Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[CH3:32])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methylbenzaldehyde. MS (ESI) m/z 483.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:12]1[CH2:15][S:14](=[O:17])(=[O:16])[CH2:13]1)[CH2:7]2.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=2[CH3:35])[NH2:31])[N:19]=1.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.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O1CCOCC1>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:29]=[C:30]([NH:31][C:2]3[C:3]4[CH2:4][CH2:5][N:6]([CH:12]5[CH2:15][S:14](=[O:17])(=[O:16])[CH2:13]5)[CH2:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH:32]=[CH:33][C:34]=2[CH3:35])[N:19]=1
Reactant: O=S1(=O)CC(N2CCc3c(Br)cccc3C2)C1
Reactant: Cc1ccc(N)cc1-c1cc2ccccc2cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cccc3c2CCN(C2CS(=O)(=O)C2)C3)cc1-c1cc2ccccc2cn1
Temperature: 96 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a reaction tube under argon containing 5-bromo-2-(1,1-dioxo-thietan-3-yl)-1,2,3,4-tetrahydroisoquinoline (70 mg, 0.22 mmol), 3-(isoquinolin-3-yl)-4-methylaniline (51 mg, 0.22 mmol), Pd2(dba)3 (22 mg, 0.022 mmol), xantphos (37 mg, 0.044 mmol), potassium phosphate (133 mg, 0.66 mmol) is added anhydrous dioxane (1 ml). The mixture is stirred at 96° C. for 18 hours, cooled to room temperature, filtered through a celite pad to remove solid. The filtrate is concentrated and purified by preparative HPLC to afford N-(3-(Isoquinolin-3-yl)-4-methylphenyl)-2-(1,1-dioxo-thietan-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine as a white solid (36.2 mg, 37%). LC-MS m/z: 470.2 (M+1); 1H NMR 400 MHz (CDCl3) δ9.31 (s, 1H), 8.00 (d, 2H, J=8.4), 7.83 (d, 1H, J=8.4 Hz), 7.72-7.70 (m, 2H), 7.61 (t, 1H, J=6.8 Hz), 7.20 (d, 1H, J=8.4 Hz), 7.13-7.09 (m, 3H), 6.94 (dd, 1H, J=2.4, 8.0 Hz), 6.70 (d, 1H, J=8.4 Hz), 5.34 (s, 1H), 4.44 (s, 2H), 3.59 (t, 2H, J=6.0 Hz), 2.97 (s, 3H), 2.82-2.78 (m, 6H), 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][C:9](=[O:14])[C:8]=2[CH:7]=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O)[CH2:2][CH3:3].[CH3:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[CH:40].C(N(CC)CC)C.CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:14])[CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C#CCCCCOc1ccccc1CCC(=O)OC
Reactant: CCCc1c(OS(=O)(=O)C(F)(F)F)ccc2c1OCCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCc1c(C#CCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 1.14 g (3.37 mmol) of 2,3-dihydro-8-propyl-7-[[(trifluoromethyl)sulfonyl]oxy]-4H-1-benzopyran-4-one, 0.94 g (3.62 mmol) of 2-[(5-hexynyl)oxy]benzenepropanoic acid methyl ester, 4.9 mL of dry triethylamine, 0.197 g (0.28 mmol) of dichlorobis(triphenylphosphine)palladium (II), and 21 mL of dry dimethylformamide was stirred and heated at 100° C. for 3 hr. The mixture was cooled, poured into ice-water, and worked-up with ether in the usual manner. The orange-red, oily residue was flash chromatographed on silica gel. Elution with 1:1 hexane-ether gave 1.25 g (83%) of 2-[6-(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)-5-hexynyloxy]benzenepropanoic acid methyl ester as a yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1>CN(C)C=O>[O:3]=[C:4]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])=[CH:13][CH:14]=2)[N:9]([CH2:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31][CH3:30])=[O:43])=[CH:34][C:35]=2[O:41][CH3:42])[CH:8]=1
Reactant: O=C(/C=C/c1ccc2c(/C=C/C(=O)N3CCCC3)c[nH]c2c1)N1CCCC1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc(/C=C/C(=O)N3CCCC3)c3ccc(/C=C/C(=O)N4CCCC4)cc32)c(OC)c1
Yield: 76.1 %

Procedure:
Sodium hydride (0.15 g of a 60% dispersion in mineral oil) was added to a stirred solution of E,E-3,6-di(3-oxo-3-pyrrolidino-1-propenyl)indole (0.97 g) in N,N-dimethylformamide (30 ml) cooled in an ice bath. After approximately 1 hr a solution of methyl-4-bromomethyl-3-methoxybenzoate (0.74 g) in N,N-dimethylformamide (10 ml) was added dropwise, the cooling bath was removed, and the mixture stirred for hr. The mixture was added slowly to vigorously stirred 1M hydrochloric acid (300 ml); the precipitate was isolated by filtration, washed with water and dried. The solid obtained was recrystallized from ethyl acetate to give methyl E,E-4-[3,6-di(3-oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoate (1.1 g, 76%) as an off-white powder; mp 226°-228°; partial NMR (250 MHz, DMSO-d6): 1.70°-2.0(m, 8H, pyrrolidino H), 3.40(m, 4H, pyrrolidino H), 3.65(m, 4H, pyrrolidino H), 3.83(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.50(s, 2H, NCH2Ar), 6.75(d, J=15.5 Hz, 1H, olefinic H), 7.0(m, 2H, olefinic H, and ArH).
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][C:10]([CH3:12])=C)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:7][C:2]([O:8][CH2:9][C:10](=[O:22])[CH3:12])([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(C)COC(C)(C)C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C)(C)OCC(C)=O
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of the product of Step 1 (1.73 g, 10 mmol) in 1,4-dioxane (75 mL) and water (25 mL) was added osmium tetroxide (4 wt % in water, 0.392 mL, 0.05 mmol), 2,6-lutidine (2.329 mL, 20 mmol), and sodium periodate (8.56 g, 40 mmol). After stirring for 14 hours, a large amount of white precipitate had built up. The reaction mixture was then partitioned between diethyl ether (100 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide methyl 2-methyl-2-(2-oxopropoxy)propanoate as a brown oil (1.74 g, 10 mmol), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 4.02 (s, 2H), 3.73 (s, 3H), 2.22 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=[S:16].N>ClCCl.CO.C(OC(=O)C)C>[CH2:1]([C:8]1[CH:9]=[C:10]([NH:11][C:15]([NH2:17])=[S:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cc2ccccc2)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=S)Nc1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-benzylaniline (183 mg, 1 mmol) and 1,1′-thiocarbonyldiimidazole (197 mg, 1.1 mmol) in dichloromethane (5 ml) is stirred at room temperature for 1.5 hours. 2 M ammonia in methanol (2.5 ml) is added to the solution and the mixture is stirred at room temperature overnight. The solution is diluted with ethylacetate, and the organic layer is washed with 5% HCl, saturated NaHCO3, and brine, and dried (anhydrous Na2SO4). The crude product is recrystallized from ethylacetate and petroleum ether to give the desired product as a white powder. 1H NMR (300 Hz, CDCl3) δ 7.93 (br s, 1H, NH), 7.73-7.02 (m, 9H, Aryl H), 6.06 (br s, 2H, NH2), 3.98 (s, 2H, CH2). MS (APCI) m/z 243 [M+H]±.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>C(O)C(F)(F)F>[CH3:14][C:12]1[C:11](=[O:15])[O:10][CH2:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Solvent: OCC(F)(F)F
Product: CC1=N[C@@H](c2ccccc2)COC1=O
Yield: 44.2 %

Procedure:
(S)-2-phenylglycinol (3.00 g, 21.9 mmol, 1.0 equiv.) and ethyl pyruvate (2.67 mL, 24.1 mmol, 1.1 equiv.) were refluxed in trifluoroethanol (50 mL) over activated 4 molecular sieves (8.00 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (7:3) to furnish the title compound as a white solid (1.83 g, 44%); m.p. 70.0-71.0° C. (lit 71.0-72.0° C.); v(max)(KBr) 3007 (C—H), 1735 (C═O), 1640 (C═N) cm−1; δH, (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.88-4.81 (1H, m, PhCH), 4.56 (1H, dd, J 4.49 Hz, T 9.48 Hz, 6β-H), 4.25 (1H, dd/13.01 Hz, JT 14.99 Hz, 6α-H), 2.41 (3H, s, CH3); δc (62.5 MHz CDCl3) 160.7, 155.9, 137.2, 129.4, 128.7, 127.5, 71.9, 60.1, 22.2; m/z (CL, NH3), 189 (M+, 25%), 159 (12%), 130 (24%), 104 (100%), 90 (21%), and 78 (6%); HRMS for C11HnNO2 requires 189.0787 found 189.0782. [α]D20 +253.0 (c 0.98 CHCl3) (the enantiomer lit. [α]D20 −237.1 (c 1.11 CHCl3)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[NH:12][C:11]2=[O:31])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:43]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]([CH3:43])[C:11]2=[O:31])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1[nH]c(=O)n2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1n(C)c(=O)n2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 368D (250 mg) in anhydrous N,N-dimethylformamide (6 mL) was added sodium hydride (34.1 mg). The mixture was stirred at 50° C. for 30 minutes. Then, iodomethane (35.6 μl) was added and the mixture was stirred at 50° C. overnight. The reaction mixture was quenched with water (30 mL), then extracted with ethyl acetate. The solution was dried (MgSO4), filtered and concentrated to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([NH:17]C=O)/[CH:6]=[C:7](\[CH2:15][CH3:16])/[CH2:8][P:9]([O:13]C)([O:11]C)=[O:10])C>O>[NH2:17][CH:5](/[CH:6]=[C:7](\[CH2:15][CH3:16])/[CH2:8][P:9]([OH:13])([OH:11])=[O:10])[C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)C(/C=C(\CC)CP(=O)(OC)OC)NC=O
Solvent: O
Product: CC/C(=C\C(N)C(=O)O)CP(=O)(O)O

Procedure:
Hydrolysis of E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester in a manner analogous to that described in Example 11 yields E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p. 176° (H2O).
Reaction SMILES: O1[C:11]2([CH3:12])[CH:2]1[C:3](=[O:14])[C:4]1[C:9]([C:10]2=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC12OC1C(=O)c1ccccc1C2=O
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(C)C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 30.5 %

Procedure:
A mixture of 1.88 g of 2,3-epoxy-3-methyl-1,4-naphthoquinone, 3.16 g of piperazinecarboxylic acid, ethyl ester and 100 ml of absolute ethanol was stirred for 12 hours at 50° C. The solvent was then removed and the remainder filtered through a one inch plug of silica gel and eluted with chloroform. The eluate was evaporated, giving 1 g of the desired product as a viscous red oil.
Reaction SMILES: [CH:1]1([C:7]2[S:21][C:10]3[N:11]=[C:12]([CH3:20])[N:13]=[C:14]([C:15](OCC)=[O:16])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>CCO.C1COCC1>[CH:1]1([C:7]2[S:21][C:10]3[N:11]=[C:12]([CH3:20])[N:13]=[C:14]([CH2:15][OH:16])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1nc(C)nc2sc(C3CCCCC3)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(CO)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
To a mixture of ethyl 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (29.3 g), calcium chloride (18 g), and THF (200 mL) was added NaBH4 (5.5 g) in small divided portions at room temperature, and then EtOH (200 mL) was slowly added thereto over 5 minutes, followed by stirring at room temperature for 4 hours. To the reaction mixture was added ice water, followed by stirring, adding 1 M hydrochloric acid until the suspension becomes a solution state, and then extracting with EtOAc. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine. To the organic layer were added MgSO4, activated carbon, and basic silica gel, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to obtain (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methanol (12.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([N:14]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([Cl:13])[CH:7]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:14][C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([Cl:13])=[C:9]([F:12])[CH:10]=2)=[O:17]
Reactant: COC(=O)C(=Cc1ccc(F)c(Cl)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2cc(Cl)c(F)cc2[nH]1

Procedure:
A mixture of 3-chloro-4-fluoro-α-azidocinnamic acid methyl ester (Japanese Patent Application Laid-Open (kokai). No. 7-149723) (1.85 g) and xylene (140 mL) was heated under reflux for 1 hour, and the solvent was distilled away. The residue was purified by silica gel column chromatography (methylene chloride), to thereby give the title compound (491 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CCCC(=O)O)CC4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.3 %

Procedure:
A solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]butanoate (Preparation 50) (100 mg, 0.201 mmol) in ethanol (6 ml) was stirred at room temp and sodium hydroxide (1.5 ml, 3.00 mmol) added. The reaction mixture was stirred at room temperature for 90 mins and was then acidified with acetic acid to pH 5, and the mixture concentrated in vacuo. The resultant residue was dissolved in EtOAc (˜30 ml) and water (˜30 ml) and the layers partitioned, the aqueous was re-extracted with EtOAc (˜20 ml) and the combined organics were passed through a phase separation cartridge and the solvent reduced in vacuo. The residue was purified by trituration with methanol, the solid filtered and dried on the sinter to yield the title compound (30 mg, 0.061 mmol, 30% yield). δH (d6DMSO, 400 MHz): 8.19 (1H, s), 8.11 (1H, d), 7.79-7.90 (2H, m), 7.44 (1H, d), 7.34 (1H, d), 4.89 (1H, sept), 3.46-3.24 (2H, hidden under H2O peak), 3.01-2.93 (4H, m), 2.68-2.59 (4H, m), 2.28 (2H, t), 1.70 (2H, quintet) 1.37 (6H, d). MS (ES): C25H2835ClN3O4 requires 469; found 470 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[O-:13][S:14]([O-:16])=[O:15].[Na+].[Na+].O>CCO>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([S:14]([OH:16])(=[O:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Yield: 73.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 1,4-difluoro-2-methyl-5-nitrobenzene (1.2 g, 6.93 mmol) in EtOH (10 ml) and Na2SO3 (1.98 g, 15.7 mmol) in EtOH:water (40 ml:25 ml) at 70° C. for 16 h gave the title compound (1.2 g, 73%) which was used in the next step without purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O.C(O)C>[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)(=O)C>[CH2:1]([NH:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NCC)n2n1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NCC)n2n1
Reaction time: 0.5 h

Procedure:
7-Bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide (0.160 g, 0.450 mmol), pyridine-3-boronic acid (0.0910 g, 0.742 mmol), sodium carbonate (0.215 g, 2.03 mmol), and bis(diphenylphosphino)ferrocene palladium (II) chloride (0.005 g) were suspended in a solution of ethylene glycol dimethyl ether/water/ethanol (7:3:2, 6.00 mL) and subjected to microwave at 80° C. for 30 minutes. The reaction mixture was acidified with acetic acid and purified by column chromatography (gradient 0-5% methanol/dichloromethane) to afford the desired product 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide MS (APCI+): m/z 354.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:36]=[CH:35][C:21]2[CH2:22][CH2:23][C:24]([CH3:34])([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:25][C:20]=2[CH:19]=1.N1C=CC=CC=1.ClCCCl>O>[CH3:16][O:17][C:18]1[CH:36]=[CH:35][C:21]2[CH2:22][CH2:23][C:24]([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:6](=[O:7])[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)[CH2:30][CH2:29]3)([CH3:34])[O:25][C:20]=2[CH:19]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc2c(c1)OC(C)(CCN1CCNCC1)CC2
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: COc1ccc2c(c1)OC(C)(CCN1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)CC2
Yield: 42.8 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (6.7 g, 0.029 mol) was added dropwise to a solution composed of 7.0 g (0.0241 mol) of 3,4-dihydro-7-methoxy-2-methyl-2-[2-(piperazin-1-yl)ethyl]-2H-benzopyran, 2.28 g of pyridine and 100 ml of 1,2-dichloroethane. The resultant mixture was stirred at room temperature for 2 hours. The reaction mixture obtained was poured into water and extracted with diethyl ether, the extract was dried over anhydrous sodium sulfate, and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 5.0 g of 1-[2-(3,4-dihydro-7-methoxy-2-methyl-2H-benzopyran-2-yl)ethyl]-4-(3,4,5-trimethoxybenzoyl)piperazine [Compound (25)] having the following physical characteristics.
Reaction SMILES: [C:1]([CH2:4][N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([OH:3])=O.Cl.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:1]([CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16])=[O:3]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)CN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O

Procedure:
Prepared from N-carboxymethyl-N-methylsulphonyl-4-nitroaniline and methylamine hydrochloride
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1>O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[C:5]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC(F)(F)F)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(O)cc(CC(F)(F)F)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A mixture of 140 (50 mg, 0.15 mmol) and Pyridine HCl (3 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The EtOAc was dried over MgSO4, concentrated to give a solid which was triturated with CH2Cl2 and filtered to give 141 (30 mg, 65%): Mp=210–213° C.; 1H NMR (DMSO-d6) δ 9.86 (s, 1 H), 9.28 (s, 1 H), 7.71 (d, 2 H, J=8.8 Hz), 7.05 (s, 1 H), 6.89–6.86 (m, 3 H), 6.69 (d, 1 H), 2.0 Hz), 3.91–3.84 (m, 2 H); MS 307 [M−H]−
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1ncc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (9.38 g, 43.2 mmol) and (trimethylsilyl)acetylene (9.16 mL, 64.8 mmol) in triethylamine (300 mL) were added bis(triphenylphosphine)palladium(II) chloride (3.34 g, 4.75 mmol) and copper(I) iodide (1.64 g, 8.64 mmol). The reaction mixture was allowed to stir for 4 h at 80° C. and then cooled to rt and filtered through Celite®. The filter pad was washed with EtOAc and the filtrate was washed with saturated aqueous NaHCO3 (500 mL) then brine (500 mL). The organic solution was dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-methyl-3-nitro-5-[(trimethylsilyl)ethynyl]pyridine (9.22 g, 91%). LCMS (FAL): Rt=11.04 min, m/z=235.1 (M+H).