Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[S:10][N:9]=[C:8]([C:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:12]=2)[N:7]=1)=O)C.C[Mg]Br.[CH2:32]([O:34]CC)[CH3:33]>>[CH:23]1([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:11]([C:8]3[N:7]=[C:6]([C:32](=[O:34])[CH3:33])[S:10][N:9]=3)=[CH:12]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOCC
Reactant: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)ns1
Agent: C[Mg]Br
Product: COc1cccc2c(-c3nsc(C(C)=O)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (dry-ice acetone bath) of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (500 mg, 1.3 mmol) in diethyl ether (50 ml) was added methyl magnesium bromide solution (0.52 ml, 3M in diethyl ether, 1.56 mmol) and the reaction stirred for 15 minutes, a further portion of methyl magnesium bromide solution (0.25 ml, 3M in diethyl ether, 0.75 mmol) was then added and the reaction mixture stirred for 5 minutes. The reaction was then quenched with saturated aqueous ammonium chloride (5 ml) and the reaction allowed to warm to room temperature. The reaction mixture was poured into a separating funnel and the organics washed with water (20 ml). The aqueous layer was then backwashed with diethyl ether (20 ml). The combined organic layers were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to give 1-[3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-ethanone (170 mg, 0.46 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:19]=O)[CH:8]=[CH:9][CH:10]=1.[CH2:22]([NH2:24])[CH3:23]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:24][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1
Reactant: CCN
Product: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1(/[CH:30]=[CH:31]/[C:32](O)=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1(/[CH:30]=[CH:31]/[C:32]([NH2:38])=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Yield: 86.6 %

Procedure:
A solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.47 g, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.30 g, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.41 g, 87.2%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[Cl:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 194.4 %

Procedure:
To a solution of 4-amino-3-chloropyridine (15 g, 116.7 mmol) in THF (60 mL) is added NaHMDS in THF (1 M, 233. mL, 233 mmol). After stirring at rt for 30 min, BOC20 (23.2 g, 106 mmol) in THF (45 mL) is added in one portion and the mixture is stirred for 3 h at rt. Additional BOC2O (2 g, 9.0 mmol) in THF (40 mL) is added and the reaction is stirred for 18 h at rt. 0.1% aqueous HCl (1.35 L) is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is recrystallized from ether to afford (3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (4 g). The mother liquor is purified by silica gel column chromatography eluting with 0-50% EtOAc in heptane. The collected product is crystallized from ether to afford additional 4.5 g of (3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (total yield 8.5 g). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.48 (s, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.18 (broad s, 1H) 1.57 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8]O)=[C:6]([CH2:10][CH3:11])[O:5][N:4]=1)[CH3:2].[Br:12]P(Br)Br>C(Cl)Cl>[Br:12][CH2:8][C:7]1[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=1[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCc1noc(CC)c1CO
Solvent: ClCCl
Product: CCc1noc(CC)c1CBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3,5-diethyl-1,2-oxazol-4-yl)methanol (710 mg, 4.6 mmol) in anhydrous DCM (30 mL) was added tribromophosphane (465 μL, 4.9 mmol). The mixture was stirred at room temperature for 5 hours, and then DCM was evaporated. The residue was dried in vacuo, affording 4-(bromomethyl)-3,5-diethyl-1,2-oxazole, which was used without further purification.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C:22]3[N:31]=[C:30]4[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]4)=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.CCOCC.[Ni]>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[N:31]=[C:30]4[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]4)=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCc2ccc(CCCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1
Yield: 69.4 %

Procedure:
7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.225 g, 0.523 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 16 hours. The reaction was filtered and concentrated to give a foam. This was dissolved in Et2O and 1M HCl in Et2O (1 equiv) was added. The precipitate was filtered and dried to give the title compound as a white solid (0.157 g, 70%). MS: APCI: M+1: 433.4 (Exact Mass: 432.29).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[NH2:25][C:23]([C:22]1[CH:21]=[C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])[S:19][C:18]=1[NH:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[N:10]=2)[N:7]=1)=[O:24]
Reactant: CC(C)NC(=O)c1cn2nc(Cl)ccc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)NC(=O)c1cn2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2n1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 6-chloro-N-isopropylimidazo[1,2-b]pyridazine-2-carboxamide (149 mg, 0.62 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (177 mg, 0.57 mmol) as starting materials.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13]C(=O)OC(C)(C)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl (trans-2-(4-cyclopropylphenyl)cyclopropyl)carbamate (260 mg, 0.951 mmol) in dichloromethane (DCM) (3 mL) was added TFA (500 μl, 6.49 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 148 mg of product as pale yellow oil. MS: (M+H)+=174.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.57-0.70 (m, 2H), 0.86-1.04 (m, 4H), 1.78-1.93 (m, 2H), 2.37-2.48 (m, 1H), 6.86-7.00 (m, 4H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5].[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45](=O)[CH2:46][N:47]2[C:51]([CH3:52])=[CH:50][N:49]=[CH:48]2)=[CH:41][CH:40]=1>>[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH2:46][N:47]2[C:51]([CH3:52])=[CH:50][N:49]=[CH:48]2)=[CH:10][C:9]2[CH:30]=[CH:31][C:6]([C:4]([O:3][CH3:2])=[O:5])=[C:7]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:8]=2)=[CH:41][CH:40]=1
Reactant: Cc1cncn1CC(=O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Agent: [Br-]
Product: COC(=O)c1ccc(C=C(Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Yield: 76 %

Procedure:
Product from step E was reacted with 1-(4-fluorophenyl)-2-(5-methylimidazol-1-yl)-ethanone using methodology as described in Example 4, compound a), step B and purified by flash chromatography eluting with CH2Cl2/EtOH (93/7) to give methyl 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenyl-benzoate as an oil. Yield=76%.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>CN(C=O)C>[Cl:33][C:31]1[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][N:28]=[C:27]([NH:15][CH2:14][C:13]2[C:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=3)=[N:9][CH:10]=[N:11][CH:12]=2)[N:32]=1
Reactant: Cc1ccc(Oc2ncncc2CN)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ncncc2CNc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: -10 °C
Yield: 27 %

Procedure:
(4-(p-Tolyloxy)pyrimidin-5-yl)methanamine (1.0 equiv.) was placed in a round bottom flask with DIEA (1.0 equiv.), and DMF (0.4 M). The flask was placed in a cooling bath and cooled to −10° C. To the flask was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv.) and stirring continued at −10° C. The reaction mixture was allowed to warm to room temperature over 3 h. The reaction mixture was loaded directly onto a silica gel column (100 g) and purified using 5-27% ethyl acetate in hexanes, followed by 27% ethyl acetate in hexanes. Fractions containing desired product (lower Rf spot by thin layer chromatography) were combined and the solvent was were removed under reduced pressure to give 4-chloro-N-((4-(p-tolyloxy)pyrimidin-5-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine (27.0% yield) as a light yellow solid. MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCCCCC.CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)OCC)cc1

Procedure:
Sodium hydride (min. 60% parafflnic dispersion, 2.95 g, about 74 mmol) was washed with anhydrous hexane in a nitrogen stream and suspended in anhydrous dimethylformamide. The obtained suspension was stirred under cooling with ice, followed by the dropwise addition of a solution of ethyl 4-hydroxybenzoate (11.2 g, 67 mmol) in dimethylformamide. The obtained mixture was stirred at room temperature for 80 minutes and cooled with ice again, followed by the dropwise addition of a solution of ethyl bromoacetate (12.9 g, 77 mmol) in anhydrous dimethylformamide. The obtained mixture was stirred at room temperature to complete a reaction. The reaction mixture was filtered to remove insolubles and the filtrate was concentrated under a reduced pressure. The residue was dissolved in diethyl ether and the obtained solution was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of common salt, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography. Yield: 16.8 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>C(OC)(C)(C)C>[N:1]1([C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: COC(C)(C)C
Product: CC(=O)CC(=O)N1CCCCC1
Temperature: -1 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 25 g (0.294 mol) piperidin in 100 ml tert.-butyl-methylether was added dropwise to a solution of 26.25 g (0.310 mol) diketene in 200 ml tert.-butyl-methylether at −5 to 0° C. After stirring for 1 hour at −1° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was distilled under vacuum. 49.55 g of product was obtained as a slightly yellow liquid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:28][N:29]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1)[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CNCC(=O)OC
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26B (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. MS (ESI) m/z 438 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 15.9 %

Procedure:
To a solution of methyl 6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 13% yield) as a white solid. MS (ES+) 286.1 (M+H)+. 1H NMR (400 MHz, DMSO): δ 12.20-11.95 (br. s, 1H), 11.90 (br. s, H), 8.10 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.35-7.20 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16](O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.O>ClCCl>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([Cl:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C1OC(Cc2ccccc2)CN1CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
5-Benzyl-3-(3-hydroxy-3-phenylpropyl)-1,3-oxazolidine-2-one (0.31 g, 1 mmol) prepared in the above (2) was dissolved in dichloromethane (3 ml). To the solution, thionyl chloride (0.08 ml, 1.1 mmol) was added and stirred at room temperature for 30 minutes. After water was added, the obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.34 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:25]#[N:26])=[N:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH:24]([C:25]#[N:26])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[N:7]1
Reactant: COC(=O)CBr
Reactant: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-4-(cyanomethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.11 g, 0.25 mmol; Example 118, step 1) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide (0.28 mL, 0.28 mmol; 1M) in THF was added over a period of 5 minutes. The reaction solution was stirred at the same temperature for 30 minutes and treated with methyl bromoacetate (43 mg, 0.28 mmol). After stirring at room temperature for two hours, the product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous ammonium chloride. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH3:6])=[O:4].CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[O:17][C:20]([CH3:22])([CH3:21])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 1-methyl 6-tert.-butyl 2,4-dihydroxyadipate (4.98 g, 20.01 mmol) in methylene chloride (2 dimethoxypropane (9.6 ml, 78 mmol) and pyridinium p-toluenesulfonate (2.01 g, 8 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 40° C. for 3 hours while azeotropically removing methanol with methylene chloride. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and poured in water. Then, the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=3:1) to give pure 2-methoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (4.89 g, 17.01 mmol). Yield, 85 %.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[CH:29]1([CH2:32][N:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39](O)=[O:40])[C:34]2=[O:42])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:1][C:2]3[CH:27]=[CH:26][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:13]=[C:14]([C:16]6[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=6)[S:15][C:8]=45)=[C:4]([F:28])[CH:3]=3)=[O:40])[C:34]2=[O:42])[CH2:30][CH2:31]1
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: O=C(O)c1nccn(CC2CC2)c1=O
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5nccn(CC6CC6)c5=O)cc4F)c3s2)cc1
Yield: 22 %

Procedure:
Prepared from 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A) and 4-(cyclopropylmethyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 8 mg (22%) of the desired product. LRMS (ESI pos) m/e 570.2 (M+1). 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.08 (dd, 1H), 8.03 (d, 1H), 7.93 (q, 4H), 7.79 (d, 1H), 7.76 (s, 1H), 7.55 (m, 1H), 7.40 (t, 1H), 6.67 (d, 1H), 4.02 (d, 2H), 2.97 (s, 3H), 1.41 (m, 1H), 0.69 (m, 2H), 0.52 (m, 2H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −128.6.
Reaction SMILES: [CH:1](=[C:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1c2[nH]c3ccc(Cl)c(Cl)c3c2CCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
2-Benzylidene-5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.7 g, 2.05 mmol) was dissolved in EtOAc (150 mL) and 10% Pd/C (0.070 g) was added under N2 atmosphere. The reaction mixture was stirred under H2 atmosphere at room temperature for 12 h then filtered through a Celite® pad. The Celite® pad was washed with EtOAc (2×20 mL) and the filtrate was concentrated in vacuo to provide the crude material which was purified by silica gel chromatography [EtOAc-hexane (1:9) as eluant] to obtain the title compound as a light green solid (0.43 g, 61%). 1H NMR (500 MHz, CDCl3, δ in ppm) 9.03 (bs, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.34-7.30 (m, 3H), 7.25-7.22 (m, 3H), 3.50-3.42 (m, 2H), 3.17-3.10 (m, 1H), 2.87-2.82 (m, 1H), 2.72-2.67 (m, 1H), 2.25-2.21 (m, 1H), 1.97-1.90 (m, 1H).