Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@@H:18]2[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][C@@H:19]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14].C(N(CC)CC)C.Br[C:46]1[S:47][C:48]2[C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=1>CO>[C:33]([O:32][C:31]([NH:30][C@@H:19]1[C@H:18]([NH:17][C:15]([C:10]2[NH:11][C:12]([CH2:13][CH3:14])=[C:8]([Cl:7])[N:9]=2)=[O:16])[CH2:23][CH2:22][N:21]([C:46]2[S:47][C:48]3[C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=[CH:51][C:49]=3[N:50]=2)[CH2:20]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)C(F)(F)F)C[C@@H]2NC(=O)OC(C)(C)C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(=O)OC(C)(C)C)C3)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Potassium carbonate (40 mg, 0.289 mmol) was added to a solution of tert-butyl [(3S,4R)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1-(trifluoroacetyl)piperidin-3-yl]carbamate obtained in Example (202c) (123 mg, 0.263 mmol) in methanol (5 mL), and the mixture was heated under reflux at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and then the filtrate was dissolved in dimethylformamide (2 mL). Triethylamine (145 μL, 1.04 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (82.1 mg, 0.287 mmol) were added at room temperature, and the mixture was stirred at 70° C. for three hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:3) to obtain 121 mg of the title compound (80%) as a colorless solid.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8].[C:11]([NH2:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]>C1(C)C=CC=CC=1>[C:11]([NH2:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].[B:1]([O:4][CH2:9][CH:7]([CH2:6][OH:5])[OH:8])([OH:3])[OH:2]
Reactant: OB(O)O
Reactant: OCC(O)CO
Agent: NC(=O)c1ccccc1O
Solvent: Cc1ccccc1
Product: OCC(O)COB(O)O
Reaction time: 8 h

Procedure:
Salicylamide/glycerol borate was prepared as follows. Boric acid (10.3 grams), glycerol (15.3 grams), and salicylamide (22.9 grams) were added to a 250 milliliter flask. One hundred fifty milliliters of toluene was then added. The reaction was allowed to proceed overnight at 110° C., and the byproduct water (˜9 grams) was continuously removed from the reaction by azeotropic distillation. The final solution was evaporated to remove toluene under vacuum, and a yellowish resinous product (˜40 grams) of salicylamide/glycerol borate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1cc2c(C)coc2cc1N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1N1CCOCC1)OCC2C

Procedure:
A mixture of 10 g (43.2 mmole) of 3,5-dimethyl-6-morpholinobenzofuran, 2 g of 5% palladium on carbon and 200 ml of ethyl acetate is hydrogenated at room temperature and a pressure of 4 bar. For completion of the reaction, 2 g, each time, of 5% palladium on carbon are added a further four times during hydrogenation. After a total of 58 hours, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. Purification of the residue by flash chromatography (silica gel, petroleum ether/ether) and distillation of the pure fractions in a bulb tube (130°-140°/6.10-2 torr) yields 3,5-dimethyl-6-morpholino-2,3-dihydrobenzofuran having a melting point of 57°-58°.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=3[CH:18]=2)=[N:6][N:5]=[N:4]1.C1CCCCC=1>C(Cl)(Cl)(Cl)Cl.O1CCOCC1>[Br:1][C:18]1[C:17]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:16]=2[O:15][C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[NH:3][N:4]=[N:5][N:6]=1
Reactant: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)cc2c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1=CCCCC1
Product: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 11.6 g of bromine in 28 ml of carbon tetrachloride is added dropwise over the course of 35 minutes to a suspension of 10.0 g of 2-[2'-(1H-tetrazol-5-yl)-phenyl]-5-methylbenzofuran in 418 ml of dioxane. After stirring for 3 hours at room temperature, 12.6 ml of cyclohexene are added dropwise and then the reaction mixture is concentrated by evaporation in vacuo. The residue is taken up in 50 ml of 2N sodium hydroxide solution and extracted with 100 ml of ether. Three clear phases form. The two lower phases are separated off, acidified with 40 ml of 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The combined ethyl acetate phases are washed with 100 ml of brine and, after removal of the solvent in vacuo, they result in a yellow oil which yields crystalline 3-bromo-2-[2'-(1H-tetrazol-5-yl)-phenyl]-5-methylbenzofuran, m.p. 167-168°, from toluene.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:18]1[CH:23]=CC=C[CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][C:18]([CH3:23])([CH3:19])[O:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccccc1
Reactant: CCCCNC(=O)CCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(=O)CCc1ccc2c(c1)OC(C)(C)O2
Temperature: 0 °C
Reaction time: 11 h

Procedure:
1.5 g of N-butyl-3-(3,4- dihydroxyphenyl)propionamide was dissolved in a mixed solvent consisting of 30 ml of benzene and 10 ml of tetrahydrofuran and 4 ml of acetonedimethylacetal was added to the solution. Then a small amount of p-toluenesulfonic acid was added to the solution and the solution was stirred for 11 hours under reflux. With a further addition of 2 ml of acetonedimethyl acetal, stirring was continued under reflux for 6 hours. After cooling, the solution was poured over ice water containing sodium hydrogen carbonate and was mixed thoroughly. The solution was extracted with ethyl acetate, washed with water and then dried with sodium sulfate anhydride. After removing the solvent by evaporation under reduced pressure, the resulting residue was purified by chromatography on silica gel column using a mixed solvent (chloroform:methanol=100:l) and thus 0.84 g of oily N-butyl-3-(2,2-dimethyl-1,3-benzodioxol-5-yl)propionamide was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:38]4[C:26](=[CH:27][C:28]5[C:29]([CH3:46])([CH3:45])[C:30]6[CH:31]=[C:32]([C:39]7[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=7)[CH:33]=[CH:34][C:35]=6[C:36]=5[CH:37]=4)[C:25]4[C:20]3=[CH:21][CH:22]=[C:23](B(O)O)[CH:24]=4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.ClCCl>O.O1CCOCC1.C1(C)C=CC=CC=1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:38]4[C:26](=[CH:27][C:28]5[C:29]([CH3:46])([CH3:45])[C:30]6[CH:31]=[C:32]([C:39]7[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=7)[CH:33]=[CH:34][C:35]=6[C:36]=5[CH:37]=4)[C:25]4[C:20]3=[CH:21][CH:22]=[C:23]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:24]=4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1cc(B(O)O)ccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: Brc1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1cc(-c2ccccc2)ccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
26.6 g (42 mmol) of 6-(4,6-diphenylpyrimidin-2-yl)-12,12-dimethyl-2-phenyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene-9-boronic acid and 8.2 g (52.4 mmol) of bromobenzene are dissolved in a degassed mixture of 135 ml of water, 315 ml of dioxane and 315 ml of toluene, and 5.33 g (50.31 mmol) of Na2 CO3 are added. The reaction mixture is degassed, and 0.96 g (0.84 mmol) of tetrakistriphenylphosphinopalladium(0) is added. The mixture is heated under reflux for 18 h. After cooling, dichloromethane is added (heterogeneous mixture), the water phase is separated off, and the organic phase is evaporated azeotropically with toluene. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The purity is 99.9%, the yield is 23 g (34 mmol, 82%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][OH:22])[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:5].[OH-].[Na+].O[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>CO>[OH:29][C:28](=[N:2][C@@H:3]([CH2:21][OH:22])[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:5])[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:26]=1
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCCCCNC(=O)[C@@H](N)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CO)N=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General procedure for synthesis of hydroxy-substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamide (Compounds II-19, II-20, and II-21): A mixture of 0.40 g (1.00 mmol) of (S)-2-amino-3-hydroxy-N-tetradecylpropanamide hydrochloride, 0.04 g (1.00 mmol) of NaOH, 1.00 mmol of hydroxybenzaldehyde, and 40 mL of methanol was stirred at room temperature for eight hours. The solvent was then evaporated under reduced pressure, and the residue was washed with cooled methanol to yield (S)-2-(hydroxybenzylideneamino)-3-hydroxy-N-tetradecylpropanamide as powder.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C.C([O:34][CH2:35][C@@H:36]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:37]1[C:38]([C:49]2[C:58]3[C:53]4=[C:54]([CH2:59][CH2:60][O:61][C:52]4=[CH:51][CH:50]=2)[CH:55]=[CH:56][N:57]=3)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH3:48])[CH:41]=[CH:40]2)(=O)C(C)(C)C>>[C:63]([O:62][C@@H:36]([C:37]1[C:38]([C:49]2[C:58]3[C:53]4=[C:54]([CH2:59][CH2:60][O:61][C:52]4=[CH:51][CH:50]=2)[CH:55]=[CH:56][N:57]=3)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH3:48])[CH:41]=[CH:40]2)[CH2:35][OH:34])([CH3:66])([CH3:64])[CH3:65]
Reactant: Cc1ccc2c(-c3ccc4c5c(ccnc35)CCO4)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc4c5c(ccnc35)CCO4)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1

Procedure:
Compound 6C was prepared following the procedure used to prepare compound 1K of Example 1 except that (2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-dimethylquinolin-6-yl)ethyl pivalate (6B) was used instead of compound 1J. LCMS-ESI+ (m/z): 433.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[CH:13])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1.[Br:24]Br.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[C:13][Br:24])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1
Reactant: BrBr
Reactant: C#CCOc1cc(-n2ncc(=O)n(C)c2=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)cnn(-c2cc(OCC#CBr)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a stirred mixture of 0.05 g (0.002 mole) of sodium hydride in 5 mL of tetrahydrofuran was added a solution of 0.55 g (0.0018 mole) of 2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 21, see Example III, Step J) in 5 mL of tetrahydrofuran. To this mixture was added a solution of 0.28 g (0.0018 mole) of bromine in 5 mL of tetrahydrofuran. After complete addition, the reaction mixture was stirred at room temperature for one hour. Water, 5 mL, was added to the mixture, and the total stirred at room temperature for two days. The mixture was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.45 g of 2-[4-chloro-2-fluoro-5-(3-bromo-2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 127°-129° C.), Compound 48 in the tables.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37](Cl)[C:32]=2[CH2:31][CH2:30]1)(=O)C.Cl.C[O-].[Na+].CO>C(O)C>[OH:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:9][CH2:10]4)=[CH:24][CH:23]=3)[C:32]=2[CH2:31][CH2:30]1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3O)cc1
Yield: 57.7 %

Procedure:
To 15 ml of ethanol were added 0.60 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3 ml of an ethanol solution of hydrochloric acid (containing 0.19 g of hydrochloric acid) was added to the mixture and the mixture was reacted under reflux for 30 minutes. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.49 g of the title compound as white crystal.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>C(#N)C>[CH2:28]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[C:6]([F:17])=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)[CH:27]=[CH2:26]
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 60), 314 (82), 288 (bp), 286 (31), 96 (36).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1>CS(C)=O>[CH:15]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]2([CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH2:4]1
Reactant: CCOC(=O)C=C1CCOCC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCOCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
51.93 g of sodium hydride (60% dispersion in oil) is taken up in 1100 ml of dry dimethyl sulphoxide under argon. 272 g of trimethylsulphoxonium iodide are added in portions over 20 minutes at room temperature, and the reaction mixture is then stirred at room temperature for 1.5 hours. 170.00 g of ethyl (tetrahydropyran-4-ylidene)acetate [130312-00-4] are added dropwise, and the reaction mixture is stirred at room temperature for 18 hours. The mixture is poured into ice and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a colourless oil from the residue by vacuum distillation (68-70° C., 0.09 mbar). Rt=3.49 (Gradient I).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14]C(=O)C)=[C:7]2[CH2:6][CH2:5]1)(=O)C.[ClH:18]>CCO>[ClH:18].[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Agent: Cl
Solvent: CCO
Product: NCc1ccnc2c1CCN2
Temperature: 70 °C

Procedure:
A mixture of N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g), HCl (conc., 3 mL) and EtOH (12 mL) was heated to 70° C. for overnight. Additional 3 mL of conc. HCl was added to the reaction and the heating was continued for 3 more days. Solvent was evaporated to give a white residue as crude C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt, which was used without further purification.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH2:20][Cl:21])=[O:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:22])[C:17](=[C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:18](=[O:19])[CH2:20][Cl:21])[CH3:14]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)C(C(=O)CCl)=C1C=Cc2ccccc2C1

Procedure:
9.85 g of 1-naphthaldehyde were reacted with 15.2 g of 4-chloroacetoacetic acid ethyl ester in the course of 10 hours as described in Example 24. After incipient distillation under a high vacuum had been carried out, a 2:1 isomer mixture which still contained traces of aldehyde remained as the residue.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[Cl:8][CH2:9][CH2:10][S:11][CH:12]([S:17][CH2:18][CH2:19][Cl:20])[C:13](OC)=[O:14]>C1C=CC=CC=1>[CH3:2][NH:3][C:13](=[O:14])[CH:12]([S:17][CH2:18][CH2:19][Cl:20])[S:11][CH2:10][CH2:9][Cl:8]
Reactant: COC(=O)C(SCCCl)SCCCl
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)C(SCCCl)SCCCl
Temperature: 50 °C
Reaction time: 21 h
Yield: 64 %

Procedure:
To a stirred suspension of methylamine hydrochloride (3.464 g; 0.051 mol) in 60 mL of dry benzene under nitrogen at room temperature was added trimethylaluminum (Aldrich, 25.65 mL of 2.0M solution in toluene). After gas evolution ceased (30 min) a solution of the ester 4b (4.500 g; 0.017 mol in 10 mL of dry benzene was added and the mixture was warmed to 50° C. After 21 h, the mixture was allowed to cool to room temperature and was then quenched by dropwise addition of 60 mL of 1.0 N HCl. The mixture was extracted several times with ethyl acetate and the combined extracts were dried (MgSO4) and concentrated under vacuum. Flash chromatography on silica gel (eluent: 2/3 ethyl acetate/hexanes) gave 2.849 g (64%) of 4c, mp 82°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:28]1[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(c4ccccc4)CC3)cc21
Yield: 54.9 %

Procedure:
2.15 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 6.5 g of 1-phenylpiperazine and 20 cm3 of pyridine were heated under reflux for 16 hours. The solvent was removed in vacuo and the residue was taken up in 20 cm3 of water. The suspension obtained was stirred and brought to pH 7 by the addition of acetic acid. The solid was filtered off and recrystallised from methyl cellosolve. 1.7 g of 6-chloro-1-ethyl-4-oxo-7-(4-phenylpiperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 234°-235° C., were obtained.
Reaction SMILES: Cl.[N:2]1[C:12]2[C:11]3[S:13][C:14]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>O1CCOCC1.C(Cl)Cl>[N:2]1[C:12]2[C:11]3[S:13][C:14]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
Following Scheme 5,2-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine and 4-(N-Boc-aminomethyl)-phenylboronic acid were reacted to give tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate. MS: (ESI+)=409.1. Hydrogen chloride in dioxane (4 ml, 4 N) was added to a solution of 67 mg (0.16 mmol) of tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate in 6 ml of methylene chloride and the mixture was stirred for 2 hours. The precipitate was collected, washed with methylene chloride and ethyl ether and dried in vacuum to give 335 (34 mg, 55%). MS: (ESI+) 309.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:24]([NH:26][CH2:27][CH:28]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])[OH:29])=[O:25])[C:8]([I:23])=[C:9]([C:21]=1[I:22])[C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])(=[O:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39]Br>>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][CH:28]([OH:29])[CH2:27][NH:26][C:24](=[O:25])[C:7]1[C:6]([I:35])=[C:5]([N:4]([CH2:39][CH2:38][O:37][CH3:36])[C:1](=[O:3])[CH3:2])[C:21]([I:22])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])[C:8]=1[I:23]
Reactant: COCCBr
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Product: COCCN(C(C)=O)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I

Procedure:
This compound is prepared from 5-acetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 2, Step B, with 2-bromoethyl methyl ether (BrCH2CH2OCH3) in the same manner as described in Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:23]4[CH2:24][CH2:25][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([OH:19])[CH2:21][CH2:22]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 32 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-hydroxy-4-phenylpiperidine, the title compound hydrochloride salt was obtained in 32% yield as a white powder, mp 260°-261° C. elemental