Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38].C(OCC)(=O)C>C(#N)C.O>[NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@@]1(C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (300 mg, 0.936 mmol) and potassium carbonate (194 mg, 1.4 mmol) in acetonitrile (4 ml) was added 1-(bromomethyl)-2-fluorobenzene (Sigma Aldrich Ltd.) (170 μl, 1.4 mmol) and the mixture was stirred overnight at room temperature. After the reaction was finished, as shown by TLC, ethyl acetate and water were added. The organic phase was then washed with brine, dried, filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (8:2 to 7:3) to afford the title compound (306 mg, 72%); Rt (HPLC): 5.88 min; Rf (cyclohexane:ethyl acetate=1:1): 0.51; 1H NMR (300 MHz, DMSO-d6) δ(ppm): 7.60-7.49 (t, 2H); 7.46-7.32 (m, 2H); 7.29-7.15 (m, 3H); 7.13-7.02 (m, 1H); 6.98-6.88 (m, 2H); 5.11 (s, 2H); 4.87-4.62 (m, 1H); 2.41-2.16 (m, 2H); 1.78-1.64 (m, 1H); 1.64-1.56 (m, 1H); 1.52 (s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: [Cl:1][CH:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[Cl:3].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][CH:2]([S:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[Cl:3]
Reactant: ClC(Cl)SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(Cc1ccccc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reactant benzyl dichloromethyl sulfoxide was prepared by dissolving 15.4 grams (g) of benzyl dichloromethyl sulfide in 100 milliliters (ml) of methylene chloride. The solution was cooled in an ice-bath and 15 g of 85% 3-chloroperbenzoic acid was added. After stirring overnight at room temperature, the solution was washed with a 5% solution of potassium carbonate. It was then dried and the solvent evaporated, yielding 15.5 g of solid white benzyl dichloromethyl sulfoxide (m.p. 84°-90° C.). Structure was confirmed by infrared spectraphotometric analysis (IR), and nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl:44][C:45]1[C:46]([F:57])=[C:47](B(O)O)[C:48]([F:53])=[CH:49][C:50]=1[O:51][CH3:52].O=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:47]3[C:48]([F:53])=[CH:49][C:50]([O:51][CH3:52])=[C:45]([Cl:44])[C:46]=3[F:57])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:23])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc(F)c(B(O)O)c(F)c1Cl
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)CCC(C)CC1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3c(F)cc(OC)c(Cl)c3F)c2)CCC(C)CC1
Reaction time: 24 h
Yield: 39.9 %

Procedure:
300 mg of 1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester, 36 mg of tris(dibenzylideneacetone)di-palladium(0), 150 mg of KF, 27 mg of tri-tert-butylphosphonium tetrafluoroborate, and 347 mg of 3-Chloro-2,6-difluoro-4-methoxyphenylboronic acid were suspended using 5 ml of anhydrous dioxane and oxygen was removed by passing argon through. Then, 12 mg of N,N-diisopropylethylamine were added and again argon passed through the suspension. Stirring was continued for 24 h at room temperature. The reaction mixture was then filtered and evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield 150 mg of the title compound, viscous oil.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C(C3C(C)=NN(C)C=3C)N=CC=4)=CC=2)CCC1.[N+:37]([C:39]1[CH:40]=[C:41]([C:45]2[N:46]=[CH:47][CH:48]=[C:49]3[C:54](=[O:55])[C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5([NH:66]C(=O)OC(C)(C)C)[CH2:65][CH2:64][CH2:63]5)=[CH:58][CH:57]=4)=[C:52]([C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)[O:51][C:50]=23)[CH:42]=[CH:43][CH:44]=1)#[C-:38].Cl>O1CCOCC1>[NH2:66][C:62]1([C:59]2[CH:58]=[CH:57][C:56]([C:53]3[C:54](=[O:55])[C:49]4[C:50]([O:51][C:52]=3[C:74]3[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=3)=[C:45]([C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([N+:37]#[C-:38])[CH:40]=3)[N:46]=[CH:47][CH:48]=4)=[CH:61][CH:60]=2)[CH2:63][CH2:64][CH2:65]1
Reactant: [C-]#[N+]c1cccc(-c2nccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)c1
Agent: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Solvent: C1COCCO1
Product: [C-]#[N+]c1cccc(-c2nccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)c1
Yield: 15 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl (1-(4-(8-(3-isocyanophenyl)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate was reacted with HCl in dioxane. The product was purified by preparative HPLC to give the title compound (5 mg, 15%). 1H NMR (500 MHz, CD3OD): δ 8.69 (d, J=8.2 Hz, 1H), 8.41 (s, 1H), 8.32-8.29 (m, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.79-7.75 (m, 1H), 7.65-7.61 (m, 1H), 7.40-7.19 (m, 9H), 2.75-2.65 (m, 2H), 2.45-2.40 (m, 2H), 2.18-2.12 (m, 1H), 1.91-1.82 (m, 1H). LC-MS (Method I): RT=4.68 min, [M+2]+=471.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH2:14]([O:13][C:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:15]
Reactant: Cc1ccc(N)cc1C
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccc(C)c(C)c1
Reaction time: 8 h

Procedure:
The above-named compound is prepared by first dissolving 51.5 grams of 3,4-dimethylaniline in 250 ml. of benzene. Then, while maintaining the solution at a temperature in the range of between 20° C. and 30° C., a benzene solution containing 23.9 grams of ethyl chloroformate is slowly added. The mixture is permitted to stand overnight at room temperature and then filtered. The filtrate is stripped by evaporation under vacuum, leaving the desired product, in the form of a dark purple liquid weighing 30 grams.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1>CN(C)C=O>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[C:12]([C:19]([N:44]2[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]2)=[O:20])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (55 mg) in N,N-dimethylformamide (5 mL) were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg) and 1-hydroxybenzotriazole (49 mg), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added thiomorpholine 1,1-dioxide (49 mg), followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol=100:0 to 95:5). To the obtained residue was added ethanol (3 mL), followed by heating and dissolving, and then stirring at room temperature for 1 hour. The precipitated colorless solid was collected by filtration, washed with a small amount of ethanol, and then dried to obtain rac-4-({2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidin-5-yl}carbonyl)thiomorpholine 1,1-dioxide (45 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:6]=[C:7]([Cl:9])[CH:8]=1>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][NH:15][CH2:14][CH2:13]3)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3cc(Cl)cc(Cl)c3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(-c2ccc3c(c2)CCNC3)c1
Yield: 18.1 %

Procedure:
A stream of hydrogen chloride gas was conducted through a solution of 3.42 g (0.0904 mol) of tert.-butyl 6-(3,5-dichloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate in 180 ml of ethyl acetate. The reaction was followed by thin-layer chromatography. The mixture was cooled to 0° and suction filtered. 2.58 g (91%) of 6-(3,5-dichlorophenyl)-3,4-dihydro-1H-isochinoline hydrochloride were obtained as white crystals; m.p. 220°-260° (dec.).
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:26])[CH:21]5[CH:22]([C:23](O)=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C([Cl:30])=O>C1(C)C=CC=CC=1>[C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:26])[CH:21]5[CH:22]([C:23]([Cl:30])=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
In 420 ml of toluene was suspended 60 g of the carboxylic acid (23) obtained in Synthesis Example 1-1-2. At 80° C., 25.3 g of oxalyl dichloride was added dropwise to the suspension, which was stirred for 4 hours. The toluene was distilled off in vacuum, obtaining the target compound. The resulting acid chloride was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35](Br)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][Si:40]([C:43]#[CH:44])([CH3:42])[CH3:41].C(N(CC)CC)C.CN(C)C=O>[Cl-].[NH4+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([C:44]#[C:43][Si:40]([CH3:42])([CH3:41])[CH3:39])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C#C[Si](C)(C)C)cn2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (1.00 g), trimethylsilylacetylene (330 mg), bis(triphenylphosphine)palladium (II) chloride (58 mg), copper (I) iodide (32 mg), triethylamine (420 mg) and dimethylformamide (5 ml) is stirred at 50° C. for three hours under argon atmosphere, and cooled to room temperature. The mixture is diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is washed with water and brine, and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=40:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-{6-[2-(5-trimethylsilylethynylpyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (837 mg) as colorless crystalline powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl-].C(CCCCCCCCCCCC[NH+](C)C)C1C=CC=CC=1.[OH-:38].[K+].Cl>COCCO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[OH:38])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: [OH-]
Agent: C[NH+](C)CCCCCCCCCCCCCc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: COCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Temperature: 65 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
45 g of 4-chloro-3-nitro-benzotrifluoride and 10 ml of 50% strength aqueous benzyldodecyldimethylammonium chloride are initially introduced into 150 ml of ethylene glycol monomethyl ether, and 100 g of 50% strength potassium hydroxide solution are added dropwise in the course of about 30 minutes, up to a temperature of 65° C. The mixture is then stirred at 65° C. for 6 hours and subsequently cooled and rendered acid with concentrated hydrochloric acid, and about 500 ml of distillate are driven over with steam. The organic phase is separated off and washed with 20 ml of dilute hydrochloric acid, and the organic phase is again separated off and dried with sodium sulphate. 38 g of 2-nitro-4-trifluoromethylphenol are obtained, which corresponds to a yield of 92% of theory.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([NH:21][CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=O.[ClH:25]>>[ClH:25].[ClH:25].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([NH:21][CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1C
Agent: Cl
Product: CNC(Cc1ccccc1N)c1ccccc1C
Reaction time: 8 h

Procedure:
2,2-Dimethyl-N-[2-[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide (12 g) was treated with 60 ml of 6N hydrochloric acid solution. After refluxing and stirring for 8 hr, the solution was decanted over 100 g of ice and basified with 25 ml of a 50% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification was accomplished by preparative HPLC (silica gel, eluted with methanol). The appropriate fractions were collected, combined and concentrated. The residue was dissolved in methanol, treated with ethereal hydrogen chloride and diluted with anhydrous ether to afford 2-amino-N-methyl-α-(2-methylphenyl)phenethylamine dihydrochloride, mp 242°-245° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[N+:25]([O-])=O)[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH2:25])[CH:12]=1)([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2N)c1
Reaction time: 3 h
Yield: 88.4 %

Procedure:
5% carbon-palladium (1.0 g) was added to an ethyl acetate (100 ml) solution of tert-butyl[1-[3-(5-chloro-2-nitrophenoxy)phenyl]-1-methylethyl]carbamate (3.3 g, 8.1 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure for 3 hours. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an amorphous solid of tert-butyl[1-[3-(2-amino-5-chlorophenoxy)phenyl]-1-methylethyl]carbamate (2.7 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[NH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38].[H-].[Na+]>CCN(CC)CC>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:33]3[C:34](=[O:37])[CH2:35][CH2:36][NH:31][C:32]3=[O:38])=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: O=C1CCNC(=O)N1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CCNC2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 55 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of dihydropyrimidine-2,4-dione, and 63 mg of NaH, 28.4 mg of the product was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1
Reactant: ClCc1ccncc1
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Product: Cc1nc2c(n1Cc1ccncc1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
Treat 5,6a(R),7,8,9,9a(S)-hexahydro-2,5-dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one from Example 19a with 4-chloromethyl pyridine in accordance with Example 47 to give the title compound as a powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:26])[C:3]([NH:5][C@@H:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:61]1[CH2:66][CH2:65][N:64]([CH2:67][C:68](O)=[O:69])[CH2:63][CH2:62]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:68](=[O:69])[CH2:67][N:64]2[CH2:65][CH2:66][O:61][CH2:62][CH2:63]2)[CH3:26])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:23][CH:22]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)N)C(=O)OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a solution of (S)-benzyl 2-((S)-2-aminopropanamido)-3-(4-methoxyphenyl)propanoate (HCl salt, 21.0 g, 53.5 mmol) in DMF (200 mL) at 0° C. was added HBTU (30.4 g, 80.3 mmol) and HOBt (10.8 g, 80.3 mmol). The mixture was stirred for 5 min then 2-morpholinoacetic acid (8.15 g, 56.2 mmol) and DIEA (46.5 mL, 214 mmol) were added. The reaction mixture was stirred at ambient temperature for 30 min. Saturated aqueous NaHCO3 (200 mL) was then added and the resulting mixture was extracted with EtOAc (300 mL×2). The combined extracts were washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash column chromatography on silica gel (heptane to EtOAc/heptane=3:2) afforded (S)-benzyl 3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (23.0 g, 89% yield) as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:45](OC(=O)C)([F:47])[F:46]>O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:45]([F:47])[F:46])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of [2-ethyl-8-fluoro-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.37 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.18 g) and acetic acid chlorodifluoromethyl ester (0.27 mL) was stirred at 80° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate gave title compound (0.19 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[C:9]#[N:10]>C1COCC1>[NH2:10][CH2:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([OH:7])[CH3:11]
Reactant: CC(O)(C#N)c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(CN)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a cool (0° C.), stirring solution of LiAlH4 (57 mg, 1.502 mmol) in THF (5 mL) was added dropwise via cannula a solution of 2-hydroxy-2-(pyridin-2-yl)propanenitrile (92 mg, 0.621 mmol) in THF (5 mL). After 1 h at 0° C., powdered Na2SO4.10H2O was added and the reaction was allowed to warm to RT until the colour dissipated. The solid was removed by filtration. The filtrate was concentrated to afford the product (65 mg) as an oil: 1H NMR (400 MHz, MeOD) δ ppm: 8.44 (1H, d, J=4.04 Hz), 7.76-7.86 (1H, m), 7.69 (1H, d, J=8.08 Hz), 7.21-7.30 (1H, m), 3.04 (1H, d, J=13.39 Hz), 2.86 (1H, d, J=13.14 Hz), 1.39 (3H, s).