Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO.O>[CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of methyl 2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate (0.015 g, 0.04 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.011 g, 80%). 1H-NMR (400 MHz, CDCl3) δ 7.86 (d, J=5.6 Hz, 1H), 7.50 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07 (dd, J=13.1, 2.8 Hz, 2H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.56 (m, 2H), 6.32 (d, J=2.0 Hz, 1H), 4.38 (dd, J=14.3, 7.0 Hz, 1H), 4.07 (t, J=5.8 Hz, 2H), 4.01 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (t, J=6.7 Hz, 2H), 2.92 (q, J=7.1 Hz, 1H), 2.08 (m, 2H), 1.12 (d, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C20H23N3O3 354.3 (M+H); Found: 354.2.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:64])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3[OH:63])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:64])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3[OH:63])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (380 mg, 0.425 mmol) in THF (5 mL) was added TBAF 1M in THF (0.851 mL, 0.851 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated approx 70% conversion so another 1 equiv of TBAF was added and the mixture was stirred for another 5 h. At this point LCMS indicated completion of reaction. Mixture was then concentrated and purified by biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (240 mg, 0.367 mmol, 86% yield) as approx 2:1 mixture of isomers. LCMS (M+H)=655.3.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.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>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of 4-amino-2-fluoro-5-methoxybenzoic acid (600 mg, 3.24 mmol), morpholine (564 mg, 6.48 mmol), HATU ((O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1.85 g, 4.86 mmol), DIPEA (diisopropyl ethylamine, 836 mg, 6.48 mmol), and CH2Cl2 (20 mL) was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography to afford the title compound (560 mg, 68%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[N:14]1([CH2:19][CH2:20][CH2:21][NH:22][C:11]([C:8]2[CH:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)=[O:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCCn1ccnc1)c1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid (7 mg) and 3-imidazol-1-yl-propyl amine (0.005 mL) in DMF was added 8 mg of HOBt, 9 mg of EDC and 0.014 mL of TEA. After stirring at room temperature for 18 hrs, the reaction solution was concentrated in vacuo. The obtained concentrate was purified by preparative HPLC to afford 4 mg of 5-furan-2-yl-isoxazole-3-carboxylic acid (3-imidazol-1-yl-propyl)-amide (Yield: 35%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:17][C@@H:18]([C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1)[CH3:19]>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:17][C@@H:18]([C:20]1[CH:21]=[C:22]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:30][CH2:31]3)[CH:23]=[CH:24][CH:25]=1)[CH3:19])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Reactant: C[C@@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Product: C[C@@H](NC(=O)c1c(O)c(=O)n(C)c2ccccc12)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 25 %

Procedure:
Following the same procedure as described for Example 3, Example 204 (12 mg, 0.022 mmol, 25% yield) was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride and (R)-benzyl 4-(3-(1-aminoethyl)phenyl)piperazine-1-carboxylate (Intermediate 33). LC-MS (ESI) m/z 541 (M+H), RT=1.64 min (Method C). Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=8.9 min, 95%}; Xbridge {RT=8.5 min, 93%}. 1H NMR (500 MHz, MeOD) δ ppm 7.55 (1 H, d, J=7.7 Hz), 7.46-7.50 (2 H, m), 7.36-7.41 (4 H, m), 7.30-7.34 (3 H, m), 7.26 (1 H, s), 7.22-7.24 (1 H, m), 7.13 (1 H, d, J=7.7 Hz), 7.03 (1 H, dd, J=8.1, 2.1 Hz), 5.28 (1 H, d, J=7.2 Hz), 5.17 (2 H, s), 3.82 (3H, s), 3.71 (4 H, d, J=3.6 Hz), 3.29 (4 H, d, J=5.5 Hz), 1.55 (3 H, d, J=7.2 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[Cl:21][C:7]([C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][C:1](=[O:3])[CH3:2])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-acetoxy-4-trifluoromethyl-benzoic acid (180 mg, 0.73 mmol) in CH2Cl2 (6 mL) were added oxalyl chloride (0.08 mL, 0.91 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 1 hour. CH2Cl2 and excess oxalyl chloride were removed in vacuo. Acetic acid 2-chlorocarbonyl-5-trifluoromethylphenyl ester was obtained as a colorless oil (190 mg) and used in the following step without further purification. To a stirred solution of [1-Methyl-6-(5-methylaminopyridin-2-yloxy)-1H-indol-2-yl]{4-[4-(2,2,2-tri-fluoroethoxy)benzyl]piperazin-1-yl}methanone (340 mg, 0.6 mmol) in AcOEt (4 mL) were added triethylamine (0.13 mL, 0.91 mmol) and acetic acid 2-chlorocarbonyl-5-trifluoromethyl-phenyl ester (190 mg, 0.73 mmol) in AcOEt (3 mL) under ice cooling. The reaction mixture was stirred for 10 minutes at 0° C. Water was added to the reaction mixture, and the aqueous layer was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to afford 0.46 g of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13]C([O-])(C)C.[K+].CI>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (339 mg, 1.50 mmol) in 15 ml dry DMF was added potassium tert-butylate (336 mg, 3.0 mmol). After the mixture was stirred for 30 min at room temperature, a solution of methyl iodide (426 mg, 3.0 mmol) in 5 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 100 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 7/3, Rf=0.21) gave 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (281 mg, 1.17 mmol, 78%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:27][CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (70.7 mg, 0.419 mmol) and tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1,4-diazepane-1-carboxylate (87 mg, 0.23 mmol) in DMSO (1.2 mL). Triethylamine (162 μL, 1.17 mmol) was added to the mixture which was then heated to 90° C. After 1 hour, UPLC indicated the reaction was complete. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (81 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.52 (m, 12H), 1.91 (s, 2H), 2.24 (s, 3H), 2.95-3.19 (m, 4H), 3.57 (d, J=5.56 Hz, 4H), 3.80 (br s, 1H), 5.90-6.01 (m, 1H), 6.49 (d, J=3.28 Hz, 1H), 6.95 (br s, 4H), 7.55 (d, J=3.03 Hz, 1H), 7.81 (d, J=6.82 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:17]2([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCC2)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (600 mg, 1.04 mmol) in methanol (10 mL) was added cyclopentanone (1.5 mL) and a catalytic amount of concentrated hydrochloric acid. The mixture was heated and stirred at 60° C. overnight. The solvent was distilled off from the reaction mixture, and the resulting residue was purified by a flash column chromatography (filler: manufactured by Kanto Kagaku, K.K., 60Nmesh40-100, developing solvent:n-hexane/ethyl acetate (volume ratio)=1/0 to 100/1) to give bis(3,5-di-t-butyl-4-hydroxyphenylthio)cyclopentane (yield 485 mg and 67%).
Reaction SMILES: C[O:2][C:3](=[O:6])[CH:4]=[CH2:5].[F:7][C:8]([F:21])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][N:10]=1.[OH-].[Li+:23]>O.C(#N)C>[Li+:23].[F:21][C:8]([F:7])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:5][CH2:4][C:3]([O-:2])=[O:6])[CH2:16][CH2:15]2)=[N:11][N:10]=1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCN1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 92 %

Procedure:
Acrylic acid methyl ester (189 mg; 2.20 mmol) is added to 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine (476 mg; 2.00 mmol) in water (1.6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. Lithium hydroxide (92 mg; 4.00 mmol) in water (2 mL) is then added and the reaction mixture is again irradiated in a mono-mode microwave oven for 10 minutes at 100° C. The mixture is then diluted with acetonitrile and the precipitate formed is filtered, collected and dried under high vacuum to afford the desired compound (580 mg; 1.84 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[CH2:15](B(CC)CC)[CH3:16].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([CH2:15][CH3:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CCB(CC)CC
Reactant: CN1C(=O)COc2cc(Br)c(N)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc2c(cc1N)N(C)C(=O)CO2
Yield: 56.2 %

Procedure:
A mixture of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.82 mmol), triethylborane (2.47 ml of 1.0 M solution in hexane, 5.56 mmol), PdCl2dppf.CH2Cl2 (0.067 g, 0.082 mmol) and Cs2CO3 0.81 g, 2.46 mmol) in DMF (6 ml) was heated at 50° C. under argon for 18 hours. The mixture was partitioned between EtOAc and water. The EtOAc layed was dried (MgSO4), filtered, concentrated under reduced pressure and purified with prep-plate TLC (hexanes:EtOAc 1:1) to give 0.095 g of 6-amino-7-ethyl-4-methyl-4H-benzo[1,4]oxazin-3-one as a tan solid, 63%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (40.5 mg, 77%), MS (ISP) m/z=309.5 [(M+H)+], mp 234.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-fluoro-phenylboronic acid (31 mg, 0.22 mmol).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][NH:21][C@H:22]1[CH2:27][NH:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:20][N:21]1[C:2](=[O:4])[N:26]2[CH2:27][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 125 %

Procedure:
Triphosgene (21.3 g, 72 mmol) was added in portions to a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL) at 0° C. After stirring at 20° C. overnight, the reaction mixture was washed with H3PO4 (10%), sat. NaHCO3 and saturated NaCl. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50%) as a yellow solid. 1H NMR (400 Mz, CDCl3): δ 7.43-7.36 (m, 5H), 5.06 (d, J=11.4 Hz, 1H), 4.90 (d, J=11.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.32-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.93 (d, J=11.9 Hz, 1H), 2.14-2.05 (m, 2H), 2.05-2.00 (m, 1H), 1.71-1.63 (m, 1H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH3:15][O:16][NH2:17].O.Cl>N1C=CC=CC=1>[CH3:15][O:16][NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CON
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.5 %

Procedure:
2-nitrobenzene sulfonyl chloride (28.8 g, 130 mmol) was added within 30 min to a solution of O-methylhydroxylamine hydrochloride (11.7 g, 141 mmol) in pyridine (100 ml) accompanied by stirring and water cooling. After the addition the mixture was stirred for a further 30 min at room temperature (RT), mixed with ice (200-300 g) and acidified with concentrated HCl to pH 2-3. The still-cold suspension was sucked out, the precipitate carefully washed with ice water and dried. 26.4 g (87%) of the sulfamide 1 was obtained as a yellowish solid with a melting point of 133-136° C. 1H-NMR (DMSO-D6, 300 MHz): δ=3.67 (s, 3H), 7.92-8.06 (m, 4H), 11.05 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:22].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:33]=[O:34])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21]([CH:33]=[O:34])=[C:11]3[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:22]
Reactant: Oc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3ccc(O)c(Cl)c3)nc12
Temperature: 45 °C
Yield: 65 %

Procedure:
To 2-chloro-4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)phenol (582 mg, 1.84 mmol) in DMF (4.5 mL) cooled to 0° C. was added phosphorous oxychloride (0.514 mL, 5.52 mmol) dropwise. The reaction mixture was stirred while warming to 45° C. over 3 h. This was cooled down to 0° C. and added slowly to an ice-cold solution of 2M NaOH while stirring. Upon completion, the mixture was stirred at room temperature for 1 h. The resulting solid was filtered off and washed with water to provide 412 mg (65%) of 5-(3-chloro-4-hydroxyphenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (ES): >95% pure, m/z 344 [M+1]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:18])[CH2:16][NH2:17])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5]>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]([OH:18])[CH2:16][NH2:17])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5]
Reactant: COC(=O)c1cc2c(C(=O)CN)ccc(O)c2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2c(C(O)CN)ccc(O)c2[nH]1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 1.14 g of 4-aminoacetyl-7-hydroxyindole-2-carboxylic acid methyl ester hydrochloride in 200 ml of methanol is combined with 110 mg of 10% palladium catalyst on active carbon and hydrogenated for 3 hours under shaking at normal pressure. The reaction mixture is then filtered and the filtrate evaporated to dryness. The residue is vigorously stirred with acetone/methanol 9/1; the resultant product is filtered off and dried under vacuum, thus obtaining 1.0 g of 4-(2-amino-1-hydroxyethyl)-7-hydroxyindole-2-carboxylic acid methyl ester hydrochloride, decomposition point 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:21]C)[CH:15]=[C:14]([O:23]C)[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([OH:21])[CH:15]=[C:14]([OH:23])[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(F)c(Cl)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(F)c(Cl)cc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 46 (0.53 g, 1.1 mmol) was subjected to demethylation using pyridine hydrochloride (5.5 g, 47.6 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>O1CCCC1>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=1[Cl:8])=[O:32]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)c2ccc3ccccc3c2)c(Cl)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a cold (-60° C.) stirred solution of 3,5-dichlorotoluene (2.5 g, 15.5 mmol) in 30 ml of dry tetrahydrofuran under a nitrogen atmosphere, a 2.6 M solution of n-butyllithium in hexane (6.3 ml, 16.3 mmol) was added slowly over 15 minutes. The reaction mixture was stirred for an additional 30 minutes at -60° C. and then treated dropwise with a solution of 2-naphthoyl chloride (2.95 g, 15.5 mmol) in 15 ml of dry tetrahydrofuran over 15 minutes. The reaction mixture was stirred for 4 hours at -60° C. and then quenched with 4 ml of saturated NH4Cl solution. The mixture was permitted to come to room temperature at which point it was diluted with 20 ml of water and 20 ml of ether. The layers were separated and the aqueous layer further extracted with ether. The combined extracts were washed with brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.76 g of crude product. This material was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.71 g of pure product.