Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26](O)(=O)CCCCCCCCC#CC#CCCCCCCCCCCCC.C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCC.C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCCCC>C(O)C>[C:1]([O:25][CH3:26])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Solvent: CCO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC

Procedure:
Alcoholic Monomer Solution of TDA/PDA: 10,12-Tricosadiynoic acid (TDA, 6 gm GFS Chemicals) and 10,12-pentacosadiynoic acid (PDA, 0.9 gm GFS Chemicals) were dissolved in 60 ml ethanol (Fisher). The solution was slightly warmed and stirred. The solution (TDA/PDA) was filtered (Whatman No. 1) to remove residual polymer. Dye colorant could be added to the alcoholic monomer solution as an indicator. Standard organic solvent based dyes were added at 2 drops per ml.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1OC

Procedure:
3,4-Dimethoxybenzaldehyde (5 g), malonic acid (4.7 g), piperidine (0.5 ml) and pyridine (15 ml) were refluxed for six hours. The reaction mixture was poured into ice-cold water and acidified with 6M hydrochloric acid. The resultant solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.OC1C=C(C=CC=1[C:32]([O:34][CH3:35])=[O:33])N.ClC1N=C(Cl)C(F)=CN=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:32]([O:34][CH3:35])=[O:33])=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: COC(=O)c1ccc(N)cc1O
Agent: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(O)c3)n2)cc1O
Yield: 41 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis-[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (105 mg, 41%). 1H NMR (DMSO-d6): δ 3.90 (s, 3H), 3.93 (s, 3H), 7.31 (dd, J=2.4, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.7 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 8.28 (d, J=3.6 Hz, 1H), 9.72 (s, 1H, NH), 9.82 (s, 1H, NH), 10.77 (s, 1H, OH), 10.80 (s, 1H, OH); 19F NMR (282 MHz, DMSO-d6): δ −161.74; LCMS: ret. time: 31.47 min.; purity: 96.03%; MS (m/e): 428.99 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester is prepared by adding (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (3.00 g, 5.63 mmol) to a mixture of Red-Al (5 ml of a 65% wt solution in toluene) in THF (50 ml) at 0° C. under N2. After stirring for 3 h at 0° C., the reaction mixture is quenched by the addition of 10 ml of 10% K2CO3 solution followed by water. The reaction mixture is extracted with ethyl acetate. The organic extracts are dried (Na2SO4), concentrated, and purified by column chromatography (EtOAc:Hex 1:1) to provide 2.01 g (67%) clean desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([OH:17])[C:11]([NH2:16])([CH2:14]O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:14]1[O:7][C@H:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[N:16]2[C:11]1([CH2:12][OH:13])[CH2:10][O:17][C@H:6]2[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(CO)(CO)CO
Solvent: Cc1ccccc1
Product: OCC12CO[C@H](c3ccc(F)cc3)N1[C@H](c1ccc(F)cc1)OC2
Temperature: 25 °C

Procedure:
As an example, para-fluorinated compounds were prepared. More specifically, a suspension of 4-fluorobenzaldehyde (27 g, 0.22 mol) and tris(hydroxymethyl)aminomethane (13 g, 0.11 mol) in toluene (350 ml) was heated at reflux temperature with azeotropic removal of water for 12 hours. The reaction mixture was concentrated, stirred at room temperature, and the precipitated, unreacted 4-fluorobenzaldehyde was filtered off. The residue obtained after removal of solvent was subjected to flash chromatography on silica gel using hexane:ethylacetate (4:1 and 1:1). Crystallization of the respective fractions afforded pure compounds TH-237A, TH-236B, and TH-OPEN in yields 66%, 5%, and 21% respectively based on an equimolar product distribution ratio. The structures of the products were assigned by spectral data and the relative stereochemistry of TH-237A was assigned from single crystal X-ray diffraction data. The ellipsoid drawing of the molecular structure TH-237A from X-ray diffraction study is shown in FIG. 1.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:35]2[N:34]3[CH2:38][CH2:39][C:40](=O)[C:33]3=[CH:32][C:31]=2[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:35]2[N:34]3[CH2:38][CH2:39]/[C:40](=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])/[C:33]3=[CH:32][C:31]=2[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CCn2c1cc1cc(OCc3ccccc3)ccc12
Reaction time: 2 h

Procedure:
To a 5000 mL 3-neck round bottom flask at room temperature under N2 equipped with a mechanical stirrer, an addition funnel, and a temperature probe containing a solution of ethyl 2-(diethoxyphosphoryl)acetate (114 mL, 577 mmol) in THF (2.0 L) was added potassium t-butoxide (1.0 M in THF, 554 mL, 554 mmol) via addition funnel over 10 minutes (temp increase from 22° C. to 29° C.). The reaction mixture was stirred for 2 h and 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (123 g, 444 mmol) was added in 4 portions. An additional amount of THF (750 mL) was added to further dissolve ketone. The mixture was stirred at room temperature for 16 h. Anaylasis of an aliquat from the reaction mixture using LC/MS revealed approximately 75-85% conversion to the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8](/[C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH:8](/[C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC/C=C\c1nc2ccccc2c(OC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCCC/C=C\C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 85.3 %

Procedure:
205 mg (1.49 mmols) of potassium carbonate and 2 ml of water were added to a solution of 483 mg (1.49 mmols) of 2-(cis-1-nonenyl)-3-methyl-4-acetoxyquinoline, 1 ml of water and 30 ml of methanol and stirred at room temperature for 13 hours. Thereafter, the solution was treated and purified in the same manner as in Example 2 to obtain 360 mg (yield 86%) of 2-(cis-1-nonenyl)-3-mehtyl-4-quinolone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([N:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:25]=3)[N:20]=[CH:19]2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:25]=4)[N:20]=[CH:19]3)[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Yield: 91.5 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (0.61 g) was added to a stirred mixture of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (1 g), triethylamine (1 g) and methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution and the organic phase was evaporated. There was thus obtained the title compound (1.28 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 2.22 (s, 3H), 2.46-2.5 (m, 4H), 3.25-3.28 (m, 4H), 7.42-7.47 (m, 2H), 7.62 (s, 1H), 7.76-7.79 (m, 2H), 7.85 (d, 1H), 7.98 (s, 1H), 8.07 (s, 1H), 8.61 (d, 1H), 10.65 (s, 1H); Mass Spectrum: M+H+ 489 & 491.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[C].[Pd].O1CCCC1>[O:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cocn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cocn2)cc1

Procedure:
5% Palladium-carbon powder was added to a suspension of 4-(4-nitrophenyl)-1,3-oxazole in mixture of ethanol and tetrahydrofuran, and the reaction mixture was stirred under 1 atm of hydrogen at ambient temperature for 12 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography, to obtain [4-(1,3-oxazol-4-yl)phenyl]amine (pale yellow solid). Electron Impact-MS (M)+:160.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([OH:20])[CH:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[N:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16]1)[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[C:18]([Cl:19])[C:2]([N:1]=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:3][C:4]=1[OH:20])[CH2:10]2
Reactant: COC(OC)N(C)C
Reactant: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Product: CN(C)C=Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl

Procedure:
Following the procedure of Example 1, the title compound is prepared from 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide and N,N-dimethylformamide dimethylacetal.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: Nc1ccccc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1ccccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of 2-phenoxyaniline (0.93 g, 5.0 mmol) in dichloroethane (50 ml) was added anhydrous acetone (0.73 ml, 10.0 mmol) and acetic acid (0.1 ml, 2.0 mmol). The mixture was stirred for 30 min, and sodium triacetoxyborohydride (3.18 g, 15.0 mmol) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by slow addition of MeOH (10 ml) and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). Organic extracts were combined and washed with brine (2×100 ml) and dried (Na2SO4), concentrated under reduced pressure to give N-isopropyl-2-phenoxyaniline (1.05 g, 91%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[C:12]([F:24])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:25](OCC)(=[O:31])[C:26](OCC)=[O:27]>CCO>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[C:7]3[NH:8][C:25](=[O:31])[C:26](=[O:27])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:11][C:12]=1[F:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1F
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-(2,3-diaminopyridin-4-yloxy)-2-fluorophenylcarbamate (1.03 g, 3.08 mmol) was dissolved in dry EtOH (10 mL), diethyl oxalate (10 mL) was added and the solution was heated to reflux for 96 h, cooled to RT and filtered. The title compound was isolated as a white solid. Yield: 820 mg (92%).
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]([CH3:32])[CH3:31])[CH:26]=3)[N:20]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cccc(C=O)c1
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N(C)C)cc3c(=O)[nH]2)c1
Yield: 48.4 %

Procedure:
According to the preparation of 42, 25 (1.0 g, 5.6 mmol) and 3-methoxybenzaldehyde (34) (0.8 g, 5.6 mmol) were used to afford 55 (0.8 g, 51.2%) as pale yellow needles.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]([CH3:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:8]([CH3:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1CN(Cc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccc(C2=CCN(Cc3ccccc3)CC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (3 g, 9.0 mmol), [3-(ethoxycarbonyl)phenyl]boronic acid (2.26 g, 11.6 mmol), PdCl2(PPh3)2 (315 mg, 0.44 mmol), and potassium carbonate (2.5 g, 18.0 mmol) in Toluene:EtOH (10:1, 50 mL) were heated to 100° C. for 18 hr. The cooled reaction mixture was partitioned between EtOAC and H2O and the aqueous layer was extrated with EtOAc (4×). The organics were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a gradient of hexane:EtOAc to yield ethyl 3-(1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(Cl)cc2)cc1
Yield: 66.2 %

Procedure:
4-Aminobenzoic acid (13.7 g., 0.1 mole) and 4-chlorobenzaldehyde (14.05 g., 0.1 mole) were mixed in dry benzene (200 ml.), 4-toluenesulphonic acid (50 mg.) was added and the mixture was boiled under reflux in an apparatus incorporating a water-trap until the theoretical amount of water (1.8 ml) had been collected. The reaction mixture was cooled in iced water, the product filtered, dried and hydrogenated at NTP in ethanol (500 ml) in the presence of platinum oxide, (Adams catalyst), (100 mg). The catalyst was filtered off and the solution added to iced water. The product was filtered, dried and crystallised from 20% aqueous ethanol to give 4[(4-chlorobenzyl)-amino]-benzoic acid (17.32 g., 78%) which melted at 206°-8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][CH:29]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 44.8 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (153 mg, 0.418 mmol) and 4-(4-(trifluoromethy)phenyl)pyridine-2(1H)-one (100 mg g, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (98 mg, 45%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 4H), 7.57-7.53 (m, 2H), 7.37 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.50 (d, J=6.7 Hz, 1H), 4.67 (s, 2H), 3.86 (br s, 2H), 3.60 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1([CH2:18][OH:19])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.Br[CH2:21][C:22]#[N:23].CC(C)([O-])C.[Li+]>C1COCC1>[NH2:1][C:2]1([CH2:18][O:19][CH2:21][C:22]#[N:23])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2
Reactant: N#CCBr
Reactant: NC1(CO)c2cc(I)ccc2Oc2ncc(Br)cc21
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(I)ccc2Oc2ncc(Br)cc21
Yield: 51.2 %

Procedure:
A solution of (5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methanol (10.00 g, 23.09 mmol) and bromoacetonitrile (12.06 mL, 173 mmol) in 25 mL THF was heated to 40° C. Lithium tert-butoxide [1N in THF (173 mL, 173 mmol)] was added drop wise via addition funnel over 5 hours. After completed addition, the reaction mixture was concentrated. The residue was purified by column chromatography [0-80% (95:5 EtOAc/MeOH)/heptane] to yield 2-((5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetonitrile (5.58 g, 11.82 mmol, 51.2% yield).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:12]1([C:10]2[S:11][C:7]3[C:8]([N:9]=2)=[C:18]2[C:4](=[CH:5][CH:6]=3)[NH:21][C:20](=[O:22])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2sc(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3sc(-c4ccccc4)nc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-nitro-2-phenyl-benzothiazole-4-yl)-acetonitrile (204.2 mg 0.692 mmol) (Starting Material 6) was suspended in concentrated H2SO4/H2O (1/1, 3 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (5 mL) heated at reflux was added excess zinc dust (0.45 g, 6.92 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[4,5-e]indol-7-one. (Yield 20 mg, 11%)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:36])[CH2:30][C:31]1([CH2:34][OH:35])[CH2:33][CH2:32]1>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:25][N:36]=[C:29]([CH2:30][C:31]4([CH2:34][OH:35])[CH2:33][CH2:32]4)[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(CC1(CO)CC1)=NO
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CC3(CO)CC3)no2)C1

Procedure:
100 mg (0.27 mmol) of the compound from Example 101A and 67 mg (0.40 mmol) of the compound from Example 67A were reacted according to the General Method 2. Yield: 33 mg (26% of theory)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9](=[O:23])[C@@H:10]([CH3:22])[NH:11]C(OCC1C=CC=CC=1)=O.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CO.[Pd]>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9](=[O:23])[C@@H:10]([CH3:22])[NH2:11]
Reactant: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)N

Procedure:
N-Benzyloxycarbonyl-D-alanine-trans-2-methylcyclohexyl ester (14.7 g, 47.5 mmol) and p-toluenesulfonic acid monohydrate (9.04 g, 47.5 mmol) were dissolved in 135 mL MeOH. The methanolic solution was hydrogenated over 2.51 g of 10% Pd/C at 40 psi in a Parr apparatus for 1 hour. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated under reduced pressure. The salt was precipitated by addition of ether. Yield: 13.8 g in 2 crops (81%) mp 145°-147°. Tlc on silica gel (CHCl3 :MeOH:HOAc=45:5:1) indicated a single ninhydrin positive spot. 250 MHz nmr (CD3OD, ppm) 0.92 (d, 3H, J=6.25 Hz, trans-2-methyl), 1.09-1.99 (m, 7H, aliphatic cyclohexyl protons), 1.53 (2d, 3H, β--CH3 of Ala), 2.37 (s, 3H, CH3 --Ar--SO3H), 4.09 (2q, 1H, J=7.35 Hz, 2.57 Hz; α--H of Ala), 4.51 (m, 1H, α--H of alcohol); 7.22, 7.69 (ABq, 4H, J=8.46 Hz, CH3 --ArH4 --SO3H).