Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(O)=O)[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([CH2:18][C:19]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Yield: 86.5 %

Procedure:
A Solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid monoethyl ester (809 mg, 2.14 mmol) in toluene (25 ml) was heated under reflux for 23 hours. The colorless solution was concentrated under reduced pressure, the residue was taken up in diethyl ether (50 ml), washed with saturated NaHCO3 and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxoethyl)-5-phenyl-pentanoic acid ethyl ester as yellow oil (617 mg); 1H NMR (CDCl3) 7.37–7.1 (m, 5H), 4.2 (m, 2H), 3.8–3.4 (m, 8H), 3.0 (m, 1H), 2.75 (dd, J=15.9, 9.4 Hz, 1H), 2.65 (m, 2H), 2.35 (dd, J=15.9, 5.1 Hz, 1H), 1.8–1.55 (m, 4H), 1.29 (t, J=7.1 Hz, 3H). MS: 334 (MH+).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 2-piperazin-1-yl-4-(trifluoromethyl)pyrimidine (250 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.1 mmol) and triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg, 1.2 mmol). After being stirred overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20%-40% EtOAc/hexanes) provided 290 mg of desired product. MS calculated for C23H34F3N5O3: (M+H) 486; found 386.1 (M-Boc+1).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:12]1[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc2c(cc1C)C(=O)OC2
Solvent: ClCCl
Product: Cc1cc2c(cc1C1CO1)COC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-ethenyl-6-methyl-2-benzofuran-1(3H)-one (1.00 g, 5.75 mmol) in 50 mL of DCM was slowly added m-CPBA (3.50 g, 17.4 mmol) in 50 mL of DCM at 0° C. The mixture was warmed to room temperature, and stirred for 2 days. The mixture was washed with aqueous Na2SO3 until KI indicator paper didn't change color. The organic layer was washed with brine and then concentrated. The residue was purified via silica column to give product 6-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. LC/MS (IE, m/z): [M+1]+=191.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([CH:8]([CH2:36][CH2:37][C:38]([F:41])([CH3:40])[CH3:39])[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.[NH2:42]N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:41][C:38]([CH3:39])([CH3:40])[CH2:37][CH2:36][CH:8]([C:6]1[NH:5][CH:4]=[N:2][N:42]=1)[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(CC(CCC(C)(C)F)c1nnc[nH]1)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of acetic acid 3-(dimethylaminomethylene-carbamoyl)-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (580 mg, 1.03 mmol) in acetic acid (2.5 mL) was added hydrazine (35 wt. % in water, 0.040 mL). The resulting solution was heated to 50° C. for 4 hours, cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate. The organic later was dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (580 mg, >100%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[NH2:14].[F:15][B-:16]([F:19])([F:18])[F:17].[N:20]#[O+]>C1COCC1>[F:15][B-:16]([F:19])([F:18])[F:17].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]#[N:20]
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2ncc([N+]#N)c(Br)c2n1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (25.2 g, 99.2 mmole) in dry THF (400 mL) was maintained at −5° C. while nitrosonium tetrafluoroborate (12.9 g, 110 mmole) was added portionwise over 30 min (approximately 2 g portions). The reaction was continued for an additional 1 hr at −5° C., at which time TLC* and LC/MS indicated that the reaction was complete. The orange solid was collected by suction filtration, washed with ice-cold THF and dried under vacuum to provide the title compound (31.42 g, 90%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][C:24]2[S:28][CH:27]=[N:26][C:25]=2[CH3:29])[CH:17]=[CH:16][N:15]=1>>[CH3:20][C:19]1[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[N:15][CH:16]=[CH:17][C:18]=1[S:21][CH2:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][C:25]=1[CH3:29]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1ncsc1CCSc1ccnc(CCl)c1C
Agent: Cl
Product: Cc1ncsc1CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-3-methyl-4-[2-(4-methyl-5-thiazolyl)ethylthio]pyridine hydrochloride gives the title compound as a colorless solid of m.p. 150°-152° C. following crystallization from dichloromethane/diisopropyl ether.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:25])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:5]=1.Cl>C1COCC1.O>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])=[O:25])=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(NC(=O)Cc2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cccc(C(=O)O)c1
Yield: 57.6 %

Procedure:
3-(2-biphenyl-4-yl-acetylamino)-benzoic acid methyl ester (133.6 mg, 0.39 mmol) in THF/H2O (1:1, 4 mL) was treated with LiOHH2O (32.7 mg, 0.78 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2. Resulting mixture was collected by filtration, and recrystallized with mixture of CH2Cl2 and MeOH to give 3-(2-biphenyl-4-yl-acetylamino)-benzoic acid as a white solid (74.4 mg, 58.1% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH:35]6[CH2:37][CH2:36]6)[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: OB(O)C1CC1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(C5CC5)c4)cc32)c1
Yield: 25 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and cyclopropylboronic acid, 174 was obtained as a yellow solid (40 mg, 25%) over two steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.13 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.66-7.70 (t, J=16 Hz, 1H), 7.14-7.17 (t, J=14.5 Hz, 1H), 6.58-6.66 (m, 1H), 6.06-6.12 (m, 1H), 5.21-5.28 (m, 2H), 4.84-4.85 (d, J=10 Hz, 2H), 3.35-3.90 (m, 7H), 2.97-2.99 (t, J=10.5 Hz, 1H), 2.71-2.73 (t, J=12 Hz, 1H), 1.87-1.89 (t, J=10 Hz, 2H); MS (ESI) m/z: 401 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1CCNCC1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.61 cm3 of piperidine. The reaction medium is refluxed for 2 hours, the precipitate formed is then filtered off on a sinter funnel and the crystals, after taking up in methanol, are purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol mixture (93/7 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 5 cm3 of diethyl ether, filtered off and dried (90 Pa; 45° C.) to give 447 mg of N-(6-chloro-1H-indazol-3-yl)-1-piperidineacetamide in the form of a white powder melting at 153° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:16][CH:17]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: ClCCCCOc1ccccc1-c1csc(-c2ccccc2)n1
Reactant: c1c[nH]cn1
Product: c1ccc(-c2nc(-c3ccccc3OCCCCn3ccnc3)cs2)cc1

Procedure:
The title compound was prepared as described in Example 13, starting with 4-(4-chlorobutoxyphenyl)-2-phenylthiazole (7.8 g, 18 mmol) and using imidazole (3.8 g, 55 mmol) in place of dibutylamine to produce 3.6 g (53% yield) of the free base of the title compound which was converted to the HCl salt, mp 178°-180° C. IR(KBr): 3500, 2720, 1615 cm-1, MS: 376(MH+). 1H NMR (CD3OD): δ9.00 (s, 1H), 8.03-6.96 (m, 12H), 4.38 (t, J=6.0 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.22-1.79 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:26])=[N:4][C:5]([C:8]2[N:9]=[C:10]([C:21]3([CH3:25])[CH2:24][O:23][CH2:22]3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:6][CH:7]=1.[N:27]([C@@H:30]([CH3:35])[CH2:31][CH2:32][O:33][CH3:34])=[C:28]=S.C(N=C=NC(C)C)(C)C>C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]2([CH3:25])[CH2:22][O:23][CH2:24]2)=[N:9][C:8]=1[C:5]1[N:4]=[C:3]2[O:26][C:28]([NH:27][C@@H:30]([CH3:35])[CH2:31][CH2:32][O:33][CH3:34])=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: CC1(c2nc(-c3ccc(N)c(O)n3)c(-c3ccc(F)cc3F)[nH]2)COC1
Reactant: COCC[C@H](C)N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C4(C)COC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
A KIMAX® tube is charged with 3-amino-6-[5-(2,4-difluorophenyl)-2-(3-methyloxetan-3-yl)-1H-imidazol-4-yl]pyridin-2-ol (2.28 g, 6.36 mmol) and ethanol (18 mL). (3S)-3-Isothiocyanato-1-methoxy-butane (1.39 g, 9.54 mmol) is added, the flask sealed, and the mixture is heated to 85° C. After 16 h, (3S)-3-isothiocyanato-1-methoxy-butane (700 mg) is added and the mixture is stirred for 48 h at 85° C. in the sealed tube. N,N′-diisopropylcarbodiimide (1.04 g) is added and the mixture is stirred 3 h at 85° C. in the sealed tube. The crude reaction mixture is concentrated under reduced pressure and the residue purified by normal phase chromatography (120 g silica-gel cartridge, hexane-ethanol). The desired compound elutes at 3% of ethanol to give the title compound as a brown solid (2.61 g, 87%). LC-ES/MS m/z 470 (M+1); [α]D22+42.2°, (c=0.50, methanol).
Reaction SMILES: [N:1]1([C:7]([O:9]C(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=O)[CH:22](C)[CH3:23]>ClCCl>[C:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)(=[O:9])[CH:22]([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCNCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl piperazinecarboxylate (2.93 g) and triethylamine (4.39 ml) were dissolved in dichloromethane (60 ml) and then, while being cooled with ice, isobutyryl chloride (1.84 ml) was added thereto. After being stirred for 30 minutes, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. To 1.79 g of part of the resulting residue, trifluoroacetic acid (9 ml) was added and the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was concentrated under a vacuum. The residue was dissolved in methanol (20 ml) and then 2N hydrochroric acid methanol solution (10 ml) was added thereto. After being stirred for 10 minutes, the reaction mixture was concentrated under a vacuum. The residue, with 10% aqueous sodium hydroxide solution added thereto, was extracted with chloroform. The extract was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum to yield 0.85 g of the aimed compound.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C@@:7]([OH:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]([O:13][C:29](=[O:30])[CH2:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@](C)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@@](C)(OC(=O)COCc1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 48 h
Yield: 74.2 %

Procedure:
In a dry flask under argon, were mixed 1.3 g (5 mmol) of methyl (S)-(+)-2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate, 1.7 mL (10 mmol) of 95% benzyloxyacetyl chloride and 6.1 mL of pyridine. The reaction stirred for 48 hours and was quenched by pouring into 100 mL of 10% aqueous HCl and 200 mL of ether. The ether fraction was separated and washed with 50 mL of 10% aqueous HCl, 50 mL of H2O, 2×50 mL of NaHCO3 solution, 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated. The product was purified over 250 g of SiO2 using initially EtOAc/hexanes (1/9) followed by EtOAc/hexanes (1.5/8.5) as eluant to yield 1.5 g (80% yield) of methyl (S)-(+)-2-[(1,1'-biphenyl)-4-yl]-2-(2-phenylmethoxyacetoyl)oxypropionate.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH:5]([C:18]2([O:21][CH3:22])[CH2:20][CH2:19]2)[CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH:3]1[CH2:7][NH:6][CH:5]([C:18]2([O:21][CH3:22])[CH2:20][CH2:19]2)[CH2:4]1
Reactant: COC1CC(C2(OC)CC2)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CNC(C2(OC)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To benzyl 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate (141 mg, 0.462 mmol) dissolved in ethyl acetate (3.1 mL) was added palladium on carbon (49.1 mg, 0.05 mmol). Hydrogen gas was added via balloon and the reaction was stirred at room temperature for 3 hours. The mixture was filtered over celite and concentrated under reduced pressure to afford 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:15]([CH2:16][CH2:17]Cl)=[C:14](Cl)[N:13]2[N:20]=[CH:21][CH:22]=[C:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH2:27])([CH2:25][CH3:26])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[C:15]2[CH2:16][CH2:17][N:27]([CH:23]([CH2:25][CH3:26])[CH3:24])[C:14]=2[N:13]2[N:20]=[CH:21][CH:22]=[C:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCc1c(COCc2ccccc2)nc2ccnn2c1Cl
Reactant: CCC(C)N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)N1CCc2c(COCc3ccccc3)nc3ccnn3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In 5.0 ml of dimethylformamide were dissolved 0.44 g of 5-(benzyloxymethyl)-7-chloro-6-(2-chloroethyl)pyrazolo-[1,5-a]pyrimidine. To the solution, were added 0.15 g of sec-butylamine and 0.26 ml of triethylamine. The mixture was stirred for 1 hour at room temperature and then for 3 hours in an oil bath heated to 100-110° C. Additional 0.06 g of sec-butylamine were added, and the resultant mixture was stirred for 6.3 hours at the same temperature. After the solvent was distilled off under reduced pressure, and 1N hydrochloric acid was added to the resudue, the mixture was extracted with chloroform. After the chloroform layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resultant crude product was subjected to column chromatography on silica gel (elution solvent: hexane:ethyl acetate=3:1) to obtain 0.33 g (yield: 75.0%) of the intended product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[OH-].[Na+].O.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])(=[O:19])=[O:20])=[CH:14][CH:13]=1)=[O:8]
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Reaction time: 2 h

Procedure:
5 g of 4-[2-(oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonamide are dissolved in 100 ml of acetone with 0.65 g of NaOH and water. 2.3 g of cyclohexyl-isocyanate are added dropwise with agitation and ice cooling, and agitation is continued for 2 hours at room temperature. Subsequently, the substantial amount of acetone is distilled off under reduced pressure, the aqueous solution is acidified and the product is reprecipitated from dilute ammonia. The N-(4-[2-(2-oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea is recrystallized from dilute ethanol, and has a melting point of 189°-190° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](=N)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:7]1([C:6](=[N:1][CH2:2][CH2:3][CH2:4][OH:5])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: OCCCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
A solution of 3-amino-1-propanol [Aldrich product # A76400] (2.0 mL, 26 mmol) in dichloromethane (79 mL) was treated with benzophenone imine (4.4 mL, 26 mmol) and stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (6.3 g, quantitative) as an oil. This material was used without further purification. LCMS for C16H18NO (M+H)+: m/z=240.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.5 g, 1.3 mmol), diisopropylethylamine (0.5 mL, 2.9 mmol), and anhydrous dichloromethane (17 mL). Cool to 0° C. using an ice bath. Add methanesulfonyl chloride (201 mg, 1.36 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.26 (silica gel, ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: BrC1CCCC1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCC3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (30 mg, 0.092 mmol) in N,N-dimethylformamide (0.9 mL) was mixed with bromocyclopentane (20 mg, 0.138 mmol) and potassium carbonate (19 mg, 0.138 mmol) at room temperature and stirred at 80° C. overnight. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate three times. The resulting organic layer was filtered through silica gel and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate=1/1) to give the desired product (25 mg, 67% yield).