Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([B:13]([OH:15])[OH:14])[C:9]([F:12])=[N:10][CH:11]=1.S([O-])([O-])(=O)=O.[Mg+2].O[C:23]([C:26](O)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([B:13]2[O:15][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:14]2)[C:9]([F:12])=[N:10][CH:11]=1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Reactant: CC(C)(O)C(C)(C)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cc(C3OCCO3)cnc2F)OC1(C)C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (14.56 g, 68.4 mmol) was suspended in PhMe (300 mL) and anhydrous magnesium sulfate (41.223 g, 342 mmol) and pinacol (8.27 g, 70.0 mmol) were added. The reaction was stirred under nitrogen at room temperature over the weekend. The suspension was filtered, and the solid was washed with EtOAc. The filtrate was washed with brine (2×200 mL), and the organic phase was dried over sodium sulfate, filtered, concentrated and dried to give 19.19 g of 5-(1,3-dioxolan-2-yl)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a light yellow powder. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=2.54 Hz, 1H); 8.28 (dd, J=8.02 Hz, 2.54 Hz, 1H); 5.84 (s, 1H); 4.17-4.04 (m, 4H); 1.37 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:59]=[CH:58][C:45]([C:46]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:47])=[CH:44][C:43]=1[CH3:60]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:59]=[CH:58][C:45]([C:46]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[O:47])=[CH:44][C:43]=5[CH3:60])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N(C)CCN2CCOCC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN4CCOCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-bromo-3,N-dimethyl-N-(2-morpholin-4-yl-ethyl)-benzamide (114 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,N-dimethyl-N-(2-morpholin-4-yl-ethyl)-benzamide was obtained, and further PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-205) as a brown oil (68 mg, 66%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].CO>C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][CH:16]3[CH2:17][CH2:18][CH:19]4[CH2:22][CH2:23][N:15]3[CH2:21][CH2:20]4)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1CC2CCN(C1)CC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CC1CCC2CCN1CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-azabicyclo[3.2.2]nonane. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=314 (M+ of free base). α[D]589 =-20.39 c=0.48, methanol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7].O.O.[Sn](Cl)Cl.N.Cl.O1CCOCC1>Cl.O>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[NH2:14])[CH2:5][CH2:6][Cl:7]
Reactant: O=[N+]([O-])c1cccc(N(CCCl)CCCl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(N(CCCl)CCCl)c1
Temperature: 25 °C
Yield: 192.1 %

Procedure:
3-[N,N-Bis(2-chloroethyl)amino]nitrobenzene (2.0 g; 7.6 mmol) was dissolved in 35 ml of concentrated hydrochloric acid, followed by the addition of 6.9 g (30.6 mmol; 4.0 equivalents) of tin(II) chloride dihydrate. The resultant mixture was stirred under heat for 1 hour over an oil bath controlled at 100° C. The reaction mixture was allowed to cool down to room temperature, followed by dilution with water. The diluted solution was basified with concentrated aqueous ammonia and then extracted twice with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue so obtained was added with 4N hydrochloric acid/dioxane and concentrated. The concentrate was then crystallized from a small amount of methanol/ether, whereby 1.97 g (7.3 mmol) of the title compound were obtained as yellow crystals (yield: 96.1%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:12][CH:8]([CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH:10]=[CH2:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CCC(O)COc1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-(4-fluorophenoxy)-1-penten-4-ol (9.81 g., 0.05 mole) in dry dimethylformamide (15 ml.) is added dropwise to a stirred suspension of hexane (2 × 10 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 2.64 g., 0.055 mole) in dry dimethylformamide (45 ml.) at 25° C. Upon cessation of gas evolution, the reaction mixture is cooled to 0°-5° C. and treated with a solution of benzyl bromide (10.3 g., 0.06 mole) in dry dimethylformamide (10 ml.). The resulting mixture is stirred at 25° C. for 16 hours, then heated at 100° C. for 1 hour. After cooling to 25° C., the reaction mixture is diluted with ice water (50 ml.) and extracted with ether four times. The combined organic extract is washed with 2 N hydrochloric acid and saturated aqueous brine, dried over magnesium sulfate and filtered. In vacuo evaporation of the filtrate leaves an oily residue which affords the title compound upon distillation as a colorless oil (13.1 g., 92%), bp0.025 112°-116° C.; pmr (CCl4) δ2.37 (2H, t), 3.5-4.0 (3H, m), 4.57 (2H, s), 4.8-5.05 (H, m), 5.05-5.25 (H, m), 5.4-6.2 (H, m), 6.6-7.1 (4H, m) and 7.19 (5H, s).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][C:36]=2[N:37]2[CH2:42][C@H:41]([CH3:43])[C@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C@H:39]([NH:49]C(=O)OC(C)(C)C)[CH2:38]2)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1[CH2:23][CH2:24][O:25][CH2:26][CH:27]=1)[CH:16]=2)=O)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:49][C@H:39]1[C@@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C@@H:41]([CH3:43])[CH2:42][N:37]([C:36]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]=2[NH:30][C:28]([C:13]2[C:12]([NH2:11])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:29])[CH2:38]1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@@H]1[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.4 %

Procedure:
To a solution of tert-butyl methyl {(3R,4S,5S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidine-3,4-diyl}biscarbamate (63 mg, 0.082 mmol) in MeOH (2.0 mL) and THF (1.0 mL), 10% Pd on carbon (16 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 20 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 30 min. then concentrated under reduced pressure. The residue was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (26 mg, 58%). LCMS calc. for C28H36N7O4 (M+H)+: m/z=534.3. Found: 534.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Reactant: C1COCCN1
Product: O=C(c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and morpholine according to Example 269f; white foam, MS 459 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 90.3 %

Procedure:
According to the similar procedure to Synthesis Example 1, by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrophenylethyl bromide (900 mg, 3.92 mmole), 890 mg (50% yield) of 2-hydroxy-5-[2-(4-nitrophenyl)ethylamino]-benzoic acid was obtained as a pale yellow solid. Melting point 234-236° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:28])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:11]=2)[CH:9]=1.CCN(C(C)C)C(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Cl:28][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)[N:11]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A solution of methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate hydrochloride (0.500 g, 1.29 mmol) in THF (20 mL) was added DIPEA (2 mL) and cyclopropyl carbonyl chloride (0.201 g, 1.9 mmol) under nitrogen atmosphere. The reaction mass was stirred at RT for 2-4 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.41-7.54 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.79 (d, 1H), 8.71 (m, H); MS (m/z): 456.97 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[O-:21][Si]([O-])([O-])[O-].[K+].[K+].[K+].[K+].OO>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: [O-][Si]([O-])([O-])[O-]
Reactant: COC(=O)Nc1cccc2c1Cc1ccccc1C2=O
Agent: OO
Agent: [K+]
Solvent: O
Product: COC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 92.8 %

Procedure:
135.5 g (0.5 mole) of 4-methoxycarbonylamino-anthrone in 1.5 liters of water are warmed to 70° C. After adding 50 ml of potassium water glass (d = 1.25), 400 ml of a hydrogen peroxide solution which contains 80 g per liter are added dropwise. The mixture is then stirred until the thin layer chromatogram of a sample which is withdrawn indicates the end of the reaction. In the course of the oxidation, the suspension has developed an intense reddish-tinged yellow color. The suspension is filtered and the product is washed until neutral and dried. 130.4 g (= 92.8%) of 1-methoxycarbonylamino-anthraquinone are obtained / melting point 214° C (from nitrobenzene).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>CO>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a mixture of L-phenylalanine (8.88 g, 53.7 mmol) and 1-fluoro-2,4-dinitrobenzene (3.24 ml, 26.9 mmol) was added triethylamine (7.86 ml, 56.4 mmol). The resulting mixture was warmed using a Biotage Initiator microwave to 100° C. for 4 min. The solid was diluted with MeOH and the slurry was dropped into distilled water. Dichloromethane was added to the slurry and the organic phase was separated. The organic phase was further extracted with 1.2 M hydrogen chloride solution and brine. The organic phase was dried over Na2SO4, filtered and the solvents were evaporated. The residue was diluted with dichlormethane and the slurry was filtered. The precipitate was then washed with a small amount of dichlormethane. The combined filtrates were evaporated and the residue was purified by flash chromatography using a dichloromethane/methanol gradient (0% to 5%) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]4[N:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH2:21]([C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:7]3[NH:6][C:5]4[CH:23]=[CH:24][C:2]([C:27]5[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=5[F:25])=[CH:3][C:4]=4[N:8]=3)[CH2:10][CH2:11]2)=[N:20][CH:19]=1)[CH3:22]
Reactant: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4[nH]3)CC2)nc1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CCc1cnc(N2CCC(c3nc4cc(-c5ccc(S(C)(=O)=O)cc5F)ccc4[nH]3)CC2)nc1
Yield: 26.2 %

Procedure:
Following the General Procedure-1, the titled compound (25 mg) was prepared from Intermediate 2 (80 mg, 0.199 mmol) and Intermediate 3 (79 mg, 0.26 mmol) as a yellow solid. M.P.: 186.5-190° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.41 (d, J 4, 1H), 8.26 (s, 2H), 7.90-7.80 (m, 3H), 7.79-7.50 (m, 2H), 7.40-7.32 (m, 1H), 4.66 (d, J 13.1, 2H), 3.29 (s, 3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 2H), 2.43 (q, J 7.73, 2H), 2.06 (d, J 12.5, 2H), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.N1C=CC=CC=1>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CCN)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
32.2 ml (0.23 mol) of trifluoroacetic acid were added dropwise to a solution of 22.3 ml (0.15 mol) of 2-(4-methoxyphenyl)ethylamine and 24.7 ml (0.23 mol) of pyridine in 125 ml of absolute THF cooled to 5° C., and the resulting solution was stirred at RT for 3 h. The reaction solution was then poured onto 750 ml of ice, and the deposited precipitate was filtered off with suction and dried at 40° C. in a high vacuum. 36.3 g of the title compound were obtained as a beige solid.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:24][CH3:25].C[Li].[Li]C(C)(C)C.Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH3:37][O:36][C:34]([C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[CH:6]3[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:13][C:14]=2[CH:15]=1)=[O:35]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Reaction time: 2 h
Yield: 110.4 %

Procedure:
At −78° C., combine 7-Bromo-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.2 g, 0.5 mmol), tetrahydrofuran (4 ml), CH3Li (0.623 ml, 1.6M), then add t-BuLi (0.59 ml, 1.7M). After 30 minutes add methyl chloroformate (0.19 g, 2.0 mmol) and remove cooling. After 2 hours at r.t., add ammonium chloride solution solution and ethyl acetate. Wash organic layer with water, dry over anhydrous sodium sulfate, remove solvent in vacuo to yield the titled compound (0.21 g, 100%). MS m/z 381 (M−1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9]/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:14][CH:13]=1>CN(C)C=O.O>[Cl:1]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:16][CH:17]=1)=[N:10]\[OH:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C=N/O)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C(Cl)=N/O)cc2)C1
Temperature: 55 °C
Yield: 100 %

Procedure:
N-chlorosuccinimide (239.0 mg, 1.790 mmol) was added to a stirred suspension of (E)-di-tert-butyl 2-(4-((hydroxyimino)methyl)phenyl)piperazine-1,4-dicarboxylate (725.8 mg, 1.790 mmol) in N,N-dimethyl formamide (10 mL). The reaction was then heated at 55° C. for 1 hour. The reaction was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with ethyl acetate (×3). Organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The sub-titled compound was used directly in the next step without further purification. (787.5 mg, assume 100% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:37][C:36]([CH3:39])([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH3:35])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CN1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (100.6 mg, 0.220 mmol) and 2-methyl-2-(4-methylpiperazin-1-yl)propanal (118.2 mg, 0.660 mmol) in DCM (5 mL) in an ice bath was added pyrrolidine (0.11 mL, 1.32 mmol) and TMS-Cl (0.11 mL, 0.880 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was loaded on silica gel plate, purified by MeOH:CH2Cl2 to obtain 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (19 mg) as a white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C:8]1([F:39])[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([C:22]2[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=2)[C:25]([O:27]CC2C=CC=CC=2)=[O:26])[CH2:20][CH3:21])=[O:17])[CH2:12][C:11](=[O:38])[NH:10][CH2:9]1>O1CCCC1.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C:8]1([F:39])[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([C:22]2[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=2)[C:25]([OH:27])=[O:26])[CH2:20][CH3:21])=[O:17])[CH2:12][C:11](=[O:38])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(F)(Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)OCc2ccccc2)c1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCC(NC(=O)N1CC(=O)NCC(F)(Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
(Step 4) To the obtained benzyl 3-[1-({[6-(5-chloro-2-methoxybenzyl)-6-fluoro-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate (20 mg) in tetrahydrofuran (1 ml) solution, platinum oxide (6 mg) was added and the mixture was stirred under hydrogen atmosphere at room temperature for 1.5 hours. Next, the catalyst was filtered out. and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate/methanol/acetic acid=8/8/1/0.1) to obtain the title compound (9.3 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Br.C(O)C.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][S:9]([O-:12])(=[O:11])=[O:10].[Na+:13]
Reactant: O=S([O-])[O-]
Reactant: ClCCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCl
Reaction time: 2 h

Procedure:
1-Chloro-3-bromopropane (104.0 g), ethanol (250 ml), and water (90 ml) were stirred under reflux, and a solution of sodium sulphite (25.0 g) in distilled water (90 ml) was added to the stirred refluxing reaction mixture over a period of two hours. After the addition, refluxing was continued for a further 2 hours after which the excess alcohol and 1-chloro-3-bromopropane were removed by distillation. The remaining aqueous solution was evaporated to dryness on a steam bath and the product was recrystallised from alcohol to yield sodium 3-chloro-propane-sulphonate as a white crystalline solid.