Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33][OH:34])[NH:27][C:26](=[O:36])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33][OH:34])[NH:27][C:26](=[O:36])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 43 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (40 mg, 43%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:7]=[CH:6]2.C(Cl)(=O)C([Cl:21])=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([Cl:21])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reaction time: 0.05 h

Procedure:
A mixture of (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid (23.09 g) and THF (41 mL) is agitated until dissolution is achieved. Oxalyl chloride (17.5 mL) is added to the flask followed by DMF (3 drops) and heptanes (50 mL). The mixture is stirred for approximately 2 hours. The resulting slurry is filtered, washed with heptane (15 mL) and aspirated for 3 minutes and vacuum dried to give 17.44 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cccc(Cl)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(Cl)c1F
Temperature: -70 °C

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 20 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After one hour at −70° 3.93 ml DMF in 7 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 15 ml of a 1 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel to yield 0.25 g 2-chloro-3-fluoro-4-methoxybenzaldehyde. Analogously to example 9, the corresponding imine is produced starting from 411 mg (2.6 mmol) 5-amino-2-methylquinolin and 490 mg (2.6 mmol) 2-chloro-3-fluoro-4-methoxybenzaldehyde in toluene. 800 mg (2.4 mmol) [(2-chloro-3-fluoro-4-methoxyphenyl)methylene]-2-methylquinolin-5-amine in THF are added to 0.42 ml (4.8 mmol) of the lithiated 1,1,1-trifluoroepoxypropane at −100° C. analogously to example 9. Typical work up and chromatographic purification on silica gel (acetone in hexane 0% to 50° A)) yield 796 mg and 100 mg of two diastereomers of {[2-chloro-3-fluoro-4-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:12]C(=O)C.[N+:16]([O-])([OH:18])=[O:17]>CC(O)=O>[NH2:12][C:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc2c(F)cccc12
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])c2c(F)cccc12
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
Compound 209A (133 mg, 0.645 mmol) was dissolved in 1 mL AcOH and the resulting solution was cooled to 10° C. At this temperature, 80.0 μL (2.00 mmol) of red fuming HNO3 was added and stirring was continued for 15 min before the reaction was quenched by the addition of crushed ice. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in 3 mL EtOH, heated to reflux and treated with 0.5 mL of 40% aqueous NaOH solution. Stirring was continued for 15 min before the reaction was cooled and diluted with H2O. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with 40 to 70% EtOAc in hexane to afford 36 mg (0.17 mmol, 27%) of compound 209B as a yellow solid.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C:19]2=[C:20]([NH:35][S:36]([CH:39]3[CH2:42][CH:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:40]3)(=[O:38])=[O:37])[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[C:22]([CH3:25])[C:23](=[O:24])[N:18]2[CH2:17][CH2:16]1)=O)(C)(C)C.CO>C(Cl)(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:21]1[C:20]([NH:35][S:36]([CH:39]2[CH2:42][CH:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:40]2)(=[O:38])=[O:37])=[C:19]2[NH:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]=1[CH3:25]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
Dioxane hydrochloride (3 mL) was added to 8-(3-benzyloxy-cyclobutanesulfonylamino)-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (250 mg) and the resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was concentrated; the concentrate was neutralized with NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 120 mg of the product (55.8% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17](F)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: O
Product: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (4.0 g) and benzylamine (50 ml) was stirred at room temperature for about 30 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was sufficiently washed with water and concentrated under reduced pressure. Triturating the residue with a mixture of ether and n-hexane, there was obtained γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-benzylamino-4-fluorobutyrophenone. M.P. 113° - 117°C. IR νmaxNujol 3350, 3300, 1639, 1600 cm-1.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(C3SC4C=CC=C(Cl)C=4C=3)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH3:37])[C:31]([C:38]([OH:40])=O)=[CH:30]2.C(OC(N1CCN(C2C=CC(N)=CN=2)CC1)=O)(C)(C)C>>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:38]([C:31]3[N:32]([CH2:36][CH3:37])[C:33]4[C:29]([CH:30]=3)=[CH:28][C:27]([Cl:26])=[CH:35][CH:34]=4)=[O:40])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)O)cc2cc(Cl)ccc21
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Product: CCn1c(C(=O)Nc2ccc(N3CCNCC3)nc2)cc2cc(Cl)ccc21

Procedure:
With a method similar to that used for the preparation of 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide, 5-chloro-1-ethyl-1,4-indole-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide was prepared from 5-chloro-1-ethyl-1H-indole-2-carboxylic acid and 4-(5-amino-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS for C20H22Cl N5O calcd. (m/e) 383, observed 384 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)#[N:2].N1CCC(NC2C=C(C=CC=2)C#N)CC1>>[NH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1
Agent: N#Cc1cccc(NC2CCNCC2)c1
Product: N#Cc1ccccc1NC1CCNCC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-[(2-cyanophenyl)amino]-1-piperidinecarboxylate (D17) using a method similar to that described for D6 in Description 6.
Reaction SMILES: [NH2-].[Na+].[CH:3]1[CH2:5][CH:4]=1.I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].C(O)C>N.CCOCC>[CH2:14]([C:3]1[CH2:5][CH:4]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: C1=CC1
Reactant: C=CCCCCCCI
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: C=CCCCCCCC1=CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 0.43 g (11 mmol) of sodium amide in roughly 15 ml of ammonia was cooled to −78° C. A chilled solution of cyclopropene in ammonia (1:1, 0.85 g, 10 mmol) was poured into the reaction mixture. The reaction mixture was stirred at −78° C. for ½ hour, warmed briefly to the ammonia boiling point, then recooled to −78° C. 8-Iodooct-1-ene (1.2 g, 5 mmol) was added by syringe, and the reaction mixture was warmed to reflux for ½ hour. A few ml of ethanol were added. Ether (25 ml) was slowly added while the ammonia was allowed to distill out of the reaction mixture. The reaction mixture was washed with water, 0.5M HCl (2×), water and brine. It was dried over MgSO4, filtered and stripped. The product was purified by chromatography on silica gel using hexane as the eluent. A 10 mg sample of 67% pure 1-(oct-7-enyl)-cyclopropene was obtained.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH:12]([CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57]([NH:11][CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)CC(O)C(O)C(N)CC1CCCCC1
Reactant: Nc1nc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)N2CCOCC2)C(=O)O)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC(O)C(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
1-N-Hydroxybenzotriazole, 190.6 g, 395.0 g of [2S (2R*,3S*,4R*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (U.S. Pat. No. 4,680,284 and 4,845,079), 682.4 g (1.62 mol) of N-(4-morpholinyl-sulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine and 20 L of ethyl acetate are charged into a 50 L reactor and the slurry is stirred. Triethylamine, 107.1 g with 0.5 L of ethyl acetate, is added to the mixture and stirred for 1 hour at 30° C. A solution of 300.0 g of dicyclohexylcarbodiimide dissolved in 2.5 L of ethyl acetate is added to the reaction mixture over 15 to 30 minutes. The slurry is warmed to 35° to 40° C. and stirred at that temperature for 48 hours, cooled to 25° C., and the solids removed by filtration. The filtrate is washed with 0.5N aqueous hydrochloric acid solution (4 L), saturated sodium bicarbonate solution (4×4 L), and water (2 L). The solution is concentrated to a thick slurry under vacuum, chilled to 5° C., and the crude product solid collected by filtration and dried under vacuum at 40° C. The crude product and 4 L of isopropanol are charged into a 12 L reactor and the slurry is heated to 45° C. Water, 1 L, is added and heating continued to 60° C. The solution is cooled slowly to crystallize the product and then chilled to 10° C. The slurry is filtered and the cake is washed with cold isopropanol. After drying at 40° C. under vacuum, 770 g of [1S-(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide is obtained as white needles of >99% purity by HPLC; mass spectrum (fast atom bombardment): 709.2 M+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.[F:17][C:18]([F:29])([F:28])[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.O.[Sn](Cl)Cl>C1(C)C=CC=CC=1>[F:17][C:18]([F:28])([F:29])[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][C:24]2([NH:8][C:6](=[O:7])[C:5]3[C:4](=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=3)[NH:1]2)[CH2:23][CH2:22]1
Reactant: O=C1CCC(OCC(F)(F)F)CC1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC2(CCC(OCC(F)(F)F)CC2)Nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 39.7 %

Procedure:
2-Nitro-4-trifluoromethylbenzamide (347 mg, 1.47 mmol), 4-(2,2,2-trifluoroethoxy)cyclohexanone (303 mg, 1.54 mmol) and tin(II) chloride hydrate (663 mg, 2.94 mmol) were added to toluene (5 ml) under argon and stirred under reflux conditions for 10 h. After cooling to room temperature, filtration with suction and thorough drying of the solid which precipitated gave 4′-(2,2,2-trifluoroethoxy)-7-(trifluoromethyl)-1H-spiro[quinazolin-2,1′-cyclohexan]-4(3H)-one (223 mg, 36% of theory) as a colorless solid. 1H NMR (400 MHz, d6-DMSO δ, ppm) 8.23 (br. 5, 1H, NH), 7.73 (d, 1H), 7.21 (br. s, 1H, NH), 7.19 (s, 1H), 6.90 (d, 1H), 4.06 (q, 2H), 3.51 (m, 1H), 1.90 (m, 4H), 1.62 (m, 4H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:12])[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]2.[OH-].[Na+]>>[CH3:12][C@H:3]([NH:2][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([Cl:13])=[CH:22][CH:21]=2)=[O:24])[C:4]([N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C[C@H](N)C(=O)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)N1CCOCC1

Procedure:
(2S)-Amino-1-morpholin-4-yl-propan-1-one hydrochloride (195 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (195 mg, 1.0 mmol) were coupled according to procedure A (washed with 1 N NaOH after acid washes) giving crude product which was triturated with ether and dried. Yield 150 mg, 45%: HPLC (60/40) 3.61 minutes (100%); PBMS 336/338 (MH+, 100%);
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.ClCCl.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]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:29]4[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26][C:25]=4[CH:24]=[C:23]3[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccn1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 1-dram vial was added 273a (40 mg, 0.074 mmol), 2-aminopyridine, (1.2 equiv), cesium carbonate (1.5 equiv), Xantphos (10 mol %) and tris(dibenzylideneacetone)dipalladium(0) (5 mol %) in dry 1,4-dioxane (0.2 M). The reaction was then stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction was then diluted with dichloromethane (3 mL) and washed with water (2×3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product 273b was then carried on to the subsequent step without purification.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:12]([C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1cnc(Cl)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a stirred solution of isopropylamine (123 mg, 2.08 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (1.04 mL of a 2M solution in toluene, 2.08 mmol). After 1 h, a solution of 2-chloro-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.522 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 6 h, the reaction mixture was cooled, quenched with Seignettes's salt solution and water, then extracted with dichloromethane. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 30% ethyl acetate in heptane) gave the title compound (100 mg, 94%) as a white solid. MS: m/e=203.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)n1
Yield: 76 %

Procedure:
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) (prepared in Example C17, step B) and 2,4-dichloro-5-fluoropyrimidine (112 mg, 0.67 mmol) in N,N-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3. The filtrate was concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light yellow gum (216 mg, 76%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)[CH3:2].CS(O[CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([S:16][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.80 g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was added 2,2-diphenylethyl methanesulfonate (1.80 g, 6.20 mmol) followed by addition of potassium carbonate (857 mg, 6.20 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 2.70 g of ethyl[[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (2.00 g, 3.99 mmol) in ethanol (8 mL)-water (2 mL) was added sodium periodate (4.30 g, 19.9 mmol) and the mixture was refluxed for 14 hours. This reaction mixture was diluted with ethyl acetate and water and, after phase separation, the aqueous layer was extracted with ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. To a solution of the above concentration residue in tetrahydrofuran (16 mL)-methanol (4 mL) was added 1N-aqueous sodium hydroxide solution (2 mL) dropwise, and the mixture was stirred at room temperature for 10 minutes. The solvent was then distilled off under reduced pressure. To the residue was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide 0.72 g of the title compound. Yield 41%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=O)[NH:11][C:10](=O)[C@H:9]2[CH2:13][CH:14]=[CH:15][CH2:16][C@@H:8]12>C1COCC1>[CH2:10]1[C@@H:9]2[C@@H:8]([CH2:16][CH:15]=[CH:14][CH2:13]2)[CH2:7][NH:11]1
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=CC[C@H]2CNC[C@H]2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A suspension of lithium aluminum hydride (21.4 g, 0.562 mol) in THF (700 mL) at room temperature was treated with cis-1,2,3,6-tetrahydrophthalimide (Aldrich; 37 g, 0.245 mol) in small portions. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and quenched carefully by the sequential addition of water (22 mL), THF (22 mL), 15% aqueous KOH (22 mL), and water (80 mL). The mixture was diluted with diethyl ether (100 mL), stirred at room temperature for 1 hour, and then filtered (methylene chloride wash). The filtrate was concentrated under reduced pressure to provide the title compound as an oil (26.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.76–2.02 (m, 2H), 2.10–2.33 (m, 3H), 2.34–2.56 (m, 2H), 2.61–2.79 (m, 2H), 2.87–3.17 (m, 2H), 5.53–6.03 (m, 2H); MS (DCI/NH3) m/z 124 (M+H)+.