Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:43]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[NH:45][NH:44]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[NH2:44][CH:43]([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]([NH2:45])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCC1CCCCCCCCC(CCCCCC)NN1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCCCC(N)CCCCCCCCC(N)CCCCCC
Yield: 68.2 %

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 190 g (0.56 mol) of 3,12-dihexyl-1,2-diazacyclododecane (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained as main fraction 130 g (68% of theory) of 7,16-diaminodocosane as colourless oil [b.p. 184° C./0.02-0.005 Torr; nD20 =1.4624; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C.C1C=C[NH+]=CC=1.[Br:32][Br-]Br.O>ClCCl>[Br:32][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)=[O:11]
Reactant: COC(=O)c1ccc(C(=O)Cc2ccc(SC)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C(Br)c2ccc(SC)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of methyl 4-{[4-(methylthio)phenyl]acetyl}benzoate (5 g) in dichloromethane (250 ml) were added acetic acid (0.65 ml) and pyridinium bromide perbromide (6.51 g) at 0° C., and the mixture was stirred for 1 h at the same temperarure. The reaction mixture was poured into water (250 ml) and extracted with ethyl acetate (250 ml). The organic layer was washed with water and brine, dried over magnesium sulfate and evapolated. The residue was washed with diisopropylethyl ether and collected by filtration to give methyl 4-{2-bromo[4-(methylthio)phenyl]acetyl}benzoate as an off-white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[C:9]([CH3:14])[N:8]=1)=[O:6])([CH3:3])[CH3:2].Cl.O1CCO[CH2:18][CH2:17]1>CC(=O)OCC.C[CH2-].C[CH2-].[Zn+2]>[CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:17][CH3:18])=[C:9]([CH3:14])[N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: Cc1nc(C(=O)OC(C)C)ccc1Br
Agent: Cl
Agent: [CH2-]C
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)OC(C)C)nc1C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Diethyl zink (9.78 g, 79.2 mmol) is added to a solution of 5-bromo-6-methyl-pyridine-2-carboxylic acid isopropyl ester (14.6 g, 56.5 mmol, prepared in analogy to 5-bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester) and Pd(dppf) (461 mg, 0.565 mmol) in dioxane (250 mL). The mixture is stirred at 80° C. for 18 h before it is cooled to rt, diluted with ice-water (150 mL) and EA (250 mL) and acidified with 2 N aq. HCl. The org. layer is separated and the aq. phase is extracted with EA (3×100 mL) and DCM (4×100 mL). The aq. phase is neutralised by adding sat. aq. NaHCO3 solution and is again extracted with DCM (4×75 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give 5-ethyl-6-methyl-pyridine-2-carboxylic acid isopropyl ester (7.08 g) as a pale yellow oil; LC-MS: tR=0.77 min, [M+1]+=207.99. 1H NMR (CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 1.41 (d, J=6.3 Hz, 6H), 2.63 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 5.30 (hept, J=6.3 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:14]=1[C:15](OC)=[O:16])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:11])[NH:12][C:13]2[C:14]([C:15]=1[OH:16])=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of methyl 2-(2-(benzyloxy)acetamido)-5-bromobenzoate (15 g, 39.7 mmol, Intermediate 11: step a) in THF (198 mL) was added KHMDS (1 M in THF, 119 mL, 119 mmol). The resulting solution was stirred at room temperature for 40 minutes and then additional KHMDS (19.8 mL, 19.8 mmol) was added and stirring continued at room temperature for 2 hours. The mixture was quenched with water (225 mL) and the layers were separated. The aqueous layer was acidified with 1 N aqueous HCl to pH 2-3. Some of the title compound precipitated out of solution and was collected by filtration. The aqueous was then extracted with EtOAc (3×200 mL). The organics were combined with the solid collected previously and sonicated. The solution was dried (Na2SO4), filtered and concentrated to dryness to provide the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[S:30][CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30][CH:29]=2)=[C:20]([C:37]([F:40])([F:38])[F:39])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3csc4ccccc34)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2csc3ccccc23)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 80-5 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][S:18][C:19]1[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>ClCCl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][S:18]([C:19]1[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc(SCc2cccs2)nc1
Solvent: ClCCl
Product: O=S(Cc1cccs1)c1ncc(Br)cn1
Reaction time: 18 h
Yield: 53 %

Procedure:
85% m-Chloroperbenzoic acid (1.5 mmol) was added to a solution of 2-(2-thienylmethylthio)-5-bromopyrimidine (1.5 mmol) in dichloromethane (25 ml) at -10° C. and the solution left at 0° C. for 18 h. The dichloromethane solution was then washed with saturated aqueous solutions of Na2SO and NaHCO3, and the dried (MgSO4) solution evaporated to leave the title compound; yield 53%, m.p. 108°-109° C. (iPrOH). 1H NMR (CDCl3) δ4.53 (CH2, 6.9 (H-3', H-4'), 7.16 (H-5'), 8.83 (H-4, H-6).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.Cl[P:11](=[O:19])(Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([P:11](=[O:19])([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: O=P(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 82 %

Procedure:
A mixture of anhydrous ethylether and dried magnesium 5 g was put in a reaction vessel, into which a solution of parabromofluorobezene 35 g dissolved in anhydrous ethylether 50 ml subsequently was added slowly to prepare a Grignard reagent. Into this Grignard reagent, a solution of dichlorophenylphosphine oxide 19.5 g dissolved in anhydrous ethylether was added for a reaction. After performing the reaction, the solution was washed with distilled water and moisture was removed therefrom with a drying agent. Thereafter, the resulting solution was concentrated under a reduced pressure and was vacuum-distilled to give 25.77 g of bis(4-fluorophenyl)phenylphosphine oxide, which was then subjected to the treatment of infrared spectrum analysis and NMR spectrum analysis to insure the existence of P=O and --P--C6H4 -- groups therein.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:14][C:15](=[O:20])[O:16][CH2:17][CH2:18]Cl>CO.C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:20]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)OCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C1OCCN1c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A solution of 11.25 g of sodium methoxide in 50 ml of methanol was added drop-by-drop to a stirred solution of 58.0 g of 1A in 400 ml of ethanol. The mixture was refluxed for 5 minutes, then the volatile materials were evaporated under reduced pressure. The residue was treated with water and extracted with ether. The extract was dried and concentrated under reduced pressure. The residue was cooled and filtered to give 3-(2-chloro-4-nitrophenyl)-2-oxazolidinone (1B), as a white solid, mp: 94°-96° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:6]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[O:17])=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Yield: 39 %

Procedure:
A solution of 30 g. of 1-methylpyrrole-2-acetonitrile and 60 g of p-toluoyl chloride in 200 ml of o-dichlorobenzene is refluxed under nitrogen for 4 hrs. The mixture is concentrated to near dryness, diluted with 250 ml. of methylene chloride, washed successively with an aqueous solution of dimethylaminopropylamine, dilute hydrochloric acid and potassium carbonate solution. Removal of the organic solvent leaves an oily residue which crystallizes in 80 ml of methanol to give 22.2 g (39%) of 1-methyl-5-(p-toluoyl)-pyrrole-2-acetonitrile. The methanol filtrate is concentrated and the residual oil is hydrolyzed to the amide by brief refluxing with aqueous ethanolic NaOH (10%). The separated solid is collected giving 10.1 g (16.4%) of 1-methyl-5-(p-toluoyl)-pyrrole-2-acetamide. Total yield = 55.4%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[Br:18][CH2:19][CH2:20]Br>CC#N>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH2:19][Br:18])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: BrCCBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCCBr)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (0.30 g, 1.74 mmol) in MeCN (5 mL) was added Cs2CO3 (0.71 g, 2.18 mmol) and 1,2-dibromoethane (1.64 g, 8.71 mmol). The resulting mixture was heated in a sealed tube at 100° C. After 1.5 h, additional Cs2CO3 (0.4 g, 1.21 mmol) was added and heated at 100° C. for another 2 h. Upon cooling, the mixture was partitioned between EtOAc and 1N NaOH. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-70% EtOAc-hexanes gradient) to afford the title compound as a white solid (0.255 g, 53% yield): MS (ES) m/z 279 and 281 (M+1 Br isotopes).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[BH3-][C:30]#N.[Na+].C=O>CO.CC(O)=O>[CH3:30][N:2]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1
Reactant: COc1ccc(-c2cnc3[nH]cc(C(=O)NC4CCNC4)c3n2)cc1OC
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)NC4CCN(C)C4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a mixture of 2-(3,4-dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid pyrrolidin-3-ylamide hydrochloride (12 mg, 0.03 mmol) in MeOH (0.5 mL) was added NaBH3CN (15 mg, 0.23 mmol). A solution of HOAc (1 drop) in MeOH (1 mL) was prepared and 2 drops of this solution was added to the reaction mixture so that the pH ˜4. Aqueous CH2O (37%, 25 μL, 0.34 mmol) was added to the reaction mixture which was then stirred at room temperature for 2 h, partitioned between saturated Na2CO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (Na2SO4) and concentrated to give a pale yellow solid. The crude product was washed with Et2O to afford 11 mg (100%) of 2-(3,4-dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-pyrrolidin-3-yl)-amide as a yellow powder. MP 193-194° C., M+H 382.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:16](=[O:17])O[CH:14]3O)=[CH:5][CH:4]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:16](=[O:17])[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/c2ccc3c(c2)C(O)OC3=O)cc1
Reactant: NNc1ccccc1
Product: COc1ccc(/C=C/c2ccc3c(=O)n(-c4ccccc4)ncc3c2)cc1

Procedure:
Following the procedure of Example 18 above trans-5-[2-(4-methoxyphenyl)ethenyl]-3-hydroxyphthalide (15 g) and phenyl hydrazine (10 ml) were reacted to give the 2-phenyl-1(2H)-phthalazinone derivative (9.8 g), mp 198°-199° C.
Reaction SMILES: C[O-].[Na+].[N:4]([N:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)S(C1C=CC(C)=CC=1)(=O)=O)=O>COC(C)(C)C>[C:18]1([CH:17]=[N+:6]=[N-:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: [N-]=[N+]=Cc1ccccc1

Procedure:
To a solution of sodium methoxide (1.2 equivalent, 4.0 ml of 1M solution in methanol) in tert-butyl methyl ether (12 ml) was added N-nitroso-N-benzyl-p-toluenesulphonamide (966 mg, 3.34 mmol) in small portions at room temperature. After the addition was finished the reaction mixture was refluxed for 15-30 minutes. The reaction mixture was cooled and washed with water (3×12 ml). The etheral solution of phenyldiazomethane was dried over sodium sulphate for 30 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C(=O)(O)[O-:13].[Na+]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:11])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cn1
Reactant: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CC(N)=O)cn1
Yield: 52.2 %

Procedure:
The compound 2-(6-methoxypyridin-3-yl)acetonitrile (0.60 g, 4.05 mmol) in poly phosphoric acid (6 g) was stirred at 95° C. for 1 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution and the compound was extracted with DCM (3×20 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude compound was washed with ether (2×5 ml) to afford 350 mg (52.2%) of 2-(6-methoxypyridin-3-yl)acetamide as white color solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Reaction time: 1 h
Yield: 54.6 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.17 g, 55%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][CH2:11][CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:13][CH2:12][CH2:11][Cl:10]
Reactant: Cc1ccc(N)cc1Cl
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NCCCCl)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 60 %

Procedure:
A mixture of 3-chloro-4-methylaniline (7.79 g, 55 mmol), 1-chloro-3-iodopropane (5.91 ml, 55 mmol), cesium carbonate (35.84 g, 110 mmol) and DMF (15 ml) was stirred at room temperature for 19 hours. To the mixture was added water (75 ml), and the mixture was extracted with hexane (60 ml, 30 ml×2). The organic layer was washed with water (10 ml), dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 200 g, hexane/ethyl acetate=1/0 to 19/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (7.30 g, 33 mmol, Yield 61%) as a pale brown oily substance.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:12]([O:22][CH3:23])[CH:11]=1)/[C:6](O)=[O:7].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(C(C)C)CC)(C)C.C(OC(C)(C)C)(=O)[NH:49][NH2:50]>ClCCl.C(OCC)(=O)C.O>[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:12]([O:22][CH3:23])[CH:11]=1)/[C:6]([NH:49][NH2:50])=[O:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\CCCCl)C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]pentanoic acid (CAS No. 870843-27-9, 10 g) was dissolved in dichloromethane (130 mL). BOPCl (4.53 g), IPEA (12.3 g) and tert-butyl carbazate (2.82 g) were added and the reaction solution was stirred at room temperature for three hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a 1 N sodium hydroxide solution and 1 N hydrochloric acid in this order. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. A solution of 4 N hydrochloric acid in ethyl acetate (100 mL) was added to the residue, and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain 3.87 g of a crude product of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH2:20]Br)[CH:13]=2)[O:9][N:8]=1.[NH3:22]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH2:20][NH2:22])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: N
Solvent: ClCCl
Product: N#Cc1cc(CN)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 50 °C
Yield: 0.8 %

Procedure:
A solution of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol) in dichloromethane (1.5 mL) was treated with a 0.5M ammonia (1.5 mL, 1.5 mmol, dioxane) and heated at 50° C. for 90 minutes. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine. Silica gel chromatography of the crude product afforded 3.5 mg (5.5%) of 3-(2-pyridyl)-5-(3-aminomethyl-5-cyanophenyl)-1,2,4-oxadiazole.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:29][CH2:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CCC2)Sc2cc(C(F)(F)F)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)Sc1ccccc1NC2=S
Yield: 106.6 %

Procedure:
Phosphorus pentasulphide (2.25 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (2 g, 6.8 mmol) in pyridine (30 ml) and the mixture heated under reflux for 6.5 hr. The mixture was allowed to cool and then poured into warm water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as yellow needles (1.68 g, m.p. 236°-239° C., Rf 0.58, hexane/EtOAc 2:1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH2:30][CH2:31][O:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:45][CH3:46])=[C:40]([CH:43]=[O:44])[CH:41]=4)[N:36]=[CH:35][CH:34]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.CO>[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH2:30][CH2:31][O:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:45][CH3:46])=[C:40]([CH2:43][OH:44])[CH:41]=4)[N:36]=[CH:35][CH:34]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(OCCn3nc(-c4cccc(CN)c4)ccc3=O)c2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(OCCn3nc(-c4cccc(CN)c4)ccc3=O)c2cc1CO
Reaction time: 19 h

Procedure:
Sodium triacetoxyborohydride (200 mg, 944 μmol) was added to a mixture of 4-(2-(3-(3-(aminomethyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethoxy)-7-methoxyquinoline-6-carbaldehyde (16 mg, 37 μmol) in CHCl3 (3 mL) and MeOH (1 mL) were added (to keep solvent volume). After 19 h, K2CO3 (500 mg) was added. After 3 h, the mixture was filtered and concentrated. The residue was purified on silica (5% (2 N NH3-MeOH) in CH2Cl2 to give a film (10 mg, 62%). LCMS (ESI pos. ion): calc'd for C24H24N4O4: 432.2; found 433.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 140 °C
Yield: 85.2 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.64 g, 0.01 mol), p-toluidine (1.07 g, 0.01 mol) in dioxane (2 mL) was heated in a sealed tube for 30 minutes at 140° C. The crude product was treated with NaOH (50 ml, 2M) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (2 g, 78%).