Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:27])[N:5]([CH2:13][CH:14]([C:21]1([CH3:26])OCC[O:22]1)[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[C:6]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH2:13][CH:14]([C:21](=[O:22])[CH3:26])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[C:4]2=[O:27]
Reactant: C=CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C(C)=O

Procedure:
Allyl 2-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (86 mg, 23%) in the same manner as described in the above Example 6 (40) from allyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.35 g, 0.92 mmol) and p-toluenesulfonic acid monohydrate (40 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:23])([F:22])[C:19](Cl)=[O:20]>O1CCCC1>[F:17][C:18]([F:23])([F:22])[C:19]([C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH2:8])[C:4]=1[NH2:9])=[O:20]
Reactant: O=C(Cl)C(F)(F)F
Reactant: Nc1cc(Cl)cnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(Cl)c(C(=O)C(F)(F)F)c1N
Reaction time: 2 h

Procedure:
5-Chloro-2,3-pyridinediamine (2.8 grams) was dissolved in 50 milliliters of tetrahydrofuran and 2.02 milliliters of triethylamine and the solution treated with trifluoroacetyl chloride (2.6 grams) in 100 milliliters of tetrahydrofuran. The addition was carried out at room temperature over a period of 2 hours, and the reaction mixture was then held at room temperature for another hour with stirring. Solvent was removed by evaporation, and the residue recrystallized from a chloroform/acetone mixture to obtain the desired N3 -trifluoroacetyl-5-chloro-2,3-pyridinediamine product, m.p., 292°-93°C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]=1[OH:33])[CH:28]=O)[CH3:23].[NH2:37][C:38]([NH2:40])=[O:39].Cl>C(O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:28]([C:27]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]([OH:33])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[NH:37][C:38](=[O:39])[NH:40][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: NC(N)=O
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(-c3ccccc3)cc2)cc([N+](=O)[O-])c1O
Yield: 2.9 %

Procedure:
To a solution of 2-(biphenyl-4-yl)-1-phenylethanone (Intermediate 5) (430 mg, 1.57 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (333 mg, 1.57 mmol), and urea (217 mg, 4.71 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (PE:EtOAc=3:1-0:1) and thin layer chromatography (PE:EtOAc=1:2) to give Compound 18 (23 mg, yield 2.9%). 1H NMR (CD3OD 400 MHz TMS): δ 7.61 (d, J=2.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.38-7.27 (m, 10H), 7.02 (s, 1H), 6.98 (d, J=8.0 Hz, 2H), 5.23 (s, 1H), 4.02-3.99 (m, 2H), 1.38 (t, J=6.8 Hz, 3H); MS (ESI): m/z 508.2 [M+1]+.
Reaction SMILES: CCN(CC)CC.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)=[CH:20][CH:19]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:14]([C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:57])([CH3:56])[CH3:58])[CH2:49][CH2:50][CH2:51]3)=[CH:44][CH:43]=2)=[CH:22][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)Nc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Et3N (36.6 μL, 0.263 mmol) and phenyl isocyanate (10.4 μL, 0.0964 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.0876 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1). The fractions were concentrated and solidified with CHCl3. The precipitated solids were collected by filtration and washed with CHCl3 to afford desired product (33.5 mg, 55.4%) as cream colored solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.16-8.11 (m, 1H), 8.03-7.99 (m, 1H), 7.54-7.48 (m, 2H), 7.38-7.21 (m, 9H), 7.16-7.05 (m, 4H), 6.95 (d, J=8.2 Hz, 1H), 6.89-6.73 (m, 3H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.29 (s, 1H), 5.19 (s, 1H), 2.61-2.23 (m, 4H), 2.20-2.06 (m, 1H), 1.95-1.80 (m, 1H), 1.49-1.16 (m, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=C(C)C=1>[Br-:1].[C:8]([C:7]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:6]=1)([OH:10])=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(CCBr)cc1
Solvent: Cc1cccc(C)c1
Product: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Yield: 82.1 %

Procedure:
p-Bromoethylbenzoic acid (15 mmol, 3.45 g) and triphenylphosphine (16.5 mmol, 4.32 g) were refluxed in 100 ml m-xylene for 9 h (oil bath temperature 150° C.). The mixture was then cooled down, the solid formed was filtered, washed with m-xylene (2×20 ml), hexanes (2×20 ml), and air-dried to give 6.05 g (82%) of beige crystals. Recrystallization from MeOH—CHCl3-hexanes (˜1:3:5) afforded 2.8 g (38%) of pure off-white crystals of 4-carboxyphenethyl(triphenyl)phosphonium bromide. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 2H, 8.4 Hz, H2, H6 Ar), 7.68 (m, 3H, Ph3P), 7.55 (m, 12H, Ph3P), 7.09 (d, 2H, 8.4 Hz, H3, H5 Ar), 3.48 (m, 2H, CH2—P), 2.86 (m, 2H, CH2—Ar)
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)=[C:2]=S.C1(C([O-])=O)C=C(C)C=C(C)C=1.[NH2:25][N+:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH2:32].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[ClH:53]>ClCCl>[Cl:53][C:28]1[C:27]2[N:26]([N:25]=[C:2]([NH:1][C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8](=[O:13])[CH2:7]4)[N:32]=2)[CH:31]=[CH:30][N:29]=1
Reactant: Nc1cncc[n+]1N
Reactant: O=C1Cc2cc(N=C=S)ccc2N1
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1cc(C)cc(C(=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1Cc2cc(Nc3nc4c(Cl)nccn4n3)ccc2N1
Reaction time: 6 h
Yield: 55 %

Procedure:
To a solution of 5-isothiocyanato-1,3-dihydro-indol-2-one (2.3 g, 12.09 mmol) in dry dichloromethane (200 ml), 1,2-diamino-pyrazinium mesitylenate (5.21 g, 15.12 mmol), diisopropylethylamine (7.81 g, 60.45 mmol) and EDCl (4.63 g, 24.18 mmol) are added and stirred for 6 hours. The reaction mixture is concentrated and the residue is taken in water (100 ml), triturated and filtered, the crude solid is purified by silica column using (60-120) mesh to get the titled product as yellow solid (2.0 g, 55%); TLC: chloroform/methanol (9.5/0.5) Rf-0.3; HPLC purity (method A): 97%, Rt (min): 2.40; LCMS: mass found (M+, 301.0), Rt (min): 2.36;
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:22])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].O>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:22][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(N)nc3cc(OCC(=O)c4ccccc4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A warm solution of 4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (266 mg, 0.891 mmol) in DMF (20 mL) was cooled to approximately 0° C. Solid cesium carbonate (580 mg, 1.78 mmol) was added. After ten minutes, 2-bromoacetophenone (186 mg, 0.935 mmol) was added in one portion, and the reaction was allowed to warm to room temperature and was stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material. Additional 2-bromoacetophenone was added, and the reaction was stirred for six hours. The reaction was poured into deionized water (200-300 mL) and stirred for 15 hours. The resulting precipitate was isolated by filtration and purified by column chromatography on silica gel (eluting with chloroform:methanol ranging in ratios from 99.5:0.5 to 98:2). The product was then recrystallized from acetonitrile, isolated by filtration, and dried overnight under high vacuum to provide 222 mg of 2-(4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)-1-phenylethanone as white crystals, mp 178.0-180.0° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:37]=[CH:38][C:39]([CH:40]=[CH:1][C:2]4[O:3][C:4]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=4)=[CH:42][CH:43]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 4, 0.4 g (1.7 mmol) of 2-(2-methyl-6phenyl-pyran-4-ylidene)-malononitrile and 0.55 g (1.7 mmol) of 4-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde} were added into 40 ml of ethanol, and 0.17 g (2.0 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
Diisopropyl azodicarboxylate (2.36 mL) was added to a solution of 4-(benzyloxy)phenol (2.0 g), tert-butyl 4 hydroxypiperidine-1-carboxylate (2.41 g) and triphenylphosphine (3.67 g) in dichloromethane (30 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated at reduced pressure. This resulting mixture was purified by silica column chromatography, eluting with a gradient of 0 to 20% ethyl acetate in hexane to give tert-butyl 4-[4-(benzyloxy)phenoxy]piperidine-1-carboxylate as a light orange oil (3.25 g); NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.65-1.77 (m, 2H), 1.83-1.93 (m, 2H), 3.24-3.34 (m, 2H), 3.65-3.76 (m, 2H), 4.27-4.35 (m, 1H), 5.01 (s, 2H), 6.80-6.93 (m, 4H), 7.28-7.45 (m, 5H); Mass Spectrum: (M-tBuOCO)+H+ 284.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.C(OC([NH:21][CH2:22][C:23]([NH:25][C@H:26]1[CH2:30][N:29](C(OC(C)(C)C)=O)[C@H:28]([C:38](O)=[O:39])[CH2:27]1)=[O:24])=O)(C)(C)C>>[NH2:21][CH2:22][C:23]([NH:25][C@H:26]1[CH2:30][NH:29][C@H:28]([C:38]([NH:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=3)=[O:39])[CH2:27]1)=[O:24]
Reactant: CCc1ccc2cc(N)cnc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCc1ccc2cc(NC(=O)[C@@H]3C[C@@H](NC(=O)CN)CN3)cnc2c1

Procedure:
3-Amino-7-ethylquinoline was coupled with trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline and deprotected according to Compound M1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH2:12].[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O.C(N(CC)CC)C.[Na]>CO>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH:12][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 37 %

Procedure:
Glycyl-L-proline methylester hydrochloride (16.0 g, 72.1 m mole) was dissolved in methanol (150 ml), and Indan-2-on (4.75 g, 36.0 m mole) and triethylamine (1.8 g, 18.0 m mole) were added thereto. Sodium syanoborohydride (2.27 g, 36.0 m mole) was gradually added thereto while cooling with ice and stirring. The mixture was stirred for 1 hour while cooling with ice and next for 5 hours at room temperature. A little insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue, water (100 ml) and ethyl ether (100 ml) were added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring to dissolve it. The ethyl ether layer was removed, and the remaining water layer was washed with ethyl ether (100 ml). The desired product was extracted from the water layer with chloroform (100 ml×3 times). The thus obtained chloroform as extracted was concentrated under reduced pressure. To thus produced tar-like residue ethyl ether and 5% sodium bicarbonate (200 ml) were added and the mixture was stirred to dissolve the solid matter. The aqueous layer was removed and the ethyl ether layer was washed with aqueous solution saturated with sodium chloride. To the ethyl ether layer water (150 ml) was added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring and ethyl ether was removed. The water layer was washed with ethyl ether (100 ml) and to the water layer chloroform (200 ml) was added. The solution was adjusted to pH 8.0 with sodium bicarbonate while stirring. The aqueous layer was removed, and chloroform layer was dried with anhydrous sodium sulfate, and the sodium sulfate was sepa rated by filtration. Separately, anhydrous hydrogen chloride gas was brown into the chloroform, and thus obtained hydrogen chloride chloroform solution was added to the above mentioned chloroform layer. After checking the solution acidic enough, the chloroform was removed off under reduced pressure, to yield N-(2-indanyl) glycyl-L-proline methylester hydrochloride (4.50 g, 13.3 m mole, yield: 37%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH2:70])[CH:65]=2)(=[O:57])=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([NH:70][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:65]=2)(=[O:57])=[O:56])[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.010 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 53% yield: LCMS (ESI) m/z 507 (MH+).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][N:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[CH:9]=1
Reactant: OCc1ccnc(OC(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2-(difluoromethoxy)pyridin-4-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 4-(bromomethyl)-2-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.78 min.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[NH:39][C:38](=O)[NH:37][C:36]=2[CH:44]=1>O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[N:39]=[C:38]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:37][C:36]=2[CH:44]=1
Reactant: CC(C)C(C)N
Reactant: O=C1Nc2cc(Cl)ccc2S(=O)(=O)N1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C1CCCCC1
Solvent: O
Product: CC(C)C(C)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 195 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
Phosphorus pentoxide (7.55 g, 53.2 mmol), N,N-dimethylcyclohexylamine (17 ml, 113 mmol) and 1,2-dimethylpropylamine hydrochloride (12.4 g, 100.4 mmol) were carefully mixed and heated with mechanical stirring on an oil bath at 190-200° C. for about 15 min. To the homogeneous mass was added 6-chloro-3,4-dihydro-3-oxo-1,2,4-benzothiadiazine 1,1-dioxide (5.84 g, 25.1 mmol) and the mixture was stirred at 235° C. for 2 h. After cooling to about 100° C., water (200 ml) was added and the dark mixture was hydrolysed by stirring over night at room temperature. The precipitate was isolated by filtration and recrystallised from ethanol with decolorising charcoal to give 2,83 g (37%) of the pure title compound; m.p. (DSC) 264.7° C.; 1H-NMR (DMSO-d6): δ 0.90 (dd, 6H, CH(CH3)2), 1.09 (d, 3H, NCHCH3), 1.76 (m, 1H, CH(CH3)2), 3.70 (m, 1H, NHCH), 7.15 (br., 1H, NH), 7.28 (m, 2H, ArH), 7.68 (d, 1H, ArH), 10.3 (br.s, 1H, NH); (C12H16N3Cl1O2S1) calc. C, 47.76; H, 5.34; N 13.92; found C, 47.66; H, 5.47; N, 13.91.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13](I)[C:8]2=[C:7]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])[N:6]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH3:37])=[C:30](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[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.C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH3:37])[C:8]2=[C:7]([NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[N:6]=1
Reactant: CCOc1ccc(F)cc1B(O)O
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc(F)cc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)nc(NC[C@@H](C)O)c12
Temperature: 180 °C
Yield: 30.6 %

Procedure:
1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (200 mg, 0.447 mmol), 5-fluoro-2-ethoxyphenyl boronic acid (246 mg), K3PO4 (285 mg), and Tetrakis(triphenylphosphine)palladium(0) CH2Cl2 (73 mg) were added to 2 mL dioxane in a microwave vial. The vial was sealed and the reaction mixture was heated to 180° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was filtered through silica gel using 10% MeOH in methylene chloride, then purified by preparative scale thin layer chromatography using 10% MeOH in methylene chloride, to give 62.9 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=460.
Reaction SMILES: [N-]=C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([C:36]2[S:40][CH:39]=[N:38][CH:37]=2)[CH:33]=[CH:32][C:31]=1[N:41]1[S:45](=[O:47])(=[O:46])[N:44](CC[Si](C)(C)C)[C:43](=[O:54])[CH2:42]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([C:36]2[S:40][CH:39]=[N:38][CH:37]=2)[CH:33]=[CH:32][C:31]=1[N:41]1[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:54])[CH2:42]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of PS-isocyanate resin (2.0 g) in THF (5 mL) is added tetrabutylammonium fluoride (1.0 M in THF, 2.17 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the filtrate is added to a solution of 5-(2-benzyloxy-4-thiazol-5-yl-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (272 mg, 0.543 mmol) in THF (1 mL) and the mixture is stirred at 50° C. for 18 h. The reaction mixture is cooled and diluted with EtOAc, washed with 1N HCl and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by column chromatography eluting with MeOH/EtOAc to afford the title compound as a yellow solid: (M+1)+=402.