Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:9][C:10]([OH:12])=O.[OH-].[Na+].[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.C(Cl)Cl.C(N(CC)CC)C.O>[Si:26]([O:12][CH2:10][CH2:9][C@H:8]([NH2:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: N[C@@H](CC(=O)O)c1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 58627.4 %

Procedure:
Under inert gas, 2.80 g of lithium aluminum hydride were added in portions to a suspension of 0.97 g of (S)-3-amino-3-(2-fluorophenyl)propionic acid in 80 ml of THF, and the reaction mixture was then stirred at a temperature of 50° C. for 3 hours. 3 ml of water, 1 ml of 12 N aqueous sodium hydroxide solution and another 10 ml of water were added and the mixture was stirred for 10 minutes. The precipitate was filtered off, the filtrate was concentrated by rotary evaporation, the residue was dissolved once again in methylene chloride, and the solution was dried over MgSO4 and concentrated by rotary evaporation. For further reaction, a solution of the residue in methylene chloride was admixed with 2.22 ml of triethylamine and 1.20 g of tert-butylchlorodimethylsilane. After stirring at room temperature overnight, the reaction solution was washed with aqueous sodium hydrogencarbonate solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 g) with a molecular weight of 283.5 g/mol (C15H26FNOSi); MS (ESI): m/e=284 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(C)c2cc(-n3cccc3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(-n3cccc3)cc21
Yield: 68.6 %

Procedure:
A mixture of 1.2 g of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, 10 ml of ethanol, 15 ml of 10% sodium hydroxide solution and 10 ml of water is heated under reflux for 2 hours. 30 ml of 8M hydrochloric acid are added, the mixture is left to cool and the product is filtered off, washed with water and recrystallized from acetic acid to give 0.75 g of a solid melting at 284°-285° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N:19]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:38]=4[N:37]=[CH:36][CH:35]=[CH:34]5)(=[O:28])=[O:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:14]3[CH:39]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N:19]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:38]=4[N:37]=[CH:36][CH:35]=[CH:34]5)(=[O:27])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:14]3[CH:39]=2)=[CH:5][CH:4]=1)(=[NH:45])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(c1ccc2nc(CNc3ccc(C#N)cc3)cn2c1)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2nc(CNc3ccc(C(=N)N)cc3)cn2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 2-[N-(4-cyanophenyl)-aminomethyl]-6-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-imidazo[1,2-a]pyridine and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:21])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nccc3c(CO)cccc23)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
1-(4-Methylphenyl)-5-hydroxymethylisoquinoline (7.5 g) was dissolved in 80 ml of chloroform, and 12.5 g of phosphorus pentachloride was added under ice cooling. The mixture was stirred at room temperature for 1 hour, and 100 ml of water was added. The mixture was stirred for 30 minutes, and neutralized with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from methanol to afford 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline as slightly yellow prisms having a melting point of 119.8° to 120.1° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one. MS(ESI): 519 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl[C:34]([O:36]CC)=[O:35].O>C(Cl)Cl>[CH2:11]([O:12][C:34](=[O:35])[OH:36])[CH3:9].[NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Agent: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Amino-9-benzyl-N-(cyclopropylmethyl)-8-oxo-8,9-dihydro-7H-purine-2-carboxamide (Example 1, 50 mg, 0.15 mmol) was taken up in 2 ml DCM under a nitrogen atmosphere at room temperature and firstly triethylamine (62 μl, 0.44 mmol) and then ethyl chloroformate (28 μl, 0.30 mmol) were added in one portion each and the whole stirred at room temperature for 4 h. The mixture was poured into water (5 ml) and extracted with DCM (3×2 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to a yellow residue which was purified by column chromatography using a gradient of 1:1 DCM:EtOAc→EtOAc as the eluant. Combination and evaporation of the appropriate fractions provided the title compound as a white solid (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([C:32]2[O:33][CH:34]=[CH:35][C:36]=2[CH3:37])=[O:31])[CH:26]=[CH:27][CH:28]=1)#[CH:22].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][S:11]([CH3:13])(=[N:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:22]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][C:36]=3[CH3:37])=[O:31])[CH:24]=2)[CH:4]=1)=[O:9])=[O:12])[CH3:19]
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: CCOC(=O)CS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
A solution of ethyl {N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}acetate, (24 mg, 0.06 mmol), 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (20 mg, 1.5 eq), bis(triphenylphosphine)palladium(II) dichloride (4.1 mg, 0.1 eq), and triphenyl phosphine (0.4 mg, 0.025 eq) in anhydrous DMF (0.5 mL) under a nitrogen atmosphere was added triethylamine (0.05 mL, 5 eq) followed by the addition of copper(I) iodide (2.2 mg, 0.2 eq). The reaction mixture was stirred at RT for 15 minutes and then poured into saturated aq NaHCO3 and extracted with EtOAc (1×). The organic extract was washed with brine (1×) and dried over anhydrous Na2SO4. The organic phase was filtered and concentrated. The residue was purified by chromatography (EtOAc-Hexanes 1:4 to EtOAc). The product containing fractions were combined and concentrated to give the title compound (14 mg, 47%).
Reaction SMILES: [O:1]=[C:2]1[NH:24][C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:12][C:13]=3[C:4]=2[N:3]1[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH2:26]1.[H-].[Na+].[CH3:43]I>CN(C)C=O>[CH3:43][N:24]1[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:12][C:13]=3[C:4]=2[N:3]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:29][CH2:30]2)[C:2]1=[O:1]
Reactant: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3cnc4ccc(-c5cnc6ccccc6c5)nc4c32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C(=O)OCc3ccccc3)CC2)c2c3nc(-c4cnc5ccccc5c4)ccc3ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A suspension of compound 48 (6.6 g, 12 mmol) in N,N-dimethylformamide (200 mL) was cooled to 0° C. Sodium hydride (1.0 g, 25 mmol) was added, resulting in bright orange slush. The reaction mixture was stirred for 1 hr at 0° C. before adding methyl iodide (890 mL, 14 mmol). After 3 hours, the reaction was quenched with methanol (100 mL) and the solids were collected by filtration to afford benzyl 4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidine-1-carboxylate (compound 49) (5.0 g, 73%).
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[N:50]1[CH:55]=[CH:54][CH:53]=[N:52][C:51]=1[C:56]1[CH:64]=[CH:63][CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59].C(N(CC)CC)C>>[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:38][C:58](=[O:59])[C:57]1[CH:61]=[CH:62][CH:63]=[CH:64][C:56]=1[C:51]1[N:50]=[CH:55][CH:54]=[CH:53][N:52]=1
Reactant: O=C(O)c1ccccc1-c1ncccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 48 mg, 0.15 mmol), 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 41 mg, 0.20 mmol) and triethylamine (0.077 ml, 0.55 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol)) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(OC)ccc(-c3ccc4c(c3)COC4=O)c2OC)COC1
Temperature: 80 °C
Yield: 17.9 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (107 mg, 0.558 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 18%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([OH:35])[C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:32](=[O:33])[CH:31]([C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[OH:35])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford the title compound: MS m/z 478.3 (M+1); Diastereomers were separated using a S,S-Whelk-O1 column (5 cm×25 cm), eluting with 70:30 heptane:iPrOH at a flow rate of 110 mL/min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C[O-].[Na+].Cl[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.Cl>CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1
Reactant: Cc1cccc(C)c1O
Reactant: ClCc1c[nH]cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(Cc2c[nH]cn2)cc(C)c1O
Yield: 54 %

Procedure:
To a solution of 12.2 g of 2,6-dimethylphenol in methanol are added 20 ml of 30% sodium methoxide solution, and the resultant mixture is warmed to 50° C. The mixture is maintained at that temperature while 5.8 g of 4-chloromethylimidazole in methanol are added, with stirring. After the addition is complete, the reaction mixture is stirred at 50°-60° C. for about 4 hours, then is cooled and poured into cold water. That mixture is acidified with hydrochloric acid and washed with ethyl acetate. The pH of the aqueous solution is then adjusted to 7-8, and the product is obtained by extraction with ethyl acetate. The desired 4-(3',5'-dimethyl-4'-hydroxybenzyl)imidazole is obtained in 54% yield. The free base is converted to the corresponding hydrochloride salt by treatment with HCl in a mixture of ethyl acetate and isopropanol. That salt melts at 210°-214° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17]1[NH:22][C:21](=[O:23])[C:20]([C:24]#[N:25])=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[CH2:1]([O:23][C:21]1[C:20]([C:24]#[N:25])=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[Cl:9])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: BrCc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1

Procedure:
In the following Examples 20-24, the procedure described in Example 19, Step C was repeated but substituting the appropriately substituted benzyl halide for benzyl bromide in the reaction with 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile to afford the following compounds:
Reaction SMILES: C([Li])CCC.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:6]3[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(O)c1cc[nH]c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (7.0 mL, 2.0 M, 14 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (0.67 g, 6.0 mmol) in THF (35 mL) at −78° C. Stirring for 45 min at −78° C. and 30 min at 0° C., 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.86 g, 5.0 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (200 mL), washed with 2N HCl (2×20 mL), NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using CH2Cl2/MeOH (20:1) on silica gel to 0.40 g (18%) of a white solid as the title compound. MS (ESI) (M+H)+=445.98.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([C:20]2([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([C:20]3([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1(c2nnc3ccc(F)cn23)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 78.6 %

Procedure:
Hexachloroethane (503 mg, 2.12 mmol) was added portionwise over 5 minutes at RT to a stirred mixture of Intermediate 99b (282 mg, 1.06 mmol), triethylamine (590 μL, 4.24 mmol) and triphenylphosphine (555 mg, 2.12 mmol) in THF (11 mL). The reaction mixture was stirred at 50° C. for 2.5 h and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH to give the title compound (207 mg, 79%). 1H NMR (400 MHz, CDCl3): 1.67-1.78 (4H, m), 2.10-2.22 (8H, m), 2.24-2.34 (2H, m), 7.15 (1H, ddd, J=10.0, 7.4, 2.3 Hz), 7.69 (1H, dd, J=10.0, 5.0 Hz), 8.65-8.68 (1H, m).
Reaction SMILES: I[Br:2].BrBr.[F:5][C:6](I)([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>>[F:5][C:6]([Br:2])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: BrI
Agent: BrBr
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Reaction time: 5 h
Yield: 92.5 %

Procedure:
With reference to FIG. 1, and H-shaped tube equipped with a Dimroth condenser and a Dimroth condenser having an IBr withdrawing cock was attached to a 500-ml four-necked flask. Into the flask were placed 200 ml (747 mM) of perfluorooctyl iodide (PFOI) and 5.0 ml (97.1 mM) of bomine, and the mixture was heated at 150° to 155° C. and irradiated with a 500-W visible light lamp. After the reaction mixture started to reflux, 49.5 ml (972 mM) of bromine was added dropwise to the mixture at a rate of 0.2 ml/min over a period of about 4 hours. The resulting IBr was drawn off at a suitable time through the IBr withdrawing Dimroth condenser. The reaction was continued for 5 hours, and the reaction mixture was thereafter cooled and washed with a 5% aqueous solution (200 ml) of sodium hydroxide to obtain 344.9 g (92.5% in yield) of perfluorooctyl bromide.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7]([C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])[CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C=C>>[C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7]([C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])[CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=Cc1ccc(O)c(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2OC)c1
Agent: C=CC(=O)O
Product: COc1c(-c2cc(C=CC(=O)O)ccc2O)cc(C(C)(C)C)cc1C(C)(C)C

Procedure:
In a manner similar to that of Example 2(h), starting with 1.23 g (3 mmol) of ethyl 3-(3′,5′-di-tert-butyl-6-hydroxy-2′-methoxy-3-biphenylyl)acrylate, 800 mg (69%) of 3-(3′,5′-di-tert-butyl-6-hydroxy-2′-methoxy-3)) -biphenylyl)acrylic acid having a melting point of 166°-7° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21].CN(C)C=O.[F-].[Cs+].[H][H]>CO.[Pd]>[CH2:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)[CH3:13]
Reactant: [H][H]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of methyl 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydroquinoline-3-carboxamido)acetate (0.59 g, 1.5 mmol) in N,N-dimethylformamide (5.0 mL, 1.5 mmol) and methanol (1.0 mL, 1.5 mmol) was added cesium fluoride (0.23 g, 1.5 mmol) under nitrogen. After stirring at room temperature for 1 hour, the mixture was concentrated to remove solvents. The resulting solid was adsorbed onto silica and purified using flash chromatography (15-80% EtOAc:Hex gradient) to afford a yellow solid. The solid was suspended in methanol (10 mL) with Pd/C (20 mol %) and exposed to hydrogen from a balloon for 16 h. The crude reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane (5'10 mL) under argon. The filtrate was concentrated to give a white solid that was further purified on silica by flash chromatography (100% chloroform). The solid was then treated with 5 N aqueous NaOH (3 mL) in THF (3 mL) for 5 hours. The mixture was acidified to pH 1 using 5 N aqueous HCl, and the resulting precipitate was collected by filtration. After washing the solid with water (5×10 mL) and ether (2×10 ml), the desired material was obtained after drying in a vacuum oven overnight at 50° C. (0.21 g, 38% yield, 3 steps).