Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCC1Cc2cc(C3CCCC3)cc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(Br)c3O2)cc1
Yield: 85.7 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14].CCN(C(C)C)C(C)C.[C:24]([C:26]1[C:27]([NH:36][C@@H:37]2[CH2:40][C@H:39]([C:41]([NH2:43])=[O:42])[C:38]2([CH3:45])[CH3:44])=[N:28][C:29](S(C)(=O)=O)=[N:30][CH:31]=1)#[N:25]>O>[C:24]([C:26]1[C:27]([NH:36][C@@H:37]2[CH2:40][C@H:39]([C:41]([NH2:43])=[O:42])[C:38]2([CH3:45])[CH3:44])=[N:28][C:29]([NH:1][CH2:2][CH2:3][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:13])[C:5]2=[O:14])=[N:30][CH:31]=1)#[N:25]
Reactant: CC1(C)[C@@H](C(N)=O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Reactant: CN1C(=O)C(CCN)c2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(CCNc2ncc(C#N)c(N[C@@H]3C[C@H](C(N)=O)C3(C)C)n2)c2ccccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
3-(2-Aminoethyl)-1-methylindolin-2-one (231 mg, 1.02 mmol) and DIEA (197 mg, 1.53 mmol) were added to the reaction mixture of (1S,3R)-3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-ylamino)-2,2-dimethylcyclobutanecarboxamide (prepared as described above) at 0° C. and stirred at 90° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the crude product, which was purified by standard methods to afford the title compound (17.7 mg, 0.041 mmol, 8% yield over two steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.12-8.01 (m, 1H), 7.42-7.33 (m, 2H), 7.17-6.93 (m, 2H), 4.36-4.09 (m, 1H), 3.62-3.60 (m, 2H), 3.23-3.13 (m, 4H), 2.60-2.25 (m, 5H), 1.39-0.88 (m, 6H). MS (ESI) m/z 433.8 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.COC(C1C=NC=CN=1)=[NH:40]>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:40][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cc(F)ccc2F)cn1
Reactant: COC(=N)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cc(F)ccc2F)cn1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2,5-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 232 and methylpyrazin-2-imidate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2[CH:30]=[CH:29][NH:28][C:27]=2[CH2:31]O)=[CH:23][CH:22]=1>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:31][C:27]1[NH:28][CH:29]=[CH:30][C:26]=1[CH2:25][C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: OCc1[nH]ccc1Cc1ccc(F)cc1
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1[nH]ccc1Cc1ccc(F)cc1

Procedure:
The acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with 3-(4-fluorobenzyl)-pyrrolylmethyl alcohol in ether as in Example 1 to give 3-(4-fluorobenzyl)-pyrrolylmethyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.O>[Cl:9][C:10]1[N:15]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:13]=[CH:12][N:11]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride/60 percent oil dispersion (286 mg, 7.1 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethanol (675 mg, 6.7 mmol). The reaction mixture was stirred for 30 minutes, then it was then added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol). The solution was then allowed to stir overnight while warming to room temperature. The solution was diluted with H2O and extracted thrice with Et2O. The organics were combined, washed with brine, dried (Na2SO4) and filtered through silica gel, eluting with ether. The product was isolated as a semi-solid, 1.1 g, 5.2 mmol, 78 percent yield.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: CON
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Product: CON=Cc1ccc(F)cc1F
Yield: 80 %

Procedure:
Reaction of 2,4-difluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (80% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.98 (3H, s, OCH3), 6.79-6.91 (2H, m, aromatics), 7.79-7.85 (1H, m, aromatic), 8.24 (1H, s, CH).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH3:2].C(N(CC)CC)C.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[C:20]([N:3]([C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH2:1][CH3:2])(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: CCNc1cnoc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N(CC)c1cnoc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, ice cooled solution of 4-ethylamino-5-methylisoxazole (Method 5 of WO 03/76436; 49.6 g, 305 mM) and triethylamine (77.0 g, 763 mM, 107 ml) in DCM (800 ml), was slowly added a solution of n-butyryl chloride (35.5, 333 mM, 35 ml) in DCM (100 ml). There was a moderate exotherm. The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water, 2N HCl, brine, sat. NaHCO3 and brine. It was dried and the solvent was evaporated to give the title compound as an oil, which crystallized to a waxy solid (45.1 g, 75%). NMR (300 Mz, DMS0-d6): 0.78 (t, 3H), 0.96 (t, 3H), 1.44 (sext, 2H), 1.93 (t, 2H), 2.33 (s, 3H), 3.49 (q, 2H), 8.68 (s, 1H); m/z 197.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:27][C:26]([OH:28])([CH2:25][CH2:24][NH:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1)[CH3:29]
Reactant: CC(C)(O)CCN
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(O)CCNc1ccc2ncc(-c3cccc(OC(F)(F)F)c3)n2n1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 47.9 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (300 mg, 0.96 mmol) and 4-amino-2-methylbutan-2-ol hydrogenchloride (493 mg, 4.78 mmol) in NMP (2.0 mL) was added NaHCO3 (516 mg, 4.78 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 2-methyl-4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)butan-2-ol (175 mg, 48%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:2]([C@H:4]([C:6]([O:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[OH:5])[OH:3].[H-].[Na+].Br[C:31](Br)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[Na+]>C(COC)OC.O>[O:5]1[C@@H:4]([C:6]([O:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[C@H:2]([C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:3][C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)[C@H](C(=O)OC(C)(C)C)O1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
3.92 g of tert-butyl diphenylmethyl L-tartarate was dissolved in 10 ml of dimethoxyethane, and 844 mg of 60% sodium hydride was added at 0° C. , followed by stirring at the same temperature for 45 minutes. Then, a solution of 3.37 g of diethyl dibromomalonate in 5 ml of dimethoxyethane, was added, followed by stirring under heating at 80° C. for 12 hours. The reaction solution was cooled to room temperature and then poured into water. The aqueous layer was saturated with sodium chloride and extracted with ethyl ether. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1→5/1) to obtain 1.73 g (yield: 44%) of the above identified compound as white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[Li]CCCC.[CH3:38][C:39]1([CH:45]=[O:46])[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][C:39]1([CH:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)[OH:46])[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CC1(C=O)CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCSCC4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 32.3 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (400 mg, 0.7 mmol) in anhydrous tetrahydrofuran (5 ml) was cooled to −78° C. and treated with nBuLi (2.23M in hexanes, 0.42 ml, 0.94 mmol) dropwise. The reaction mixture was stirred for 30 seconds and then treated with a solution of 4-methyl-tetrahydro-thiopyran-4-carbaldehyde (0.305 mg, 2.1 mmol) in anhydrous tetrahydrofuran (2 ml), dropwise. The reaction mixture was allowed to stir at −78° C. for 30 minutes. The reaction mixture was partitioned between EtOAc/saturated aqueous NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellowish oil. The oil was purified by silica gel chromatography using 3-100% EtOAc in hexanes as eluant to provide 97 mg (32%) of (4-methyl-tetrahydro-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanol as a pale yellow solid. M+H=430.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: O=C(Nc1cccc(-c2cccc3[nH]ccc23)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 52% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24](O)=[O:25])[S:21][C:20]=2[CH:27]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:24]([C:22]2[S:21][C:20]3[CH:27]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=3[CH:23]=2)=[O:25])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3ccc(Cl)cc3s2)C1

Procedure:
65.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-benzo[b]thiophene-2-carboxylic acid (prepared according to WO 2001007436) to give (R)-3-{[(6-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 392.9 ([M−H]−)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13](=[O:15])[NH:12][N:11]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13](=[O:15])[NH:12][N:11]=1
Reactant: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1n[nH]c(=O)o1
Yield: 93.1 %

Procedure:
A solution of 2-nitrobenzoylhydrazine (9.05 g, 0.05 mol) in dioxane (30 mL) was slowly added to a solution of trichloromethyl chloroformate (4.6 mL, 0.04 mol) in dioxane (30 mL) at room temperature. On completion of the addition the reaction was heated to reflux for 4 hours. The solvent was evaporated off and the residue re-crystallised from 96%. ethanol (50 mL) to give 7.15 g of the 5-(2-nitrophenyl)-3H-[1,3,4]oxadiazol -2-one. M.p. 157-158° C. A solution of the nitro compound (2 g, 9.7 mmol) in 96% ethanol (25 mL) was hydrogenated over 5% palladium on charcoal to give desired 1.6 g of the desired amine.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([O:53]C)=O)=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.N>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([NH2:2])=[O:53])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: N
Product: NC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and ammonia. m/e+ 355 for C17H13F2N6O (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:9]=2)=[S:7])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc2c(c(C(=S)c3ccc(C)cc3)c1)OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3c2OCC3)cc1

Procedure:
A solution of ethyl 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetate (10.0 g), 50 ml of methanol, 200 ml of water, and 4 g of sodium hydroxide was heated at reflux for approximately 2 hours. The reaction mixture was cooled and washed with ether. The ether washed aqueous residue was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The combined organic extracts were washed with water and evaporated to give a residue which was crystallized from acetone/hexane to give 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid, m.p. --150°-152° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]1([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:1]([NH:3][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: BrCc1ccccc1Oc1ccccc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2 Cl2 /EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccnc1N
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 2-nitro-3-methoxypyridine (32 g, 208 mmol) in EtOAc (150 mL) and MeOH (35 mL) under a nitrogen atmosphere was added 10% palladium on carbon (1.5 g, 1.4 mmol). This mixture was purged with H2 three times and the mixture was stirred for 3 h under a hydrogen atmosphere. The reaction mixture was purged with N2 three times, filtered through Celite, and the filter cake was washed with EtOAc (2×35 ml). The combined filtrate were concentrated and dried over high vacuum to afford 25.8 grams (100%) of 2-amino-3-methoxypyridine: LCMS (m/z): 125.0 (MH+); 1H NMR (300 MHz, CDCl3): 7.66 (m, 1H), 6.90 (m, 1H), 6.61 (m, 2H), 4.64 (s, br, 2H), 3.83 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][CH:13]1[C:20](OC)([O:21]C)[CH2:19][CH2:18][C:15]2([O:17][CH2:16]2)[C:14]1([OH:29])[C:25]([CH3:28])=[CH:26][CH3:27]>CC(C)=O.O>[Br:12][CH:13]1[C:20](=[O:21])[CH2:19][CH2:18][C:15]2([O:17][CH2:16]2)[C:14]1([OH:29])[C:25]([CH3:28])=[CH:26][CH3:27]
Reactant: CC=C(C)C1(O)C(Br)C(OC)(OC)CCC12CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC=C(C)C1(O)C(Br)C(=O)CCC12CO2
Yield: 81.3 %

Procedure:
1.9 g (9.96 mmol) of para-toluenesulphonic acid are added at room temperature to a solution of 3.2 g (9.96 mmol) of the compound obtained in Step B in 120 ml of an acetone/water mixture (3:2). When the reaction, followed by thin-layer chromatrography, is complete, the acetone is evaporated off. The aqueous phase remaining is then extracted with ethyl acetate (200 ml). After conventional treatment of the organic phase, 2.23 g (8.1 mmol) of the expected product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2.O>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (362 mg), ethyl 5-hydroxy-1H-2-indolecarboxylate (277 mg), and 4-dimethylaminopyridine (195 mg) were suspended in o-xylene, and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane on silica gel to give the title compound (161 mg, yield 30%).