-d6): δ5.418 (s, 2H); 6.999 (s, 1H); 11.238 (s, 1H); 11.776 (s, 1H). HRMS: calcd for C8H5N3O2Cl2 (M+) m/z: 244.9757; found 244.9769. Potency relative to DCK: 8.6%.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[OH-:10].[Na+:11].C>O>[Na+:11].[CH2:1]([P:3]([OH:4])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Temperature: 70 °C
Yield: 93 %

Procedure:
15.2 g (0.1 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 5) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Pt and 1% Bi is added, the suspension is heated to 70° C. and air is passed through the suspension at 10 l/h. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH in solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, the filter residue is washed and the water is distilled off in vacuo to obtain 19.5 g (93% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[C:13]([O:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9](C)[CH:10]=2)[N:5]=1)([CH3:3])[CH3:2].C(C1C(OC2C(N)=NC(N)=NC=2)=CC2C(=C(C)C=CC=2)N=1)(C)C>>[CH:1]([C:4]1[C:13]([O:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc2nc(C(C)C)c(Oc3cnc(N)nc3N)cc2c1
Agent: Cc1cccc2cc(Oc3cnc(N)nc3N)c(C(C)C)nc12
Product: CC(C)c1nc2ccccc2cc1Oc1cnc(N)nc1N

Procedure:
Similarly prepared were 5-(2-Isopropyl-6-methyl-quinolin-3-yloxy)-pyrimidine-2,4-diamine (MP=239.4-242.1° C.) and 5-(2-Isopropyl-8-methyl-quinolin-3-yloxy)-pyrimidine-2,4-diamine (MP=248.3-249.4° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([OH:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)CCCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc2c(c1)CCCC2(C)C
Yield: 85.3 %

Procedure:
A mixture of 5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (2.0 g, 11.3 mmol), 60% sodium hydride (542 mg, 13.2 mmol), tert-butyl bromoacetate (3.3 g, 17 mmol) and tetrahydrofuran (THF) (10 ml) was treated in the same procedure described in Example 3(a) to furnish 2.8 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[C:2]#[CH:3].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1I>C(N(CC)CC)C.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.[Cu]I>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:3]#[C:2][CH2:1][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13]
Reactant: C#CCN1Cc2ccccc2C1=O
Reactant: Fc1ccc(I)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CC#Cc1ccc(F)cc1F
Reaction time: 8 h
Yield: 24.3 %

Procedure:
2-Prop-2-ynyl-2,3-dihydro-isoindol-1-one (50.0 mg, 0.29 mmol) was dissolved in triethylamine (2 mL). To this was added Pd(PPh3)4 (13 mg, 0.012 mmol), CuI (6.7 mg, 0.035 mmol) and 2,4-difluoro-1-iodo-benzene (52.0 μL, 0.438 mmol) and the reaction was allowed to stir overnight. The solvent was evaporated and the residue was purified by prep. TLC (30% EtOAc/Hexanes) to afford the title compound (20.0 mg, 24%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.45 (m, 4H), 6.84 (t, 2H), 4.72 (s, 2H), 4.59 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:21]>>[CH3:18][O:19][C:20]([CH2:22][CH2:23][C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25])=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: COC(=O)CCC(=O)Cl
Product: COC(=O)CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 66 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.057 mMol) 3-methoxycarbonylpropionyl chloride, 0.01 gm (67%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:36][C@@H:37]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=3)[C:38](O)=[O:39])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[C:49]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:37]([NH:36][C:34](=[O:35])[O:33][CH2:32][CH:30]2[C:31]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:38]([N:5]([CH2:6][CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[O:39])=[CH:47][CH:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CCOC(CNCc1ccc(F)cc1F)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1ccc(F)cc1F)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Reaction time: 8 h
Yield: 36.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1 with the modification that the reaction was carried out overnight, N-(2,4-difluorobenzyl)-2,2-diethoxyethanamine (Compound IX-17) (49.3 g, 190 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (49.0 g, 36%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:14])=[O:13]>C([O-])(O)=O.[Na+].ClCCl.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([CH3:11])(=[O:14])=[O:13])(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
A mixture of orcinol monohydrate (1.68 g, 12 mmol) and 2-methylsulfonylbenzenesulfonyl chloride (3.0 g, 11.8 mmol) in saturated NaHCO3 (25 mL) and dichloromethane (25 mL) was stirred vigorously at room temperature for one week. The reaction mixture was diluted with 50 mL of water and extracted into dichloromethane (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was treated with dichloromethane and ether to initiate crystallization. The mixture was filtered to provide 1.05 g (26% yield) of a white solid. 1H-NMR (300 MHz, CDCl3) δ2.22 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H), 6.51 (t, 1H), 6.54 (s, H), 6.61 (s, 1H), 7.74 (td, 1H, J=7.7, 1.4 Hz), 7.87 (td, 1H, J=7.7, 1.3 Hz), 8.12 (dd, 1H, J=7.8, 0.7 Hz), and 8.44 (dd, 1H, J=7.8, 0.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][C:3]=1[O:25][CH:26]([F:28])[F:27].Cl.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].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>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH3:30])[CH:39]([CH3:41])[CH3:40])=[N:10][CH:9]=2)=[CH:4][C:3]=1[O:25][CH:26]([F:27])[F:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74 %

Procedure:
(S)-tert-Butyl 2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.873 mmol) was dissolved in DCM (10 mL) and treated with HCl (4.0 M in dioxane, 2 mL). The reaction mixture was stirred at RT for 50 min, then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (168 mg, 0.960 mmol), HATU (365 mg, 0.960 mmol) and DMF (4 mL) then cooled to 0° C. DIPEA (0.760 mL, 4.37 mmol) was added dropwise and the reaction mixture was stirred for 30 min. After warming to RT, the mixture was diluted with EtOAc and the organic solution was washed with saturated aqueous NaHCO3, and brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (333 mg, 74%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C@H:10]1[OH:20])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:6]([N:8]([C@@H:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C@H:10]1[OH:20])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:7]
Reactant: CCN[C@@H]1CCCc2ccccc2[C@H]1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)CCl)[C@@H]1CCCc2ccccc2[C@H]1O
Reaction time: 0.5 h

Procedure:
A solution of 0.75 ml (0.022 m) of chloroacetyl chloride in 10 ml of methylene chloride was added dropwise to a solution of 2.3 g (0.0112 m) of trans-6-(N-ethylamino)-6,7,8,9-tetrahydro-5H-benzo cyclohepten-5-ol and 3.2 ml (0.023 m) of triethylamine in 90 ml of methylene chloride. The mixture was stirred 1/2 hour, water is added, and the layers are separated. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:5]=1
Reactant: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCOc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the crude 1-(6-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (0.86 g, 3.89 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (4.3834 g, 19.4 mmol) and the mixture was heated under reflux with stirring. After 1.5 h, the mixture was cooled to rt. To the mixture was added 2 M aqueous Na2CO3 (20 mL) followed by EtOAc (50 mL). The resulting white precipitate was filtered off and washed the white solid with EtOAc (50 mL). The filtrated was separated in a reparatory funnel. The aqueous layer was extracted with EtOAc (30 mL×1). The combined organics were washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give dark syrup. The dark syrup was purified by column chromatography on a silica gel column using 0 to 100% gradient of DCM-MeOH—NH4OH (89:9:1) in DCM as eluent to give 1-(6-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone as a red syrup: Mass Spectrum (ESI) m/e=193.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16]1([CH:22]([CH3:26])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CC(C(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C(C)c2ccccc2)cn1
Yield: 64.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (300 mg, 1.3 mmol), 2-phenylpropanoic acid (225 mg, 1.5 mmol), triethylamine (300 mg, 3 mmol), DMAP (61 mg, 0.5 mmol), and EDC (386 mg, 2 mmol) were stirred together in DCM (10 mL) at room temperature for 4 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated, on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-phenylpropanamide (272 mg, 81%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, 3H, J=7.2 Hz), 2.10 (s, 3H), 2.37 (s, 3H), 3.70 (m, 1H, J=6.8 Hz), 5.06 (s, 2H), 7.20 (t, 1H, J=8.4 Hz), 7.31-7.28 (m, 4H), 7.38 (s, 1H), 7.91 (s, 1H), 10.10 (s, 1H). LC/MS; [M+H] calculated for C18H20N4O2; expected 325.16; found 325.5. Melting point: 129-130° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:14]1[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=1[O:20][CH3:21])(=[O:17])=[O:18]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., 5-bromo-2-methoxybenzenesulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.07 g of N-(2-aminophenyl)-5-bromo-2-methoxybenzene sulfonamide. 1H NMR (CDCl3, 400 MHz): δ 4.08 (s, 3H), 4.22(bs, 2H), 6.52 (m, 2H), 6.75 (m, 2H), 7.01 (d, 1H), 7.03 (m, 1H), 7.65(dd, 1H), 7.88 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.055 g, 0.14 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.021 mL, 0.14 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 4 hours, yielding the benzamide derivative. Boc-deprotection was completed through the addition of formic acid (5 mL) and concentrated HCl (0.5 mL) added dropwise directly to the reaction mixture. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD72. ESI-MS m/z [M+H]+ found 468.5, calculated 468.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([CH2:37][CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[C:12]([C:14]1[NH:15][C:16](=[O:36])[C:17]([O:34][CH3:35])=[C:18]2[C:23]=1[CH2:22][CH2:21][N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=1)[C:19]2=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[C:12]([C:14]1[NH:15][C:16](=[O:36])[C:17]([O:34][CH3:35])=[C:18]2[C:23]=1[CH2:22][CH2:21][N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=1)[C:19]2=[O:33])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c2c(c(C(=O)N(CCCCO[Si](C)(C)C(C)(C)C)CCOCc3ccccc3)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c2c(c(C(=O)N(CCCCO)CCOCc3ccccc3)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(benzyloxy)ethyl]-N-(4-{[tert-butyl(dimethyl)silyl]-oxy}butyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.41 g, 0.59 mmol) in THF, a solution of tetra-n-butyl-ammonium fluoride (0.65 mL, 1M) in THF was added. The reaction mixture was stirred at room temperature overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3% methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCOCCO.O.CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCOCCOCCO
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82.7 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of triethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.4 g of 2-cyano-4'-methylbiphenyl.