Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:30]2[C:25](=[N:26][C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:29]=2)[N:24]([CH3:39])[CH:23]=1.CNCCNC>O1CCOCC1.[Cu]I.O>[CH3:39][N:24]1[C:25]2=[N:26][C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:29]=[C:30]2[C:22]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:23]1
Reactant: CCOC(=O)N1CCNC(=O)C1
Reactant: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CCN(c2cn(C)c3nc(OCc4ccccn4)ccc23)C(=O)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 45.5 %

Procedure:
Ethyl 3-oxo-piperazine-1-carboxylate (161.4 g, 937.2 mmol), copper(I) iodide (27.65 g, 145.20 mmol) and potassium phosphate (tribasic, n-hydrate) (205.1 g, 937.2 mmol) is charged into a glass reactor at room temperature under nitrogen. A solution of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (210 g, 660.0 mmol) in 1,4-dioxane (2.73 L) is added, followed by N,N′-dimethylethane-1,2-diamine (24.34 g; 270.6 mmol). The reaction mixture is heated to 100° C. and stirred for 20 h. Further copper(I) iodide (10.06 g, 52.80 mmol) and N,N′-dimethylethane-1,2-diamine (10.95 g, 105.6 mmol) is added and the reaction stirred for a further 23 h. The reaction mixture is combined with a smaller batch made in a similar manner starting with 23.68 g of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine. The mixture is cooled to room temperature, then poured into water (4.2 L) and extracted with EtOAc (3×1.7 L). The organic extracts are combined and washed with 3% w/w aqueous ammonia (3×400 mL), then water (2×2 L), then brine (600 mL), and dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica, eluting with 50 to 100% EtOAc in isohexane. The appropriate fractions are combined, evaporated and recrystallized from ethanol (525 mL). The solid is dried to give the title compound (125.6 g, 0.3 mol). MS (m/z): 410.1 (M+1). 1H-NMR (400 MHz, CDCl3): δ 1.31 (t, 3H), 3.72 (s, 3H), 3.80-3.78 (t, 2H), 3.86 (t, 2H), 4.22 (q, 2H), 4.34 (s, 2H), 5.59 (s, 2H), 6.71 (d, 1H), 7.01 (s, 1H), 7.20 (dd, 1H), 7.49 (d, 1H), 7.70-7.66 (m, 2H), 8.60 (d, 1H). DSC (onset) mp=143.42° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH2:20]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[C:42]([CH:47]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl.[Cl-].[Na+].O.O>[CH2:45]([O:44][C:42](=[O:43])[CH:47]=[CH:20][C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (0.535 mL, 6.14 mmol) in methylene chloride (3 mL) cooled to -70° under nitrogen is added dropwise dimethylsulfoxide (0.830 mL, 10.7 mmol) im methylene chloride (3 mL). After 20 minutes of stirring at -70°, a solution of (S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propan-1-ol (1 g, 3.05 mmol) in methylene chloride (3 mL) is added, followed by triethylamine (2 mL, 14.3 mmol). The solution is allowed to warm up to room temperature over a 1 hour period then poured into brine. Methylene chloride (50 mL) and water (80 mL) are added. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude aldehyde is dissolved in methylene chloride (15 mL) and treated with (carboethoxymethylene)-triphenylphosphorane (2.1 g, 6.1 mmol). After stirring at room temperature for 18 hours, silica gel (2 g) is added and the solvent is evaporated under vacuum. The product is purified by flash-chromatography on silica gel, eluting with 25% ethyl acetate in hexane. (S)-4-(t-Butoxycarbonylamino)-5-(biphenyl-4-yl)-pentenoic acid ethyl ester is obtained a white solid, m.p. 91°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][C:31]1[N:36]=[N:35][CH:34]=[C:33]([C:37]([OH:39])=O)[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C:33]2[CH:32]=[C:31]([CH3:30])[N:36]=[N:35][CH:34]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C(=O)O)cnn1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: Cc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cnn1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 6-methyl-pyridazine-4-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 6-methyl-pyridazine-4-carboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 557.9 [M]+.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:57])[C@@H:22]([NH2:56])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:56][C@@H:22]([CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:21](=[O:57])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-14-amino-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonic acid diethyl ester (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at room temperature overnight and then concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title compound as a white solid. 1H NMR (CDCl3): δ 8.80 (br s, 1H), 5.13-5.24 (m, 1H), 4.35 (dd, 1H), 4.15 (dd, 1H), 3.45-3.88 (m, 15H), 3.31-3.45 (m, 2H), 3.03-3.17 (m, 2H), 2.82-2.96 (m, 1H), 2.76 (dd, 1H), 2.30 (q, 4H), 1.78-2.00 (m, 2H), 1.51-1.66 (m, 4H), 1.17-1.37 (m, 32H), 0.86 (t, 6H). LRMS [M+H]=799.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH:15]2[CH2:17][CH2:16]2)=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[N:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]2=[C:20]([C:27](Cl)=[O:28])[CH:19]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH:15]2[CH2:17][CH2:16]2)=[C:6]([C:8]2[C:12]([NH:13][C:27]([C:20]3[CH:19]=[N:18][N:22]4[CH:23]=[CH:24][CH:25]=[N:26][C:21]=34)=[O:28])=[CH:11][NH:10][N:9]=2)[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: Nc1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC1CC1)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine (0.2 g, 0.8 mmol) was dissolved in 15 mL of anhydrous THF. Pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.17 g, 0.96 mmol) was added followed by DIPEA (0.2 g, 1.6 mmol). The mixture was stirred at room temperature for 2 h, then evaporated to dryness. The residue was purified by silica gel chromatography (EtOAc as eluant) to afford 0.3 g of the title compound. Yield: 95%. 1H NMR (DMSO-d6, 400 MHz) δ: 12.93 (d, 1H), 9.56 (d, J=5.2 Hz, 1H), 9.34 (d, J=7.2 Hz, 1H), 8.75-8.74 (m, 1H), 8.65 (s, 1H), 8.22 (s, 0.5H), 8.05 (s, 0.5H), 7.55-7.25 (m, 4H), 3.97-3.94 (m, 1H), 0.70-0.44 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]4[N:28](C5CCCCO5)[N:29]=[CH:30][C:25]4=[C:24]([C:37]4[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]4[NH:28][N:29]=[CH:30][C:25]4=[C:24]([C:37]4[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=4)[N:23]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3c2cnn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoroacetic acid (0.15 mL, 1.86 mmol) was added to a solution of N-(3-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (10 mg, 0.018 mmol) in CH2Cl2 (4 mL) and the reaction mixture was stirred for 16 h at room temperature, after which the solvent was removed in vacuo. The residue was purified by flash chromatography (6% CH3OH/CH2Cl2) to yield the title compound as an off white solid. 1H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 8.31 (s, 1H), 7.99 (d, 1H, J=7.6 Hz), 7.75 (m, 3H), 7.54 (m, 1H), 6.99 (m, 2H), 6.46 (m, 2H), 5.81 (dd, 1H, J=2.4 Hz and 9.6 Hz), 3.17 (m, 4H), 2.64 (m, 4H), 2.35 (s, 3H); ESI-MS: 455.27 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)(/C=C/B1O[C:40](C)([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:42]=[CH:40]/[C:39]([OH:38])([CH3:45])[CH3:44])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Reactant: CC(C)(O)/C=C/B1OC(C)(C)C(C)(C)O1
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: CN(C)C=O
Product: CC(C)(O)/C=C/c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-[(2,6-dichloro-4-iodophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 156, Step 1) (30 mg, 0.06 mmol) in DMF (1.5 mL) were added sodium carbonate (2 M, 0.5 mL), tetrakis(triphenylphosphine)palladium (0) (14.3 mg, 0.12 mmol), and (3E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (13.2 mg, 0.06 mmol). The solution was degassed by bubbling nitrogen gas and heated to 80° C. overnight. After cooling to room temperature, the mixture was extracted with 3:1 CHCl3/iPrOH. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)(=[O:4])[CH2:2][CH3:3].C([O-])(O)=O.[Na+].[Br:20]Br>CCOCC>[Br:20][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)=[O:4]
Reactant: CCC(=O)c1ccc2c(c1)CCCS2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(Br)C(=O)c1ccc2c(c1)CCCS2
Temperature: 5 °C
Yield: 86 %

Procedure:
To a solution of 32 gr. of 6-propionyl-thiochromane in 400 ml of anhydrous ether, 8 ml of bromine are dropwise added, temperature being maintained at ±5° C. After addition, the mixture is still stirred for 2 to 3 hours at room temperature, than an aqueous saturated NaHCO3 solution is slowly added. The aqueous phase is twice extracted with 100 ml ether, combined organic phases are dried on MgSO4, filtered, and solvent is evaporated in vacuo. The residue so obtained is treated with 100 ml of petroleum ether; 38 gr. of α-bromo-6-propionyl-thiochromane are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([CH:12]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=[N:22]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
To a solution of 2-(4-methoxyphenyl)malondialdehyde (797 mg, 4.48 mmol, 1 eq) in 20 ml of ethanol are added m-anisidine (551 mg, 4.48 mmol, 1 eq) and 10 ml of conc. HCl. The reaction mixture is stirred at 80° C. for 3 days, and after cooling to RT, the reaction is stopped by adding a 10% sodium carbonate solution. The mixture is extracted with dichloromethane, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. After purification by column chromatography with hexane/ethyl acetate as the eluent, the product was obtained in a yield of 19% (221 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CC(C)=O>[C:17]([NH:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
11.05 g (0.05 mole) 2,6-di-t-butyl-4-aminophenol is dissolved in 25 ml acetone and 7.03 g (0.05 mole) benzoyl chloride is added thereto. The reaction is exothermic. The mixture is shaken and 10 ml of 5 N sodium hydroxide is added thereto, portionwise, accompanied by agitation. A solid material separates and is allowed to stand for one hour, cooled and there is then added thereto 50 ml water. The mixture is filtered, washed with 50 ml water and then four times each time with 50 ml portions of petroleum ether to remove the red color. The solid material is air dried and there is obtained 14.72 g (a yield of 90.6%) of the 4-benzamido-2,6-di-t-butylphenol product. The solid material is dissolved in 100 ml of 90% ethanol, contacted with a charcoal adsorbent (Darco G-60) and then crystallized. The crystalline material is cooled, filtered, washed with 30 ml cold 90% ethanol and then dried in vacuo over phosphorus pentoxide. The pure product is characterized by a melting point of 209°-210° C.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1
Reactant: [I-]
Reactant: Cn1nnc(SCCl)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 5-chloromethylthio-2-methyltetrazole (987 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.00 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 5-iodomethylthio-2-methyltetrazole (1.43 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][N:18](S(C)(=O)=O)[CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([N:18]1[CH2:19][CH2:20][C:14]2([CH2:15][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13]2)[CH2:16][CH2:17]1)=[O:33]
Reactant: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methanesulfonyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using methyl chloroformate in place of methanesulfonyl chloride. The title compound was obtained as a colourless oil (20 mg, 28%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH:38]([OH:40])[CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:39][CH:38]([OH:40])[CH2:37]5)[CH2:32][CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CN(C2CCNCC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(O)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.157 g, 0.40 mmol), 1-piperidin-4-ylazetidin-3-ol (0.075 g, 0.48 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 20:80) to give 554 as a white solid (0.145 g, 68%). LCMS (Method I): RT=2.20 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.27-7.20 (m, 2 H); 4.27-4.19 (m, 4 H); 3.80 (s, 3 H); 3.77 (t, J=4.7 Hz, 4 H); 3.74 (s, 2 H); 3.44 (t, J=7.1 Hz, 2 H); 3.26 (q, J=7.4 Hz, 3 H); 2.78-2.70 (m, 2 H); 2.62 (t, J=7.1 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.99-1.90 (m, 1 H); 1.60 (d, J=11.0 Hz, 2 H); 1.33 (t, J=7.4 Hz, 3 H); 1.21-1.10 (m, 2 H)
Reaction SMILES: CS[CH2:3][C@@H:4](C(O)=O)[NH:5][C:6](=O)[CH3:7].C(N)C.[CH2:15]([S:17][CH2:18][C@@H:19]([C:24]([OH:26])=O)[NH:20][C:21](=[O:23])[CH3:22])[CH3:16].N1CCCC1>>[C:21]([NH:20][C@H:19]([C:24]([N:5]1[CH2:4][CH2:3][CH2:7][CH2:6]1)=[O:26])[CH2:18][S:17][CH2:15][CH3:16])(=[O:23])[CH3:22]
Reactant: CSC[C@H](NC(C)=O)C(=O)O
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Agent: CCN
Solvent: C1CCNC1
Product: CCSC[C@H](NC(C)=O)C(=O)N1CCCC1

Procedure:
N-(N-Acetyl-S-ethyl-L-cysteinyl)pyrrolidine was synthesized in exactly the same manner as described in Example 14 except that the S-methyl-N-acetyl-L-cysteine and aqueous 70% ethylamine solution used in that example were replaced by S-ethyl-N-acetyl-L-cysteine and pyrrolidine, respectively.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[C:12]([OH:13])=[CH:11][N:10]=[CH:9][N:8]=1.[CH3:32][O:33][C:34](=[O:38])[CH:35](Br)[CH3:36].[Cl-].[NH4+]>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[C:12]([O:13][CH:35]([C:34]([O:33][CH3:32])=[O:38])[CH3:36])=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncncc3O)c(Cl)cc2F)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cncnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a mixture of 32 mg of Sodium hydride and N,N-dimethylformamide, 0.35 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-hydroxypyrimidine was added and stirred at room temperature for 1 hour. Then 0.135 g of methyl2-bromopropionate was added to the mixture, and stirred for 2 hours at room temperature, then for 1 hour at 50° C. The mixture was poured into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.319 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 3-52].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](OC)=O)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:25]1CCCC1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:25])[CH3:15])=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1ccc(OC2CCCCO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1ccc(OC2CCCCO2)cc1

Procedure:
A solution of 57 g. of methyl 4-(tetrahydropyran-2-yloxy)phenylacetate, in 2 l. of anhydrous tetrahydrofuran is added dropwise, over a 30 minute period to a stirred suspension of 20 g. of lithium aluminum hydride in 1 l. of anhydrous tetrahydrofuran, under nitrogen atmosphere. The mixture is refluxed for 90 minutes, cooled and cautiously treated with 20 ml. of ethyl acetate, to destroy the excess reagent. Solid sodium sulfate is added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate. Upon evaporation of the combined organic filtrates there is obtained 4-(tetrahydropyran-2-yloxy)phenylethanol.