Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]([O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)COCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 179.8 %

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) prepared according to the method of C. Malanga et al, Synthetic Communications, 12,(1), 67-70 (1982)) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in tetrahydrofuran (400 ml) (hereinafter abbreviated to THF), followed by adding dimethylformamide (hereinafter abbreviated to DMF) (200 ml), agitating the mixture for 2 hours, dropwise adding benzyl bromide (140.8 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, (S)-1-benzyloxy-2-tetrahydropyranyloxypropane, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture to 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing it with water, distilling off toluene, and distilling the residue to obtain (S)-1-benzyloxy-2-hydroxypropane (98 g)(b.p. 94.0° C./2.5 mmHg). A mixture of this (S)-1-benzyloxy-2-hydroxypropane (60 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (115.2 g). On the other hand, a solution of 4-hydroxy-4'-octyloxybiphenyl (50 g, 0.17 mol) in THF (200 ml) was dropwise added to a mixture of sodium hydride (8.5 g, 0.35 mol) with THF (100 ml), followed by dropwise adding a solution of the above (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (64.5 g)(0.20 mol) in DMF (100 ml), agitating the mixture at 60° C. for 4 hours, allowing the mixture to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH and further with water, drying over anhydrous magnesium sulfate, distilling off toluene, dissolving the residue in a mixture of ethanol (250 ml) with ethyl acetate (250 ml), adding Pd/C catalyst (10 g), agitating the mixture in hydrogen gas, filtering off the Pd/C, distilling off the solvent, and recrystallizing the residue from heptane (150 ml), to obtain (R)-4-(2'-hydroxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (m.p. 107.9° C.).
Reaction SMILES: [NH2:1][CH:2]([CH3:32])[CH:3]([C:14]1[C:15]([CH3:31])=[C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[CH2:23]([O:22][C:21]([NH:20][C:16]1[C:15]([CH3:31])=[C:14]([CH:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=4)[NH:6][C:5]=3[CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:1][CH:2]2[CH3:32])[CH:19]=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)N
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NC(C)C(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a homogeneous solution of benzyl (3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate (4.00 g, 8.12 mmol) in dioxane (200 mL) under nitrogen was added 50% ethyl 2-oxoacetate in toluene (3.22 mL, 16.3 mmol) followed by 4 M hydrochloric acid in 1,4-dioxane (4.06 mL, 16.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (75 mL), and washed with brine (75 mL). The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate in a quantitative yield as a burgundy solid. The mixture was used in the next step without any further purification. LC/MS M+1=576.2 and 578.2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:23]([CH3:22])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CNCCO
Product: CN(CCO)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-methylamino-ethanol according to the GPA affording 25 mg (71%) of an orange-dark powder. Rt=2.98 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:21](=N)(OCC)[CH2:22][CH3:23].CCN(CC)CC>CCO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][C:21]([CH2:22][CH3:23])=[N:17][N:16]=2)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1nnc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzohydrazide (6.0 g, 21.4 mmol; reported in Tanaka, A. et al. J. Med. Chem. 1998, 41, 2390) and ethyl propionimidate hydrochloride (3.5 g, 25.7 mmol; preparation reported in WO2007/73299 A1) in EtOH (120 mL) was added Et3N (2.59 g, 25.7 mmol). The mixture was stirred at room temperature for 1 hr then concentrated in vacuo. The residue was partitioned into EtOAc and H2O and the organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (EtOAc-hexanes) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole as a brown oil (3.0 g, 44% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:18]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[CH2:18]([N:25]([S:26]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 36901.3 %

Procedure:
The mixture was heated in an oil bath at 50° C. overnight and then was heated in an oil bath at 100° C. for 1.5 days. The mixture was poured into 800 ml of water and extracted with ethyl acetate. The extract was washed with water, 2N citric acid, water, brine and dried (Na2SO4). The solvent was removed and the residue chromatographed on silica gel with hexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as a solid, mp 170-1720. From a larger scale run of 5.07 g (0.02 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 8.0 g (0.0289 mmol) of benzyl-(4-methoxybenzenesulfonyl) amine (as sodium anion) in 30 ml of 1-methyl-2-pyrrolidinone heated at 90° C. for 3 days there was obtained 3.65 g of product.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:6][CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:9]=1)([O-])=O>CO.[Pd]>[O:19]1[CH2:20][CH2:21][N:16]([C:5]2[C:4]([NH2:1])=[CH:9][C:8]([N:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[CH:7][N:6]=2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cc(N2CCSCC2)cnc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N2CCSCC2)cnc1N1CCOCC1

Procedure:
A solution of 4-(3-nitro-5-thiomorpholinopyridin-2-yl)morpholine (140 mg, 0.45 mmol) in MeOH (100 mL) was reduced using a continuous flow hydrogenation reactor (flow rate: 1 mL/min, 10% mol Pd/C, temperature 35° C., H2 pressure: 10 bar) to give 2-morpholino-5-thiomorpholinopyridin-3-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH2:25](I)[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)[CH2:26][CH3:27]
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCn1nc(-c2ccncc2)nc1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mole) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1 g. 0.024 mole) and the mixture is heated 45 minutes at reflux. The suspension is concentrated to a solid, N,N-dimethylformamide (70 ml.) and n-propyl iodide (0.022 mole) are added. The mixture is stirred 0.5 hour at ambient temperature followed by heating on the steam bath for 4 hours. The solution is concentrated to a gum, water is added and the material solidifies. Following recrystallization from methylcyclohexane there is obtained 1-n-propyl-3,5-bis(4-pyridyl)-1,2,4-triazole, m.p. 88°-89.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(Nc3cc(C(F)(F)F)nc(-c4ccncc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and p-toluoyl chloride in pyridine (5 ml) was stirred at room temperature for 15 h. Then water was added to the mixture. The resulting precipitate was filtered, washed with excess water and dried to give a tan solid (26 mg, 94%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.8, 4.5 Hz, 2H), 8.00 (s, 1H), 7.83 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=7.5 Hz, 2H), 7.01 (s, 1H), 6.73 (s, 1H), 2.44 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]=[C:21]2[C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:25]=3[NH:24][C:23](=[O:31])[N:22]2[CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[C:2]([N:28]1[CH2:29][CH2:30][C:25]2[NH:24][C:23](=[O:31])[N:22]3[CH:32]=[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[F:12])[N:20]=[C:21]3[C:26]=2[CH2:27]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (57 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 1 hour, then poured into ice water. The precipitate was collected, washed with 95% ethanol and ether, and subsequently dried to give 9-Carbobenzyloxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 44). Recrystallization from aqueous ethanol afforded Compound 41 as an off-white solid. m.p. 250° C. (d).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:24]2[CH2:25][CH2:26][S:27][CH2:28][CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 37 (0.16 g, 0.392 mmol) in dry CH2Cl2 (2 mL) was added TFA (2 mL) slowly. After stirring at 0° C. for 3 h, the reaction mixture was concentrated to give a yellow solid. The crude product was purified by flash column chromatography on silica gel using a CH2Cl2:MeOH gradient (100:0 to 0:100) to give compound 38 a yellow foam (0.074 g, 54%). 1H NMR (400 MHz, DMSO-d6): δ 2.42-2.46 (m, 4H), 2.63-2.66 (m, 4H), 6.46 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.39 (s, 1H), 12.38 (s, 1H). LRMS (ESI) m/z 353 (M+H)+. HRMS (ESI) Calcd for C21H21O3S: 353.1211 (M+H)+. Found: 353.1208.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[NH:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([NH:38][C:39]([C:41]4[N:42]([CH3:50])[C:43]5[C:48]([CH:49]=4)=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:40])=[C:23]([O:22][CH3:21])[CH:28]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2CCCN1CCOCC1
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: O
Solvent: COCCOC
Product: COc1cc(-c2nn(CCCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 56.2 %

Procedure:
A solution of 3-iodo-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.244 g, 0.629 mmol) in ethylene glycol dimethyl ether (16 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.281 g, 0.692 mmol), tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol), and a solution of sodium carbonate (0.160 g, 1.51 mmol) in water (8 mL). The reaction mixture was stirred for 4.5 h at 80° C. The organic solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 10% methanol in dichloromethane to 50% methanol in dichloromethane as the eluent. The column afforded 0.191 g (56%) of pure N2-{4-[4-amino-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.440 (s, 1H), 8.260 (s, 1H), 8.1229-8.1026 (d, 1H, J=8.12 Hz), 7.7184-7.6986 (d, 1H, J=7.92 Hz), 7.5983-7.578 (d, 1H, J=8.08 Hz), 7.345-7.290 (m, 4H), 7.172-7.133 (m, 1H), 4.421-4386 (m, 2H), 4.04 (s, 3H), 3.958 (s, 3H), 3.521-3.500 (m, 4H), 2.349-2.314 (m, 6H), 2.035-2.001 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 541.3.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])[CH3:3].[NH2:16][OH:17].O>C(Cl)Cl>[C:6]([NH:16][OH:17])([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: NO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NO
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Boc anhydride (5.91 g, 0.026 mole) was added in one portion to a stirred solution of amino alcohol in anhydrous DCM (150 mL), and the reaction mixture stirred at ambient temperature under argon for 4.5 h. Water (200 mL) was added to the reaction mixture and the organic layer separated. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated to give N-boc amino alcohol as a colorless liquid that became a colorless glass upon standing. The material was used without further purification. Yield: 9.0 g (quantitative); LCMS: (+) ESI: m/z=368 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:4]=2[N:3]=1.[C:22](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:22])[C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCCOC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCCOC
Reaction time: 18 h
Yield: 142.3 %

Procedure:
To a solution of 8-chloro-3-({[2-(methyloxy)ethyl]oxy}methyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2 g, 6.37 mmol) in anhydrous DMF (15 ml) was added sodium carbonate (0.743 g, 7 mmol). After 10 minutes stirring at room temperature methyliodide (0.44 ml, 7 mmol) was added and stirring continued under nitrogen at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with brine (100 ml). The organic extract was dried (MgSO4) filtered and evaporated to afford the title compound as a tan oil (85% pure) (2.98 g, quant.), m/z 329.2[MH+]
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:27]([C@@H:34]([CH3:37])[CH2:35]O)[CH2:28][C@H:29]([OH:33])[CH2:30][O:31][CH3:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl:38]C(Cl)(Cl)Cl>>[CH2:20]([N:27]([CH2:28][C@H:29]([OH:33])[CH2:30][O:31][CH3:32])[C@@H:34]([CH3:37])[CH2:35][Cl:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC[C@@H](O)CN(Cc1ccccc1)[C@@H](C)CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC[C@@H](O)CN(Cc1ccccc1)[C@@H](C)CCl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triphenylphosphine (10.09 g) was added to a solution of (2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-1-propanol (8.86 g) in tetrachloromethane (4.06 ml) at room temperature. After being stirred at room temperature for 2 days, the solution was concentrated under reduced pressure. The residue was triturated with diisopropyl ether (200 ml) three times, and the soluble portions were separated by decantation and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-1-[N-benzyl-N-[(1S)-2-chloro-1-methylethyl]amino]-3-methoxy-2-propanol (4.90 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[F:10].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:12]2[CH:22]=[C:16]3[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]3[C:14](=[O:23])[N:13]=2)=[CH:4][C:3]=1[F:10]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: NCc1ccc(Cl)c(F)c1
Product: CN1CCCn2c1cc(NCc1ccc(Cl)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (4-chloro-3-fluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3](=[O:2])[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 98.7 %

Procedure:
A solution of 36.12 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at room temperature with 2.76 g of para-toluenesulfonic acid. Then, it is concentrated by evaporation in a vacuum to 1/3 of the volume, taken up with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 31.7 g of 3-hydroxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one is obtained as crystals with a melting point of 194°-196° C.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[CH:13]=[CH:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:25]>C(O)(C)C.O.[Pd]>[ClH:25].[C:16]1([N:15]2[C:11]3([CH2:23][CH2:24][NH:8][CH2:9][CH2:10]3)[CH2:12][CH2:13][C:14]2=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C=CC2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: O=C1CCC2(CCNCC2)N1c1ccccc1
Reaction time: 5 h

Procedure:
To a suspension of Pd/C (30 mg, 10%) in isopropanol (5 mL), water (5 mL) and hydrochloric acid (0.04 mL) was added 8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (150 mg 0.5 mmol). The mixture was hydrogenated under H2 (50 psi) at 20° C. for 5 hours. After filtration, the filtrate was evaporated under reduced pressure to give 1-phenyl-1,8-diazaspiro[4.5]decan-2-one hydrochloride. 1H NMR (300 MHz, MeOD) δ 7.42-7.52 (m, 3H), 7.15-7.41 (m, 2H), 3.29-3.33 (m, 2H), 3.06-3.16 (m, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.31 (t, J=8.1 Hz, 2H) 1.96-2.00 (m, 2H), 1.78-1.89 (m, 2H).