Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:18])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](Cl)=[O:9].[NH:19]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44]N=1)CC)C>C(N(CC)CC)C>[CH3:4][C:5]1[CH:6]=[C:7]([C:8]([N:19]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][N:28]([C:8]([C:7]3[CH:11]=[C:47]([CH3:42])[C:46]([O:17][C:15](=[O:14])[CH3:16])=[C:45]([CH3:44])[CH:6]=3)=[O:9])[CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:9])[CH:11]=[C:12]([CH3:18])[C:13]=1[O:14][C:15](=[O:17])[CH3:16]
Reactant: CCN(CC)c1ccccn1
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Reactant: C1COCCOCCNCCOCCOCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(C(=O)N2CCOCCOCCN(C(=O)c3cc(C)c(OC(C)=O)c(C)c3)CCOCCOCC2)cc1C
Temperature: 25 °C
Yield: 570.5 %

Procedure:
To 50 ml of methylene chloride were dissolved 0.9 g/4 mmol of 3,5-dimethyl-4-acetoxybenzoyl chloride and 0.5 g/1.9 mmol of 1,10-diaza-4,7,13,16-tetraoxacyclooctadecane, and to this solution was added 2.2 ml of triethylamine and a catalytic amount (40 mg/0.3 mmol) of diethylaminopyridine in an ice bath. The reaction mixture was refluxed under heat for 4 hours, and allowed to cool to room temperature. The reaction solution was washed with 1N hydrochloric acid, distilled water, saturated aqueous solution of sodium hydrogencarbonate, and saturated aqueous solution of sodium chloride, in this order. The organic layer was dried with anhydrous sodium sulfate, and after removing the drying agent, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride-methanol for the eluting solution to obtain 1.1 g of the desired 1,10-bis(3',5'-dimethyl-4'-acetoxyphenylcarbonyl)-1,10-diaza-4,7,13,16-tetraoxacyclooctadecane. MS: 642 (M+), 451, 191. 1H-NMR (CDCl3): δ2.15 (6H, s), 2.34 (12H, s), 3.6 (16H, br), 3.8 (8H, br), 7.05 (4H, s).
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:14]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)NNC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (12.0 g, 1.2 eq) in pyridine (100 mL) was added 2-methylbenzoyl chloride (crude afforded in step 1, 1.0 eq) dropwise at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, diluted with water (30 mL), adjusted to pH 12 with NaOH (aq), and the solid was collected by filtration and washed with water (20 mL) to afford 2-(2-methylbenzoyl)hydrazinecarboximidamide (5.0 g, 35% of two steps) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(OCC)(=O)C>[C:1]([O:5][C:6]([C:22]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])([NH2:23])[CH2:21][CH2:20][NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([CH:22]([NH2:23])[CH2:21][CH2:20][NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(N)(CCN)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C(N)CCN
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Mono-t-butyloxycarbonyl (BOC) 1,3-propanediamine was prepared as follows. 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (18 g, 73 mmol) was added portionwise over 10 minutes to a solution of 1,3-diaminopropane (12.5 g, 184 mmol) in 100 mL of tetrahydrofiran cooled to 0° C. After four hours at 0° C. the reaction was allowed to warm to 25° C. for two hours. The reaction was diluted with 150 mL of ethyl acetate and washed twice with 100 mL of saturated aqueous sodium chloride. The organic phase was extracted with three 100 mL volumes of 10% aqueous citric acid, the combined aqueous portions were then washed twice with 100 mL of ethyl acetate. The aqueous phase was cooled in an ice bath and the pH was adjusted to approximately 13 with 50% sodium hydroxide. The basic aqueous phase was then extracted with three 100 mL volumes of dichloromethane. The organic portion was then dried with potassium carbonate and filtered. Solvent was removed by rotary evaporation to yield mono-tert-butyloxycarbonyl-1,3-diaminopropane.
Reaction SMILES: [CH:1]1[C:13]2[CH:12](CCCC(O)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[C:1]1([CH2:25][CH2:21][CH2:22][CH2:23][OH:24])[C:13]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCCC1c2ccccc2-c2ccccc21
Agent: B
Product: OCCCCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of the acid material 6 (3.50 g; 13.90 mmol) in 30 mL of THF was cooled to 0° C. and treated with 13.90 mL of a 1.0M solution of borane in THF (13.90 mmol). The resulting mixture was stirred overnight, then quenched with saturated ammonium chloride (30 mL). The product was extracted into ethyl acetate, and the organic phase was washed successively with 3% HCl, saturated sodium bicarbonate, and brine. Removal of the solvent furnished the alcohol (2.90 g; 88%), which crystallized to a waxy solid on standing and did not require further purification. 1H NMR (CDCl3): δ 1.22 (m, 2H); 1.49 (m, 2H); 1.98 (m, 2H); 3.50 (t, 2H); 3.95 (t, 1H); 7.33 (m, 4H); 7.49 (d, 2H, J=7.3); 7.73 (d, 2H, J=7.3).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=O)[CH2:5][CH:4]([CH3:8])[O:3]1.CC([O-])=O.[Na+].[NH2:14][OH:15].Cl>CCO>[CH3:1][CH:2]1[C:6](=[N:14][OH:15])[CH2:5][CH:4]([CH3:8])[O:3]1
Reactant: CC1CC(=O)C(C)O1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1CC(=NO)C(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,5-dimethyldihydrofuran-3(2H)-one (20 g, 0.175 mol) and NaOAc (43 g, 0.526 mol) in EtOH (300 mL), NH2OH.HCl (15.8 g, 0.228 mol) was added portion in the mixture at 0° C. After addition, the reaction was stirred at rt for 3 h. Filtered, the filtrate was concentrated and the residue was dissolved in DCM, filtered, the filtrate was concentrated to give 2,5-dimethyldihydrofuran-3(2H)-one oxime. 1H NMR (ppm, 300 MHz, CDCl3) δ 3.7-4.9 (m, 2H), 2.0-3.0 (m, 2H), 1.2-1.4 (m, 6H).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]2[CH:44]=[CH:43][S:42][C:41]=2[CH:45]=O)(=[O:39])=[O:38])[CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:45][C:41]2[S:42][CH:43]=[CH:44][C:40]=2[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])=[C:20]1[CH3:29]
Reactant: O=Cc1sccc1S(=O)(=O)c1cccnc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccnc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.7 %

Procedure:
A mixture of triethylsilane (0.42 g), trifluoroacetic acid (0.25 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.055 g), 3-(pyridine-3-sulfonyl)thiophene-2-carbaldehyde (0.075 g) and 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was treated with additional triethylsilane (0.42 g) and trifluoroacetic acid (0.25 g), and stirred at room temperature for 3 hours and then at 50° C. for 20 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and ethyl acetate (1:0 to 0:1 by volume), followed by trituration with diethyl ether to afford the title compound as a white solid (0.027 g).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][S:14]2)=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)([CH2:3][CH:2]=[CH2:1])[CH2:13][S:14]2)=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Temperature: 10 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
Allyl bromide (5.7 ml, 66.56 mmol) was added dropwise to a solution of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.64 mmol) in dimethyl sulfoxide (34 ml). To this mixture, a solution of potassium tert-butoxide (5.22 g, 46.55 mmol) in dimethyl sulfoxide (70 ml) was slowly added dropwise at 10° C., followed by stirring for 2 hours at 10° C. and for 15 hours at room temperature. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/9) to give 7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.78 g, Yield 79%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:29][CH3:30])[CH3:28]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:29]([CH2:27][CH3:28])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Product: CCN(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 42 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using ethylmethylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 42%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[N:35]=[CH:34]1.[O:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH:52]1[O:57][CH2:58][CH2:59][N:60]1[C:64]([Sn](CCCC)(CCCC)CCCC)=[CH:63][N:62]=[CH:61]1.C(#N)C>C1C=CC([P]([Pd]([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)=CC=1>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:36]5[N:35]=[CH:34][N:33]([CH2:32][CH2:31][O:30][CH:25]6[CH2:26][CH2:27][CH2:28][CH2:29][O:24]6)[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20].[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:64]5[N:60]([CH2:59][CH2:58][O:57][CH:52]6[CH2:53][CH2:54][CH2:55][CH2:56][O:51]6)[CH:61]=[N:62][CH:63]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1CCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(CCOC4CCCCO4)cn3)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cncn3CCOC3CCCCO3)cc1OCC2
Temperature: 140 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (84.0 mg 0.0727 mmol) was added last to a degassed solution of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (272 mg, 0.727 mmol) and regioisomers 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole (600 mg, 1 mmol) in acetonitrile (5 mL, 100 mmol). The reaction was heated in the CEM microwave at 140° C. for 30 minutes with complete conversion by LCMS. Concentrated in vacuo and flash purified 0 to 100% methanol/dichloromethane. The product tubes were concentrated in vacuo to give 270 mg of the regioisomers 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. These inseparable compounds were dissolved in 4 N HCl in dioxane (10 mL) and the solution was stirred for 30 minutes at room temperature. Complete deprotection was confirmed by LCMS to give the final compounds which were purified by SFC to separate the regioisomer 208 (27 mg, 9% yield, M+1 406.1)
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].ClCCl.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(N(CC)CC)C>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH2:3][O:4][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(CO)CO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C)CO[Si](C)(C)C
Temperature: 0 °C

Procedure:
0.6 g of 2,2-dimethyl-1,3-propandiol was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, thereto was added 2.09 ml of triethyl amine, followed by the addition of 1.76 ml of trimethylsilyl chloride. The mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.23 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)=[O:24])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)c(Cl)c4)CC3)cccc2n1
Yield: 63 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3,4-Dichlorobenzoyl chloride (85.9 mg; 0.41 mmol) to obtain 52.5 mg. (63% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (br s, 1H), 7.75 (m, 2H), 7.47 (m, 1H), 7.4 (t, J=8.0 Hz, 1H), 7.18 (br s, 1H), 6.98 (dd, J=8.4, 0.8 Hz, 1H), 6.85 (dd, J=7.6, 0.8 Hz, 1H), 5.93 (s, 2H), 4.55 (br s, 1H), 3.61 (br s, 1H), 3.45 (br s, 1H), 3.14 (m, 3H), 2.79 (m, 2H). ESIMS+419.3 m/z
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.N1C=CC=CC=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: Nc1csc(Br)n1
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1csc(Br)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (52 g, 0.2 m) was suspended in acetic anhydride (200 ml) then treated dropwise with pyridine (100 ml), maintaining the temperature at 0° C. by means of an ice bath. After the addition was complete, the reaction mixture was stirred for 2 h. at room temperature then poured onto 20% aqueous sodium acetate (2 l.). The solution was cooled, filtered and the precipitate washed with water (2×200 ml.). The product was air dried and recrystallised from acetone to give the title compound (35 g, 80%) m.p. 165° C.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Br:4][C:5]1[S:19][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][NH:15][C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1>>[Br:4][C:5]1[S:19][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([CH2:1][CH3:2])[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1
Reactant: O=c1cc2c(n[nH]1)-c1cc(Br)sc1SCC2
Reactant: CCBr
Product: CCn1nc2c(cc1=O)CCSc1sc(Br)cc1-2

Procedure:
The reaction and procedure are conducted in the same manner as in Example 36 using ethyl bromide in place of methyl iodide and using 9-bromo-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in place of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as used in Example 36 to give 9-bromo-2-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 149°-151° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12](=O)[CH2:11][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:21]I.O.CN(C)[CH:26]=[O:27]>>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:26](=[O:27])[C:11]([CH3:12])([CH3:21])[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1OC)C(=O)CC2
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCCCc1cc2c(cc1OC)C(=O)C(C)(C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (0.02 mol) of 5-hexyl-6-methoxyindan-1-one dissolved in 20 ml of dimethylformamide are added dropwise to a suspension of 1.8 g (0.04 mol) of sodium hydride in 20 ml of dimethylformamide at 25° C. The mixture is stirred for 15 minutes at this temperature, and 11.4 g (0.1 mol) of methyl iodide are then added, while maintaining the temperature below 30° C. The reaction medium is stirred for 16 hours at 25° C. A further 0.9 g (0.0375 mol) of sodium hydride is added, and 15 minutes later 11.4 g (0.1 mol) of methyl iodide are added and the mixture is stirred for 2 hours at 25° C. The mixture is then heated for 1 hour at 50° C. It is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and then evaporated under reduced pressure. The orange oil obtained is purified by flash chromatography (dichloromethane, 3.54 g; 65%).
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[C@@H:68]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:69]([O:71]C)=[O:70]>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[C@@H:68]([CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[C:69]([OH:71])=[O:70]
Reactant: COC(=O)[C@H](Cc1ccccc1)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)CN([C@@H](Cc2ccccc2)C(=O)O)C3=O)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 87 %

Procedure:
The compound of example 382 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 381.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:26]=1
Reactant: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide (example B.56) (167 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (139 mg, 47%). MS (ISN) 588.0 [(M−H)−]; mp 152° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl-].[NH4+].[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:23]1[O:19][CH2:20][C:21]#[C:22][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C(#CC1c2ccccc2C=Cc2ccccc21)COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This preparation illustrates methods according to step 1 of the process for preparing the compounds of formula A. In this preparation a solution containing 8 g. of 5-chloro-5H-dibenzo[a,d]cycloheptene in 200 ml. of anhydrous tetrahydrofuran is added dropwise, under nitrogen, to a stirred solution containing 0.042 moles of 3-(2-tetrahydropyranyloxy)-prop-1-ynyl-1-magnesium chloride in 210 ml. of anhydrous tetrahydrofuran, at room temperature. The resulting mixture is heated for 2 hours at reflux and then allowed to stand, with stirring, for 16 hours at room temperature. The reaction mixture is then treated, first with 25 ml. of saturated aqueous ammonium chloride solution, then with 75 ml. of water, and then concentrated under reduced pressure to remove most of the organic solvent resulting in a two-phase liquid-liquid system, which is then shaken and extracted with three 60 ml. portions of ethyl ether. The ethereal extracts are combined and washed consecutively with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. The washed extracts are dried over sodium sulfate-potassium carbonate and then evaporated under reduced pressure affording a residue of 5-[3-(2-tetrahydropyranyloxy)-prop-1-ynyl]-5H-dibenzo[a,d] cycloheptene, which is divided into two portions, one of which is further purified by column chromatography on silica gel. The other portion is used directly as starting material for the next step.
Reaction SMILES: [OH:1][CH:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: CC(O)CNC(=O)c1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
154 g N-(2-hydroxy-propyl)-isonicotinamide in 500 mL dichlormethane was added to a solution of Dess-Martin reagenz in 1.5 L dichlormethane at 0° C. under nitrogen. The reaction was stirred for 30 min. at 0° C. and 4 h at RT. The mixture was concentrated and the crude product was purified by chromatographie on silica to give 91 g of the desired product.