Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Nc1ccccc1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To an ice cooled solution of ethyl-o-aminobenzoate 1 (33 g, 0.2 mole) in acetone (270 ml) was added with stirring an ice cooled solution of potassium carbonate (36.7 g, 0.27 mole) in water (214 ml) followed by addition of ethyl chloroformate (43 g, 0.4 mole). Stirring was continued at 0° C. for 11/2 hour and at 25° C. for 2 hours. The mixture was poured in water (300 ml) and extracted with three 300 ml portions of ether. The combined and dried (MgSO4) ether phases were evaporated in vacuo to give pure 2 (46.7 g, 98%). The product was recrystallized (EtOH, H2O) to give colorless crystals, mp <40° C. (Calc. for C12H15NO4 : C 60.75; H 6.37; N 5.90). (Found C 60.75; H 6.29; N 5.85) 1H NMR (CDCl3) δ= 1.3 (3H, t, J=7 Hz) 1.4 (3H, t, J=7 Hz) 4.2 (2H, q, J=7 Hz) 4.3 (2H, q, J=7 Hz) 6.9-8.5 (4H, AA'BB'). IR (CCl4): 3300(m), 2980(m), 1735(s), 1690(s), 1600(s), 1510(w), 1450(s).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[NH:14][CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)CN1CCc2ccc(N)cc2CC1
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)NC)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(3-methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (117 mg, 52%). LCMS (m/e) 526 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.08 (s, 1H), 7.40-7.33 (m, 1H), 7.33-7.24 (m, 2H), 7.18 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, J=8.1 Hz), 6.85 (s, 1H), 6.20-6.13 (m, 1H), 3.46-3.36 (m, 2H), 3.12 (s, 2H), 2.87 (d, 3H, J=4.9 Hz), 2.87-2.81 (m, 2H), 2.81-2.74 (m, 2H), 2.72-2.63 (m, 4H), 1.15 (t, 3H, J=7.3 Hz).
Reaction SMILES: C(OC([N:8]([C@H:13]1[C:21]2[C:16](=[C:17]([C:22]3[S:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([C:37]#[N:38])[CH:28]=4)=[N:25][N:26]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][C:10]([OH:12])=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[C:37]([C:29]1[CH:28]=[C:27]([C:24]2[S:23][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH2:15][CH2:14][C@H:13]4[NH:8][CH2:9][C:10]([OH:12])=[O:11])=[N:26][N:25]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:38]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4N(CC(=O)O)C(=O)OC(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NCC(=O)O)s2)cc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of (R)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid (20 mg, 0.03) mmol in 1,4-dioxane (0.5 mL) was added 4N HCl in 1,4-dioxane (0.2 mL). The mixture was stirred at 50° C. for 2 h before it was concentrated and triturated with ether to afford 13 mg of (R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid as yellow-green solid. LCMS-ESI (m/z) calculated for C23H22N4O3S: 434.14, found 435.2 [M+H]+, tR=2.51 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][N:22]([CH2:33][CH2:34][CH:35]=O)[C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:35][CH2:34][CH2:33][N:22]([CH3:21])[C:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CN(CCC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.21 g, 4.10 mmol) and phenylmethyl methyl(3-oxopropyl)carbamate (1.63 g, 7.39 mmol) in glacial acetic acid (15 mL) was treated with sodium trisacetoxyborohydride (1.74 g, 8.21 mmol) and stirred under nitrogen at ambient temperature. After approximately 1 hour, additional sodium triacetoxyborohydride (1.00 g, 4.72 mmol) was added. After an additional 3-4 hours, additional phenylmethyl methyl(3-oxopropyl)carbamate (1.00 g, 4.52 mmol) and sodium triacetoxyborohydride (1.00 g, 4.72 mmol) was added. The reaction mixture was evaporated in vacuo and the residue was dissolved in CH2Cl2 and treated with 2N KOH. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organic layers were washed with water, dried over MgSO4, filtered, evaporated in vacuo and purified on silica eluting with 3% MeOH in CH2Cl2 to provide the product as an oil: 1H NMR (CDCl3) δ 7.88 (1H, s), 7.77 (1H, s), 7.26-7.37 (5H, m), 7.11 (2H, b), 6.97 (2H, t, J=8.8), 6.74 (1H, d, J=31 Hz), 5.12 (2H, s), 4.42 (2H, q, J=7 Hz), 3.90 (2H, s), 3.41 (2H, t, J=7), 3.06-3.20 (2H, m), 2.92 (3H, s), 1.86 (2H, b), 1.42 (3H, t, J=7 Hz); ES+ MS: 480 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([N:40]2[CH2:45][CH2:44][S:43][CH2:42][CH2:41]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[CH:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:39])[C:7]=1[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Sn]([C:59]#[N:60])(CCCC)(CCCC)CCCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]1[N:6]2[N:25]=[CH:26][C:27]([CH:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:39])=[C:5]2[N:4]=[C:3]([N:40]2[CH2:45][CH2:44][S:43][CH2:42][CH2:41]2)[C:2]=1[C:59]#[N:60]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn12
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-thiomorpholinodioxo-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (35 mg, 0.051 mmoL), Bu3SnCN (32.3 mg, 0.10 mmoL), Pd[P(t-Bu)3]2 (5.2 mg, 0.010 mmoL) in Dioxane (3 mL) was heated at 100° C. overnight. The mixture was cooled to room temperature and the solvent was evaporated. Purification by column chromatography afforded 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-5-thiomorpholinodioxo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS tR=2.76 Min (5 min run, UV254nm). Mass calculated for, M+ 678.28, observed LC/MS m/z 679.20 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH:36]1([CH2:41][C:42](Cl)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][C:42]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CCCC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and cyclopentylacetyl chloride (Lancaster, Cat. No. L14562). LCMS (M+H)+: m/z=595.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>C(N(CC)CC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: Brc1cccc(Cc2ccco2)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: FC(F)Oc1ccc(C#Cc2cccc(Cc3ccco3)c2)cc1
Yield: 61.1 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 2-(3-bromobenzyl)furan (385 mg, 1.62 mmol) in triethylamine (1.5 mL). Copper iodide (80 mg, 0.40 mmol), Tetrakis(triphenylphosphine) palladium (140 mg, 0.121 mmol) and 1-(difluoromethoxy)-4-ethynylbenzene (0.270 mg, 1.60 mmol) were added at room temperature. The reaction was capped and irradiated in a CEM Explorer microwave at 80° C. for 30 minutes then forced air-cooled. The crude material was loaded onto silica gel. Purification by chromatography (2% EtOAc in hexanes) afforded 0.317 gm of an oil (61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 2H) 6.16 (dd, J=3.1, 0.8 Hz, 1H) 6.37 (dd, J=3.1, 2.0 Hz, 1H) 7.21 (d, J=8.8 Hz, 2H) 7.28 (ddd, J=7.5, 1.6, 1.6 Hz, 1H) 7.31 (t, J=73.7 Hz, 1H) 7.34-7.42 (m, 3H) 7.53 (dd, J=1.9, 0.7 Hz, 1H) 7.61 (d, J=9.0 Hz, 2H); MS (EI) m/z 324.0 [M+·].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[C:12]1=[O:13].[H][H]>[Ni].COCCOC.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]2[C:12](=[O:13])[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:20]2=[O:21])[CH:4]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Agent: [Ni]
Solvent: CCO
Solvent: COCCOC
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 94.9 %

Procedure:
Wet Raney Nickel (0.9 g) is added to a solution of N-(2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (1.0 g, 3.4 mmol) in a 4:1 ethylene glycol dimethyl ether/ethanol solution. The reaction mixture is hydrogenated over 45 psi of hydrogen until the reaction mixture takes up 9 psi. The reaction mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a yellow residue. Chromatography of the residue gives the title product as a yellow-orange solid (0.84 g, mp 134°-136° C.) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:11]=1.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.CO>[C:28]([O:27][C:25](=[O:26])[N:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)[CH2:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccnc1CN(Cc1ccc(CO)cc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Lithium aluminum hydride (1.0 g) was suspended in THF (95 ml). After that, a THF solution (95.1 ml) containing the compound (3.17 g) obtained in Example 21-1 was gradually dropped therein at room temperature. Then, the whole was stirred for additional 1 hour. The reaction solution was added with ethyl acetate, methanol, and a 10% aqueous sodium potassium tartrate solution and the whole was stirred for 1 hour, followed by extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.37 g) as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([C:7]([N:9](C(=O)C2C=CC(OC)=CC=2)[C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]([CH3:32])[CH3:31])[CH:16]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:19]([C:20]#[N:21])=[C:18]([N:22]=[CH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]([CH3:31])[CH3:32])[CH:16]=3)[N:11]=2)=[O:8])=[CH:43][CH:44]=1
Reactant: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccccc3)c2C#N)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2nc3ccc(N(C)C)cc3c(N=Cc3ccccc3)c2C#N)cc1

Procedure:
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 20 mL of acetonitrile, 5 mL of 1N methanolic potassium hydroxide solution is added. The reaction mixture is heated under reflux conditions for 10 minutes, 1.5 mL of glacial acetic acid is added to it, then it is neutralized with 15 mL of 1M sodium hydrogen carbonate solution. The precipitate is filtered off, the yellow crystalline material is recrystallized from the mixture of 5 ml of dimethylformamide and 40 mL of ethanol. After drying 1.3 g of the title compound is obtained, m.p.: 185° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CCO.O>[CH:12]([NH:11][C:8]1[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1coc(NC(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To 2-isopropylamino-oxazole-4-carboxylic acid ethyl ester (2.5 g, 10.9 mmol) in EtOH (42 mL) and water (28 mL) was added NaOH (3.1 g, 77.4 mmol). The mixture was stirred at rt for 16 h, then cooled in an ice-bath and acidified to pH 3 with conc. HCl. The mixture was concentrated in vacuo to remove ethanol. The remaining aqueous phase was extracted with CH2Cl2 (3×200 mL). The organic phases were combined, dried over MgSO4 and concentrated to give 2-isopropylaminooxazole-4-carboxylic acid (1.86 g, 87% yield). LCMS found 171 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:5][CH2:6][S:7][CH3:8].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:32].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:32].[ClH:32].[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH2:5][CH2:6][S:7][CH3:8]
Reactant: COC(=O)C(CCSC)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(=O)C(CCSC)Nc1ccc(N)cc1

Procedure:
The 4-methylsulfanyl-2-(4-nitrophenylamino)butyric acid methyl ester (28) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[N:20]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(O)(=O)C.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[NH:20][C:21](=[O:25])[CH:22]=[CH:23][CH:24]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1cccc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1-c1ccc2cc(Nc3cccc(=O)[nH]3)ncc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 3.2 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine (80% pure, 175 mg, 0.390 mmol) in acetic acid (3 mL, 50 mmol) was added hydrogen bromide (2 mL, 20 mmol) (48% in acetic acid). The reaction mixture was stirred at 100° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then evaporated in vacuo. The resulting residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) followed by reverse phase HPLC purification and lyophilization to yield 4.3 mg (3.2%) of 6-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-one. LCMS (ESI): RT (min)=5.219, M+H=346.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.85 (broad s, 1H), 9.15 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.54-7.29 (m, 2H), 7.16 (t, J=9.6 Hz, 2H), 5.93 (m, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[N:21][CH:22]=1>C(O)C.C(OCC)(=O)C.Cl.CCO>[Br:16][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH:22]=1
Reactant: Oc1ccc(Br)cn1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1ccc(Br)cn1CC1(O)CCN(Cc2ccccc2)CC1
Yield: 78.5 %

Procedure:
Referring to the method 2 of Example 1, N-benzyl-1-oxa-6-azaspiro[2,5]-octane and 5-bromo-2-hydroxy-pyridine were used for preparing a free base. Melting point: 146-148° C. The product was dissolved in ethanol-ethyl acetate and salified with HCl-EtOH to obtain a hydrochloride, yield 78.5%. Melting point: 148-150° C. 1H-NMR (D2O, ppm) δ: 7.594 (1H, d, J=2.80 Hz), 7.495 (1H, dd, J1=9.52 Hz, J2=2.52 Hz), 7.24-7.34 (5H, m), 6.365 (1H, d, J=9.52 Hz), 4.112 (2H, s), 3.891 (2H, s), 3.208 (2H, d, J=13.15 Hz), 3.031 (2H, t, J1=11.20 Hz, J2=12.60 Hz), 1.742 (2H, t×d, J1=11.20 Hz, J2=3.95 Hz), 1.573 (2H, J=14.57 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]2)[O:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CCOCC>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][CH:3]2[CH2:7][S:6][C:5]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]3)[O:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1CCC2(C1)OC(CO)CS2
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)CC1CCC2(C1)OC(COS(=O)(=O)c1ccc(C)cc1)CS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of the product of Example O (2.60 g, 10 mmol) in pyridine (30 ml) is added p-toluenesulfonyl chloride (1.91 g, 10 mmol) in portions over 15 minutes. When the addition is completed the reaction is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ether and washed with water, 0.5N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated on a rotary evaporator to give the titled compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH:13]2[OH:19].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][C:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][C:13]2=[O:19]
Reactant: CC12CCC(CC1O)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC12CCC(CC1=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxalyl dichloride (31.75 g, 0.25 mol) in DCM (300 mL) was added at −78° C. in consecutive order DMSO (19.5 g, 0.25 mol), a solution of 1-methylbicyclo[2.2.1]heptan-2-ol (21 g, 0.167 mol) in DCM (50 mL) and then triethylamine (50 g, 0.5 mol). The mixture was stirred at room temperature overnight and then poured into 200 mL, water. The resulting mixture was extracted with DCM (2×100 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude methylbicyclo[2.2.1]heptan-2-one, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford 12.4 g (0.10 mol, yield: 60%) of this compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cc(F)cc(F)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3,5-difluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (51 mg, 30%) which was obtained as a white solid (ESI). MS: m/e=337.9 [M+H]+.
Reaction SMILES: O[N:2]=[C:3]([NH2:13])[CH2:4][C:5]1([CH:10]([CH3:12])[CH3:11])OCC[O:6]1.Cl>C(O)C>[CH:10]([C:5]1[O:6][N:2]=[C:3]([NH2:13])[CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)C1(CC(N)=NO)OCCO1
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(N)no1
Temperature: 120 °C
Yield: 67.8 %

Procedure:
N′-Hydroxy-2-(2-isopropyl-1,3-dioxolan-2-yl)acetimidamide (1.8 g, 9.57 mmol) was dissolved in ethanol (12 ml) and acidified to pH=1 with 37% aqueous hydrochloric acid. The mixture was subjected to microwave heating at 120° C. for 30 minutes. After concentration under reduced pressure the residue was diluted with dichloromethane, a solution of saturated sodium bicarbonate was added until the solution became basic (pH=11) and the organic layer separated. After multiple extractions of the water phase with dichloromethane, the organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to afford 5-isopropylisoxazol-3-amine (819 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 5.52 (s, 1H), 3.89 (bs, 2H), 2.96-2.91 (m, 1H), 1.27 (d, 6H); LC-MS (ESI) m/z 127 (M+H)+.