Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[CH2:10][CH2:11][C@@H:12]3[C@@H:17]([C:8]=2[CH:7]=[CH:6][C:5]=1[O:18]C)[CH2:16][NH:15][CH2:14][CH2:13]3.B(Br)(Br)[Br:21].C(=O)=O.CC(C)=O>C(Cl)Cl>[BrH:21].[CH2:16]1[C@@H:17]2[C@@H:12]([CH2:11][CH2:10][C:9]3[C:4]([OH:3])=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=32)[CH2:13][CH2:14][NH:15]1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CC[C@H]1CCNC[C@H]21
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Br
Product: Oc1ccc2c(c1O)CC[C@H]1CCNC[C@@H]21
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A solution of 17a (0.050 g, 0.177 mmol) in dry CH2Cl2 (15 mL) in a flame-dried single-neck flask was cooled to −78° C., and 0.55 mL of a 1.0 M solution of BBr3 in CH2Cl2 were added dropwise to the flask. The reaction was stirred at −78° C. for 2 h and then at room temperature for 2 h. The reaction was returned to the dry ice/acetone bath and carefully quenched by the addition of 3 mL anhydrous MeOH. The quenched reaction was evaporated to dryness, taking care to keep the water bath below 40° C. The solid residue was redissolved in MeOH, and evaporated again, repeating this process a total of four times. The resulting tan solid was dried under high vacuum overnight and then crystallized from MeOH-Et2O to yield a fine, white powder (0.043 g, 0.144 mmol, 81.1%); mp>250° C. 1H NMR: (500 MHz, DMSO): δ 9.08 (s, 1H, ArOH); 8.47 (m, 1H, NH2); 8.34 (m, 1H, NH2); 8.19 (s, 1H, ArOH); 6.60 (d, 1H, J=8.0 Hz, ArH); 6.43 (d, 1H, J=8.0 Hz, ArH); 3.18-3.06 (m, 2H, ArCHCH2NH2CH2); 2.99-2.88 (m, 3H, ArCHCH2NH2CH2); 2.79 (dd, 1H, J=3.5, 17.5 Hz, ArCH2); 2.45-2.33 (m, 1H, ArCH2); 2.04-1.87 (m, 3H, ArCH2CH2CHCH2); 1.71 (bd, 1H, J=16.0 Hz, ArCH2CH2CHCH2); 1.58-1.52 (m, 1H, ArCH2CH2). ESIMS (M+H)=220.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=[O:18])=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.N[C:25]1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.C12CC(C=C1)C1C(OC(=O)C21)=O>>[ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C@@H:15]3[CH:23]4[CH2:25][CH:20]([CH:21]=[CH:22]4)[C@@H:16]3[C:17]([OH:19])=[O:18])=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C1OC(=O)C2C3C=CC(C3)C12
Product: Nc1nc2ccc(NC(=O)[C@@H]3C4C=CC(C4)[C@@H]3C(=O)O)cc2[nH]1
Yield: 94 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride (8), tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.114 g, 0.254 mmol) was reacted with Bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (0.042 g, 0.254 mmol) to make the title product (0.084 g, 94% yield) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.35 (d, 1H), δ 7.13 (s, 1H), δ 6.99 (d, 1H), δ 6.23 (s, 2H), δ 3.51 (s, 2H), δ 3.37 (s, 2H), δ 1.68 (dd, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 178.1, 151.7, 134.8, 134.6, 130.6, 129.8, 129.6, 128.1, 122.8, 111.5, 110.7, 52.0, 46.8, 45.9, 45.5, 45.4 ppm; HRMS (ESI) Calcd for C16H16N4O3 (M+) 312.1222. Found 312.1226.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.C1COCC1.O.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:2][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Fc1ccc(-c2c(Cl)nc3nccn3c2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2cn3ccnc3nc2Cl)cc1
Temperature: 25 °C

Procedure:
5.3 g (18.9 mmol) 5,7-Dichloro-6-(4-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 480 mL ethanol, 184 mL THF and 342 mL water. After addition of 4.7 g (89.5 mmol) NH4Cl and 7.9 g (120 mmol) zinc the mixture is vigorously stirred at rt for two and a half hours. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent has been removed and the residue redissolved in ethyl acetate (1 L). After washing twice with brine the solvent is evaporated (without prior drying due to solid material in the solvent). 3.83 g (81.8%) of the desired product containing 11% of the bisdeschloro compound are obtained which is used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.[CH3:23][O:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([Cl:32])[N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[Cl:32][C:27]1[N:26]=[C:25]([O:24][CH3:23])[N:30]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:28]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Yield: 13.6 %

Procedure:
Argon is bubbled through a mixture of N-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazol-2-yl]-acetamide (1.12 g, 3.52 mmol), 2-methoxy-4,6-dichloropyrimidine (700 mg, 3.91 mmol), Na2CO3 (625 mg, 5.9 mmol), and bis(triphenylphosphine)palladium(II) chloride (280 mg, 0.4 mmol), in dimethoxyethane (8 mL), water (3.4 mL) and EtOH (2.2 mL) for 10 minutes. The mixture is irradiated by microwave at 160° C. for 10 minutes added water (20 mL) and extracted with EtOAc (40 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford N-[6-(6-chloro-2-methoxy-pyrimidin-4-yl)-benzothiazol-2-yl]-acetamide (160 mg) as a solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 5.4 %

Procedure:
A mixture of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3, 2-(6-benzyl-pyridin-3-yl)-acetohydroximoyl chloride (88 mg, 0.34 mmol) described in Manufacturing Example 210-1-7, triethylamine (77 mg, 0.76 mmol), and tetrahydrofuran (5 mL) was stirred for 25 minutes at 50° C. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1, ethyl acetate) to obtain the title compound (4.6 mg, 5.3%).
Reaction SMILES: [CH2:1]=[O:2].OS(O)(=O)=O.C([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])C=C.[OH2:22]>>[O:2]1[CH2:19][CH2:20][CH:13]([CH2:12][C:20]2[CH:19]=[CH:18][CH:17]=[C:14]3[C:15]([NH:11][C:12](=[O:21])[C:13]=23)=[O:16])[O:22][CH2:1]1
Reactant: C=O
Reactant: O
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)c2c(CC3CCOCO3)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of paraformaldehyde (245 g) was heated to 70° C. in a solution of H2SO4 (360 mL) and H2O (90 mL) using a hot water bath until the mixture became homogenous. Solid N-allylphthalimide (133 g, 0.71 mol) was then added over 10 minutes, keeping the exotherm generated under control. The solution was then stirred at this temperature for an additional 0.5 hour and poured into ice water (1.5 L). The mixture was extracted with ethyl acetate (3×1 L), dried (MgSO4), filtered and concentrated under reduced pressure. The crude solid was then purified through a silica gel plug (1 kg SiO2) from CH2Cl2 as the eluent. This afforded the desired 1,3-dioxane-4-ylmethylphthalimide as a white solid (95 g, 54%).
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:30]=4[NH:31]3)=[CH:27][CH:26]=2)[C:22]([CH2:39][CH3:40])=[C:21]([O:41]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.C(Cl)Cl.[SiH](C(C)C)(C(C)C)C(C)C>C(O)(C(F)(F)F)=O>[CH2:39]([C:22]1[C:21]([OH:41])=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[O:8])[NH:24][C:23]=1[C:25]1[CH:33]=[C:32]2[C:28]([C:29]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:30]=3[NH:31]2)=[CH:27][CH:26]=1)[CH3:40]
Reactant: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C)CC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C)CC4)[nH]c(=O)c(C(=O)O)c1O
Yield: 100 %

Procedure:
The intermediate from Step 2 (19 mg, 0.030 mmol) was stirred in TFA (0.2 mL), CH2Cl2 (0.2 mL) and TIPSH (0.2 mL) at room temperature for 15 h. The solvents were removed and the residue was dissolved in CH2Cl2 (0.5 mL), then HCl (2.0M in Et2O, 1.0 mL) was added. The precipitate was collected by filtration and washed by ether to afford the title compound as an off-white solid (12 mg, 0.030 mmol, HCl salt) in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][S:33][CH3:32])[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CSC)ccc21
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide (175 mg) prepared as described in Example No. 84, in DMF (1.5 11) is added sodium thiomethoxide (40 mg). The mixture is stirred for 18 h, then added to 25 ml of rapidly stirred water. The solid is filtered, washed well with water, dried in vacuo, and recrystallized from acetonitrile to afford 139 mg of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CCOC(C)=O>[C:1]([O:5][C:6]([C:7]1[C:8]([C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[F:15])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Reactant: Cc1ccc(B(O)O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Compound A (22.8 g, 88.6 mmol) and 2-fluoro-4-methylphenylboronic acid (15.0 g, 97.4 mmol) were suspended in isopropyl alcohol (75 mL, 980 mmol). A solution of sodium carbonate (16 g, 150 mmol) in water (75 mL, 4.2 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (1.0 g, 880 μmol) was then added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, EtOAc (200 mL) and water (200 mL) were added, and the mixture was filtered. The liquor was extracted with EtOAc (2×100 mL), washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography (0-15% EtOAc in hexanes) to yield compound B as a colorless oil (14.9 g, 96% purity).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[C:5](=[O:15])[C:4]([CH3:16])=[CH:3]1.CN1C2C(=CC=C([N+]([O-])=O)C=2)C(=O)C(C)=C1.[H][H]>CO.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5](=[O:15])[C:4]([CH3:16])=[CH:3][N:2]2[CH3:1]
Reactant: [H][H]
Reactant: Cc1cn(C)c2cccc([N+](=O)[O-])c2c1=O
Agent: [Pd]
Agent: Cc1cn(C)c2cc([N+](=O)[O-])ccc2c1=O
Solvent: CO
Product: Cc1cn(C)c2cccc(N)c2c1=O
Yield: 28 %

Procedure:
A mixture of 1,3-dimethyl-5-nitroquinolin-4(1H)-one and 1,3-dimethyl-7-nitroquinolin-4(1H)-one Compound 299B, 2.2 g, 10 mmol) in MeOH (150 mL) was hydrogenated over 5% Pd/C (0.8 g) at 40° C. under 40 psi hydrogen pressure overnight. The catalyst was filtered off and the filtrate was concentrated and purified by HPLC to give the title compound (540 mg, 28%) as a pure regioisomer. 1H NMR (DMSO-d6, 400 MHz): δ=1.92 (s, 3 H), 3.69 (s, 3 H), 6.63 (d, J=8.0 Hz, 1 H), 6.80 (d, J=8.4 Hz, 1 H), 7.40 (t, J=8.0 Hz, 1 H), 7.91 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C[O:30][C:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3[CH2:38][C:33]4[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:31]3=[O:30])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1Cc2ccccc2C1=O
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.38 mmol) and N,N-diisopropylethylamine (72 μL, 0.41 mmol) in acetonitrile (6 ml) at 0° C. was added 2-bromomethyl-benzoic acid methyl ester (43 mg, 0.19 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was diluted in ethyl acetate (50 ml), washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 50 mg (68%) of 2-amino-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+].O1CCCC1>[CH2:15]([O:14][C:12]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1(O)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude 4-hydroxypiperidine-4-carboxylic acid obtained in the above step (a) was dissolved in a mixed solvent of 1 N aqueous sodium hydroxide (1.4 ml) and tetrahydrofuran (2 ml), and the solution was added with benzyl chloroformate (0.1 ml). The reaction mixture was stirred at room temperature for 2 hours and 30 minutes, and then acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain crude 1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid. This crude 1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([N:13](CC)CC)C.N[C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[S:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([C:10]4[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][CH:9]=4)[C:4]([NH2:13])=[O:5])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1c(C(N)=O)cccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e]-[1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:29][C:30]1[C:35]([Pb+3])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:29][C:30]1[C:35]([CH:4]2[C:3](=[O:12])[CH:2]3[CH:6]([CH:7]4[O:10][CH:1]3[CH2:9][CH2:8]4)[C:5]2=[O:11])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (166 mg, 1 mmol) and 4-dimethylaminopyridine (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry chloroform (5.6 ml), and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 2.4 ml, 1.2 mmol). The reaction mixture is heated at reflux for 1 hour, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid, filtered and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphen-4-yl)-10-oxa-tricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2N)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2NC(=O)Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-[4-(dimethylamino)phenyl]pyrazin-2-amine (7n) (315 mg, 749 μmol) and 4-(dimethylamino)pyridine (14.8 mg, 121 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was hetated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11n (200 mg, 300 μmol, 40.0%) as a yellow solid. Rf=0.26 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.23 (s, 6H), 0.95 (s, 9H), 0.97 (s, 9H), 2.95 (s, 6H), 3.50 (s, 2H), 6.52-6.65 (AA′BB′, 2H), 6.75-6.85 (AA′BB′, 2H), 6.95-7.05 (AA′BB′, 2H), 7.10-7.20 (AA′BB′, 2H), 7.56-7.66 (AA′BB′, 2H), 8.04-8.10 (AA′BB′, 2H), 8.82 (s, 1H), 10.41 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 39.8 (2C), 41.8, 111.3 (2C), 119.5 (2C), 120.3 (2C), 124.4, 128.05, 128.07 (2C), 128.9 (2C), 129.2, 130.4 (2C), 135.8, 142.0, 147.78, 147.84, 150.5, 153.8, 156.6, 169.3; IR (KBr, cm−1) 527, 685, 781, 839, 914, 1080, 1167, 1256, 1371, 1441, 1508, 1607, 1668, 2857, 2928, 2955, 3233.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>O1CCCC1>[CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([S:41]([CH3:44])(=[O:43])=[O:42])[C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:32]=[N:31][C:30]([NH2:33])=[N:29][CH:28]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (140 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 ml) followed by the addition of triethylamine (68 μl) and mesyl chloride (28 μl) with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:5 to 0:10) to give a white solid (115 g, 67%).