Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[S:8][CH:9]=[CH:10][C:2]1=2.[CH2:11](O)[CH2:12][OH:13]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[S:1][C:2]2[CH:10]=[CH:9][S:8][C:3]=2[CH:4]=1
Reactant: O=Cc1cc2sccc2s1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: c1cc2sc(C3OCCO3)cc2s1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of thieno[3,2-b]thiophene-2-carboxaldehyde (8) (23.30 g., 138.5 mmole); ethylene glycol (31 mL., 34.39 g., 554.0 mmole); pyridinium tosylate (2.5 g., 10 mmole); and benzene (200 mL) was stirred and refluxed and the water (3.2 mL) was removed by a Dean-Stark trap (~4 hours). The reaction was cooled to room temperature, extracted with water three times and then with a saturated solution of sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated to leave a crystalline mass. Trituration with a small amount of ether removed the color to give 24.72 g of a white crystalline product, mp. 88°-90° C. An additional 1.43 g of product was collected from the ether washing, mp 88°-89° C., yielding a total of 26.15 g of 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[N:8]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:39]2[S:43][C:42]([C:44]3([OH:48])[CH2:45][CH2:46][CH2:47]3)=[N:41][CH:40]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[N:8]([S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=3)(=[O:31])=[O:30])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C4CCNCC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 50A) (120 mg, 0.169 mmol) in dichloromethane (846 μl) was added trifluoroacetic acid (652 μl, 8.46 mmol). The reaction was stirred for 1 hour and was then concentrated to dryness. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous bicarbonate solution (1 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 609.4 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH:11]([C:14]1[C:19]([NH2:20])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH:11]([C:14]1[C:19]([N:20]=[C:8]=[S:10])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:12])[CH3:13]
Reactant: S=C=S
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g of triethylamine in 10 ml of pyridine is cooled to from -5° C. to -10° C., and 20 ml of carbon disulfide are added dropwise. At -10° C., a solution of 15.0 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-3-aminopyridine in 27 ml of pyridine is slowly added dropwise. The mixture is further stirred at -10° C. for 1 hour. A solution of 10.0 g of N,N'-dicyclohexylcarbodiimide in 10 ml of pyridine is then added. After a further 3 hours at -10° C., the mixture is stirred for 18 hours at room temperature. The reaction mixture is concentrated by evaporation and hexane is added to the residue. Thehhexane solution is filtered off and concentrated by evaporation. 2,4-Diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate is obtained in the form of a yellow oil, which is used for the next reaction without being further purified; IR (CCl 4): 2090, 1490, 1220 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(O)cc1
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-hydroxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.6, 60.5, 116.0, 126.4, 127.2, 128.2, 129.2, 138.1, 143.8 and 158.1.
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.[Pt]=O>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 20 h
Yield: 66.4 %

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (320 mg, 1.13 mmol) was dissolved in 3 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (250 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 20 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with a mixture of iso-propanol and CH2Cl2 and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was partitioned between H2O and CHCl3. The aqueous portion was made basic by addition of 10% NaOH solution until pH >12. The layers were separated and the organic portion was washed successively with 10% NaOH (2×), H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a tan foam. Crystallization from ethyl acetate gave the title compound (215 mg) as light amber crystals, mp 158.0-160.0° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2Cc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of the compound obtained in Example 6 (3) (3.0 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (0.7 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 15 minutes. 4-Fluorobenzyl bromide (3.1 mg) was then added thereto at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with toluene. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) to obtain 2.4 mg of the desired product as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Oc2ccccc2)c(F)cc1Cl

Procedure:
4-Chloro-2-fluoro-5-methylaniline (5 g, 31.4 mmol) was dissolved in tetrahydrofuran (100 ml) and potassium carbonate (6.0 g, 37.7 mmol) and phenyl chloroformate (5.9 g, 37.7 mmol) were added. Solution was refluxed for 3 hr and the solvent was removed under reduced pressure. Product was purified by column chromatography on silica gel (eluent, methylene chloride:hexane, 6:4; 7.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:24][CH2:23][CH:22]([NH:25]C(=O)C(F)(F)F)[CH2:21]2)=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[NH2:25][CH:22]1[CH2:23][CH2:24][N:20]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH2:21]1
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(NC(=O)C(F)(F)F)C1)c1cnn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1CCN(c2ccc(Cl)cc2NC(=O)c2cnn3cccnc23)C1
Yield: 76.1 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {5-chloro-2-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-phenyl}-amide (50 mg), methanol (2 mL) and an aqueous solution of sodium hydroxide (4 M, 1 mL) was heated at 60° C. for 1 hour. The resulting mixture was cooled, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 30 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl]-amide (light yellow foam) without further purifications. MS=356 [M]+.
Reaction SMILES: C1COCC1.[Br-].[F:7][CH2:8][CH2:9][CH2:10]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]>O>[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:10][CH2:9][CH2:8][F:7])[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]
Reactant: CCOc1c(F)cc(C2CCC(=O)CC2)cc1F
Reactant: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(F)cc(C2CCC(CCCF)CC2)cc1F
Temperature: -50 °C
Yield: 21 %

Procedure:
THF (100 ml) was added to the above 3-fluoropropyltriphenylphosphine bromide (22.0 g, 54.6 mmol), followed by cooling the mixture down to -50° C. in a nitrogen atmosphere, adding to the mixture, a 70 ml THF solution of potassium-t-butoxide (6.10 g, 54.5 mmol), stirring the mixture for 3 hours, dropwise adding to the reaction solution, a 80 ml THF solution of 4-(3,5-difluorophenetyl)-1-cyclohexanone (10.0 g, 42.0 mmol), stirring the mixture for one hour at the same temperature, and heating it up to room temperature for 4 hours, adding water (200 ml) to the resulting reaction solution, extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying the organic layer over magnesium sulfate, distilling off the solvent under reduced pressure, purifying the residue according to column chromatography treatment using toluene as a developing solvent, hydrogenating the resulting purified substance in the presence of 5% Pd/C catalyst, in ethanol, and thereafter filtering off the catalyst to obtain 4-(3,5-difluorophenetyl)-1-(3-fluoropropyl)cyclohexane (2.51 g, 8.83 mmol). Yield: 21.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:29])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].S(OC)(O[CH3:36])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:25])([F:26])[F:24])[N:17]=[C:16]2[O:29][CH3:36])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.51 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-pentafluoroethyl -1(2H)-pyrimidinyl ]-4-fluorobenzoate are added at room temperature while stirring to a suspension of 0.93 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes. The mixture is subsequently treated with 4.04 g of dimethyl sulphate and stirred at 50° C. for 4 hours. The reaction mixture is cooled and poured into 500 ml of water, and the aqueous solution is extracted twice with 100 ml of ethyl acetate each time. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is separated by chromotography on a silica el column using n-hexane/diethyl ether (2:1) as the eluent. The product is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-benzoate, m.p. 82°-84° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17](=[O:19])[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc2cc(CCC(=O)O)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(CCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 5-(2-carboxy-ethyl)-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 5 mmol) in 10 mL of dimethylformamide, was added 1,1′-carbonyldiimidazole (973 mg, 6 mmol). The mixture was stirred under nitrogen at room temperature for 30 mins. To the reaction mixture was added pyrrolidine (1.3 mL, 15 mmol) dropwise. After stirring at room temperature for overnight, the reaction was diluted with dichloromethane (300 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried and concentrated to give 1.5 g (95%) of 5-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.ClCCl>N1C=CC=CC=1>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([NH:6][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 3,5-dimethoxylaniline (24.0 g, 156.9 mmol) and p-toluenesulfonyl chloride (29.8 g, 156.9 mmol) in anhydrous pyridine (70 mL) was stirred and heated to reflux for 30 min under argon atmosphere. The reaction mixture was cooled to room temperature and poured into 400 mL of ice-cold water. Dichloromethane was added to extract the product. The organic layer was separated and washed with water, 5% HCl aqueous solution, water and brine and dried with anhydrous Na2SO4. Removal of solvent provided yellow solid crude, which was purified by re-crystallization in diethyl ether to afford 42.6 g (89.0%) of the title compound as light yellow crystalline solid. mp 103-104° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[C:5]([Br:21])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(N)c2c(c1)CC(CO)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1Br)CC(CO)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (7-amino-5-methyl-2,3-dihydrobenzofuran-2-yl)methanol (7d) (0.80 g, 4.5 mmol) in DMF (13 mL) at 0° C. was added NBS (0.08 g, 4.5 mmol), it was stirred at 0° C. for 15 min. The mixture was extracted with EtOAc (150 mL), washed with NaHSO3 (50 mL), water, brine, dried and concentrated to give the title compound (7e) as a yellow solid. MS-ESI (m/z): 258 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Mg].[CH3:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N:12]=1.Cl>CCOCC>[C:11]([NH:12][C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8])=[O:17])(=[O:16])[CH3:10]
Reactant: Cc1ccc2nc(C)oc(=O)c2c1
Reactant: Clc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C)cc1C(=O)c1ccccc1Cl

Procedure:
The Grignard reagent prepared from 312.5 g (1.63 mol) of 2-bromochlorobenzene and 39.6 g (1.63 mol) of magnesium in 1.2 liters of anhydrous ether is added dropwise, in 2.5 hours, to a stirred solution of 270 g (1.54 mol) of 2,6-dimethyl-4H-3,1-benzoxazin-4-one in 4 liters of absolute ether at room temperature. The mixture is then allowed to react for a further 2 hours at the same temperature. While cooling in ice, the mixture is cautiously hydrolysed with 2N hydrochloric acid and then the aqueous phase is separated off. The organic phase is washed first with dilute sodium hydroxide solution and then with water. The organic phase is dried and concentrated. The resulting residue is induced to crystallise with isopropyl ether.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:22]O>>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: CN1CCN(c2cc(CC(=O)O)ccn2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 85 °C
Yield: 78 %

Procedure:
Thionyl chloride (0.9 ml) was added to a solution of 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetic acid (900 mg, 3.82 mmol) in MeOH (15 ml) at 0° C. The reaction mixture was heated for 4 h at 85° C. and concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 750 mg (78%) of methyl 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetate as a colorless liquid.
Reaction SMILES: [C:1]([N:6]=[N:7][C:8]([C:15]#[N:16])([CH3:14])[CH2:9][CH2:10][C:11](O)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>CCCCC>[C:1]([N:6]=[N:7][C:8]([C:15]#[N:16])([CH3:14])[CH2:9][CH2:10][C:11]([Cl:18])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC(C)(C)N=NC(C)(C#N)CCC(=O)O
Solvent: CCCCC
Product: CCC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 83.4 %

Procedure:
To a stirred slurry of 10 grams (.0443 moles) of 4-t-amylazo-4-cyanovaleric acid in 50 mls. of pentane in a 100 ml. flask was added 9.37 grams(.045 moles) of PCl5 over a 10 minute period. After the addition was complete, the reaction was stirred at room temperature for another 50 minutes and poured into 100 mls. of ice water. The pentane layer was separated, washed with 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated to leave 9.0 grams (84% yield) of 4-t-amylazo-4-cyanovaleryl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH2:8][Br:18])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: O
Product: COc1ncc(CBr)cc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-2-methoxy-5-methyl-pyridine (Step AM3) (3.0 g, 14.7 mmol), was added NBS (3.1 g, 17.6 mmol) and AIBN (121 mg, 0.7 mmol) and the mixture was stirred at 80° C. for 1 h. H2O and CH2Cl2 were added and the phases were separated. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (heptane/EtOAc, 95:5→0:100). tR: 1.10 min (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:30]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[6-(3,4-dichloro-phenylmercapto)-hexyloxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])#[N:2].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:20][CH2:19]1)=[O:17])#[N:2]
Reactant: N#CCCCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCN1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix 1-[(4-cyanobutyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.0 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.