Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:37])([F:38])[F:36])[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.056 mmol), β-alanine (503 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (15-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a light tan solid. MS: (+) m/z 589.30 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NC(N)=[S:15].[OH-].[Na+]>O>[CH:1]1([NH:7][C:8](=[O:11])[CH2:9][CH2:10][SH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)NC1CCCCC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCS)NC1CCCCC1
Temperature: 60 °C
Yield: 90.4 %

Procedure:
A mixture of N-cyclohexylacrylamide (15.3 g), concentrated hydrochloric acid (19.4 g, 37.6%), thiourea (7.6 g) and water (10 g) was heated to 60° C. for 2 hours, cooled to 20° C. and sodium hydroxide (50%, 16 g) was slowly added under nitrogen keeping the temperature below 30° C. The resulting mixture was heated to 60° C. for 1 hour and extracted with methylene chloride (2×50 ml). Removal of the solvent afforded N-cyclohexyl-3-mercaptopropionamide (16.9 g) which was purified by vacuum distillation at 0.05 mm and 130° C. to yield 13.7 g of N-cyclohexyl-3-mercaptopropionamide; m.p. 73.5°-75.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:27]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 29.3 %

Procedure:
Example 16 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2-chlorophenyl)acetic acid (0.034 g) to give the title compound (0.025 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][OH:3].[CH3:5][C:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:20]=[C:21]([C:25]4([C:31](OCC)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[N:7]=1>C(O)C>[OH:3][CH2:2][CH2:1][NH:4][C:31]([C:25]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18][C:15]3[CH:16]=[CH:17][C:12]([N:8]4[C:9](=[O:11])[NH:10][C:6]([CH3:5])=[N:7]4)=[CH:13][CH:14]=3)[CH:20]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:32]
Reactant: NCCO
Reactant: CCOC(=O)C1(c2cccc(Sc3ccc(-n4nc(C)[nH]c4=O)cc3)c2)CCOCC1
Solvent: CCO
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)NCCO)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
2-Ethanolamine (6.0 mmol) is added to a solution of ethyl 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxylate (1.0 mmol) (example 19) in ethanol and the mixture are refluxed. All the volatiles are removed under reduced pressure and the residue is purified by column chromatography over silica gel to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-methoxy-4-nitrophenol (2.54 g) and triphenylphosphine (10.20 g) in dichloromethane (60 ml) was added dropwise diethyl azodicarboxylate (3.1 ml) in an ice bath and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/2 as an eluant to give the desired compound (4.36 g, yield 82%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([C:16]3[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)[CH3:15])[CH2:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[Cl-].Cl[CH2:27][CH2:28][NH+:29]([CH3:31])[CH3:30]>CC(N(C)C)=O>[CH:1]1([N:4]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:5]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][N:14]([C:16]3[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)[CH3:15])[CH2:11][CH2:12]2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[NH+](C)CCCl
Reactant: CN(C[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C(=O)[C@H]1CC[C@H](CN(C)c2ncc(Br)cn2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
0.12 g (0.33 mmol) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropylamide was dissolved in 10 mL of DMA and treated with 0.21 g (4.90 mmol, 14 eq) of NaH (55% in oil) at 0° C. then warmed to RT. The mixture was then treated with 0.47 g (3.27 mmol, 10 eq) of N-(2-chlorethyl)-N,N-dimethylammonium chloride at 0° C. and warmed to RT. The reaction was stirred for 27 h, then partitioned between Et2O (×3)/aqueous 10% NaHCO3, washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel (20g) with CH2Cl2:MeOH 95:5 to yield 0.09 g (68% over 2 steps) of pure trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropyl-(2-dimethylamino-ethyl)-amide, MS: 438 (MH+, 1Br).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.[I-].[Na+]>COCCOC>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:29]5[CH2:34][CH2:33][S:32][CH2:31][CH2:30]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: C1CSCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCSCC1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 454.0 mg (4.4 mmol) of thiomopholine and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 108.4 mg (53.5%) of the product as a light yellow solid, m.p. 213-215° C., mass (electrospray, m/e): M+H 461.0.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl

Procedure:
A mixture of 2.565 g (16.28 mmol) of 2-chloronicotinic acid, 20 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The resulting reaction solution was allowed to cool, and then concentrated under reduced pressure to obtain 2-chloronicotinoyl chloride. The compound thus obtained was dissolved in 15 ml of acetone. The solution thus obtained was then added dropwise to a solution of 1.363 g of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 5 minutes to obtain a solution of 4-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a solution of 1.363 g of N-(2-hydroxyethyl)aniline in 15 ml of THF with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was then recrystallized from ethanol to obtain 777 mg of 2-[N-(2-hydroxyethyl)-N-phenylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([CH2:20][C:14]3[C:13]([O:12][CH3:11])=[CH:18][CH:17]=[CH:16][C:15]=3[F:19])[C:22]([NH2:23])=[N:1]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1cc(F)ccc1C=O
Product: COc1cccc(F)c1Cc1cc2ccc(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluorobenzaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH3:21][CH2:22][O:23][C:24]([CH2:26]Br)=[O:25]>>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:26][C:24]([O:23][CH2:22][CH3:21])=[O:25])=[CH:16][CH:15]=3)[N:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Product: CCOC(=O)COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A mixture of 5.58 g of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with ethyl bromo acetate as described in Example 255, giving 1.8 g of the desired product as yellow crystals, mp 109°-111° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:46]([OH:47])[CH:41]6[CH:42]([O:43][CH2:44][CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:48]([CH3:50])[CH3:49])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:48]([CH3:50])[CH3:49])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:46]([OH:47])[CH:41]1[O:40]3)[O:36]2)[CH3:45]
Reactant: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Yield: 62.3 %

Procedure:
21.2 mg of compound (28) was dissolved in 6 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature for 50 minutes. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was dissolved in 4 ml of methanol and washed with 4 ml of n-hexane twice. The methanol layer was concentrated in vacuo to give 10.0 mg of compound (29) as a colorless oily substance.
Reaction SMILES: Br.Br.[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1.CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([N:7]3[CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5][CH2:6]3)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C(=O)CCl)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
A solution of 4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl dihydrobromide (as prepared in Example 67, step (c), 0.28 g, 0.60 mmol) in CH2Cl2 (6 mL) was treated with Et3N (0.27 mL, 1.9 mmol) and cooled to 0° C. The mixture was treated with chloroacetyl chloride (53 μL, 0.66 mmol) as a solution in CH2Cl2 (2 mL) and stirred at 0° C. for 15 min then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.18 g, 80%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.21 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 4.11 (s, 2H), 3.84-3.76 (m, 4H), 3.76-3.61 (m, 4H), 3.13-3.05 (m, 1H), 3.04-2.92 (m, 2H), 1.7-1.66 (m, 2H), 1.45-1.38 (m, 2H), 1.38-1.25 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C17H24ClN5O3, 382.1 (M+H), found 382.1.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacui, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:12]=[CH:13][C:14]([CH3:15])=[N:5]2)=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1Cl
Reactant: C/C=C/C=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc2ccc(C)nc2cc1Cl
Temperature: 100 °C
Yield: 50.1 %

Procedure:
To 3-chloro-4-methoxyaniline (1A) (5.0 g, 31.7 mmol) was added 6 M HCl (100 mL) and the reaction was heated to 100° C. with stirring. Toluene (30 mL) was added followed by the slow addition of crotonaldehyde (5.3 mL, 63.5 mmol) at 100° C. The mixture was stirred at 100° C. for 2 hours and cooled to room temperature. The water layer was separated and neutralized with 2 M NaOH solution to pH ˜8. The solid that formed was filtered and collected. The crude product was purified by flash column chromatography to give 1B as white solid (3.3 g, 50%). LCMS-ESI+ (m/z): 208.2, 210.2 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH3:33])=[C:9]([CH3:32])[CH:10]=[C:11]2[C:19]=1[N:18]=[C:17]1[N:12]2[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][C:15]2[N:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=21.B(OC)(OC)[O:35]C>C1COCC1>[OH:35][C:7]1[C:8]([CH3:33])=[C:9]([CH3:32])[CH:10]=[C:11]2[C:19]=1[N:18]=[C:17]1[N:12]2[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][C:15]2[N:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=21
Reactant: Cc1cc2c(nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n23)c(Br)c1C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc2c(nc3c4ccc(C(C)(C)C)nc4cc(C(C)(C)C)n23)c(O)c1C
Temperature: 25 °C

Procedure:
13.2 ml (33 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise with vigorous stirring to a solution, cooled to −78° C., of 13.2 g (30 mmol) of 10-bromo-3,6-di-tert-butyl-8,9-dimethyl-4,6a,11-triazabenzo[α]fluorene in 300 ml of THF, and the mixture is stirred for a further 30 min. 4.7 ml (42 mmol) of trimethyl borate are added to this solution in one portion, the mixture is stirred for a further 1 h and then allowed to warm to room temperature. The solvent is removed in vacuo, the residue is taken up in 1000 ml of ethyl acetate, the solution is cooled to 5° C., 19 ml of aqueous H2O2 solution (30% by weight) are added with vigorous stirring, and a solution of 825 mg of NaOH in 20 ml of water is then added dropwise. After stirring for 3 h, 300 ml of saturated ammonium chloride solution are added, the organic phase is separated off, washed twice with 200 ml of water each time, dried over magnesium sulfate, and the org. phase is then evaporated to a volume of about 50 ml in vacuo. 200 ml of methanol are added to the crystal slurry, the crystals are filtered off with suction and washed once with 50 ml of methanol and dried in vacuo.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:2].[N-:24]=[N+:25]=[N-:26].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:24]1[C:1]([CH:3]2[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:2][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C#N)C1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn[nH]2)C1
Temperature: 95 °C
Yield: 98.6 %

Procedure:
1-Benzyl 4-ethyl 2-cyanopiperidine-1,4-dicarboxylate (2.5 g, 7.90 mmol) was dissolved in toluene (50 mL) and sodium azide (0.822 g, 12.64 mmol) and triethylamine hydrochloride (1.740 g, 12.64 mmol) were added and the mixture was heated at 95° C. overnight. The reaction mixture was allowed to cool to room temperature and was washed with 2 M HCl. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over Na2SO4 and evaporated to yield 1-benzyl 4-ethyl 2-(1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (2.8 g, 99%). MS m/z 360 (M+H)+
Reaction SMILES: C[C@@H]([O:8][C:9]([CH2:11][C@@H:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[Cl:35])[CH2:15][CH2:14][CH2:13]1)=[O:10])CCCCC.[OH-].[Na+].Cl>CO>[C:9]([CH2:11][C@@H:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:26][C:25]=2[Cl:35])[CH2:15][CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: CCCCC[C@@H](C)OC(=O)C[C@H]1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a suspension of (5R)-5-((R)-2-heptyloxycarbonylmethyl)-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (33 g) in methanol (500 ml) is added a 5N aqueous sodium hydroxide solution (25.8 ml), and the mixture is heated with stirring at 40-50° C. for two hours. To the mixture is further added a 5N aqueous sodium hydroxide solution (15 ml), and the mixture is heated with stirring at 50° C. for three hours. The reaction solution is acidified with hydrochloric acid, and concentrated under reduced pressure to remove the methanol, and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to remove the ethyl acetate. The resultant is crystallized from ethyl acetate--diethyl ether, washed with diethyl ether--n-hexane to give (5R)-5-carboxymethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (21.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:20](=[O:22])[CH3:21])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2cn(C(C)=O)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of compound 1 was added to the mixture of 50 ml each of acetic anhydride and pyridine, and then the solution was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The resulting crude crystals were recrystallized from chloroform to obtain 3-(p-methoxybenzoyl)-N-acetylindole (compound 5) in the form of white crystals. (Yield: 90%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+].Cl>CO.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ncnc21
Temperature: 30 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.31 g, 0.57 mmol), lithium hydroxide monohydrate (0.060 g, 1.4 mmol) in methanol (6.0 mL) and water (2.5 mL) was stirred at 30° C. overnight. The mixture was adjusted to pH=4 with aqueous HCl, and concentrated under reduced pressure to remove MeOH. The resulted solid was filtered, washed with water and ether, and then dried in vacuum to afford the desired product (0.25 g, 83%). LCMS (M+H)+: m/z=532.3