Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([NH:26][C:27](Cl)=[O:28])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>CCOC(C)=O>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([NH:26][C:27]([N:1]3[CH2:6][CH2:5][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:8](=[O:15])[O:7]4)[CH2:3][CH2:2]3)=[O:28])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)NC1CCC2(CC1)OCCO2
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C1OC2(CCN(C(=O)NC3CCC4(CC3)OCCO4)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
Add spiro[isobenzofuran-1,4′-piperidin]-3-one (100 mg, 0.49 mmol) to 1 mL of the stock solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-carbamoyl chloride (˜0.2 M in toluene) and heat to 60° C. for 16 hours. Cool the solution, dilute with EtOAc and wash with brine. Dry the solution (Na2SO4) and concentrate under reduced pressure. Purify the crude product using preparative plate chromatography and triturate the resulting material with ether to obtain 1′-(1,4-dioxa-spiro[4.5]dec-8-yl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)c1cccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3-(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 373 (M+1). Mp: 138.9-140.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:32])[S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](Br)[CH:25]=1)(=[O:23])=[O:22]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:26]1[CH:25]=[C:24]([S:21]([N:20]([CH3:32])[CH3:19])(=[O:22])=[O:23])[CH:29]=[CH:28][C:27]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N,N-dimethyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][CH:2]([F:12])[CH:3]([NH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:4]C=C.[Mn]([O-])(=O)(=O)=O.[K+].[C:19]([OH:22])(=[O:21])[CH3:20]>O>[F:1][CH:2]([F:12])[CH:3]([NH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:20][C:19]([OH:22])=[O:21]
Reactant: C=CCC(NC(=O)OC)C(F)F
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)NC(CCC(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1,1-Difluoro-2-methoxycarbonylamino-4-pentene prepared as in Step F (4.00 g, 20.7 mM), dissolved in glacial acetic acid (60 ml), is added to potassium permanganate (9.80 g, 62 mM) in water (300 ml) at 0° C. After stirring for 15 hours at room temperature, the excess of potassium permanganate is destroyed with a 10% sodium bisulfite solution and the mixture saturated with sodium chloride. Extraction with diethyl ether and evaporation of the solvent in vacuo affords 1,1-difluoro-2-methoxycarbonylamino-5-pentanoic acid as a colorless oil. Crystallization from ether/petroleum ether gives 3.200 g of pure acid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:22]O>>[C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([O:16][CH3:22])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(C(=O)NC(C)(C)C)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)noc1C(=O)NC(C)(C)C
Reaction time: 48 h

Procedure:
5.0 g of 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are dissolved in 200 ml of methanol, and 5 ml of concentrated H2SO4 are added. After 2 days, the mixture is evaporated down, the residue is partitioned between ethyl acetate and water and the organic phase is evaporated down. 4.0 g of methyl 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylate are obtained as a colorless oil (compound No. 1007).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:34])[NH:16][C:17]1[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:18]=1[O:32][CH3:33])[N:9]2[CH3:14])(=[O:3])[CH3:2].Br[C:36]1[N:37]=[C:38]([C@H:46]2[CH2:51][CH2:50][C@H:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[N:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[C:40]=12>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:34])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:36]3[N:37]=[C:38]([C@H:46]4[CH2:47][CH2:48][C@H:49]([N:52]5[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]5)[CH2:50][CH2:51]4)[N:39]4[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[C:40]=34)=[CH:19][C:18]=1[O:32][CH3:33])[N:9]2[CH3:14])(=[O:3])[CH3:2]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC(C)=O)cccc2n1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC(C)=O)cccc2n1C

Procedure:
Reaction of 2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoyl)-1-methyl-1H-indol-4-yl acetate (36 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% methanol (+ few drops ammonia)) gave 2-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamoyl)-1-methyl-1H-indol-4-yl acetate. This product was stirred with 7N ammonia in methanol for 1 h by room temperature, concentrated in vacuo, solved in acetonitril and filtered. The filtrate was concentrated in vacuo to give 4-hydroxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (15 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:25])[C:10](=O)[CH2:11][CH2:12][N:13]([CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:3]=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:25])[CH2:10][CH2:11][CH2:12][N:13]([CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(N(C)C(=O)CCN(C)c2ccc([N+](=O)[O-])cc2)c1
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N(C)CCCN(C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
Borane-dimethylsulfide complex (0.72 mL, 7.02 mmol) was added to a solution of N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide (600 mg, 1.75 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture was warmed to room temperature then heated at reflux overnight. After cooling to room temperature the solvent was evaporated in vacuo. The residue was quenched into ice water, extracted with ethyl acetate then the organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate in hexane as eluent afforded N-(4,6-dimethyl-pyridin-2-yl)-N,N′-dimethyl-N′-(4-nitro-phenyl)-propane-1,3-diamine (350 mg, 61%) as yellow semi solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:15][OH:16].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[N:15][OH:16])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
3.0 g (16 mmol) of the N-trimethylacetyl-4-piperidone obtained according to the procedure above and 1.2 g (17 mmol) of hydroxylamine hydrochloride were placed into a 50 mL flask with 20 mL of ethanol. To the resulting mixture was added 1.9 g (18 mmol) of Na2CO3, and the resulting mixture was allowed to stir at room temperature overnight. The ethanol was removed in vacuo, and the resulting solid was triturated with ethyl acetate (2×50 mL). Combined ethyl acetate washings were washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The ethyl acetate solution was concentrated to yield 2.4 g (74%) of N-trimethylacetyl-4-hydroxyiminopiperidine as a white solid: 1H NMR (300 MHz, CDCl3) δ3.75 (dd, 4H, J=12.3, 6.2 Hz), 2.68 (dd, 2H, J=6.2, 6.2 Hz), 2.39 (dd, 2H, J=6.2, 6.1 Hz), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ176.66, 156.34, 45.02, 43.51, 38.77, 31.13, 28.31, 24.93.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NCC(O)CO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCC(O)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.4 g of (+/−) 3-amino-1,2-propanediol are heated at 60° C. for 2 h in 10 ml of ethanol. The crystals precipitating on cooling are filtered off and washed with ethanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2,3-dihydroxypropyl)acetamide remains as colorless crystals of m.p. 180-181° C.
Reaction SMILES: Br.C(O)(=O)C.[C:6]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]3[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)[CH:18]=2)[CH2:13]1)(=[O:10])[CH2:7][CH2:8][CH3:9].CS(C)=O>C(O)(=O)C>[C:6]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24](=[O:27])[NH:25][N:26]=3)[CH:18]=2)[CH2:13]1)(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCC(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.1 %

Procedure:
20 m of a 25% hydrogen bromide-acetic acid solution was added to 4.00 g of 2-butyrylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 45 ml of acetic acid, and then 1.14 ml of dimethyl sulfoxide was added to the mixture. The resulting mixture was stirred at room temperature for 3.5 hours. Hydrogen bromide-acetic acid was removed, and the residue was recrystallized from hydrous ethanol to obtain 3.50 g of 2-butyrylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11](=[S:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Na].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([S:14][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C)Br
Reactant: S=c1ncn(-c2ccc(Cl)c(Cl)c2)[nH]1
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Sc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An 11.5 g portion of 1-(3,4-dichlorophenyl)3-thiono-1,2,4-1H-triazole was dissolved in 100 ml of dry dimethylsulfoxide, and was added to 1.1 g of sodium dissolved in 50 ml of absolute ethanol. The mixture was warmed at 60°-80° for 1 hour, and then 8.5 g of ethyl 2-bromopropionate was added and the mixture was held at 100°-110° for 2 hours. It was then cooled and poured over ice-water, and the aqueous mixture was extracted with dichloromethane. The organic layer was washed with brine, and was dried over magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by chromatography, eluting with 2:1 hexane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain 11 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:22]=4[O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O>C(#N)C.CC(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:22]=4[O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1ccc(OCC(=O)OC(C)(C)C)c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(OCC(=O)O)c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
tert-Butyl 2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-4-[3-(ethoxycarbonyl)propoxy]phenoxyacetate (200 mg) was dissolved in a mixed solvent of acetnitrile (10 ml) and acetone (1 ml) and methanesulfonic acid (62 mg) was added. The resulting solution was stirred at 80° C. for two hours. The reaction mixture was concentrated and diluted with water and neutralized with sodium hydrogen carbonate solution. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate. After concentration, the product was crystallized with a mixed solvent of diisopropyl ether and n-hexane (1:2), filtered and dried to give 2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-4-[3-(ethoxycarbonyl)propoxy]-phenoxyacetic acid (117 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:19]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:19])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1ccc(N2CCN(C)CC2)cc1
Reactant: N
Product: CN1CCN(c2ccc(CC(N)=O)cc2)CC1
Yield: 57 %

Procedure:
Methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate (0.45 g, 1.81 mmol) in methanolic ammonia (15 ml) was heated at 100° C. in a pressure bomb overnight. Excess MeOH was concentrated under reduced pressure to give the crude compound. This was washed with n-pentane and dried in vacuo to afford 0.24 g (57%) of 2-(4-(4-methylpiperazin-1-yl)phenyl)acetamide as a brown color solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([NH:16][CH3:17])[CH:13]=[CH:12][N:11]=1.C([O-])(=O)C.[K+]>CC(O)=O>[Cl:9][C:10]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([Cl:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CNc1cc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 18 %

Procedure:
N-Chlorosuccinimide (0.623 g, 4.67 mmol) was added to 2-chloro-N-methyl-pyridin-4-amine (0.50 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in AcOH (25 mL) and the mixture was stirred at 80° C. for 1.25 hours. The mixture was cooled and concentrated in vacuo. The concentrated mixture was diluted with water, neutralised with aqueous NaOH and extracted with EtOAc (×3). The organic extracts were evaporated onto silica gel. Gradient chromatography, eluting with 10-50% EtOAc:c-Hex, gave 2,5-dichloro-N-methylpyridin-4-amine (0.114 g, 0.699 mmol, 18% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[C:14]([S:18][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1
Reactant: Cc1cccc(S)c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cccc(Sc2cccc([N+](=O)[O-])c2)c1
Yield: 84.8 %

Procedure:
The general procedure in example 39 was followed. 3-Nitroiodobenzene (249 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-nitrophenyl 3-tolyl sulfide (208 mg, 85% yield) as yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.95-7.99 (m, 2 H), 7.46 (dt, 1 H, J=7.5 Hz, 0.9 Hz), 7.38 (t, 1 H, J=8.1 Hz), 7.12-7.28 (m, 5 H), 2.36 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 141.0, 140.0, 134.3, 134.2, 131.7, 130.8, 130.0, 129.9, 129.8, 123.1, 122.9, 120.9. MS (EI) m/z (relative intensity) 245 (100), 184 (80).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9]CN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].COC1C=CC(N)=C([C:27]([F:30])([F:29])[F:28])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:16][C:17]=1[C:27]([F:30])([F:29])[F:28])=[C:2]=[S:3]
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: COc1ccc(N=C=S)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-methoxy-2-trifluoromethylaniline. Title compound: 1H NMR [400 MHz, (CD3)2SO]: 7.70-7.55 (m, 1H), 7.35-7.15 (m, 2H), 3.28 (s, 3H); single peak at tR=5.61 min (System 2).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-:12])=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:3]=1.[Br:25]N1C(=O)CCC1=O>CO.C(Cl)(Cl)Cl>[Br:25][C:3]1[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N+:5]([O-:12])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(O)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [O-][n+]1c(CCCCCCCCCCCO)c(Br)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
In this example, 1 m mole of 4-hydroxy-2-(11-hydroxyundecyl) quinoline-N-oxide is dissolved in a liquid mixture of methanol-chloroform (5:1), and 1 m mole of N-bromosuccinimide is added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the solvent is removed therefrom by distillation, and the residue is recrystallized from ethanol, whereby the captioned compound is obtained (yield: 70.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH2:21]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH:21][C:9]([C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1)=[O:10]
Reactant: CCOc1cscc1C(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cscc1C(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8.8 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride is dissolved in 100 ml. of methylene chloride and added dropwise to a mixture of 6.6 g. of 5-chloro-2-hydroxyaniline in 100 ml. of methylene chloride and 6.5 ml. of triethylamine. This mixture is stirred at ambient temperature overnight, concentrated to 100 ml. and filtered. The filtrate is allowed to stand overnight and the precipitate which forms is collected, washed with water and dried in vacuo. This combined precipitate is recrystallized from 200 ml. of ethanol, treated with charcoal, filtered through diatomaceous earth and concentrated giving 5'-chloro-4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide as red brown crystals.
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C@H:16]([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C@@H:16]([CH3:35])[NH2:12])=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[(1R)-2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 47, 251.1 mg) was dissolved in dichloromethane (2 mL) to give a pale orange solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes the solvent was evaporated under vacuum affording a yellow oil which was charged on a 5 g SCX cartridge and flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (170.0 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1
Product: CC(=O)N1CCC(Nc2ncc(C(=O)c3ccc(Cl)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone (Example 362) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-chloro-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 374.