Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:13][N:14]=1>C1COCC1.CO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[O:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:21])=[O:4])=[N:14][N:13]=1
Reactant: COC(=O)CCCCc1nnc(-c2ccccn2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCc1nnc(-c2ccccn2)o1
Yield: 26.7 %

Procedure:
Add 2 N sodium hydroxide (20 mL) to a solution of 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid methyl ester (8.16 g, 31 mmol) in THF (60 mL) and methanol (20 mL) at room temperature under nitrogen and heat the mixture at reflux for 12 hours. Remove the solvent under reduced pressure, dilute the residue with water (500 mL), and wash with ethyl acetate (200 mL). Adjust the pH of the aqueous layer to pH 3 with concentrated HCl and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate, and remove the solvent under reduced pressure to afford 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid (2.05 g, 27%). APCI mass spectrum m/z 246 [C12H13N3O3+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:24]=2)=[CH:16][CH:15]=1>>[CH3:32][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3ccc4[nH]ccc4c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 5-Indole boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 372.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13]O)[CH3:12]>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][CH2:12][C:11]([CH3:15])([CH3:13])[CH2:10][O:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1ccc(Cl)s1
Product: CC1(C)COB(c2ccc(Cl)s2)OC1
Yield: 54 %

Procedure:
The title compound (54%, crystals) was prepared from 5-chlorothiophen-2-boronic acid and neopentylglycol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:14](C(CC)(CC)C([O-])([O-])[O-])[CH3:15].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A mixture of 2-chloro-5-nitroisonicotinic acid (Intermediate 208) and 16 ml triethylorthoacetate in 100 ml toluene was heated at reflux for 2 h. The mixture as stirred with 1N HCl for 30 min before being partitioned between EtOAc and water. The EtOAc was separated, washed with water and brine, dried (MgSO4) and concentrated. Chromatographed on silica gel (100% hexanes with gradient elution to 100% CH2Cl2 to give product as an oil. MS (ES) (MH+): 231 for C8H7ClN2O4; NMR (d6-DMSO): 1.3 (t, 3H), 4.4 (m, 2H), 8.1 (s, 1H), 9.2 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[NH2:15])[CH2:7][S:8][C@H:3]12.[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41](N2C(=S)N(C)N=N2)=[O:42])[N:39]=1>C1COCC1>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41]([NH:1][CH:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[NH2:15])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1
Reactant: Nc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1

Procedure:
Acylation of diphenylmethyl 7-amino-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (25 mg, 0.054 mmol) with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (19.5 mg, 0.066 mmol) in THF (0.25 mL), according to the procedure described in Example 13, afforded the title compound as a granular yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)[C:7]2=[O:19])[CH3:3].CC(C)=O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:15][N:16]=[N:17][N:18]=1)[C:7]2=[O:19])(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1

Procedure:
To a solution of 2.58 parts of 6-(1-hydroxyethyl)-3-(1H-tetrazol-5-yl)chromone in 700 parts by volume of acetone kept at 9°-15° C there is added dropwise over a period of 30 minutes 4.5 parts by volume of a solution which is prepared from chromium trioxide, 97% sulfuric acid and water in a ratio of 6.0 parts: 3.6 parts by volume: 18 parts by volume. The reaction mixture is concentrated at a temperature lower than 30° C to a one-tenth volume and then admixed with 700 parts by volume of water to give precipitates. The precipitates are recovered by filtration and recrystallized from dimethylformamide. The procedure yields 1.70 parts of 6-acetyl-3-(1H-tetrazol-5-yl)chromone as colorless crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[ClH:31].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:39]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:40])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 32.8 mg (0.21 mmol) of 4-chlorophenyl isocyanate. After 16 h at room temperature, the mixture is concentrated in vacuo. The residue is dissolved in a 1:1 mixture of water and acetonitrile and purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 29 mg (55.2% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Ic1cn[nH]c1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cn[nH]c4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 4-iodo-1H-pyrazole.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[CH:12]1([NH:18][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH2:3]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=C1CC(Br)c2ccccc21
Solvent: c1ccccc1
Product: O=C1CC(NC2CCCCC2)c2ccccc21
Yield: 83.5 %

Procedure:
3-Bromo-2,3-dihydro-1H-inden-1-one (100 mg, 475 μmol) and cyclohexylamine (94 mg, 951 μmol) were dissolved in 2 mL of dry benzene and stirred under N2 until precipitation ceased (˜15 min). The cyclohexylamine•HBr was removed by filtration. The filtrate was applied to a flash SiO2 column that was developed with 8:1 hexanes-EtOAc to give the title compound as a clear oil (91 mg, 84% yield).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1(O)C=CC=CC=1.[C:16](=[O:18])=[O:17]>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: O
Solvent: Oc1ccccc1
Product: O=C(O)c1ccc(O)cc1

Procedure:
In a pressure reaction vessel were charged 100 g of potassium phenolate, 35 g of phenol and 500 g of a mixture of hydrogenated triphenyls, and a reaction was allowed to proceed at 250° C. and at a carbon dioxide pressure of 7 kg/cm2 (G) for 20 minutes, with stirring. The reaction mixture was cooled and charged into 200 ml of water, followed by separation into the reaction medium layer and the water layer at 60° C. The water layer was made acid with dilute sulfuric acid to give 81.6 g of p-hydroxybenzoic acid (having a purity of 99%). The yield based on potassium phenolate was 77.3%, and the recovered potassium phenolate was 21.0 g, with the selectivity being 99.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 600 mg, 1.35 mmol) and (1S*,2R*)-2-phenylcyclohexanol (240 mg, 1.36 mmol) in DMSO (6.0 mL), sodium hydride (63%; 100 mg, 2.63 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (200 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (270 mg, 33%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[CH:24][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(=O)c1ccc(Br)cc1
Product: CC(=O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1

Procedure:
2-[(4-acetylphenyl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.2 g, 0.640 mmol) and 1-(4-bromophenyl)ethanone (0.127 g, 0.640 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br.Br>[Fe]>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([C:8]([F:9])([F:10])[F:11])=[CH:3][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Fe]
Agent: Br
Product: Nc1cc(C(F)(F)F)ccc1Br
Reaction time: 2 h

Procedure:
to 161.0 g of m-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35°-40°, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional 2 hours and then distilled in vacuo to give 4-bromo-3-aminobenzotrifluoride.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: CC[C@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of (S)-2-hydroxybutanoic acid (105 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one (300 mg, 95%). LC/MS: m/z 407.5 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.92 (d, J=7.0 Hz, 1H), 4.28 (q, J=6.5 Hz, 1H), 3.89 (m, 8H), 2.52 (s, 3H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.CC(C)(C)[C:27](OC(=O)C(C)(C)C)=[O:28]>C(Cl)(Cl)Cl>[CH:27]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([OH:15])[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)=[O:28]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Reactant: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C=O)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of 6,7-dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (2.26 g, 6.86 mmole) in chloroform (60 ml) was added formic trimethylacetic anhydride (1.16 g, 8.91 mmole) at 0° C. The mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give intermediate 1 (2.23 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:42]=[CH:43][CH:44]=1)[CH2:23][O:24][C:25]1[CH:26]=[C:27]([NH2:41])[CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)[CH:30]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[NH:41][C:27]2[CH:28]=[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)[CH:30]=[C:25]([O:24][CH2:23][C:22]3[CH:42]=[CH:43][CH:44]=[C:20]([C:18]#[N:19])[CH:21]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#Cc1cccc(COc2cc(N)cc(OCc3cccc(C#N)c3)c2)c1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3cccc(C#N)c3)cc(OCc3cccc(C#N)c3)c2)CC1
Yield: 62.5 %

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.41 g (1.68 mmol) and [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-amine (0.6 g, 1.68 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 79.8%, (M−1)=580.0-1.
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]3[CH:38]=[N:39][C:40]([C:41]([NH2:43])=O)=[C:30]3[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:41]([C:40]1[N:39]=[CH:38][N:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[N:29][C:30]=12)#[N:43]
Reactant: NC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ncn2c1nc(N1CCOCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bromine (0.15 ml) was added dropwise to a solution of triphenylphosphine (0.8 g) in 15 ml of methylene chloride at 5° C. 5-morpholino-imidazo[1,5-a]quinazoline-3carboxamide (0.5 g) and triethylamine (0.83 ml) were added to the solution. The resulting reaction mixture was stirred at room temperature for 3 hours and evaporated in vacuo. Ethyl acetate (10 ml) was added to the residue and crude crystals of the title compound were isolated by filtration. The dried crystals were dissolved in acetone (30 ml) and an excess of hydrogen chloride in diethyl ether was added separating the hydrochloride of the title compound as beige crystals. M.p. 225°-228° C. Yield 0.3 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][C:28](=[O:31])[CH2:29][CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:28](=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)CBr
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Product: CCC(=O)COc1ccc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)cc1F

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and 1-bromobutan-2-one, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C:9]1([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C1Cc2ccccc2N1N1CCCCC1
Product: O=C1N(N2CCCCC2)c2ccccc2C1(Cc1ccccc1)Cc1ccccc1

Procedure:
By substituting 1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one and benzyl chloride in Example 8, the desired product was obtained; m.p. 94°-96° C. (hexane). Anal. (C27H28N2O): C,H,N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]#[N:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1.C([Sn](=O)CCCC)CCC.[N:44]([Si](C)(C)C)=[N+:45]=[N-:46]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:46][N:45]=[N:44][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CC#N)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC

Procedure:
To 1 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybenzenesulfonamide dissolved in 20 ml of THF are successively added 0.3 g of dibutyltin oxide and 2.6 ml of azidotrimethylsilane, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, to give 0.95 g of the expected product.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[P:6]12([S:18]P3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:7].S>>[CH3:1][CH:2]([CH3:5])[CH2:3][O:4][P:6]([SH:18])(=[S:7])[O:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)CO
Agent: S
Product: CC(C)COP(=S)(S)OCC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a four-necked flask equipped with a stirrer, condenser, dropping funnel and thermometer were added 608 g (8.2 moles) of 2-methyl-1-propanol and the contents were heated to 60° C. At that temperature, 444.5 g (2.0 mole) of phosphorus pentasulfide was added portion-wise over a 3-hour period with agitation. After all of the sulfide reactant was introduced, the temperature was raised to 65° C. and held for 3 hours. The evolution of hydrogen sulfide gas was trapped by a caustic scrubber which indicates a substantially complete reaction. The reaction was then allowed to cool to ambient temperature under a nitrogen blanket and the solution was filtered through diatomaceous earth to produce a greenish fluid (927 g) as the desired phosphorodithioic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:6][CH:7]=3)[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2coc(-c3ccccc3)n2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-phenyl-oxazole (100 mg, 0.5 mmol, example 19) in DMF (2 mL) is added methyl 2-methyl-6-[(3-hydroxy-phenoxy)-methyl]-benzoate (136 mg, 0.5 mmol, example 5) followed by K2CO3 (75 mg, 0.54 mmol). The resulting mixture is heated to 60° C. and stirred at this temperature for 8 h. This mixture is then cooled to room temperature, diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ESI) 429 (M+H)+.