Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH2:19][C:20]#[N:21])[C:6]=2[N:7]=1.B(O)O.[C:31]([O-:34])(=O)C.[K+].[C:36](#[N:38])[CH3:37]>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>[C:20]([CH2:19][C@@H:8]1[C:6]2[N:7]=[C:2]([C:8]3[CH:19]=[CH:20][C:36]([NH:38][C:31]([NH:3][CH2:4][CH3:5])=[O:34])=[CH:37][CH:6]=3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]=2[CH2:11][CH2:10][N:9]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:21]
Reactant: CC#N
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Cl)nc2N2CCOCC2)C1CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [K+]
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OC(C)(C)C)[C@@H]3CC#N)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compounds xy1 and xy2: Tert-butyl 2-chloro-8-(cyanomethyl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.803 g, 0.00204 mol), [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.778 g, 0.00268 mol), Tetrakis(triphenylphosphine)palladium(0) (0.148 g, 0.000128 mol) Sodium carbonate (0.334 g, 0.00315 mol) and Potassium acetate (0.330 g, 0.00336 mol) were combined, nitrogen purged three times, added dry Acetonitrile (17.0 mL, 0.325 mol) followed by deoxygenated Water (10.0 mL, 0.555 mol), heated at 90° C. and stirred overnight. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (40 g, 0-100% EtOAc in heptane), purified by HPLC, and the enantiomers were separated by SFC. Enantiomer 1 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.24 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.19 (t, J=5.5, 1H), 5.16 (t, J=5.9, 1H), 4.22 (s, 1H), 3.84-3.73 (m, 2H), 3.73-3.55 (m, 4H), 3.34 (m, 3H), 3.17-2.90 (m, 4H), 2.82 (s, 1H), 1.48 (s, 9H), 1.13 (t, J=7.2, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+522.2 (M+H)+; Enantiomer 2 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.24 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.19 (t, J=5.6, 1H), 5.16 (t, J=5.9, 1H), 4.18 (s, 1H), 3.78 (dd, J=8.7, 6.2, 2H), 3.72-3.55 (m, 4H), 3.41-3.25 (m, 3H), 3.17-2.90 (m, 4H), 2.84 (d, J=11.0, 1H), 1.47 (d, J=9.3, 9H), 1.14 (t, J=7.2, 1H), 1.09-1.01 (m, 3H). LC/MS-m/z+522.3 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CCN(CC)CC.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22].N#N>C1(C)C=CC=CC=1.O.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.[Cu]I>[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[C:22][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 70 °C
Yield: 89.2 %

Procedure:
To a solution of 3-bromo-5-nitropyridin-2-amine (1.0 g, 4.6 mmol) in toluene/water (5 mL/2.5 mL), was added Et3N (1.2 mL, 9.2 mmol), Pd(PPh3)2Cl2 (0.3 g, 0.46 mmol), CuI (35 mg, 0.18 mmol) and 3,3-dimethyl-but-1-yne (0.75 g, 9.2 mmol) successively under N2 protection. The mixture was heated at 70° C. for 2.5 h. The solid was filtered and the organic layer was separated. The aqueous layer was exacted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford 3-(3,3-dimethylbut-1-ynyl)-5-nitropyridin-2-amine (0.9 g, 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.87 (d, J=3.2 Hz, 1H), 8.25 (d, J=3.2 Hz, 1H), 5.80 (brs, 2H), 1.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)(O)[CH2:9][O:10]C)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CC(c1cccc(Cl)c1)c1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 1,1-bis-(3-chlorophenyl)-2-methoxyethanol (47 g) (obtained by reaction of (3-chlorophenyl)magnesium bromide on methyl 2-methoxyacetate in tetrahydrofuran) in formic acid (44 cc) is refluxed for 5 hours, cooled and poured into a mixture of saturated sodium carbonate solution (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×250 cc) and with saturated sodium chloride solution (200 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis-(3-chlorophenyl)acetaldehyde (36.9 g) in the form of a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2ncccc2c1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc2ncccc2c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a solution of methyl quinoline-6-carboxylate (148 g, 0.79 mol) in methanol (600 ml.), aqueous ammonia (800 ml) was added and then stirred at 45° C. for 12 h. The reaction mixture was concentrated to afford the title compound as a dark red solid (120 g, 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:32].NN.[C:35](=[O:38])([O-:37])O.[Na+].[O:40]1[CH2:44][CH2:43][CH2:42]C1>>[C:44]([OH:40])(=[O:9])/[CH:43]=[CH:42]/[C:35]([OH:37])=[O:38].[CH3:24][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([S:8]([C:5]2[CH:6]=[N:7][CH:2]=[C:3]([CH3:32])[CH:4]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)cnc1Cl
Reactant: C1CCOC1
Agent: NN
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C)c2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C

Procedure:
To a solution (5 mL) of tert-butyl {[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (237 mg) in tetrahydrofuran was added hydrazine (160 mg) with stirring at room temperature. After stirring at the same temperature for 3 hr, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically-treated product, 1.0 g) was added, the mixture was stirred at room temperature for 10 min. The reaction product was filtered through celite, and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give N-Boc-compound (129 mg) of the title compound. The obtained N-Boc compound was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (93 mg) was dissolved in methanol (3 mL), and fumaric acid (29 mg) was added. The mixture was stood at room temperature for 30 min, and the precipitated crystals were collected by filtration and washed with methanol to give the title compound as a colorless solid (yield 91 mg, 40%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(Cl)Cl>CN(C)C(=O)C.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
At the room temperature, anhydrous Na2CO3 (16 g, 0.15 mol) was added into a mixture of 4-methoxy-phenol (14.8 g, 0.12 mol) and 5-chloro-2-fluoro-benzaldehyde (16 g, 0.10 mol) in N,N-Dimethylacetamide (100 mL). After the mixture was refluxed for 3 h, it was cooled to room temperature. Then DCM and water were added. The organic phase was separated, washed with aqueous NaOH (1 N) and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (16 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([CH:23]=1)[NH:15][C:16](=[O:22])[C:17]([O:19]CC)=O)#[N:9]>CO>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([CH:23]=1)[NH:15][C:16](=[O:22])[C:17]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])#[N:9]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)ccc1O
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C(=O)C(=O)Nc2cc(C#N)ccc2O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a mixture of 1.2 g of N-methylpiperazine and 20 ml of methanol was added gradually 2 g of ethyl 5-cyano-2-hydroxyoxanilate and after stirring the mixture for 3 hours at room temperature, crystals formed were recovered by filtration, washed successively with isoporpnaol and ether, and dried to provide 2 g of 1-(5-cyano-2-hydroxyoxanilyl)-4-methylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].[CH:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]>>[OH:16][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: CC(C)CC=O
Reactant: Cc1nc(C)c(C)nc1C
Product: Cc1nc(C)c(CC(O)CC(C)C)nc1C
Yield: 60.7 %

Procedure:
The reaction of 13.6 grams (0.1 mole) of tetramethylpyrazine with 8.6 grams (0.1 mole) isovaleraldehyde was carried out in the manner described in Example II. The crude reaction mixture was washed with 50 milliliters of 6N HCl, and the aqueous layer was separated and washed with two 50 milliliter portions of methylene chloride. The acidic solution was neutralized with sodium carbonate and the oil that separated was dissolved in methylene chloride. The organic solution was dried over sodium sulfate, and the solvent was evaporated to give 13.5 grams of an oil. Distillation of the oil yielded 7.7 grams (35%) of product, b.p. 98°-100° C./0.05 mm Hg.
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Amino-2-methylbenzoic acid (6.16 g) was heated at reflux for 30 minutes in concentrated HBr. The mixture was cooled to 0° C. and treated with a solution of NaNO2 at 0° C. (2.8 g in 5.6 mL H2O). The resultant diazonium salt solution was slowly added to a preheated (60-70° C.) solution of CuBr (3.8 g) in 3.2 mL concentrated HBr. After the addition, the mixture was stirred overnight at room temperature and filtered. The recovered filter cake was washed first with water and then with 10% HCl, and dried in air to yield 6.93 g of 3-bromo-2-methylbenzoic acid as a light purple powdery solid. This material was dissolved in ethyl acetate, washed twice with 5% HCl, dried over Na2SO4, and recrystallized from 4:1 hexanes:ethyl acetate first at room temperature and then under refrigeration. 1H NMR (DMSO, 200 MHz), δ (ppm): 7.72 (dd, 2H), 7.2 (t, 1H), 2.5 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([S:27](=[O:34])(=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]([S:27](=[O:33])(=[O:34])[N:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.8 113 g of methyl 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoate are dissolved in 300 ml of methanol and 300 ml of THF, 600 ml of 2 N NaOH are added, and the mixture is stirred at room temperature for 14 hours. Some of the solvent is removed, and the mixture is neutralised using dilute HCl with ice-cooling. The precipitated product is separated off and dried, giving 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoic acid in quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[O:21]C(C)(C)C)=[CH:15][CH:14]=3)[C:5]=2[N:4]=[CH:3]1.[C:27]([C:31]1[CH:35]=[C:34]([N:36]=C=O)[N:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:35]=[C:34]([NH:36][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[C:5]4[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=4[N:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)=[O:21])[N:33]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2)cc1
Yield: 55 %

Procedure:
Method E1 was used with Tert-butyl 4-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to obtain the title compound (yield 55%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: COCCOCCOCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonyloxy}-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C41H48Cl2F2N3O10 [(M+H)+]: 850, found: 850.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl.[NH2:53][NH:54][C:55]([NH2:57])=[O:56].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[NH2:53][NH:54][C:55]([NH2:57])=[O:56].[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 22; 250 mg, 0.4 mmol), trifluoroacetic acid (0.8 ml) and dichloromethane (1.2 ml) was stirred at room temperature overnight and concentrated in vacuo. The residue was treated with semicarbazide hydrochloride (355 mg, 3.2 mmol), triethylamine (1 ml, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (457 mg, 4.2 mmol), and 4-N,N-dimethylaminopyridine (35 mg, 0.28 mmol). The mixture was stirred at room temperature over weekend, quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (278 mg, 55%).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[NH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][NH:34][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: NCCO
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using (S)-phenyl 4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenylcarbamate (intermediate 10) and 2-amino ethanol.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[C:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(C)(O)c1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.84 g. of 1-acetoxy-3-p-biphenylyl-3-butanol and 2 g. of NaOH in 30 ml. of 80% ethanol is boiled for 3 hours. Water is added and the mixture is extracted with chloroform and the extract is evaporated to give 3-p-biphenylyl-1,3-butanediol, m.p. 115- 117°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[CH2:9][CH2:8][CH2:7][N:6]3[C:5]=1[CH3:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][C:4]1[C:14]2=[C:15]3[C:10](=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13]2)[CH2:9][CH2:8][CH2:7][N:6]3[C:5]=1[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(CCBr)c2cccc3c2n1CCC3
Agent: O=S(=O)(O)O
Product: Cc1c(CCBr)c2cc([N+](=O)[O-])cc3c2n1CCC3
Temperature: 0 °C

Procedure:
5 g 1-(2-bromoethyl)-2-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline were added to 10 ml of concentrated sulfuric acid cooled to 0° C. The reaction mixture was kept at a temperature of about 0° C., and a mixture of 1.15 ml of concentrated sulfuric acid and 0.84 ml of nitric acid was added dropwise as a nitrating agent. The reaction mixture was kept for a further hour at 0° C. and one more hour at room temperature. To work up the reaction mixture it was poured onto 30 g of ice and extracted with dichloromethane. The organic phase was dried and concentrated. The residue which remained was heated in 10 of ethanol, and the resulting yellowish precipitate was filtered out. 2.26 g of 1-(2-bromoethyl)-2-methyl-8-nitro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline were obtained as an ochre-colored powder.
Reaction SMILES: Br[C:2]1[C:3]([O:13]C)=[C:4]([CH3:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:2]2[C:3]([OH:13])=[C:4]([CH3:12])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1c(C)cc2cccnc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCOC(C)=O
Product: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of product from step 2 (1.66 g, 6.58 mmol) and [1,4]Diazepane-1-carboxylic acid tert-butyl ester (4 g, 20 mmol) was heated via microwave to 140° C. for 1 h. After being cooled to rt, it was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4 and then purified by flash column chromatography on silica gel to give the desired product (0.8 g, 35%). MS (ES) m/z 358 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1([F:30])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22]1>>[ClH:19].[F:30][C:21]1([F:20])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCCN1CCC(F)(F)C1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCC(F)(F)C3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 39 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with [3-(3,3-difluoro-pyrrolidin-1-yl)-propyl]-amine as described in Step 5, Example 24 to give the title compound (39% yield). LC/MS: RT 1.69 min; m/e=446 (M+H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[CH3:24][O:25][CH:26]([O:37][CH3:38])[C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30]([CH2:35][OH:36])=[CH:29][CH:28]=1.O>CN(C)C=O>[Si:10]([O:36][CH2:35][C:30]1[C:31]([O:33][CH3:34])=[N:32][C:27]([CH:26]([O:37][CH3:38])[O:25][CH3:24])=[CH:28][CH:29]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1nc(C(OC)OC)ccc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C(OC)OC)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Imidazole (1.47 g) and t-butyldiphenylchlorosilane (3.54 g) was added to a solution of [6-(dimethoxymethyl)-2-methoxypyridin-3-yl]methanol (2.3 g) in N,N-dimethylformamide (23 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→10:1) to give 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5.47 g, 99%) as a colorless oil.