Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C[Si]([C:26]#[N:27])(C)C.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1([C:26]#[N:27])[CH2:19][CH2:20][O:16][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCOC1
Reactant: C[Si](C)(C)C#N
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(N(Cc2ccccc2)Cc2ccccc2)CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.3 %

Procedure:
To a cooled solution of dibenzylamine (31.9 g, 162 mmol) in acetic acid (100 mL) at 0° C., dihydrofuran-3(2H)-one (7.0 g, 81 mmol) was added followed by trimethylsilyl-formonitrile (14.4 g, 145.8 mmol). After being stirred at room temperature for 16 hours, the reaction mixture was poured into water (100 mL), adjusted to pH 7 with sodium bicarbonate, exacted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to afford 2.2 g of the desired product (yield was 9.28%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:10][C:8]1([F:11])[O:9][C:5]2=[CH:4][C:3]3[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:24]([C:23](=[O:28])[C:22]([F:30])([F:29])[F:21])[C:25]([CH3:26])=[N:1][C:2]=3[CH:12]=[C:6]2[O:7]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OC(F)(F)O2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2cc3c(cc2c(-c2ccccc2)c1C(=O)C(F)(F)F)OC(F)(F)O3
Reaction time: 16 h
Yield: 30 %

Procedure:
The title compound was prepared from (6-Amino-2,2-difluoro-benzo[1,3]dioxol-5-yl)-phenyl-methanone [example A10] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 30%; MS: m/z=396 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH2:8][C:7](=[O:9])[CH:6]=1)(=O)C.C(O)C.[CH:13]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([NH+:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH:9][C:7]1[CH2:8][C:5](=[O:4])[CH:6]=1
Reactant: CN(C)C1CCCCC1
Reactant: CC(=O)OC1=CC(=O)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[NH+](C)C1CCCCC1
Product: O=C1C=C(O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
3.24 g of 3-acetoxy-2-cyclobuten-1-one (triketene, 25.0 mmol) was dissolved in I.90 g of absolute ethanol (41.3 mmol) and 40 g of ethyl acetate. 6.45 g of cyclohexyl-dimethylamine (99 percent; 50.0 mmol), dissolved in 10 g of ethyl acetate, was instilled in this solution at 20° C. within 20 minutes. After 2 hours of stirring at room temperature, the suspension was filtered and dried under vacuum. 4.09 g of the title product with a content of 94.5 percent (according to HPLC), corresponding to a yield of 73.2 percent, relative to the 3-acetoxy-2-cyclobuten-1-one (triketene), was obtained. Data for the title compound was:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:20].CO>CC#N.[N+](C)(C)(C)C.[Cl-]>[Cl:20][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(O)n1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CC#N
Solvent: CO
Product: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added Me4NCl (1.6 g, 14.72 mmol) and POCl3 (6.8 g, 44.16 mmol). The mixture was heated at 80° C. for 6 h. After concentration under vacuum, the residue was subjected to EA extractive work up. Trituration with methanol (20 mL) gave the title compound (1 g, yield: 49.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.50 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 3.09 (s, 3H), 1.31-1.28 (m, 1H), 0.70-0.65 (m, 2H), 0.39-0.36 (m, 2H). LCMS: 277.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=O)[O:19]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.C(N(CC)CC)C.Cl.[F:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:38][CH2:37][CH2:36][F:35])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Reactant: NCCF
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirring solution of phenyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 30) (1.6 g, 4.48 mmol) in dry DMF was added triethylamine (2.03 mL, 14.55 mmol) and 2-fluoroethanamine hydrochloride (2.23 g, 22.40 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was then removed in vacuo affording the title compound which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[Cl:40])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1.O[Li].O>C1COCC1.O>[ClH:40].[Cl:40][C:31]1[C:32]([C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:14]([CH2:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:41])=[O:2]
Reactant: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.7 %

Procedure:
To a solution of 3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-benzoic acid methyl ester (0.200 g, 0.344 mmol) in THF (7.5 mL) and H2O (2.5 mL) at RT LiOH.H2O (0.029 g, 0.688 mmol) was added. The mixture was stirred overnight at RT. The mixture was then treated with more LiOH.H2O (0.058 g, 1.376 mmol) and heated at 50° C. overnight. The completed reaction was cooled to 0° C. and was quenched with a minimal amount of H2O. The mixture was the acidified to a pH=2 with concentrated HCl. The mixture was then extracted three times with EtOAc and was dried, filtered and concentrated to afford a foam that was purified via preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to yield the title compound (0.14 g, 72%); MS (ES+) m/e 569 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:26]=4[F:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(F)cc1F
Yield: 81.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.194 g (1.1 mmol) of 2,4-difluorobenzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.37 g of crystals, m.p. 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C:31]1[C:32]([C:37]([OH:39])=O)=[N:33][CH:34]=[CH:35][CH:36]=1.[CH3:40]OC(OC)OC.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O>O1CCCC1>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:37](=[O:39])[C:32]6[N:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[CH:40]5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: Nc1cccnc1C(=O)O
Reactant: COC(OC)OC
Agent: O=[N+]([O-])O[La](O[N+](=O)[O-])O[N+](=O)[O-]
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5cccnc5c4=O)c3C)c12
Temperature: 95 °C
Yield: 5 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (60 mg, 0.154 mmol), 3-aminopicolinic acid (53.1 mg, 0.384 mmol), trimethoxymethane (0.151 mL, 1.383 mmol), and tris(nitrooxy)lanthanum, 6H2O (19.96 mg, 0.046 mmol) in tetrahydrofuran (0.2 mL) was heated at 95° C. in a sealed vial for 16 hr. The mixture remained heterogeneous and very little (<5%) of the desired product was formed. DMF (0.5 mL) was added to the reaction mixture. Also added were additional 3-aminopicolinic acid (26.5 mg, 0.192 mmol) and tris(nitrooxy)lanthanum, 6H2O (10 mg, 0.023 mmol). The mixture was heated at 90° C. for two days. It was diluted with ethyl acetate (100 mL) and washed sequentially with water (25 mL), 1 N NaOH solution (25 mL), water (25 ml), and brine (25 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (7.1 mg, 0.013 mmol, 8.51% yield) as a yellow solid. LCMS (M+H)+=521.03. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.91 (m, 1H), 7.37 (s, 1H), 4.18 (m, 2H), 3.73 (m, 2H), 3.35 (s, 3H), 1.84 (s, 3H).
Reaction SMILES: [N:1]1([C:45](OC(C)(C)C)=O)[CH2:44][CH2:43][CH2:42][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:38](NN)=[O:39])[CH2:29][CH2:30][C:31](=[O:37])[O:32]C(C)(C)C)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:52][C@H:53]([C:59]([NH:61][C@H:62]([C:67]([NH2:69])=[O:68])[CH2:63][CH2:64][S:65][CH3:66])=[O:60])[CH2:54][CH2:55][CH:56](C)C.Cl.N1(C(OC(C)(C)C)=O)CCC[C@H:72]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N)=O)CCSC)=O)CC(C)C)=O)CCC(=O)OC(C)(C)C)=O)CC1C=CC=CC=1)=O)CC1C=CC=CC=1)=O.Cl>C(O)(=O)C>[NH:1]1[CH2:45][CH2:44][CH2:43][CH2:42][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:38]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:67]([NH2:69])=[O:68])[CH2:63][CH2:64][S:65][CH3:66])=[O:60])[CH2:54][CH:55]([CH3:56])[CH3:72])=[O:39])[CH2:29][CH2:30][C:31](=[O:37])[OH:32])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCC(C)C)C(N)=O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-Phe-Glu(tBu)NHNH2 (0.570 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 0.560 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) have BocPro-Phe-Phe-Glu(tBu)-Leu-MetNH2 in 77% yield. De-t-butylation and de-t-butoxycarbonylation of BocPro-Phe-Phe-Glu(tBu)-Leu-MetNH2 using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Glu-Leu-MetNH2, which was isolated as the amorphous off-white solid hydrochloride salt in 38% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[N+]([O-])=O.[O-:14][CH2:15][CH3:16].[Na+].O.[CH2:19](O)C>>[CH2:1]([O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[O:14][CH2:15][CH3:16])[CH3:19]
Reactant: CC[O-]
Reactant: CCO
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C)[n+]([O-])nc1OCC
Temperature: 25 °C

Procedure:
3-Methoxy-6-methyl-4-nitropyridazine 1-oxide (2 g) was initially charged in ethanol (100 ml) at RT. Thereafter, solid sodium ethoxide (1.4 g) was added in portions while stirring. After stirring at 55° C. for 1.5 h, the reaction mixture was cooled to RT and admixed with water, and the aqueous phase was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC. The clean, product-containing fractions were combined, freed of the acetonitrile and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 176 mg of the desired product were obtained. The aqueous phase was freeze-dried to obtain 781 mg of the desired product. To obtain further product, the contaminated fractions from the chromatography were combined and freeze-dried. The residues were purified again by means of preparative HPLC, and the clean product was isolated as described above. A further 130 mg of product were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:40]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][CH2:49][C:50](O)=[O:51])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:50](=[O:51])[CH2:49][CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1

Procedure:
5-Amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.100 g, 0.213 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}-β-alanine (0.040 g, 0.213 mmol), DIPEA (0.19 mL, 1.07 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.163 g, 0.639 mmol) in a similar manner as in the general procedure described herein to afford crude 1,1-dimethylethyl {3-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-3-oxopropyl}carbamate as a yellow solid. This crude material (0.027 g, 0.042 mmol) was suspended in dichloromethane (1 mL) and treated with trifluoroacetic acid (0.25 mL, 3.24 mmol) at RT for 1 h. The solvent was evaporated and the residue was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.017 g, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 10.01 (s, 1H), 9.00 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.63-7.79 (m, 2H), 7.44-7.57 (m, 2 H), 7.31-7.44 (m, 1H), 7.22-7.31 (m, 1H), 7.11 (s, 1H), 4.57 (s, 2H), 2.94-3.19 (m, 2H), 2.62-2.77 (m, 2H). MS: m/z 540 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.N1C=CN=C1.CN(C=O)C.[CH3:48][C:49]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])[CH3:50]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([O:17][Si:52]([C:49]([CH3:51])([CH3:50])[CH3:48])([CH3:54])[CH3:53])[CH:16]=3)[C:3]=12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (example 40, 0.20 mmol) and imidazole (40.8 mg, 0.60 mmol) in DMF (1 ml) TBDMSCl (45.2 mg, 0.30 mmol) was added at RT and the mixture was stirred for 2 hrs. Additional imidazole (16 mg) and TBDMSCl (36 mg) were added and the mixture was stirred at the same temperature for further 2 hrs. Additional imidazole (27 mg) and TBDMSCl (121 mg) were added and the stirring was continued at room temperature overnight. The reaction mixture was diluted with DCM and washed with 0.5M HCl. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by filtration on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford 3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate Q.1, 112 mg, 0.184 mmol, 92%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(NCCN)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.95 ml), and then diphenylphosphinic chloride(1.34 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylamino)-5-methoxypyridine(1.17 g) added thereto, was stirred for 8 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.22 g of the aimed compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([O:17][P:18]([CH:25]([OH:28])[CH2:26][CH3:27])(=[O:24])[O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[H][H]>C(#N)C>[CH2:13]([O:17][P:18]([CH:25]([O:28][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:26][CH3:27])(=[O:24])[O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCOP(=O)(OCCCC)C(O)CC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCOP(=O)(OCCCC)C(CC)OC(=O)c1ccc(N)cc1
Yield: 42.5 %

Procedure:
A solution of 15 g of 4-nitro-benzoyl chloride in 100 ml of acetonitrile is added dropwise to a solution of 20 g of α-hydroxy-propanephosphonic acid dibutyl ester and 8 g of pyridine in 20 ml of acetonitrile at 0° C. After 16 hours the mixture is filtered, the filtrate is evaporated and the residue is extracted with 200 ml of diethyl ether. After evaporation, and purification by column chromatography, 13 g of pure α-(4-nitro-benzoyloxy)-propanephosphonic acid dibutyl ester are obtained. This is reduced with hydrogen as indicated in Example 2. 12.5 g of α-(4-amino-benzoyl-oxy)-propanephosphonic acid dibutyl ester are obtained. After condensation with o-methoxybenzoylacetic acid methyl ester according to Example 6, and purification by column chromatography, the compound of the formula (142 ) is obtained in the form of a yellow resin.