Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:28][C:29]([NH2:31])=[O:30])([O-:3])=[O:2].Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:28][C:29]([NH2:31])=[O:30])=[C:9]([NH:8][CH2:7][C:6]4[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)[CH3:37]
Reactant: CCN(CC)CCCl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCN1CCN(c2ccc(Nc3cc(NCc4cccc([N+](=O)[O-])c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
40 mg of 4-[(3-nitrobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 224) was dissolved in 0.3 mL of N,N-dimethylformamide, to which 18.5 mg of 2-chloro-N,N-diethylethylamine hydrochloride and 25 mg of potassium carbonate were added, and stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 43 mg (88%) of the title compound as an orange crystalline powder.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[N:5]=1)#[N:3].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C@@H:10]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:21][C@H:9]1[N:6]1[N:5]=[C:4]([C:2](=[S:1])[NH2:3])[CH:8]=[N:7]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2ncc(C(N)=S)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 98 %

Procedure:
Hydrogen sulfide was passed through a suspension of 2.0 g of 7 in ethanol (60 ml) to which 3.5 ml of triethylamine had been added. After 2 1/2 hr passage of hydrogen sulfide was ceased and the solvent was removed. The resultant syrup was dissolved in a minimum of chloroform and added to a silica gel column (2 × 38 cm) packed in chloroform. The column was eluted with chloroform (0.25 liter) and chloroform-ethyl acetate (9:1, 0.5 liter); 20 ml fractions were collected. Fractions 19-34 provided 2.6 g (98%) of 9 as a syrup; nmr (DMSO-d6) δ 6.36 (d, 1, J1',2' 2.0 Hz, 1'--H), 8.39 (s, 1,5--H); (CDCl3) δ 6.24 (d, 1, J1'2' 3.0 Hz, 1'--H), 8.32 (s, 1, 5--H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:20][CH2:21][CH:22]=[CH2:23].[H-].[Na+].O>CN(C=O)C>[CH2:23]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:22][CH:21]=[CH2:20]
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a solution of 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.29 g (1 mmol) and 4-bromobut-1-ene 0.3 g (2 mmol) in DMF (2 ml) was added NaH 0.1 g (2 mmol of 55% dispersion in oil) and the mixture stirred for 6 h. The reaction was then poured into water and extracted with EtOAc, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/n-heptane 1:1) afforded the title compound 0.09 g (25%) as a yellow gum. MS: 313.2 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH:12]([OH:13])[CH2:11][CH2:10][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)C.[OH-].[Na+]>CO>[OH:13][CH:12]1[CH2:11][CH2:10][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCC1CC(c2ccccc2)CCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC1CC(c2ccccc2)CCC1O
Yield: 71 %

Procedure:
A solution of 0.68 g. (0.0025 M) of ethyl-4-hydroxy-1-phencyclohexane-3-propionate(g) (obtained in Example 4A) and 1 ml. of 50% sodium hydroxide in 10 ml. of methanol is heated at reflux for about 20 hours. Most of the solvent is removed under vacuum and the residue dissolved in water. The aqueous solution is washed with ether and made acidic with concentrated hydrochloric acid. A solid precipitate is collected on a filter and recrystallized from benzene to give 0.44 g. (71% yield) of 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h) having a melting point of 153.5 to 155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=3[N:24]2[CH3:27])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=5[N:24]4[CH3:27])=[CH:20][CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 25.5 %

Procedure:
4((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (259 mg, 1.09 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (400 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (145 mg, 25%) as a yellow solid: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:20][CH2:19]1.[CH2:32]=[O:33]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][N:28]([CH2:32][OH:33])[C:27]2=[O:31])[CH2:20][CH2:19]1
Reactant: C=O
Reactant: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Solvent: C1CCOC1
Product: O=C1N(CO)CCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 50 °C

Procedure:
To a solution of 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-indole (4.4 g) in tetrahydrofuran (25 ml) at room temperature was added dropwise a 30% aqueous solution of formaldehyde (800 mg). The mixture was heated at 50 ° C. for 2 h. Solvents were evaporated in vacuo and excess H2O was removed by evaporation with toluene. By addition of acetone the title compound crystallized. Recrystallization from acetone afforded 3.2 g of pure 5a. Mp: 118°-119 ° C. 1H NMR: δ1.85 (2H, dq), 2.05 (2H, broad d), 2.20 (2H, t), 2.60 (2H, t), 2.85 (1H, tt), 3.10 (2H, broad d), 3.40 (2H, t), 3.50 (4H), 4.80 (2H, s), 7.0-7.7 (8H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+]>O>[C:1]1([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1ccc2nccnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccccc1)c1ccc2nccnc2c1
Yield: 100 %

Procedure:
To a stirred and cooled (5° C.) solution of 20 parts of intermediate 2, namely phenyl (6-quinoxalinyl)methanone in 160 parts of methanol were added portionwise 3.2 parts of sodium tetrahydroborate. Upon completion, the reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated to dry, yielding 20 parts (100%) of α-phenyl-6-quinoxalinemethanol as an oily residue (interm. 3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: O=C1OCCc2cc(O)ccc21
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Temperature: 70 °C

Procedure:
A mixture of 6-hydroxyisochroman-1-one (332 mg), methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (284 mg), cesium carbonate (1.28 g) and DMF (8 ml) was heated to 70° C. for 7 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 248.28 (C14H16O4); MS (ESI): 249 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1>O.CCO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=3)[CH:12]=[N:11]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1csc(-c2cnn(Cc3ccc(OC)cc3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(-c3nc(C(=O)O)cs3)cn2)cc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
According to Scheme 1 Step 6: A solution of NaOH (38.4 mmol, 12.8 mL) in water (3 M) was added at 0° C. to a solution of ethyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4 mmol, 5.28 g) in EtOH (38 mL) and the reaction mixture was heated at 50° C. overnight. After evaporation of the solvent, the crude residue was partitioned between a solution of NaOH (1 M) and EtOAc. After extraction, the organic phase was washed with a solution of NaOH (1 M). The aqueous phase was then acidified and the beige precipitate formed was filtered off, washed with water and dried to yield 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (13.6 mmol, 4.29 g, 88%) as a beige solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[Li].[Li][S:33][CH3:34]>O1CCOCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][S:33][CH3:34])[C:17]=2[CH:16]=1
Reactant: [Li]SC
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Agent: [Li]
Solvent: C1COCCO1
Solvent: O
Product: CSCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reaction time: 9 h

Procedure:
A mixture of the bromide (58) (60.0 mg, 0.124 mmol) prepared as described in example 172 and lithium thiomercaptide (13 mg, 0.2481 mmol) in p-dioxane (5 mL) was refluxed for 16 h. A further 10 mg of LiSMe was added and refluxing was continued for a further 9 h. The mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to drynessto give the sulfide (130 directly (47.1 mg, 84%) which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 218–220° C. 1H NMR δ [(CD3)2SO] 11.07 (br s, 1H), 9.39 (br s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.61–7.56 (m, 2H), 7.53–7.43 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.01 (m, 2H), 2.00 (s, 3H). FABMS found [M+H]+: 453.0840, 451.0859. C24H20ClN2O3S requires 453.0854, 451.0883.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=Cc1ccccc1OCCCCCCl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 100 g (0.82 mol) of salicylaldehyde in 2000 ml of iPrOH was added 228 g (1.23 mol) of 1-bromo-5-chloro-pentane, followed by 113 g (0.82 mol) of potassium carbonate. The reaction was refluxed under nitrogen and followed by TLC. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to remove all solvent. The liquid residue was purified by fractional distillation under reduced pressure: 1st fraction: 45°-50° C., 0.4 mm Hg [Br(CH2)5Cl] 2nd fraction: 159.8 g (86% yield), 145°-150° C., 0.3 mm Hg colorless liquid product. The remaining residue proved to a dialdehyde by-product. TLC: Starting aldehyde Rf=0.46 (30% ether/pet. ether). Desired aldehyde: Rf=0.35. By-product: Rf=0.15.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]([F:13])([F:12])[CH2:10][OH:11].C(N(CC)CC)C>O1CCCC1>[C:1]([O:11][CH2:10][C:9]([Br:8])([F:13])[F:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OCC(F)(F)Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
Pivalic acid chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl pivalate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(pivaloyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 94.3 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (1.02 g, 4.44 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.76 g, 3.42 mmol) and triethylamine (1.42 ml, 10.3 mmol) in tetrahydrofuran (20 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22 g, 95%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[CH3:28][CH:27]([CH3:29])[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(C)C(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(C)C(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 11 μL (0.11 mmol) isobutyryl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[C@@H:15]3[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]5[O:24][CH:9]6[C:10]([CH2:12][CH2:13][C@:14]3([OH:25])[C@:8]6([C:18]=45)[CH2:7][CH2:6]2)=[O:11])[CH2:2]1.[ClH:26]>O>[CH:22]1[C:17]2[CH2:16][C@H:15]3[N:5]([CH2:4][CH:3]4[CH2:1][CH2:2]4)[CH2:6][CH2:7][C@:8]45[C@H:9]([C:10]([CH2:12][CH2:13][C@@:14]34[OH:25])=[O:11])[O:24][C:19]([C:18]=25)=[C:20]([OH:23])[CH:21]=1.[ClH:26]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Agent: Cl
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 3.5 °C

Procedure:
70 kg Naltrexone base is taken in 210 Lit DM water and pH was adjusted to ˜2.0 with Conc.HCl and heated to 70-75° C. to get clear solution, filtered to make particle free and slowly cooled to 2-5° C. in 6-8 hrs period, filtered and then dried. The base was generated from filtrate by treatment with sodium hydroxide and converted to HCl salt by repeating the above mentioned process. Yield: 59.8 kg
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]([O:28]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([CH3:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]3=[N:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:30]([NH2:32])=O>>[CH3:17][C:15]1[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[CH:30][NH:32][C:26](=[O:28])[C:3]=4[N:4]=3)[CH:9]=[C:10]2[N:16]=1
Reactant: NC=O
Reactant: COC(=O)c1nc(-c2cnc3c(c2)nc(C)n3COCC[Si](C)(C)C)ccc1N
Product: Cc1nc2cc(-c3ccc4nc[nH]c(=O)c4n3)cnc2n1COCC[Si](C)(C)C
Yield: 36 %

Procedure:
1.00 g of methyl 3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine-2-carboxylate in 16 ml of formamide are heated at 130° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 48 hours). The excess formamide is distilled off (120° C., 1 mbar). The residue is dissolved in dichloromethane, washed with water, dried and purified by means of column chromatography (gradient EA: methanol 0-50% in 15 min), giving 0.40 g of 6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-one as reddish solid (yield 36%, content 95%); MS-FAB (M+H+)=409.1; Rf (polar method): 2.01 min.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[C:20]#[N:21])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.[OH-:25].[K+].[Cl-].[NH4+]>CC(O)(C)C.CS(C)=O>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[C:20]([NH2:21])=[O:25])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(C(N)=O)c4)cc3c(=O)c21
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 51.7 %

Procedure:
A mixture of 3-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 28, step 2, 100 mg, 0.32 mmol) and powdered potassium hydroxide (89 mg, 1.59 mmol) in 2-methyl-2-propanol (5 ml) and dimethylsulfoxide (2 ml) was stirred at 65° C. for 4.5 h. After cooling to room temperature, the mixture was poured into saturated aqueous ammonium chloride (50 ml), and the precipitate was collected by filtration. This yellow powder was washed with water, methanol and dichloromethane to give 55 mg (52%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[NH2:8][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH2:3]2)=[O:16])=[CH:13][CH:12]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=CC=CN(C(=O)c2ccc(N)cc2)C1

Procedure:
3-Aminopyridine, 60, is first reacted with 4-nitrobenzoyl chloride in the presence of pyridine at 80° C. (step 1) and the product, 62, is subsequently hydrogenated in the presence of ethanol (step 2) to give N-(p-aminobezoyl) -3-aminopyridine, 64. In a separate reaction, 2,5-dimethyl-1,4-phenylenediamine, 66, is converted to 2,5-dimethyl-1,4-dinitrobenzene in a "reverse" Sandmeyer reaction with isoamyl nitrite and acetic acid (step 3), and subsequently treated with copper sulfate in the presence of sodium nitrite (step 4) to produce the intermediate, 68. This intermediate, 68, is oxidized with CrO3 and chlorinated with SOCl2 (step 5) to give 2,5-dinitroterephthaloyl chloride 70. One equivalent of N-(p-aminobezoyl)-3-aminopyridine, 64, and 0.5 equivalent of 2,5-dinitroterephthaloyl chloride, 70, are reacted in pyridine (step 6) to produce a bis-anilide derivative of 2,5-dinitroterephthaloyl chloride 72, and the product is again hydrogenated and activated with isoamyl nitrite (step 7) to yield the final activated product 74.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCCOC1CCOCC1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCOC1CCOCC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (400 mg, 1.95 mmol), (prepared as described for the starting material in Example 1), 4-(2-hydroxyethoxy)tetrahydropyran (371 mg, 2.54 mmol) and triphenylphosphine (820 mg, 3.12 mmol) in methylene choride (15 ml) was added diethyl azodicarboxylate (492 μl, 3.12 mmol) in portions. After stirring for 30 minutes, triphenylphosphine (512 mg, 1.95 mmol), 4-(2-hydroxyethoxy)-tetrahydropyran (142 mg, 0.98 mmol) and diethyl azodicarboxylate (308 μl, 1.95 mmol) were added. The volatiles were removed under vacuum and the residue was purified by column chrolatography eluting with methylene chloride/ethyl actetate/methanol (60/40/0 followed by 50/50/0, 40/60/0, 60/39/1, 60/38/2 and 50/46/4) to give 4-chloro-6-cyano-7-(2-(tetrahydropyran-4-yloxy)ethoxy)quinoline (519 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:38][CH:37]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:7][CH:6]=2>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:40][CH:41]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C)c(OC)c3cc(OCc4ccccc4)ccc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(C)c(-c2ccc(OCc3ccccc3)cc2)c(Oc2ccc(/C=C/C(=O)O)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
Synthesized in a manner similar to Example 46 (Step 7) using ethyl (2E)-3-{4-[(3-methyl-4-(methyloxy)-6-[(phenylmethyl)oxy]-2-{4-[(phenylmethyl)oxy]phenyl}-1-naphthalenyl)oxy]phenyl}-2-propenoate (257). 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=9.1 Hz, 1H), 7.57 (d, J=16.0 Hz, 1H), 7.45-7.18 (m, 1H), 7.07 (dd, J=9.0, 2.5 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H) 6.53 (d, J=8.6 Hz, 2H), 6.53 (d, J=8.6 Hz, 2H), 6.16 (d, J=16.0 Hz, 1H), 5.16 (s, 2H), 4.95 (s, 2H), 3.81 (s, 3H), 2.12 (s, 3H). LRMS (ESI) m/z 621 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.44.