Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC([O-])(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:27]=[CH:28][N:29]([CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)[CH:30]=3)[S:25][C:18]=12.Cl.NC1C=CC(O)=C(F)C=1.C1([O-])C=CC=CC=1>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH2:31][CH2:32][N:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)[CH:30]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Cl)c4s3)c2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)c2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenol x HCl (1.64 g, 10.05 mmol) in NMP (30 mL) was added t-BuOK (2.25 g, 20.1 mmol). After 30 min, compound 305 (3.75 g, 8.37 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. A solution of 4-amino-2-fluorophenol HCl (1.64 g, 10.05 mmol) in NMP (30 mL) in a separate flask was treated with t-BuOK (2.25 g, 20.1 mmol) and the resultant phenolate solution was added to the reaction mixture at 100° C. After 30 min, the reaction was quenched by addition of water and the precipitate was collected by filtration, dried and triturated with MTBE to afford the title compound 306 (2.10 g, 3.90 mmol, 47% yield) as a beige solid. MS (m/z): 539.39 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]1C=C(C)N=[CH:19][N:18]=1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:33]>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]1[N:18]=[CH:19][CH:5]=[C:10]([CH3:11])[N:9]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:33]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)c1cc(C)ncn1
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN(C)c1nccc(C)n1
Yield: 183.1 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (365 mg, 0.8 mmol) in methanolic ammonia (30 ml of a 3M solution) was stirred at ambient temperature for 16 hours. The volatiles were removed by evaporation, the residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidinyl)amino)ethoxy)-3,4-dihydroquinazolin-4-one (250 mg, 92%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](Cl)=[O:13]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:19])[C:3]=2[CH:2]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COc1ccccc1
Product: COc1ccc2c(c1)C(=O)c1ccccc1C2=O
Yield: 79.8 %

Procedure:
The method was similar to that in Example 1, using 10.8 g (0.1 mols) of anisole and 20.2 g (0.1 mols) of phthalic acid dichloride. The product was 19.0 g (60% yield) of 2-methoxy-9,10-anthraquinone (13), m.p. 195°-197° C.
Reaction SMILES: Cl.[CH:2]1([NH2:15])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23]([NH:15][CH:2]2[C:14]3[NH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]=3[CH2:5][CH2:4][CH2:3]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccccc21
Agent: Cl
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccccc21

Procedure:
N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea was prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride and phenyl isocyanate in a similar manner as described above to give a white solid (60% yield). 1H-NMR (DMSO-d6): δ 10.72 (s, 1H), 8.28 (s, 1H), 7.43-7.33 (m, 3H), 7.29-7.17 (m, 3H), 7.00 (m, 1H), 6.94-6.83 (m, 2H), 6.52 (d, 1H), 4.95 (m, 1H), 2.62 (m, 2H), 1.99 (m, 1H), 1.88-1.70 (m, 3H); MS m/z 304 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][N:22]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:30])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[CH:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ncnn2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a solution of ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (160 mg, 0.35 mmol) in methanol (2 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25° C. for 10 hr. The mixture was filtered to obtain the title compound as a white solid (45 mg, yield 30%). LC-MS (ESI) m/z: 420 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H), 4.91-4.99 (m, 2H), 6.91-6.95 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.05-7.08 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.20-7.23 (d, J=8.0 Hz, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.79 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14].[CH:32]([O-:35])([CH3:34])[CH3:33].[Na+]>O>[CH:32]([O:35][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:35][CH:32]([CH3:34])[CH3:33])[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14])([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ccc(S(C)(=O)=O)c(OC(C)C)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2F)CC1

Procedure:
0.27 mmol of 2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 4.15) was added to a solution of sodium isopropanolate (prepared by dissolving 3 mmol of sodium in 2 ml of isopropanol). The reaction mixture was heated under reflux for 5 hours, cooled, diluted with water and extracted with ethyl acetate, yielding the title compound as a slightly yellow solid. MS (m/e): 557.3 (MH+, 66%)
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([NH:22][C:23](=[O:32])[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.O>CN(C=O)C>[F:20][CH:19]([F:21])[S:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]3[CH2:4][O:32][C:23]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[N:22]3)=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(SC(F)F)cc3)cc2)CO1
Reaction time: 3 h
Yield: 72 %

Procedure:
A portion of 0.093 g (1.16 mmol) of sodium hydroxide solution (50%) was added dropwise to 0.53 g (1.16 mmol) of N-[2-chloro-1-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]ethyl]-2,6-difluorobenzamide in 3.5 mL of DMF. After 3 h, a further portion, 0.045 g (0.56 mmol) of sodium hydroxide solution (50%) was added. When the reaction was completed by TLC, the mixture was poured into water (50 mL). The aqueous mixture was extracted with 3×50 mL of ethyl acetate. The combined extracts were dried and the solvent was removed under reduced pressure. The residue was dissolved in 100 mL of ether. The ethereal solution was washed with 50 mL of water, dried, and the solvent was removed under reduced pressure gave the product, 0.35 g (72% yield), as a pale yellow solid, indistinguishable from the product of Example 6.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][CH:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[CH:16]1([O:19][C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]3([C:30](O)=[O:31])[CH2:29][CH2:28]3)=[O:25])=[CH:22][CH:21]=2)[CH2:18][CH2:17]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:16]1([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]3([C:30](=[O:31])[NH:11][CH:10]4[CH2:9][CH2:8][C:7]5[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=5[N:5]5[CH:1]=[CH:2][N:3]=[C:4]45)[CH2:29][CH2:28]3)=[O:25])=[CH:33][CH:34]=2)[CH2:18][CH2:17]1
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(OC2CC2)cc1
Reactant: NC1CCc2ccccc2-n2ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CC1)c1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a mixture of 5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (400 mg, 2.01 mmol), 1-(4-cyclopropoxybenzamido)cyclopropanecarboxylic acid (577 mg, 2.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (462 mg, 2.41 mmol) and 1-hydroxybenzotriazole hydrate (369 mg, 2.41 mmol) in dichloromethane (8 mL), add triethylamine (1.26 mL, 9.03 mmol) and stir the mixture at ambient temperature for approximately 16 hours. Purify the crude mixture by flash chromatography (0% to 5% MeOH/dichloromethane) to give the title compound (791 mg, 89%) as a tan foam: MS (m/z): 443 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of ethyl (2E)-3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)acrylate (0.86 g, 0.0025 mol) in ethyl acetate (10 mL, 0.1 mol) was added palladium (600 mg, 0.006 mol). The mixture was stirred at rt under an atmosphere of hydrogen for 2 h. The reaction solution was filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (40% ethyl acetate/hexane) to give the desired product as a white solid (609 mg, 70%). LCMS for C14H14ClFN3O4(M+H)+: m/z=342.1.
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])=[O:4]>O1CCOCC1>[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[O:12])=[O:4]
Reactant: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCN(C(=O)OC(C)(C)C)C3)c(NC(N)=O)s2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCNC3)c(NC(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
hydrochloride. To a stirred solution of tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azepane-1-carboxylate (0.9 g, 1.8 mmol) in 1,4-dioxane (10 mL) was added 4.0N HCl in 1,4-dioxane (10 mL, 40 mmol). A precipitate forms shortly and the reaction is stirred for an additional 4 h at room temperature. Due to the hygroscopic nature of the salt form, the solvent was removed under vacuum. The residue was dissolved in methanol and concentrated under vacuum (2×) to yield and off-white solid. Recrystallization from using 2-propanol gave 0.45 g (59%) of a white solid. 1H NMR (d6-DMSO, δ 10.9, s, 1H; δ 9.58, br s, 1H; δ 9.29, br s, 1H; δ 8.39, d, 1H; δ 7.82, s, 1H; δ 7.48, d, 2H; δ 6.96, d, 2H; δ 4.36, m, 1H; δ 3.77, s, 3H; δ 3.29, m, 1H; δ 3.20, m, 2H; δ 3.07, m, 1H; δ 1.98, m, 1H; δ 1.84, m, 4H; δ 1.59, m, 1H), LC/MS (APCI, ES, M+H=389).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:19](=O)[CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)[CH2:6][CH2:5][N:4]([CH2:19][CH2:20][CH3:21])[CH2:3]1
Reactant: CCC=O
Reactant: CC1(c2nc3c(C(N)=O)cccc3[nH]2)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC(C)(c2nc3c(C(N)=O)cccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A solution of the free base of Example 10E (70 mg, 0.3 mmol) in methanol (5 mL) was treated with propionaldehyde (25 mg, 0.4 mmol) at room temperature overnight. Sodium triacetoxyborohydride (254 mg, 1.2 mmol) was then added and the solution was stirred at rt for 3 h. After concentration under vacuum, the residue was separated by HPLC (Zorbax C-8, 0.1% TFA/CH3CN/H2O) to give 55 mg of desired product. Yield: 35%. MS (APCI) m/z 287 (M+H)+; 1H NMR (500 MHz, CD3O): δ 0.89 (t, J=7.33 Hz, 2 H), 1.60 (s, 3 H), 1.63-1.77 (m, 2 H), 2.12-2.40 (m, 1 H), 2.59-2.73 (m, 1 H), 3.03-3.40 (m, 5 H), 3.69 (s, 1 H), 3.96-4.50 (m, 1 H), 7.21 (t, 1 H), 7.56 (s, 1 H), 7.76 (s, 1 H); Anal. Calcd for C16H22N4O.2.0 TFA: C, 46.70; H, 4.70; N, 10.89. Found: C, 46.89; H, 4.68; N, 10.98.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=O.[CH3:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19]P(=O)(OCC)OCC)=[CH:17][CH:16]=1.C[O-].[Na+]>CN(C)C=O>[CH3:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[CH:1][C:3]2[S:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CCOP(=O)(Cc1ccc(C)cc1)OCC
Reactant: O=Cc1ccc(-c2ccccc2)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C=Cc2ccc(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
To a stirred solution of 1.52 gram (0.008 mole) of 2-formyl-5-phenylthiophene and 2.0 grams (0.00820 mole) of diethyl 4-methylbenzylphosphonate in 40 mL of N,N-dimethylformamide was added 0.53 gram (0.0098 mole) of sodium methoxide. The reaction mixture was stirred at room temperature for approximately 18 hours and then was quenched with 50 mL of an aqueous solution saturated with ammonium chloride. A precipitate formed and was collected by filtration. The filter cake was washed with water. The washed solid was purified by column chromatography on silica gel, eluting with chloroform:n-hexane (10:90) yielded 1.1 gram of 2-(4-methylphenyl)-1-(5-phenylthien-2-yl)ethene as a solid, m.p. 159°-160° C.
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH:2]1C(O)=O.OS(O)(=O)=O.[N-:23]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[NH2:23][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:14]([CH2:13][CH2:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:1]1
Reactant: O=C(O)C1CCC2c3ccccc3CCC2C1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC1CCC2c3ccccc3CCC2C1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a mixture of 11.7 g (0.05 mole) of 1,2,3,4,4a,9,10,-10a-octahydrophenanthrene-2-carboxylic acid, 80 ml of conc. H2SO4 and 200 ml of CHCl3 is added with stirring at 50°-60° 3.64 g of sodium azide in small portions. After completed addition, heating at 50° is continued for 1 hr longer, the the mixture poured onto ice and then rendered alkaline with caustic. The product is extracted into CHCl3, dried and freed of solvent to give about 9 g of 2-amino-1,2,3,4,4a,-9,10,10a-octahydrophenanthrene, which is subjected to a Birch reduction as per Example 1E and then reacted with hydrogen peroxide in the presence of formic acid as per Example 1F to form the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH:16]=[CH:15]N=C1>>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:15]=[CH:3][CH:2]=[CH:1][CH:6]=3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cocn1
Reactant: c1ccc(-c2ncco2)cc1
Product: c1ccc(-c2cnc(-c3ccccc3)o2)cc1

Procedure:
FIG. 11 shows the molecular structures of the resultant molecule 2-phenyloxazole when the starting heterocycle is 1,3-oxazole, and its 1H NMR spectrum. 2,5-Diphenyloxazole is also produced in the synthesis. The synthesis of 2-phenyloxazole and 2,5-diphenyloxazole is conducted using copper(I) iodide (19.1 mg, 0.1 mmol), oxazole (69 mg, 1.0 mmol), iodobenzene (612 mg, 3.0 mmol), t-BuOLi (160 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 15 mg (7%) of a light tan solid (2,5-diphenyloxazole, Rf=0.30 (1/9 ethyl acetate/hexanes)) and 85 mg (59%) of a colorless oil (2-phenyloxazole, Rf=0.27 (1/9 ethyl acetate/hexanes)) are obtained. 1H NMR spectrum for 2-Phenyloxazole (300 MHz, CDCl3): δ7.23 (s, 1H), 7.42-7.49 (m, 3H), 7.71 (s, 1H), 8.01-8.10 (m, 2H). 1H NMR spectrum for 2,5-Diphenyloxazole (300 MHz, CDCl3): δ 7.31-7.38 (m, 1H), 7.40-7.52 (m, 6H), 7.70-7.75 (m, 2H), 8.08-8.15 (m, 2H). Table III, entry 1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)=[CH:6][CH:7]=1.[N:19]#[C:20][NH2:21].[Na]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN1CCCC1=O.S(=O)(=O)(O)O>[C:20]([NH:21][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)=[CH:6][CH:7]=1)#[N:19]
Reactant: N#CN
Reactant: CCOc1cc(-c2ccc(Cl)nn2)ccc1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CCOc1cc(-c2ccc(NC#N)nn2)ccc1OC

Procedure:
2.7 g 3-chloro-6-(3-ethoxy-4-methoxyphenyl)pyridazine, 1.3 g sodium cyanamide and 0.5 g benzyltriethylammonium chloride are heated at 150° C. in 30 ml N-methylpyrrolidone for 3 hours. After cooling the reaction solution is diluted with 200 ml 1N sulphuric acid and extracted 3 times with 50 ml chloroform each time. The combined extracts are dried over sodium sulphate and evaporated and the residue is boiled up in isopropanol. The crystalline product is filtered off with suction, washed with isopropanol and dried in vacuo. This gives 2.6 g (96.3%) of the title compound of m.p. 206° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 4 h

Procedure:
A suspension of 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (56.34 g, 185 mmol, see Takagishi, S. et al., Synlett (1992)) in dioxane (100 mL) was treated with the dropwise addition of 4 N hydrochloric acid solution in dioxane (250 mL, 1.0 mol), and the mixture was stirred for 4 h. Analysis by LC/MS indicated that the reaction was not complete, so additional 4 N hydrochloric acid solution in dioxane (250 mL, 1.0 mol) was added, and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction still contained c. 5% of the starting material, so additional 4 N hydrochloric acid solution in dioxane (100 mL, 0.4 mol) was added, and the mixture was stirred for 4 h. Analysis by LC/MS indicated that the reaction was now complete. The mixture was concentrated in-vacuo, and the residue was stripped 2× from methylene chloride to remove any remaining HCl. The 2-amino-5-(trifluoromethyl)benzoic acid, hydrochloride thus obtained was used immediately in the next step. MS (ES+)=206 (M+H+).
Reaction SMILES: C([C:3]([CH3:13])([CH3:12])[C:4]#[C:5][C:6]([OH:11])([CH3:10])[C:7]([OH:9])=O)C.[C:14]([O:18][C:19]([NH:21][CH2:22][C:23]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:24]=1[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:10][C:6]([OH:11])([C:5]#[C:4][CH:3]([CH3:12])[CH3:13])[C:7]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:23]=1[CH2:22][NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[O:33])=[O:9]
Reactant: CCC(C)(C)C#CC(C)(O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)C#CC(C)(O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of ethyl 2-hydroxy-2,5-dimethyl-3-hexynoic acid from the previous step (0.033 g, 0.21 mmol), L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.080 g, 0.22 mmol) and HOBT hydrate (0.088 g, 0.24 mmol) in DMF (3 mL) was added EDC (0.032 g, 0.24 mmol). Diisopropylethylamine was then added in portions (˜0.15 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oil residue was purified by preparative reverse-phase HPLC using a Waters PrepPak column and a gradient of 5-95% CH3CN:H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and lyophilized to give 1-(2,5-dimethyl-2-hydroxy-3-hexynoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a white solid. (72 mg, 68%; HPLC RT=2.61 min, method B; LC-MS M+H=506). 1H NMR, 400 MHz, DMSO-d6, 8.22 ppm (d, J=15.9 Hz, 2H); 7.17-7.32 ppm (m, 2H); 4.25-4.30 ppm (m, 2H), 4.06 ppm (s, 2H); 3.69-3.73 ppm (m, 1H); 2.51-2.56 ppm (m, 1H); 2.07-2.09 ppm (m, 2H); 1.91-1.94 ppm (m, 2H); 1.68-1.78 ppm (m, 2H); 1.45 ppm, (d, J=7.69 Hz, 3H); 1.35 ppm (s, 9H); 1.04-1.08 ppm, (m, 6H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(Cl)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (4.6 mg, 25%). MS (m/e): 441.4 (MH+).