Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:25]1([S:22]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][C:11]4[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]=4[C:18]=3[CH:17]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCN(Cc1ccccc1)CC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCNCC3

Procedure:
A mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (VIII, Step II, 453 mg, 1.09 mmol) in methanol (50 mL) is treated with palladium hydroxide (118 mg) and hydrogenated at 30 psi for 5 days. The mixture is filtered, rinsing with methanol and methylene chloride, and the filtrate concentrated under reduced pressure to give an amorphous solid. The material is purified by flash chromatography (Biotage 40M; methanol/methylene chloride, 5/95; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give the title compound. Analytical data for the hydrochloride salt, mp=290-291.5°; IR (drift) 3382, 2751, 2698, 2689, 2646, 2438, 1297, 1150, 1131, 1095, 801, 759, 722, 684 and 616 cm−1; NMR (300 MHz, DMSO-d6) 11.65, 7.35, 8.05-8.15, 7.85-7.95, 7.40-7.65, 3.20-3.40 and 3.10-3.25 δ; MS (EI) m/z 326 (M+), 298, 297, 286, 285, 284, 143 and 77; HRMS (FAB) calculated for C18H19N2O2S=327.1167, found 327.1165.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=O)C(F)(F)F.CI.[H-].[Na+]>C1COCC1>[CH3:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: COC(=O)CCOCCOCCOCCOCCNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNCCOCCOCCOCCOCCC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere of argon, in a round bottom flask, with magnetic stirring, 120.1 mg of 3-[2-(2-{2-[2-(2,2,2-trifluoro-acetylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-propionic acid methyl ester, 1 ml of anhydrous THF and 59.8 μl of CH3I and successively introduced. The reaction medium is cooled with a ice/water bath at about 0° C., and 16.1 mg of NaH (50% pure in oil) is slowly added by small portions. After 15 min at 0° C., and 1 hr at RT, the crude reaction medium is concentrated to dryness under RP, and diluted with 0.5 ml of THF and 0.8 ml of water. At RT, 30.6 mg of LiOH is then added to the reaction medium. The crude reaction medium is kept 2 hrs at RT, 16 hrs at −20° C., and then purified by flash-chromatography on 30 g of C18-grafted silica gel (gradient of elution water:acetonitrile from 95:5 to 5:95 by volume). After concentration of fractions containing the desired product under RP, 115.3 mg of 3-(2-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][Si:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(OC(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[AlH4-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][Si@H:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCCCCCC[Si]1(OC(C)C)CCC(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC[Si@H]1CC[C@H](c2ccc(F)cc2)CC1

Procedure:
Subsequently, the reaction mixture was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced triethylamine hydrochloride to be precipitated and separated by filtration. The resultant filtrate was concentrated to obtain 28.2 g of 4-(p-fluorophenyl)-1-n-heptyl-1-isopropoxy-1-silacyclohexane. This silacyclohexane product was dissolved in 100 ml of THF and was added to 100 ml of a THF solution of 10.9 g of lithium aluminohydride, followed by agitation under reflux for 2 hours. The cis-trans isomer mixture was subjected to quantitative gas-chromatographic analysis in the same manner as set out in Example 1, revealing that a ratio of the cis isomer (retention time: 5.65 minutes) and the trans isomer (retention time: 5.71 minutes) was 15.85. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The extract was subjected to ordinary procedures of washing with brine, drying and concentration, followed by purification through silica gel chromatography to obtain 19.0 g of the intended product (yield: 72.6%). The result of IR and 13C-NMR analysis of the product are shown below.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 480 (M+H).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)([CH3:14])[CH2:12][CH3:13]
Reactant: NCc1ccncc1
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2ccncc2)c(=O)c1=O
Yield: 60.9 %

Procedure:
A solution of the above 3-butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (1.197 g, 5.0 mmol) and 4-aminomethylpyridine (0.541 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 23 hours. The mixture was freed of solvent and the residue was triturated with diethyl ether and dried to provide 1.154 g of a buff solid. Recrystallization (twice) of the crude product from methanol gave 0.832 g (61%) of 3-(1,1-dimethylpropylamino)-4-[(pyridin-4-ylmethyl)-amino]cyclobut-3-ene-1,2-dione as a white compound: mp 258.0°-259.5° C. dec (softens 257.5° C.); 1H NMR (DMSO-d6): δ 8.56 (m, 2H), 7.86 (m, br, 1H), 7.46 (s, br, 1H), 7.32 (m, 2H), 4.77 (d, 2H), 1.67 (q, 2H), 1.32 (s, 6H), 0.83 (t, 3H). IR (KBr): 3270, 1790, 1650 cm-1 ; MS (m/z) 273 (M+).
Reaction SMILES: N[C:2]1[CH:30]=CC2NC(C3C(=O)N(CCC(C)C)C4C(C=3O)=CC=CN=4)=NS(=O)(=O)C=2[CH:3]=1.[OH:31][C:32]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:34](=[O:47])[C:33]=1[C:48]1[NH:53][C:52]2[CH:54]=[CH:55][C:56]([NH:58][S:59]([N:62]3[CH2:66]CC(NC(=O)OC(C)(C)C)[CH2:63]3)(=[O:61])=[O:60])=[CH:57][C:51]=2[S:50](=[O:76])(=[O:75])[N:49]=1.C(N(CC)CC)C>ClCCl>[OH:31][C:32]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH:44]([CH3:45])[CH3:46])[C:34](=[O:47])[C:33]=1[C:48]1[NH:53][C:52]2[CH:54]=[CH:55][C:56]([NH:58][S:59]([N:62]3[CH2:66][CH2:30][CH2:2][CH2:3][CH2:63]3)(=[O:61])=[O:60])=[CH:57][C:51]=2[S:50](=[O:75])(=[O:76])[N:49]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N4CCC(NC(=O)OC(C)(C)C)C4)ccc3N2)c(O)c2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N4CCCCC4)ccc3N2)c(O)c2cccnc21
Yield: 371.9 %

Procedure:
A mixture of the product of Example 205 (2 mg, 0.1 ml), the product of Example 451A (17 mg, 0.1 mmol) and triethylamine (0.1 mL) in dichloromethane (2 mL) was stirred for 18 hours at 25° C., diluted with dichloromethane (25 mL) and washed with 1 N HCl and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mM ammonium acetate in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min to provide the title compound (10 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.43 (s, 6 H) 1.57 (m, 2 H) 1.69 (m, 1 H) 3.14 (s, 4 H) 4.49 (m, 2 H) 7.51 (m, 1 H) 7.53 (s, 1 H) 7.60 (d, J=2.21 Hz, 1 H) 7.72 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.47 (s, 1 H) 14.06 (s, 1 H) 15.05 (s, 1 H). MS (ESI−) m/z 573 (M−H)−.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[O:6].[C:13]([NH:16][CH:17]([C:23](=O)[CH2:24]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14].CN(C)C1C=CC=CC=1>C(O)C>[C:13]([NH:16][CH:17]([C:23]1[N:10]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:11])[Cl:12])=[O:6])[S:9][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.51 g. of N-(β,β,β-trichloroethoxycarbonyl)thiourea and 2.66 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in 50 ml. of ethanol is added 1.8 g. of N,N-dimethylaniline. The mixture is stirred for 24 hours at room temperature, and condensed under reduced pressure. The residue is dissolved in 30 ml. chloroform and the solution is washed with 3 N-HCl, water, and dried. The solid matter which is obtained by removal of chloroform is purified by silica gel chromatography to give ethyl α-acetamido-2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetate. 1.43 g. Melting point: 161.9° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][S-:11].[Na+]>CN(C=O)C>[CH3:10][S:11][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccncc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cnccc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a mixture of 2.0 g of 3-chloroisonicotinonitrile and 8 ml of DMF, 1.02 g of sodium thiomethoxide was added while ice-cooling. The reaction mixture was stirred at 0° C. for one hour. The reaction mixture was concentrated under reduced pressure, to which ethyl acetate was added for filtering out insoluble matters. Filtrates were concentrated under reduced pressure, and the resultant residue was subjected to silica gel column chromatography to give 2.11 g of 3-methylthioisonicotinonitrile.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:13])[C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6](N)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>CN(C=O)C.O>[F:29][C:28]([F:30])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:1][N:2]2[C:6](=[O:7])[C:5]3[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:13])=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)c1ccccc1C(=O)NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirring solution of N-hydroxy phthalamide (5.25 g, 32.3 mmol) in DMF (30 mL) was added cesium carbonate (15.80 g, 48.5 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (5 ml, 32.3 mmol) at RT. Reaction mixture was stirred for 3 h. and then diluted with water. Precipitated product was filtered and dried to get titled compound in 87% yield.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([CH3:38])([NH2:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.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>C(OCC)(=O)C.O.CN(C=O)C>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([NH:37][C:19]([C:15]2[N:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:10]3=[N:17][C:16]=2[CH3:18])=[O:21])([CH3:38])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Reactant: CC1(N)CCN(Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1(C)CCN(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A mixture of 860 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 992 mg of 1-benzyl-4-methylpiperidine-4-amine dihydrochloride, 170 mg of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate, 3 mL of diisopropylethylamine, and 10 mL of DMF was stirred for 1 day. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1.25 g of N-(1-benzyl-4-methylpiperidin-4-yl)-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C([B:20]2[O:28][C:25]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:23])[O:21]2)=C(C)ON=1.O1CCOCC1.C([O-])(=O)C.[K+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:7][N:6]1[C:2]([B:20]2[O:28][C:25]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:23])[O:21]2)=[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[N:5]1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1ncc(-c2ccccc2)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1ncc(-c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C
Yield: 134.1 %

Procedure:
5-bromo-1-methyl-4-phenyl-1H-pyrazole (87 mg, 0.37 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (373 mg, 1.47 mmol) was added to a 1,4-dioxane (2 ml). To the above mixture were added Pd(dppf)Cl2 (27 mg, 0.037 mmol) and potassium acetate (181 mg, 1.85 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 45% EtOAc/Hexane) to afford 141 mg product 1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.N(OC(C)(C)C)=O.[I:21]I.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[I:21][C:5]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: II
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(I)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
3-methoxy-5-(trifluoromethyl)aniline (100 mg, 0.52 mmol) was dissolved in CHCl3 (5.2 mL) and t-butyl nitrite (124 μL, 1.05 mmol) was added dropwise by syringe. Iodine (266 mg, 1.05 mmol) was added and then the reaction was slowly heated to 50° C. and was maintained at this temperature for an hour and thirty minutes. The reaction was then cooled to room temperature and poured into aq. NaHSO3 (50 mL). The mixture was extracted with EtOAc (50 mL) and the organic extracts were washed with aq. NaHSO3 (3×50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 1% to 15% EtOAc/hexanes afforded 1-iodo-3-methoxy-5-(trifluoromethyl)benzene. Rf=0.75 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.53 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]([C:16]#[N:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([C@H:37]([CH2:40][CH:41]=[CH2:42])[CH:38]=O)[CH:33]=[CH:34][C:35]=1[Cl:36].C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.C(O)(=O)C>[ClH:29].[C:16]([C:15]1[C:6]([S:5][CH2:4][CH2:3][NH:2][CH2:38][C@H:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:40][CH:41]=[CH2:42])=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)#[N:17]
Reactant: C=CC[C@H](C=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1c(SCCN)c(C#N)cc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@H](CNCCSc1c(C#N)cc2ccccc2c1C(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(2-aminoethyl)thio]-3-cyano-1-naphthoate hydrochloride (Intermediate 3, 530 mg, 1.65 mmol) in methanol (100 mL) was added triethylamine (250 μL, 1.82 mmol). After 30 min (2S)-2-(3,4-dichlorophenyl)pent-4-enal {Intermediate 4, 525 mg (72% pure), 1.65 mmol} and the pH was adjusted to 4–5 with acetic acid. After 30 min a solution of sodium cyanoborohydride (200 mg, 3.20 mmol) in methanol (2 mL) was added and reaction mixture stirred at ambient temperature overnight. Reaction mixture volume reduced by half and 20% K2CO3 (50 mL) was added. Reaction mixture volume reduced further to about 50 mL and methylene chloride (100 mL) was added. The organic layer was washed with brine, dried (Na2SO4), and evaporated to an oil which was chromatography on silica gel in 5% MeOH/CHCl3 to give 730 mg of the free base. The free base was dissolved in HCl/MeOH and evaporated to dryness to give 780 mg of the title compound.
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:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:22])[CH:16]=1)[CH:7]=[CH:6]2.[CH3:23][C:24]1[O:25][C:26](=O)[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[C:26](=[O:25])[C:27]4[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:29]=[C:24]3[CH3:23])=[C:17]([CH3:22])[CH:16]=1)[CH:7]=[CH:6]2
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: COc1ccc2cc(C#Cc3ccc(N)c(C)c3)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2cc(C#Cc3ccc(-n4c(C)nc5ccccc5c4=O)c(C)c3)ccc2c1

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 2-ethynyl-6-methoxynaphthalene (25c, 182 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((6-methoxynaphthalen-2-yl) ethynyl)-2-methyl benzenamine (26c) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl-4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylbenzenamine (26c) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c). Reaction of 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c, 430 mg, 1 mmol) with 3,4,5-trimethoxybenzaldehyde (30l, 196 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (61) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][N:16]=[C:15]1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH3:1][N:2]([CH2:25][C:15]1[N:14]([CH3:13])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][N:16]=1)[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCc2cccnc21
Reactant: Cn1c(C=O)nnc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1nnc(-c2ccccc2)n1C)C1CCCc2cccnc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.39 g, 2.40 mmol) in 1,2-dichloroethane (4 mL) was added 4-methyl-5-phenyl-4H-1,2,4-triazole-3-carbaldehyde, 36, (0.41 g, 2.20 mmol), sodium triacetoxyborohydride (0.84 g, 3.90 mmol), and AcOH (1 drop). The reaction mixture was heated to 65° C. and stirred for 18 h. The reaction mixture was cooled to room temperature, poured into saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine then dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified via chromatography on basic alumina (0-5% methanol/dichloromethane) yielding BP: 1H NMR (400 MHz, CDCl3) δ 8.39, (d, J=4.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.46-7.39, (m, 3H), 7.32, (d, J=8.4 Hz, 1H), 7.01, (dd, J=7.2, 4.4 Hz, 1H), 4.04-3.92, (m, 2H), 3.78, (d, J=14.0 Hz, 1H), 2.85-2.74, (m, 1H), 2.71-2.62 (m, 1H), 3.33, (s, 3H), 2.12-1.94 (m, 3H), 1.74-1.62 (m, 1H); ESI+ MS: m/z (rel intensity) 334 (100, M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34]([OH:36])=O)[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:36])[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccccc1)CC2
Reactant: CS(N)(=O)=O
Product: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)NS(C)(=O)=O)cnn3c1Nc1ccccc1)CC2
Yield: 74.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)-7-phenylaminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.030 g, 0.063 mmol) obtained in step 4 and methanesulfonamide (0.030 g, 0.313 mmol), the title compound (0.026 g, 60%) was obtained.