Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([N:19]2[CH2:22][CH:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH2:20]2)=[O:13])=[C:5]([CH3:7])[N:6]=1
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a mixture of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7, 0.484 g, 2.10 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 0.41 g, 2.10 mmol), HOBT (0.085 g, 7.40 mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 mL) was added DIEA (1.09 mL, 6.3 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organic layer was washed with brine (3×30 mL) and the combined aqueous phases were back extracted with EtOAc (2×50 mL). All organic extracts were combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc to 5% MeOH in EtOAc) to yield the title compound as a white solid (0.35 g, 45%). m/z (ES+) 371 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.66 (d with fine str., J=8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d with fine str., J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 4.77-4.56 (m, 2H), 4.35-4.18 (m, 2H), 3.97-3.87 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:26])[C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:8]([C@@H:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:26])[C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:11]=2)=[O:27])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCNC3)cc2)cnn1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The compound from Preparation 18 (R)-tert-Butyl 3-(N-(3-chloropyridin-2-yl)-4-(5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)benzamido)piperidine-1-carboxylate (145.87 g, 256.8 mmol) was dissolved in 1.4 L of DCM and then treated with hydrochloric acid (3 mol/L in cyclopentyl methyl ether, 428 mL, 1284 mmol). The reaction was stirred at room temperature for 19 h then 500 mL of DCM was added followed by warming to 40° C. and then filtering through Celite®. The filtrate was concentrated to 500 mL total volume in vacuo and then added to 1.4 L of EtOAc, resulting in precipitation of solids which were isolated via filtration. After drying, the hydrochloride salt of the title compound was isolated as an off-white solid (125.2 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:14]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1)[CH3:12]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 2-amino-4-nitrophenol (2.00 g, 12.98 mmol) and triethyl orthopropionate (4.57 g, 25.95 mmol) in anhydrous ethanol (15 ml) was treated with p-toluenesulphonic acid (20 mg) and the resulting mixture refluxed for 3 h. On cooling to room temperature a precipitate formed which was filtered off and dried to afford the title compound (2.11 g) as a beige solid m.p. 88-90°. δH (CDCl3) 1.48 (3H, t, J 7.6 Hz), 3.02 (2H, q, J 7.6 Hz), 7.57 (1H, d, J 9.0 Hz), 8.27 (1H, dd, J 2.3, 9.0 Hz) and 8.55 (1H, d, J 2.3 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:24]([C:40]([NH:42][C@H:43]([C:56](O)=[O:57])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:24]([C:40]([NH:42][C@H:43]([C:56]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:57])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Yield: 67.6 %

Procedure:
compound SP307P. Same procedure as above with Trp-NHCH2Ph (120.7 mg, 0.411 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (246.9 mg, 0.411 mmol), EDC (87.1 mg, 0.45 mmol) and HOBt (62.1 mg, 0.46 mmol) in CH2Cl2/DMF (1.8 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (243 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.61 (m, 6H, 3 CH2 Lys), 1.29 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.64 (m, 1H, CH2 Tyr), 2.86 (m, 3H, CH2 Lys, CH2 Tyr), 3 (dd, J=14.1 Hz, J=7 Hz, 1H, CH2 Trp), 3.14 (dd, J=14.1 Hz, J=6 Hz, 1H, CH2 Trp), 4.11 (m, 1H, CHα), 4.26 (m, 3H, CH2 (Bn Trp), CHα), 4.59 (m, 1H, CHα), 5.02 (broad s, 2H, CH2 (Bn)), 6.72 (m, 1H), 6.85-7.4 (m, 19H), 7.59 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 8.1 (d, J=7.4 Hz, 1H), 8.38 (m, 1H), 10.8 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.4, 29.2, 32 (3 CH2 Lys), 27.8 (CH2 Trp), 28.1, 28.2 (2 (CH3)3), 36.3 (CH2 Tyr), 39.8 (CH2 Lys), 42 (CH2 (Bn) Trp), 52.4, 53.5, 55.8 (CHα Tyr, Lys, Trp), 69.1 (CH2 (Bn)), 77.3, 78 (2 C(CH3)3), 109.7, 111.2, 114.3, 118.2, 118.4, 120.8, 123.5, 126.5, 126.9, 127.3, 127.5, 127.7, 128, 128.3, 130.1, 130.2, 136, 137.2, 139 (25 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 171, 171.3, 171.6 (3 CO amide). Anal. Calcd. for C50H62N6O, 2H2O: C, 65.91; H, 7.30; N, 9.22. Found: C, 65.59; H, 7.06; N, 9.09.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[N:18]1([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:23][C:25]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[C:2]([CH3:1])=[CH:7][N:6]=3)=[CH:14][CH:13]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(Br)c2cc[nH]c12
Reactant: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1Nc1ccc(C)c2[nH]ccc12
Yield: 16 %

Procedure:
A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (92 mg of HCl salt, 15%) as a white solid.
Reaction SMILES: [Br-].[C:2](O[K])([CH3:5])([CH3:4])[CH3:3].O=C1C[CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11]C1>O1CCCC1>[CH2:3]=[C:2]1[CH2:5][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 159.7 %

Procedure:
51.1 g of methyltoluphenylphosphonium bromide was added to a mixture of 16.1 g tert-butoxy potassium and 500 ml tetrahydrofuran, and then stirred for 1 hr and 20 min at room temperature. 16.1 g of benzyl 4-oxo-1-piperidinecarboxylate was added thereto, and the mixture was stirred for 2 hr and 40 min at room temperature. The reaction solution was evaporated, diethyl ether was added thereto, and then filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 25.5 g of benzyl 4-methylene-1-piperidinecarboxylate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:13][N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[C:9]2=[CH:10][CH:11]=1)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH2:13][N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[C:9]2=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCO)ccc43)c21
Yield: 58.7 %

Procedure:
To a stirred solution of (R)-tert-butyl 5-(2-ethoxy-2-oxoethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.039 g, 0.0770 mmol) in THF (0.4 mL) was added dropwise DIBAL-H (0.308 ml, 0.308 mmol) (1M in THF) at 0° C. under nitrogen. The reaction was stirred with warming to about room temperature for 1 hour. The reaction mixture was added dropwise to a saturated solution of Rochelle's salt (6 mL) and stirred overnight. The reaction was extracted with EtOAc (×3). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to yield (R)-tert-butyl 5-(2-hydroxyethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.021 g, 59%). LCMS (APCI+) m/z 465 [M+H]+; Rt=3.39 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15](O)=[O:16])[CH2:11][C@H:10]1[O:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:21]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[NH4+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15](=[O:16])[NH2:21])[CH2:11][C@H:10]1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1C[C@H](C(=O)O)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CO[C@@H]1C[C@H](C(N)=O)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
A solution of the acid (f) (5.0 g, 18 mmol) and 1-hydroxy-7-azabenzotriazole (2.73 g, 20 mmol) in DMF (200 ml) was treated with (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (3.87 g, 20 mmol) and ammonium hydrogen carbonate (5.8 g, 73 mmol). The mixture was stirred at room temperature for 18 hours then evaporated to dryness. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated. Trituration with ether and filtration afforded a white solid (3.72 g, 75%).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][O:29][CH:30]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:16]([O:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:12][CH2:13][CH3:14])[C:2]=1[C:26]1[CH:27]=[N:28][O:29][CH:30]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:17]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1Br
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnoc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Methyl 4-bromo-3,5-diethoxybenzoate (456 mg) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (438 mg) were dissolved in THF in a nitrogen atmosphere, and potassium phosphate (954 mg), palladium acetate (33 mg) and dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (62 mg) were added to it, and degassed. The reaction liquid was stirred overnight at 85° C., then cooled to room temperature, water was added to it, and filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and the organic layer was dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexanelethyl acetate=100/0 to 80/20) to obtain the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH2:3][N:4]([S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:19].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2](=[O:34])[CH2:3][N:4]([S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH3:18])[C:11]([OH:13])=[O:12])[C:6]1=[O:19]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
tert-Butyl (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.4 g) was dissolved in DCM (35 ml), and trifluoroacetic acid (35 ml) was added. The mixture was stirred at room temperature for 2 h and then evaporated under reduced pressure. The residue was azeotroped with anhydrous dichloromethane and then dried under high vacuum. The residual viscous oil was triturated with diethyl ether to give the title compound (1.23 g) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[N:38](C(OC(C)(C)C)=O)[C:37]([CH3:47])([CH3:46])[CH2:36][CH2:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:35][CH2:36][C:37]([CH3:47])([CH3:46])[NH:38]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCC(C)(C)N4C(=O)OC(C)(C)C)ncn3)cccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCC(C)(C)N4)ncn3)cccc2s1

Procedure:
The title compound was prepared by reacting tert-butyl 5-((2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-2,2-dimethylpyrrolidine-1-carboxylate [Example 59 (g)] with TFA under the condition of Example 3(c). MS (ESI, pos. ion.) m/z: 619 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].Br.Br.[NH2:15][CH2:16][C:17]([NH2:19])=[NH:18]>>[NH2:19][C:17]1[CH:16]=[N:15][C:8]2[CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:18]=1
Reactant: CC(=O)N1CCCC(=O)C(=O)C1
Reactant: N=C(N)CN
Agent: Br
Product: CC(=O)N1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 13 by reacting a mixture of 1-acetyl-hexhydroazepine-4,5-dione and 1-acetyl-hexahydroazepine-3,4-dione (prepared from 1-acetyl-hexhydroazepine-4-ones by selenium dioxide oxidation in dioxane/water) with 2-amino-acetamidine dihydrobromide.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[C:13]=2[CH:28]=1)C1C=CC=CC=1>CCCCCC>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([CH:14]2[C:13]3[CH:28]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=3[O:16][C:15]2([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(C2c3cc(NCc4ccccc4)ccc3OC2(C)C)cc1
Solvent: CCCCCC
Product: CC(C)c1ccc(C2c3cc(N)ccc3OC2(C)C)cc1
Yield: 98 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 85, the title compound was synthesized in the same manner as in Reference Example 30. Yield 98%. Melting point: 109-110° C. (hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1F
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1F
Yield: 88 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 88% of theory, C28H29FN6O3 (516.6) Rf value: 0.08 (silica gel; dichloromethane/ethanol=4:1) ##EQU57##
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH2:21]([OH:24])[CH:22]=[CH2:23]>>[CH2:21]([O:24][C:18]1[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:11])=[O:10])=[N:14][CH:15]=[C:16]([Cl:20])[N:17]=1)[CH:22]=[CH2:23]
Reactant: C=CCO
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: C=CCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using allyl alcohol (10 mL) as solvent and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.35 g). Yield 0.32 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:34])=[C:4]([S:9]([NH:12][C:13]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:14]=2[CH2:15][NH:16]C(=O)OC(C)(C)C)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:16][CH2:15][C:14]1[C:24]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=[CH:27][C:13]=1[NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:34])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1c(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1N1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1c(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1N1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of 47 (75 mg) in dichloromethane (5 mL) was added TFA (0.5 mL). The solution was stirred overnight. Followed by usual workup. The title compound was obtained as an off-white solid (35 mg).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:30]([CH3:31])[CH3:29])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Product: CN(C)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and dimethylamine, the title compound was obtained as a colorless oil after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)=[O:8].Cl>O.CCO>[OH:3][C:4]1[CH:5]=[C:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(O)c1)c1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1cccc(C(O)c2cccc(O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of sodium borohydride (NaBH4) (0.19 g, 5.14 mmol) in H2O (5 mL) was added to an orange solution of 3,3′-dihydroxybenzophenone (1.00 g, 4.67 mmol) in EtOH (15 mL) and the resulting mixture was stirred for 1 h. After this time, the reaction mixture was added to ice-water (40 mL) containing conc. HCl (2.5 mL) and the solution was extracted with EtOAc (2×60 mL). The combined organic layers were washed with NaOH (3M, 2×50 mL) and the combined basic washes were acidified with conc. HCl. The organic components that appeared were extracted with EtOAc (2×100 mL). The combined EtOAc extracts were dried (MgSO4) and the solvent was removed in vacuo to give the crude product as a brown oil which solidified on standing. Purification was achieved by recrystallisation from H2O to give the title compound as a brown crystalline solid (0.86 g, 85%, mp 141-142° C.); δH (270 MHz, d6-DMSO) 9.27 (2H, br s, ArOH), 7.05 (2H, t, J=8.2, ArH), 6.84-6.72 (4H, m, ArH), 6.63-6.54 (2H, m, ArH), 5.72 (1H, br s, CHOH), 5.50 (1H, s, CHOH); δC (68 MHz, d6-DMSO) 157.1 (2×C), 147.2 (2×C), 128.9 (2×CH), 117.0 (2×CH), 113.6 (2×CH), 113.1 (2×CH), 74.1 (CH); LCMS (ES−) 215.0 ([M−H]−, 30%), 196.9 (10), 168.8 (15), 120.7 (100); HRMS (FAB+) Found 216.0785, C13H12O3 requires 216.0786.