Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([CH2:9][OH:10])[CH3:8].[C:11]([C:15]([C:18](F)=[O:19])([F:17])[F:16])([F:14])([F:13])[F:12]>C([O-])(O)=O.[Na+]>[C:11]([C:15]([C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([CH2:9][O:10][C:18]([C:15]([C:11]([F:12])([F:13])[F:14])([F:16])[F:17])=[O:19])[CH3:8])=[O:19])([F:17])[F:16])([F:14])([F:13])[F:12]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Reactant: CC(CO)OCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(COC(=O)C(F)(F)C(F)(F)F)OCCCCOC(=O)C(F)(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
HO(CH2)4OCH(CH3)CH2OH (18.8 g) obtained in Example 2-3 was put into a round bottom flask and stirred while maintaining the internal temperature at 30° C. Together with nitrogen, CF3CF2COF (276 g) was supplied over 6 hours while maintaining the internal temperature at 30° C. After completion of the reaction, stirring was continued for 2 hours at an internal temperature of 30° C. while supplying nitrogen gas, whereupon a 5% NaHCO3 aqueous solution (300 ml) was added at an internal temperature of at most 15° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:10][C:9]=2[CH:18]=1)=[O:4].[Li+].[I-]>N1C=CC=CC=1>[CH3:17][CH2:16][O:15][C:13]([C:11]1[S:10][C:9]2[CH:18]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH:12]=1)=[O:14]
Reactant: CCOC(=O)c1cc2ccc(C(=O)OC)cc2s1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(C(=O)O)cc2s1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of benzo[b]-thiophene-2,6-dicarboxylic acid 2-ethyl ester 6-methyl ester (16.19 g, 61.26 mmol) and LiI (34.68 g, 259.11 mmol) in 500 ml anhydrous pyridine was refluxed for 3 days. After cooling to rt, the mixture was poured into ice-cold 2N HCl (1000 mL). The solid was collected, washed with water and dried. The solid was crystallized from methanol to give benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester as a pale solid (11.65 g, 76%). MS: calc'd 251 (MH+), exp 251 (MH+). 1H NMR (d6-DMSO, 400 MHz), 8.69 (s, 1H), 8.26 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.98 (d, 1H, J=8.4 Hz), 4.37 (q, 2H, J=6.8 Hz), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:17][CH2:18][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1
Reactant: COc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(c4ccccc4)CC3)sc2-c2ccc(Cl)cc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3Cl)s2)CC1
Reaction time: 3 h

Procedure:
2.8 g of the compound obtained in stage 1F) and 19.8 ml of a 1M solution of BBr3 in CH2Cl2 are added to 70 ml of CH2Cl2 at the temperature of melting ice. The temperature is allowed to rise to AT while continuing to stir over 3 hours. The reaction medium is subsequently poured onto water and the organic phase is recovered and subsequently dried and then evaporated. After crystallizing from an ether-ethyl acetate mixture, 1.8 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:31])([F:32])[F:30])(=[O:4])=[O:3]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Methanesulphonyl chloride (2.65 g) was added dropwise to a solution of 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6.7 g) and diisopropylethylamine (9.7 ml) in NMP (40 ml). The mixture was stirred at room temperature for 3 hours. After adding ice (100 g), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy]propyl methane-sulfonate (7.4 g). 1H NMR (DMSO) δ: 8.69 (s, 1H), 8.62 (s, 1H), 8.45 (d, 1H), 8.41 (s, 1H), 7.47 (d, 1H), 4.40 (t, 1H), 4.32 (t, 2H), 3.99 (s, 3H), 3.18 (s, 3H), 2.21 (tt, 2H).
Reaction SMILES: C([O:4][CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH:8]1[CH:12]([C:13]#[N:14])[CH2:11][CH:10]([OH:15])[C:9]1=[O:16])(=O)C.[BH4-].[Na+]>CO.[OH-].[Na+]>[OH:16][CH:9]1[CH:10]([OH:15])[CH2:11][CH:12]([C:13]#[N:14])[CH:8]1[CH2:7][CH2:6][CH:5]([OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(CCC1C(=O)C(O)CC1C#N)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(O)CCC1C(C#N)CC(O)C1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A stirred solution of 2-(3-acetoxyoctyl)-3-cyano-5-hydroxycyclopentanone (23.5 g.) [prepared as described in (j) above] in methanol (135 ml.) was treated dropwise, during 15 minutes, with a solution of sodium borohydride (13.2 g.) in 0.2N aqueous sodium hydroxide solution (70 ml.) at 15°-20°C. After 1 hour the solution was slowly heated pg,42 to 50°C., stirred at 50°C. for 3 hours, and then allowed to stand at room temperature overnight. Methanol was removed in vacuo, water (75 ml.) was added and the mixture acidified by means of concentrated hydrochloric acid. The mixture was extracted with diethyl ether and the ethereal extract was washed with water, dried with magnesium sulphate and evaporated in vacuo to give crude 3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentane carbonitrile (16 g.), which was used in the following preparation (1) of 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbonitrile without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[CH:32]2[CH2:37][CH:34]([CH2:35][CH:36]=1)[C:33]2([CH3:39])[CH3:38])(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:31]2[CH:32]3[CH2:37][CH:34]([CH2:35][CH:36]=2)[C:33]3([CH3:39])[CH3:38])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC1(C)C2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Product: CCOC(=O)c1ccc(C2=CCC3CC2C3(C)C)cc1

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (1.45 g, 3.30 mmol) and 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl trifluoromethanesulfonate (0.981 g, 3.63 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane afforded the crude title compound a yellow oil.
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate (109.8 mg, 0.29 mmol, 1.00 equiv, 90%) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (65.6 mg, 1.64 mmol, 5.00 equiv) in water (3 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The filtrate was concentrated under vacuum. The resulting solids were collected by filtration and washed with methanol and water. This resulted in 58 mg (59%) of 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1ccc(-c2cc(CCl)ccn2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccc(F)cc3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][CH:14]=3)[C:9]2=[O:18])=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1(=[O:18])[C:10]2[C:15](=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: COc1ccc(CN2CCc3cnccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1NCCc2cnccc21
Yield: 27.1 %

Procedure:
2-(4-Methoxybenzyl)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (I-67g: 300 mg, 1.119 mmol) was reacted with p-toluene sulfonic acid (851 mg, 4.476 mmol) and toluene (10 mL) at 110° C. for 4 hours. The reaction mass was concentrated under reduced pressure, neutralized with 1N HCl solution to pH 7 and extracted using DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 45 mg of the product (27.10% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Reactant: NNC(=O)c1ccco1
Solvent: CN1CCCC1=O
Product: Nc1nc(NNC(=O)c2ccco2)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Temperature: 25 °C

Procedure:
A solution of the title A compound, 4-chloro-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol) and 2-furoic acid hydrazide (49 mg, 0.39 mmol) in 1 mL of NMP is heated at 150° C. for 3 h. After cooling to RT, the crude reaction is purified by column chromatography on silica gel, eluting with a gradient of 5% to 10% of MeOH in EtOAc. Fractions containing the product are combined and evaporated to dryness to 4-yl)furan-2-carbohydrazide as a yellow solid: LC/MS (M+1=483.2).
Reaction SMILES: CO.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH2:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Solvent: CO
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
200.23 g of crude carbinol, 400 ml of toluene and 1 g of paratoluenesulfonic acid (PTSA) were weighed and put in a 1-liter reaction flask, and azeotropic dehydration was carried out under toluene refluxing (94°-116° C.) for 2 hours. The resulting product was washed with water after cooling, washed with a 2% aqueous solution of soda ash, washed with water, dried over magnesium sulfate, and concentrated to obtain 190.09 g of crude 1,1-diphenylethylene (9a, Ar=R=Ph). Crude 1,1-diphenylethylene (9a) was distilled in a Claisen flask equipped with a vigreux to obtain 174.06 g of 1,1-diphenyl-ethylene (9a).
Reaction SMILES: [H-].[Na+].[C:3]1([C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[O:14])=[CH:16]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCn1cc(C(=O)c2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (1.1 g, 30 mmol, 60% in mineral oil) in DMF (100 ml) under nitrogen was added solid 3-(1-naphthoyl)-1H-indole 1 (5.43 g, 20 mmol). After stirring at room temperature for 1 h, a solution of ethyl 6-bromohexanoate (6.6 g, 30 mmol) in DMF (10 ml) was added slowly with stirring over a period of 15 min and the mixture was then heated at 60° C. for 3 h. The solvent was removed under high vacuum and the crude product was suspended in water (150 ml) and extracted by ethyl acetate (2×150 ml). The combined ethyl acetate phases were washed by water (1×100 ml), brine (1×100 ml), dried over sodium sulphate filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (8/2) to give the title compound 2 as an oil which became solid in the cold (7.1 g, 86%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[N:20]1(C(OC(C)(C)C)=O)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O>[N:20]1([CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2nc(CN3CCNCC3)ccc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 2-chloromethylquinoline hydrochloride (5 mmol) in anhydrous acetone (100 mL) was added, anhydrous potassium carbonate (15 mmol) and tert-butyl piperazine-1-carboxylate (7 mmol) and the reaction mixture was stirred under reflux conditions for 12 h. Reaction was cooled to r.t. and filtered through celite. Filtrate was concentrated on Rotavapor under vacuum and the crude residue was purified on SiO2 using Biotage SP1 to give a pure 2-(piperazin-1-ylmethyl)quinoline (6.3, 92%, pale yellow solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OC

Procedure:
207.0 g of 3,4-dimethoxybenzaldehyde, 100.0 g of ammonium acetate and 125 ml of nitromethane are heated to boiling for 3-4 h in 1.0 l of glacial acetic acid. After cooling in an ice bath, the precipitate is filtered off with suction, rinsed with glacial acetic acid and petroleum ether and dried. M.p.: 140-141° C. Yield: 179.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11](=[O:31])[C@:10]([CH2:33][C:34]#[N:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:36]1[C:34]([CH2:33][C@@:10]2([CH3:32])[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]2=[O:31])=[N:35][N:38]=[N:37]1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 120 h

Procedure:
To a solution of (S)-tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (101 mg, 0.196 mmol; Example 128, Step B) in DMF (0.50 mL) was added sodium azide (127 mg, 1.96 mmol) and NH4Cl (105 mg, 1.96 mmol). The resulting mixture was stirred at 90° C. for 5 days. Then, the reaction was quenched (aq. 10% citric acid), extracted (2×EtOAc), and washed (3×sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by RP-HPLC (60 to 85% AcCN/H2O, gradient elution) provided the title compound as a white solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:15]2([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([O:29]C)[CH:22]=3)[O:20][C:18](=O)[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13]C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([C:15]2[C:21]3[C:26](=[CH:25][C:24]([OH:27])=[C:23]([OH:29])[CH:22]=3)[C:18]([OH:20])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: COc1ccc(C2(c3ccc(OC)c(OC)c3)CCC(=O)O2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(O)c3cc(O)c(O)cc23)cc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
A solution of boron tribromide (20 g. 80 mmol) in methylene chloride (20 mL) is added dropwise to a vigorously stirred solution of 4,4-bis(3,4-dimethoxyphenyl)butyrolactone (10.0 g. 27.9 mmol) in methylene chloride (200 mL) at -78° C. Stirring is continued for 3 hours at 78° C., and then at room temperature overnight. Ice (100 g) is added to the mixture, and organic layer is separated. The aqueous layer is extracted with ethyl acetate (3×100 mL). The combined organic solutions are dried over sodium sulfate, and concentrated in vacuo. The residue is chromatographed over a silica gel colum using a mixture of chloroform and ethanol (98:2 v/v) as the eluent to give 1-(3,4-di-hydroxyphenyl)-4,6,7-trihydroxynaphthalene (4.5 g. 53%), mp 224°-226° C. 1H NMR (Me2SO-d6) δ9.6-8.8 (5H, m, OH, exchangeable), 7.4-6.5 (7H, m, aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-chloro-4-fluorobenzaldehyde (10.0 g) and methyl acrylate (8.5 mL) in acetonitrile (63 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.41 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (11.5 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc([Mg]Br)cc1
Product: CCSc1ncc(C(=O)c2ccc(OC)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-methoxyphenylmagnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-4-methoxy-phenyl-methanone. MS (M+H)+, 290.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN1CCCC1=O.[Cu]>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=[CH:5][N:4]2[CH:8]=1
Reactant: Brc1ccccc1
Reactant: Cc1cn2cccc(O)c2n1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cn2cccc(Oc3ccccc3)c2n1

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (14.8 g), bromobenzene (15.7 g), copper powder (1.0 g) and powdered potassium hydroxide (5.6 g) in N-methyl pyrrolidone was heated under reflux for 4 hrs. The solvent was removed by distillation and the residue suspended in dichloromethane, washed with 10% sodium hydroxide solution and the dichloromethane was evaporated to give 2-methyl-8-phenoxyimidazo[1,2-a]pyridine. Treatment of this compound in accordance with Examples 10 and 11 yields the desired product.
Reaction SMILES: IC1C=CC=CC=1N([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C(=O)CNC(NC1C=C(C)C=CC=1)=O.[CH3:31][O:32][C:33]1[CH:66]=[CH:65][C:36]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[NH:45][C:46]([CH2:48][NH:49][C:50](=[O:64])[NH:51][C:52]2[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=2)[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])=[O:47])=[O:38])=[CH:35][CH:34]=1>>[C:27]([O:26][C:24]([CH2:23][CH:48]([C:46](=[O:47])[NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37](=[O:38])[C:36]1[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:66][CH:65]=1)[NH:49][C:50](=[O:64])[NH:51][C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2I)c1
Reactant: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccc(OC)cc2)c1
Product: C=CCOC(=O)c1cccc(NC(=O)NC(CC(=O)OC(C)(C)C)C(=O)Nc2ccccc2C(=O)c2ccc(OC)cc2)c1

Procedure:
According to the synthesis method of the compound 24, the compound 42b is used to synthesize the titled compound. Mp. 190°-191° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]1[N:16]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:15][CH2:14][N:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:12]12>>[N:1]1([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:16]2[CH2:15][CH2:14][N:13]3[CH2:23][CH2:24][CH2:25][CH2:26][CH:12]3[CH2:11]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(CCCN1CCN2CCCCC2C1)N1CCCc2ccccc21

Procedure:
The procedure is as for Example 2 using as substrate 3,4-dihydro-2H-quinoline and the compound obtained in Step B of Example 2.