Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](Cl)=[C:8]([Cl:11])[N:7]=[C:6]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].CN([CH:21]=[O:22])C>C1COCC1>[CH2:1]([N:5]1[C:9]([CH:21]=[O:22])=[C:8]([Cl:11])[NH:7][CH:6]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N2CCOCC2)nc(Cl)c1Cl
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCN1C(C=O)=C(Cl)NC1N1CCOCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-BuLi (12.1 mL, 19.3 mmol, 1.6M in hexane) at −78° C. is added to a solution of 4-(1-butyl-4,5-dichloro-1H-imidazol-2-yl)-morpholine (3.48 g, 12.5 mmol) in anhydrous THF (50 mL) over a 30 minute period. After stirring for 2 hours at −78° C., anhydrous DMF (3 mL) is added at −78° C. Then the reaction mixture is allowed to warm to room temperature over a 2 hour period. The reaction is then quenched with water. The reaction mixture is extracted with ethyl acetate and dried over MgSO4. The extract is evaporated in vacuo to dryness and purified by flash column chromatography on silica gel using a mixture of hexane-ethyl acetate (4:1 to 3:1) as eluent to give 1-butyl-4-chloro-2-morpholin-4-yl-3H-imidazole-5-carbaldehyde as a colorless oil. 1HNMR (CDCl3) δ 9.59 (1H, s), 4.06 (2H, t, J=7.1 Hz), 3.78 (4H, t, J=4.6 Hz), 3.15 (4H, t, J=4.6 Hz), 1.60–1.70 (2H, m), 1.19–1.30 (2H, m), 0.90 (3H, t, J=7.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C@@H:7]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:22]=[N:23][C:24]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[CH:25][C:26]=3[C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)=[CH:18][CH:19]=2)[C:14](=[O:42])[C:13]([C:43]([O:45]CC)=O)=[CH:12]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:49][NH2:50].C(O)C>>[CH2:40]([NH:39][C:37](=[O:38])[NH:36][C:24]1[N:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:11]([C@@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:48])[CH:12]=[C:13]([C:43](=[O:45])[NH:50][CH3:49])[C:14]3=[O:42])=[C:26]([C:27]2[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=2)[CH:25]=1)[CH3:41]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](C(=O)OC(C)(C)C)C(C)C)cn1
Reactant: CN
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC)cn3[C@H](C(=O)OC(C)(C)C)C(C)C)cn1

Procedure:
A solution of (S)-ethyl 1-(1-tert-butoxy-3-methyl-1-oxobutan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline -3-carboxylate (Example 137, 0.100 g, 0.15 mmol) in 33 wt. % methylamine solution in absolute ethanol (3 mL, 24.1 mmol) was heated in the microwave to 80° C. for 15 min. The mixture was conconcentrated in vacuo and purified by column chromatography (silica, 95:5 methylene chloride/methanol) to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:11])[CH:3]=1.[C:12]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH2:25][CH2:24]OS2(=O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][CH2:25][CH2:24][C:2]2[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:5]=[C:4]([Cl:11])[CH:3]=2)=[CH:28][CH:29]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: Clc1cc(Br)cc(C2CC2)c1
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Product: CC(C)(C)c1ccc(CNCCc2cc(Cl)cc(C3CC3)c2)cc1
Yield: 63.8 %

Procedure:
The title compound was synthesized in analogy to example S6-C using 1-bromo-3-chloro-5-cyclopropylbenzene (96 mg, 0.71 mmol) and 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (36 mg, 0.89 mmol). The residue was purified by flash column chromatography to give the desired product (155 mg, 39%) as a colorless oil. MS (ISP) 342.2 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[N+:16]([O-:18])=[O:17])C>S(=O)(=O)(O)O>[CH3:15][O:14][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[C:8]2[C:13]([CH:4]=[CH:5][NH:6][C:7]2=[O:19])=[CH:12][CH:11]=1
Reactant: CCOC(CNC(=O)c1cccc(OC)c1[N+](=O)[O-])OCC
Agent: O=S(=O)(O)O
Product: COc1ccc2cc[nH]c(=O)c2c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of N-(2,2-diethoxyethyl)-3-methoxy-2-nitrobenzamide (296a, 92 g, 0.295 mol) in concentrated sulfuric acid (1 L) was stirred at 70° C. for three hours. After cooling to room temperature, the mixture was slowly poured into ice water (3 L), causing a solid precipitate to form. The precipitate was collected by filtration. The filter cake was washed with water (1 L) and dried to yield 7-methoxy-8-nitroisoquinolin-1(2H)-one (296b, 60 g, 92% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.89 (d, J=9.2 Hz, 1H), 7.81-7.79 (d, J=9.2 Hz, 1H), 7.18-7.15 (t, J=6.6 Hz, 1H), 6.66-6.64 (d, J=7.2 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][N:28]=1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:9][N:8]1[C:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Reactant: Cc1ncc(C=O)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 51.7 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (300 mg, 0.88 mmol) in anhydrous DMF (5 mL) were added 2-methylpyrimidine-5-carbaldehyde (108 mg, 0.88 mmol) and Iron (III) chloride hexahydrate (0.88 g, 0.24 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (5 g). The resulting mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with brine (10 mL), and dried over MgSO4. The solution was filtered, and concentrated under reduced pressure. The resulting solids were triturated with 15 mL of diethyl ether (15 mL) for 30 min. The precipitate was collected by vacuum filtration to give 201 mg (51% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.16 (s, 2H), 8.33 (s, 1H), 7.18-7.11 (m, 1H), 6.98-6.87 (m, 3H), 4.55 (t, 1H), 3.86 (s, 3H), 2.71 (s, 3H), 2.34 (dd, 2H), 1.84 (d, 2H); MS (EI) for C23H23N9O: 442.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:19])[CH3:18]
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution 3-[4-(4-chlorophenyl)-2-oxazolyl]propanol (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), followed by stirring for 30 minutes at 50° to 60° C. The reaction mixture was poured into water. The precipitated crystals were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl acetate (0.535 g, 91%). Recrystallization from ether-hexane gave colorless prism crystals of mp 37°-37.5° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:31])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:31])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)c3ccccc3)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (130 mg, 0.29 mmol) in ethanol (3 mL) and THF (3 mL) was added a solution of sodium hydroxide (879 uL, 1.0 N) at room temperature. The resulting clear solution was stirred overnight. The solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum afforded (115 mg, 91.3%) [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 10.46 (s, 1 H), 7.91-8.04 (m, 5 H), 7.86 (s, 1 H), 7.51-7.68 (m, 3 H), 7.47 (dd, J=8.8, 1.8 Hz, 1 H), 7.23 (d, J=8.5 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 3.85 (s, 2 H), 2.12 (s, 3 H). HRMS calcd. for C26H21ClNO3 [(M+H)+] 430.1205, obsd. 430.1205.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.[CH:30]1(N2C3N=CN=C(N4CCC(N5C6C=CC=CC=6NC5=O)CC4)C=3N=C(OC)C2=O)C[CH2:31]1.[OH-].[Na+]>CO>[CH:1]1([N:2]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][C:8]3[C:3]2=[N:4][CH:5]=[N:6][C:7]=3[N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:31][CH2:30]1
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C2CC2)c1=O
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1

Procedure:
9-Cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid was prepared in the same manner as 9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid. The 8-cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one (0.836 g, 1.93 mmol) was treated with 2M sodium hydroxide (10 mL, 20 mmol) in methanol at 80° C. for 18 hours gave 0.789 of 9-cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.20 (br s, 1H), 8.07 (s, 1H), 6.93 (m, 1H), 6.71 (m, 3H), 5.19 (broad s, 2H), 4.27 (m, 1H), 3.40 (m, 2H), 3.19 (t, 2H), 2.43 (m, 2H), 1.82 (d, 2H), 1.15 (m, 2H), 0.84 (m, 2H). MS (EI) for C21H21N7O4: 420 (MH+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[OH:15][CH2:14][CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: OCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(C=O)ccc1OCCO
Yield: 40 %

Procedure:
25.9 g (170 mmol) vanillin (Aldrich), 33.3 g (266 mmol) 2-bromoethanol (Aldrich), 35.2 g (255 mmol) potassium carbonate (Sigma-Aldrich), and 20 g molecular sieves (Aldrich) were combined in a 1 liter round bottom flask equipped with magnetic stirrer and nitrogen inlet. Acetone (600 ml) (Chromasolv for HPLC, >99.9%, Sigma-Aldrich) was added and the reaction mixture was refluxed for 16 hours using an external glycerol heating bath set to 65° C. The solids were filtered and the solvent was removed via rotary evaporation to yield a yellow oil. White crystals were obtained by recrystallization in ethyl alcohol at −20° C. (40% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and benzylamine (114 mg, 1.06 mmol) in DMF (3 mL) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (164 mg, 1.06 mmol) and N-hydroxybenztriazole (162 mg, 1.06 mmol) at 0° C. The mixture was stirred at room temperature overnight and aqueous 0.1N HCl was added. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 384 mg of the title compound (99%): mp 152.5°~153° C.; 1H NMR (270 MHz, DMSO-d6) δ12.01 (s, 1 H), 11.52 (t, 1H, J=5.6 Hz), 7.34 (m, 5H), 7.21 (d, 1H, J=1 Hz), 7.07 (d, 1H, J=1 Hz), 5.17 (dd, 1H, J=17, 10 Hz), 4.32 (d, 2H, J=5.6 Hz), 3.74 (dd, 1H, J=17, 10 Hz), 3.20 (dd, 1H, J=17, 5 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8](=[O:16])[CH2:7]2)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=[C:26]([O:25][C:20]2[CH:19]=[C:18]([N:1]3[CH2:2][CH2:3][C:4]4([C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8](=[O:16])[CH2:7]4)[CH2:5][CH2:6]3)[N:23]=[C:22]([CH3:24])[N:21]=2)[CH:35]=1
Reactant: O=C1CC2(CCNCC2)c2cccnc2N1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)CC(=O)Nc2ncccc23)n1

Procedure:
26 mg (0.12 mmol) 1H-spiro[[1,8]naphthyridin-4,4′-piperidin]-2(3H)-one, 35 mg (0.12 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 42 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred for 4 days at 60° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([NH2:17])(=[O:16])[CH2:14][CH3:15]>>[CH3:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:17][C:13](=[O:16])[CH2:14][CH3:15])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: CCC(N)=O
Product: CCC(=O)Nc1cc(C(=O)OC)cc(C)n1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (2.16 g, a pale yellow solid) from methyl 2-chloro-6-methylisonicotinate (3.00 g, 16.2 mmol) and propionamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7]([CH2:10][CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])(O)=O.[Na+]>Br>[OH:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7]([CH2:10][CH2:11][CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Temperature: 110 °C
Yield: 56.8 %

Procedure:
A mixture of 6-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.1.1 g, 0.288 mmol) in 48% aqueous HBr (10 mL) was heated at 110° C. for 16 hours. The mixture was made basic by addition of saturated NaHCO3 and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (3→6% MeOH—CH2Cl2) gave the title compound (0.055 g, 57%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:33]1[C:34](=[O:35])[CH2:36][NH:30][C:31]1=[O:32]
Reactant: O=C1CNC(=O)N1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)CNC2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol), hydantoin (14 mg, 0.14 mmol) were treate as described in the preparation of compound 219. Purification was done by flash chromatography (petroleum ether/ethyl acetate 1:1) to provide the title compound, which was impure. The product was further purified by preparative TLC (petroleum ether/ethyl acetate 1:1) to furnish the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:30]([CH2:29][N:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9]1)#[N:31]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(F)c2)nn1CC#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of Intermediate 4B (7.0 g, 29.9 mmol) in DMF (45 mL), is added dropwise a solution of LHMDS (31.4 mL, 31.4 mmol, 1M in THF). The reaction mixture is allowed to stir for 5 min. and the ice bath is subsequently removed. 2-Chloroacetonitrile (2.482 g, 32.9 mmol) was added to the reaction mixture. The reaction was allowed to warm to RT and stir for 18 h. The reaction was quenched by the addition of 1.0 mL of a satd. aq. solution of NH4Cl. The reaction was diluted with equal parts water and EtOAc and the resulting mixture was allowed to stir vigorously for 15 min. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (120 g REDISEP® column, eluting with a gradient from 0-40% EtOAc in hexanes). Fractions containing the product were combined and concentrated to afford Intermediate A131A (6.15 g, 75%) as a white solid. MS(ES) m/z=274 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[F:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][C:27]4[CH:29]=[CH:30][C:31]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:25]([F:24])[CH:26]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCOCC4)c(F)c3)(CC1)CC2
Yield: 36.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.3 mg) and 3-fluoro-4-morpholinylaniline (62.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-fluoro-4-morpholinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.6 mg).
Reaction SMILES: [C:1]([C:4](=[CH:7]N(C)C)[C:5]#[N:6])(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[CH2:20][CH2:19]1>C(O)C>[CH3:2][C:1]1[C:4]([C:5]#[N:6])=[CH:7][N:30]=[C:28]([NH:27][CH2:26][CH2:25][CH2:24][CH:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:29]=1
Reactant: CN1CCC(CCCNC(=N)N)CC1
Reactant: CC(=O)C(C#N)=CN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Reaction time: 24 h

Procedure:
To a 5-L round-bottom flask equipped with overhead mechanical stirrer, nitrogen inlet, and thermocouple probe were added 2-acetyl-3-dimethylamino-acrylonitrile (103.65 g, 0.75 mol), anhydrous potassium carbonate (powdered, not granular) (165.85 g, 1.2 mol), and N-[3-(1-methyl-piperidin-4-yl)-propyl]-guanidine (119.02 g, 0.60 mol) in ethanol (2.125 L). The resultant mixture was heated to reflux with stirring and held for 24 h. The resultant mixture was then concentration and the resultant residue partitioned between ethyl acetate (1.5 L) and 1 N NaOH (1.5 L). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2×1.5 L). The combined organic layers were concentrated to yield the title compound as a solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: NC(=O)C1C2C=CC(C2)C1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
In an analogous procedure to Example 651, part c, 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide as a white solid. 1H-NMR (CDCl3) δ 9.12 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.70 (m, 1H), 7.52 (m, 1H), 7.46 (d, J=21.2 Hz, 1H), 7.26 (s, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.35 (s, 1H), 6.27 (s, 1H), 4.13 (m, 1H), 3.31 (s, 3H), 2.87 (s, 1H), 2.77 (s, 1H), 2.56 (m, 6H), 2.45 (m, 4H), 2.10 (d, J=8.6 Hz, 1H), 1.95 (m, 2H), 1.40 (d, J=8.8 Hz, 1H), 1.31 (m, 2H). LC/MS (ESI+)=509 (M+H).
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=[O:4].[C-:13]#[N:14].[K+].C(O)(=O)C>CO>[NH2:14][CH2:13][C@H:3]([OH:4])[C@@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:1]
Reactant: [C-]#N
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 5.25 g (30.4 mmol) of tert-butyl (1S)-1-methyl-2-oxoethylcarbamate in 30 mL of methanol at 0° C. was added 2.18 g (33.4 mmol) of potassium cyanide, followed by 1.74 mL (33.4 mmol) of acetic acid. The reaction mixture was warmed to room temperature, left stirring for 16 h, and then filtered and concentrated under vacuum. The residue was dissolved in 80 mL of acetic acid, and 0.8 g of platinum oxide on carbon was added. The reaction mixture was then stirred under 40 psi of hydrogen for 4 h. The catalyst was filtered off over celite, and the filtrate was washed with methanol and concentrated to afford 3.06 g (49%) of tert-butyl (1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl (1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 6.74, 6.59 (d, J=8 Hz, 1H), 3.61–3.38 (m, 3H), 2.80 (m, 1H), 2.51 (m, 2H), 1.45 (br s, 1H), 1.38 (s, 9H), 0.97 (m, 3H). GC-MS m/z 205 (M+H).