Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:5]2[N:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]([N:15]3[CH2:16][CH2:17][N+:18]([CH3:21])([O-:31])[CH2:19][CH2:20]3)[N:5]2[N:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2n(n1)C(N1CCN(C)CC1)=Nc1ccccc1C2
Solvent: ClCCl
Product: Cc1nc2n(n1)C(N1CC[N+](C)([O-])CC1)=Nc1ccccc1C2

Procedure:
To a solution of 5 g of 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine in 50 ml of methylene chloride is added in portions 3.75 g of m-chloroperbenzoic acid with stirring at 0°. The mixture is then stirred at room temperature overnight and evaporated to dryness. The foamy residue is passed through 100 g of Amberlite IRA-400 ion exchange resin using water as eluent. Evaporation of the eluent gives 2-methyl-5-(4-methyl-4-oxido-1-piperazinyl)-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([OH:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][O:26][C:25]([CH3:30])([CH3:29])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][C:25]1([CH3:30])[CH2:24][CH:23]([CH2:22][O:20][C:19]2[C:10]([C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[F:1])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:28][CH2:27][O:26]1
Reactant: CC1(C)CC(CBr)CCO1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2CCOC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-hydroxynicotinate (739 mg) and 4-(bromomethyl)-2,2-dimethyltetrahydro-2H-pyran (828 mg) in DMF (20 mL) was added potassium carbonate (736 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (950 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:48]([Si:52]([CH3:55])([CH3:54])Cl)([CH3:51])([CH3:50])[CH3:49].Cl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([O:42][Si:52]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:55])[CH3:54])[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate in N,N-dimethylformamide were added imidazole and tert-butyldimethylchlorosilane at room temperature. After stirring at room temperature for 15 minutes and at 35° C. for 3.5 hours. The reaction mixture was poured into 0.05N hydrochloric acid at room temperature. The products were extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (11.22 g).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:30]3[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=3[N:22]=C2)[C@H:17]([OH:31])[C@@H:16]1[OH:32])([O:4]P(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].N1C=C2C(N=CN2)=NC=1>>[NH2:28][C:27]1[N:29]=[C:30]([NH:20][CH:18]2[O:19][C@H:15]([CH2:14][O:13][P:1]([OH:4])([OH:3])=[O:2])[C@@H:16]([OH:32])[C@H:17]2[OH:31])[C:23]([NH2:22])=[C:24]([OH:25])[N:26]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: c1ncc2[nH]cnc2n1
Product: Nc1nc(O)c(N)c(NC2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1

Procedure:
As noted above, in bacteria and fungi, GTP cyclohydrolase II (EC 3.5.4.25) catalyzes the reaction of GTP with a purine to produce 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine; diaminohydroxyphosphoribosylaminopyrimidine deaminase (EC 3.5.4.26) catalyzes the reaction of 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine to produce 5-amino-6-(5-phosphoribosylamino)uracil; 5-amino-6-(5-phosphoribosylamino)uracil reductase (EC 1.1.1.193) catalyzes the reaction of 5-amino-6-(5-phosphoribosylamino)uracil to produce 5-Amino-6-(5′phosphoribitylamino)uracil; lumazine synthase catalyzes the reaction of 5-Amino-6-(5′phosphoribitylamino)uracil to produce 6,7-Dimethyl-8-ribityl lumazine; and riboflavin synthase (EC 2.5.1.9) catalyzes the reaction of 6,7-Dimethyl-8-ribityl lumazine to produce riboflavin
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1.[C:35](=O)([O-])[O-].[K+].[K+]>C1COCC1.[NH4+].[Cl-].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]>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:5]3=[N:6][CH:7]=[C:2]([CH3:35])[N:3]=[C:4]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cnc2sc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)cc2n1
Yield: 13 %

Procedure:
A solution of 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (40 mg, 0.082 mmol), potassium carbonate (22.56 mg, 0.163 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (5.91 mg, 8.16 μmol) in THF was heated to 60° C. for 6 h. The reaction mixture was poured in NH4Cl solution and extracted twice with EtOAc. Organic layer was washed with water, brine, dried and evaporated. Crude product triturated twice with CH2Cl2 to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-methylthieno[2,3-b]pyrazine-6-carboxamide 251 (5 mg, 13%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.26 (s, 3H), 2.68 (s, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.75 (m, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.96 (d, J=7.4 Hz, 1H), 8.06 (s, 1H), 8.47 (s, 1H), 8.67 (s, 1H), 10.40 (s, 1H), 10.54 (br s, 1H). (m/z)=470 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[C:38]([CH:3]=[O:4])[C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(C)n(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(-n2nc(C)c(C=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 1 h

Procedure:
At room temperature, a mixture of N,N-dimethylformamide 20 ml and phosphorus oxychloride 0.85 ml was stirred for one hour. To the above-mentioned mixture was added 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 3) 2.0 g and was stirred at 100° C. for three hours. At room temperature, to the resulting mixture was added water 10 ml. The mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-4-formyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 51”) 1.7 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11]
Reactant: COC(=O)[C@H](CCSC)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 84.9 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 55 (3.7 g), 1 mol/L of an aqueous sodium hydroxide solution (18 mL), and methanol (180 mL), to give the captioned compound (3.0 g, 85%) as crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8].C(N(CC)CC)C>C(Cl)Cl>[OH:8][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][NH:5][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(O)c1ccccc1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A solution of acetyl chloride (10 ml, 0.146 moles) in 200 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 2-amino-1-phenylethanol (20.0 g, 0.146 moles) and triethylamine (20 ml, 0.146 moles) in 300 ml of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 3 hours and overnight at room temperature. The reaction was extracted with 1N HCl. The organic layer was separated and the aqueous layer was extracted with methylene chloride and then 10% methanol-methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a solid material. Recrystallization of this solid from isopropyl alcohol gave N-(2-hydroxy-2-phenyl-ethyl)-acetamide (9.0 g, 34%) as a white solid, mp 120-122° C.
Reaction SMILES: N[C:2]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=3)[N:16]([CH3:18])[CH:17]=2)=[CH:9][CH:8]=1)(C)[CH3:5])=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:54])C.O>>[NH2:54][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=3)[N:16]([CH3:18])[CH:17]=2)=[CH:9][CH:8]=1)([CH3:5])[CH3:2]
Reactant: CC#N
Reactant: COC(=O)CCc1ccc(-c2nc(-c3ccc(C(C)(C)C(N)=O)cc3)cn2C)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: COC(=O)CCc1ccc(-c2nc(-c3ccc(C(C)(C)N)cc3)cn2C)cc1

Procedure:
Prepared from 4-[4-(2-aminocarbonyl-2-propyl)-phenyl]-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-1-methyl-imidazole by treating with [bis(trifluoroacetoxy)iodo]benzene in acetonitrile/water at ambient temperature.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([OH:25])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[C:23]([NH2:3])=[O:25]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(O)ccc2ccccc12
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 345.7 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 1 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Hydroxy-1-naphthoic acid (0.37 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 13 h 20 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (85% ethyl acetate-hexanes) to give the 2-hydroxy-naphthalene-1-carboxylic acid amide derivative (1.1 mg, 100%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[N:17][C:16]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[S:19][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=2)=[C:16]([CH3:28])[N:17]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3Cl)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3Cl)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(2,4-dichloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(2,4-dichloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:6]=[CH:5][C:4]1=2)#[N:2]>P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>[C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:8][C:9]=2[C:10]([CH3:13])([CH3:14])[CH2:11][CH:12]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C#N)O[Si](C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C#N)cc1
Temperature: 115 °C

Procedure:
To 215 mg (0.48 mmol) of ethyl 4-[(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 107) was added 0.5 ml of pyridine and 3 drops of phosphorous oxychloride. The resulting dark mixture was gently refluxed at 115° C. for 30 minutes, cooled to room temperature and poured into crushed ice. The mixture was extracted with Et2O and the combined organic layers were washed with water, dilute HCl and water. The organic phase was concentrated in vacuo to a gummy residue which was purified by flash chromatography (silica, 20% EtOAc-hexane) to yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])=[N:23][C:22]=1[CH3:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:27]2=[O:32])=[N:23][C:22]=1[CH3:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(CCCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 10 %

Procedure:
Following the procedure as described in Example 3, making variations as required to use 3-phenylpropanal in place of cyclopropanecarbaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 10% yield: mp 140-141° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.10 (m, 10H), 5.98 (t, J=4.7 Hz, 1H), 4.55 (d, J=5.3 Hz, 2H), 4.31-4.19 (m, 1H), 4.04-3.91 (m, 1H), 2.69-2.47 (m, 6H), 2.11-1.78 (m, 4H), 1.76-1.53 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.8, 162.7, 157.0, 152.2, 142.0, 137.9, 128.8, 128.4, 128.3, 127.9, 127.6, 125.9, 119.2, 47.9, 44.1, 42.2, 35.9, 31.4, 28.9, 25.5, 21.3, 17.4; MS (ES+) m/z 448.21 (M+1).
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[CH:13]=[CH:12][C:11]([N:14]([C:19]2[C:38]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][C:22]3[C:23]([C:33](=[O:36])[NH:34][CH3:35])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:5]=1[C:6](OC)=[O:7]>C1COCC1.CO>[Br:3][C:4]1[CH:13]=[CH:12][C:11]([N:14]([C:19]2[C:38]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][C:22]3[C:23]([C:33]([NH:34][CH3:35])=[O:36])=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:25][C:21]=3[CH:20]=2)[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:5]=1[CH2:6][OH:7]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 3 h
Yield: 99 %

Procedure:
LiBH4 (1.593 mL, 3.19 mmol) solution (2M in THF) was added dropwise to a solution of methyl 2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (0.76 g, 1.062 mmol) in tetrahydrofuran (6.0 mL) and methanol (0.600 mL) at 0° C. under N2. The mixture was stirred for 3 hours at the same temperature. It was quenched with 1M NaOH and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4. It was concentrated to dryness to give the crude product (>99%) as tan foam which was used for the next step without further purification. LCMS (m/z, ES+)=587 (M+H+).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:27]=[CH:26][N:25]=[C:24]3[C:15]=2[CH:16]=[CH:17][C:18]2[C:23]3=[N:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1.O>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([C:21]2[CH:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18]3[C:23](=[C:24]4[C:15](=[CH:16][CH:17]=3)[C:14]([C:11]3[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=3)=[CH:27][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:25]4)[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5ccccc5)nc4c3n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Under a nitrogen atmosphere, 15 ml of a 1.6 mol/l phenyllithium solution (24 mmole) was added to a stirred suspension of 2.0 g of bathophenanthroline (6 mmole) in a mixture of 60 ml of toluene and 20 ml of THF, and the resulting mixture was cooled to 0° C. The resulting deep-red solution was stirred overnight at room temperature, and 10 ml of water was then added. The organic layer was separated, and the aqueous layer was extracted with 40 ml of dicholormethane three times. The combined extracts were stirred with 30 g of MnO2 for 2 hours. The mixture was dried over 30 g of anhydrous MgSO4, filtered, and evaporated to give 2.6 g of a light yellow solid in a yield of 90 percent. 1H NMR (500 MHz, CDCl3), ppm: 8.50 (d, J=7.5 Hz, 4H), 8.09 (s, 2H), 7.81 (s, 2H), 7.61-7.57 (m, 8H), 7.55 (dd, J=7.5, 7.5 Hz, 4H), 7.52-7.47 (m, 4H). Analysis for PBP. Found: C, 88.62, H, 4.56, N, 5.82. Calculated: C, 89.23, H, 4.99, N, 5.78.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:4]([OH:18])[CH:3]=1.CCO.CC(O)=O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:18])=[C:5]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)[CH:6]=1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2O)c1=O
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cn1nnn(-c2cc(N)c(F)cc2O)c1=O
Reaction time: 2 h
Yield: 99 %

Procedure:
A round-bottom flask was charged with 1-(4-fluoro-2-hydroxy-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (500 mg, 1.96 mmol), EtOH (20 mL), HOAc (250 uL), and 10% Pd/C (50% in water, Degussa type E101; 100 mg, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 2 h using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness, and the product dried in vacuo with a water bath at 45° C. to remove any residual HOAc to provide 1-(5-amino-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (437 mg, 99%) as a brown solid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 9.46 (s, 1H), 6.67-6.72 (m, 2H), 4.80 (bs, 2H), 3.56 (s, 3H); 19F NMR (282 MHz; d6-DMSO) δ −128.6 (t); m/z=225 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH2:59][CH2:60][C:61]([NH2:63])=[O:62])[CH:56]=[CH:57][CH:58]=1.O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH2:59][CH2:60][C:61]([NH2:63])=[O:62])[CH:56]=[CH:57][CH:58]=3)[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: NC(=O)CCc1cccc(N)c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(CCC(N)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (xxx) (2 gm, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0.597 g, 5.57 mmol) and 3-(3-aminophenyl)propanamide (intermediate xxvi) (0.915 gm, 5.57 mmole). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and added water until a solid precipitate was obtained. The solid was filtered, washed with water and small amount of MeOH. The solid was purified by silica gel column chromatography, eluting with DCM:Methanol (9:1), to yield the titled compound (1b) (1.7 g) [m/z=710.20 (M+1)].