Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].O>CC#N>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1
Reactant: CC(C)C(=O)Cl
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.057 g, 0.163 mmol), K2CO3 (45 mg, 0.327 mmol) and isobutyryl chloride (21 mg, 0.196 mmol) in dry CH3CN (1.5 ml) was stirred at 60° C. for 1 h. Water was added, the solution was extracted 3 times with CH2Cl2, the combined organic layers were washed once with brine, dried over Na2SO4, filtrated and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8b).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][C:32](=[O:33])[N:34]([CH3:36])[CH3:35])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 15 h

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)-3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 111 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[5-difluoromethoxy-1-(2-dimethylcarbamoyl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].CC#N.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:13]([N:4]([CH3:5])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:2][CH3:1])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(C)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
A mixture of S,N-dimethyl-N'-nitroisothiourea (0.5 g), CH3CN (6 ml) and pyridine (1 ml) was cooled to 0° C. To the cooled mixture was added benzoyl chloride (1 g) dropwise in 5 minutes under stirring. After stirring at the same temperature for 1 hour, benzoyl chloride (0.4 g) was added to the mixture which was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of 2N hydrochloric acid and the resulting mixture was extracted with CHCl3. The extract was dried over MgSO4 and evaporated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (5:1) to afford 0.71 g of crude N-benzoyl-S,N-dimethyl-N'-nitroisothiourea as an oil. To the solution of the product (0.636 g) in CH3CN (4 ml) was added a solution of 2-chloro-5-thiazolylmethylamine (0.37 g) in CH3CN (2 ml) dropwise at 0° C. over 5 minutes. After stirring at the same temperature for 25 minutes, precipitates were collected by filtration and the product was applied to column chromatography on silica gel. The column was eluted with CH2Cl2 -MeOH (20:1) to afford 0.344 g of 1-benzoyl-3-(2-chloro-5-thiazolylmethyl)-l-methyl-2-nitroguanidine (Compound No. 15) as a crystal, m.p. 170°-172° C.
Reaction SMILES: C([O:4][C@@:5]1([CH2:38][CH3:39])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([S:26][CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])(=O)C.NN.Cl>CO.O1CCOCC1>[CH2:38]([C@:5]1([OH:4])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([S:26][CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])[CH3:39]
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CCC(C)C)C(SC)=N3
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CCC(C)C)C(SC)=N3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.2 %

Procedure:
To a solution of (9S)-9-acetoxy-9-ethyl-1-(3-methylbutyl)-2-methylthio-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (43.0 mg, 0.08 mmol) in methanol (2 ml) and 1,4-dioxane (2 ml) was added anhydrous hydrazine (200 μl). The mixture was stirred at room temperature for 2.5 hr. 10% HCl in methanol was added dropwise to acidify the reaction mixture and the mixture was stirred at room temperature for 2 hr. After concentrated under reduced pressure, the obtaining residue was partitioned between dichloromethane and water. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=100/1) to give the product (33.2 mg, 84%) as an orange powder.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][S:28][CH2:29][CH2:30]N)[CH3:22]>C(O)C>[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)[CH3:22]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1cccc(CSCCN)c1
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)cn1

Procedure:
A mixture of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (1.0 g),2-[3-(dimethylaminomethyl)benzylthio]ethylamine (1.30 g, 1.5 equivalents) and ethanol (3 ml) was heated under reflux for 29 hours and evaporated to dryness. The residue was dissolved in water and the solution was adjusted to pH13 and extracted with ether (which was discarded). The aqueous phase was adjusted to pH 10.5 with hydrochloric acid and the solution was extracted with ether and chloroform. The combined organic extracts were evaporated to dryness and the residue was crystallised from acetonitrile to give 2-[2-[3-(dimethylaminomethyl)benzylthio]ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone m.p. 122°-125°. Treatment with hydrogen chloride in ethanol gives the trihydrochloride salt and treatment with hydrogen bromide in ethanol gives the trihydrobromide salt.
Reaction SMILES: COC1C=C(SC)C2CCN(C)CCC=2C=1.Cl.C[O:19][C:20]1[CH:21]=[C:22]([S:32]([CH3:35])(=[O:34])=[O:33])[C:23]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][C:24]=2[CH:31]=1.[BrH:36]>>[BrH:36].[OH:19][C:20]1[CH:21]=[C:22]([S:32]([CH3:35])(=[O:34])=[O:33])[C:23]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][C:24]=2[CH:31]=1
Reactant: COc1cc2c(c(S(C)(=O)=O)c1)CCN(C)CC2
Agent: Br
Agent: COc1cc2c(c(SC)c1)CCN(C)CC2
Agent: Cl
Product: CN1CCc2cc(O)cc(S(C)(=O)=O)c2CC1

Procedure:
Following the procedure of Example 4, 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 8-methoxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride which is treated with hydrobromic acid to give 8-hydroxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17](C(OC(C)(C)C)=O)[CH:16]=[CH:15]4)[C:4]2=[N:3]1.[OH-].[Na+].CO>C1COCC1>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([C:11]3[C:4]4=[N:3][S:2](=[O:28])(=[O:1])[CH2:7][CH2:6][N:5]4[CH:8]=[CH:9][CH:10]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc4[nH]ccc4c3)C2=N1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a mixture of tert-butyl 5-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)-1H-indole-1-carboxylate (500 mg) in THF (dry) (80 mL) was added 8 M NaOH aq. (8 mL). The mixture was stirred at 50° C. for 30 min. MeOH (20 mL) was added and the mixture was stirred at 50° C. for 4 hr. The precipitate was collected by filtration and dried in vacuo to give the title compound (324.1 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>CN(C)C=O>[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40])=[O:25])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCCNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Triethylamine (0.63 ml, 4.52 mmol) is added to a solution of 6-(benzyloxycarbonylamino)hexanoic acid (1.00 g, 3.77 mmol) in dimethylformamide (20 ml) and the mixture is left to stir at ambient temperature and under argon for 30 minutes. The solution is cooled to 0° C. and ethyl chloroformate (0.43 ml, 4.52 mmol) is added dropwise. After two hours at ambient temperature, N-hydroxysuccinimide (0.52 g, 4.52 mmol) is added and the mixture is left to stir overnight at ambient temperature. The mixture is evaporated to dryness before taking up the residue in water to which ethyl acetate is added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated to dryness before purification on a silica gel column with an ethyl acetate/pentane mixture (75/25 v/v) as eluent. The fractions, once evaporated, give 1.13 g of succinimidyl 6(benzyloxycarbonylamino)hexanoate in the form of an oil.
Reaction SMILES: Br[C:2]1[C:15]([OH:16])=[CH:14][C:13]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]3)[CH:6]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:5][C:4]=2[CH:3]=1.C[O-].[Na+].CN([CH:30]=[O:31])C>C(OCC)(=O)C>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH:6]2[CH2:5][C:4]3[CH:13]=[C:14]([O:31][CH3:30])[C:15]([OH:16])=[CH:2][C:3]=3[CH:12]3[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]3)=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc(C2Cc3cc(Br)c(O)cc3C3CCCCC23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Yield: 100 %

Procedure:
Combine 2-Bromo-9-(4-hydroxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-ol (chiral) (0.033 g, 0.09 mmol), CuCl2 (0.008 g, 0.06 mmol), 5 M NaOMe (in methanol, 1.5 ml), DMF (0.5 ml) and heat 15 hours at 110° C. Cool, add ethyl acetate and wash with 1N HCl, then water. Dry organic layer over anhydrous sodium sulfate and remove solvent in vacuo. Chromatograph over silica gel 2× first with 20% ethyl acetate/hexanes, then 5-20% ethyl acetate/hexanes to yield the titled compound (0.010 g, 100%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.0 (s, 1H), 6.85 (d, J=8.8 Hz, 2H), 6.69 (s, 1H), 3.91 (s, 3H), 3.2 (m, 4H), 2.85 (dd, J=4 and 11 Hz, 1H), 2.45 (d, J=14.9 Hz, 1H), 2.1-0.8 (m, 7H). MS m/z 323(M−1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: COCCN1CCNCC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccc(Cl)c(Cl)c3)C4)cc2)CC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 1-(2-methoxyethyl)piperazine and triethylamine as described in general procedure 2 to give a yellow solid. M.p.=248-250° C. 1H NMR 400 MHz (DMSO-d6) δ 9.63 (s, br, 1H) 8.33-8.29 (m, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.52-7.42 (m, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.10 (m, 2H), 7.03-7.00 (dd, J=2.0, 8.4 Hz, 2H), 4.46 (t, J=6.4 Hz, 1H), 3.78-3.36 (m, 17H), 3.15 (t, J=6.0 Hz, 2H), 3.01 (m, 2H). LCMS m/e 588 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:2]=[O:3].[NH2:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1>N1C=CC=CC=1>[CH2:13]([CH:12]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH:45][C:46]1[NH:47][C:48]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCc1cc(=O)nc(N)[nH]1
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCc1cc(=O)nc(NC(=O)NCCCCCCCCC(CCCCCCCCCC)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc2nc(=O)cc(CCCCCCCCCCCCCCC)[nH]2)[nH]1
Reaction time: 24 h
Yield: 99.3 %

Procedure:
In a 250 mL round-bottomed flask fitted with a reflux condensor was added 11,12-bis(8-isocyanatooctyl)docosane (diamer diisocyanate, Cognis Corp.) (5.18 g, 8.39 mmol) and 2-amino-6-pentadecylpyrimidin-4(1H)-one (5.67 g, 17.63 mmol) in Pyridine (50 mL) to give a white suspension. The mixture was heated to 75 deg/C under argon and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform. The hazy solution was filtered and the resulting clear solution was concentrated to 50 ml and the viscous solution was poured into a rapidly stirring solution (1 L) of MeOH upon which a white solid formed. The solid was collected by filtration and dried under vacuum for 24 h to give 10.5 g 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(4-oxo-6-pentadecyl-1,4-dihydropyrimidin-2-yl)urea)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][C:12]#[N:13])[CH:3]=1.[NH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6]([OH:7])=[N:13][C:12]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:11]2
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCc1cc(Br)ccc1C(=O)O
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(Br)ccc3c(O)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 4-Bromo-2-cyanomethyl-benzoic acid, 3-amino-5-methylpyrazole and acetic acid to give 6-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 319 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:12]([S-:14])#[N:13].[K+].BrBr.O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]=[C:12]([NH2:13])[S:14][C:10]=2[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step-1: To a mixture of 4-butylaniline 67 mmol) and KSCN (26 g, 268 mmol) in acetic acid was added Br2 in acetic acid (70 mL) dropwise over 6 min at RT. The mixture was stirred at RT overnight and poured into water (2 L). The precipitate was collected, washed with water and dried to afford 6-butylbenzo[d]thiazol-2-amine. MS (ESI+) m/z 207.20 [M+H]+
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[CH3:47][C:48]1([CH2:53]CO)[O:52][CH2:51][CH2:50][O:49]1>>[Na:1].[CH3:35][C:18]1[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])=[N:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:47][C:48]1([CH3:53])[O:52][CH2:51][CH2:50][O:49]1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: CC1(CCO)OCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 14.4 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 2-(2-methyl-1,3-dioxolan-2-yl)ethanol obtained in the step (69b) to obtain the title compound (410 mg, total 14.4% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1C=C2C(=CC=1O)NC(=O)CC2)[CH:2]=C.[CH2:16]([C:19]1[C:20]([OH:30])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18].C(Br)C=C>CO.[OH-].[K+]>[CH2:16]([C:19]1[C:20]([O:30][CH2:4][CH:1]=[CH2:2])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18]
Reactant: C=CCc1cc2c(cc1O)NC(=O)CC2
Reactant: C=CCc1c(O)ccc2c1NC(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: CO
Product: C=CCOc1ccc2c(c1CC=C)NC(=O)CC2
Yield: 60 %

Procedure:
6.1 Grams of the mixture of 6-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 8-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone obtained in Example 8 was dissolved in 200 ml of methanol containing 1.8 g of potassium hydroxide. Under stirring, 3 ml of allyl bromide was added thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and further stirred at 60° C. for 1 hour. After the reaction was finished, the reaction mixture was concentrated under reduced pressure, next 200 ml of water was added and stirred vigorously, then extracted with 500 ml of ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to dryness. This mixture was subjected to purification by means of a flush column chromatography by using methylene chloride-methanol (100:1). The first eluted portion was collected and concentrated under reduced pressure, there was obtained 4.4 g (60%) of 8-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless needle-like crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 119°-121° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCc1ccccc1)C(=O)CCC2
Yield: 62.8 %

Procedure:
A mixture of 4.5 g (0.0233 mole) of 7-hydroxy-6-methoxy-1-tetralone, 5.4 g (0.032 mole) of benzyl bromide and 10 g (0.072 mole) of K2CO3 in 150 ml of acetone was heated to reflux overnight. The reaction as cooled, poured into water and extracted with EtOAc. The EtOAc was dried over Na2SO4 and evaporated to give 7 g of crude product. Crystallization with Et2O gave 4.13 g of product as a white solid, mp 110-111° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:7]2[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]12)=[O:4].[F:24][C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.O>O1CCCC1>[ClH:1].[ClH:1].[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[N:7]3[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[F:24])[CH2:33][CH2:32]3)[CH2:10][C:9]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1ccccc1CN1CCNCC1
Reactant: CC1=C(c2cccc(Cl)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(c2cccc(Cl)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3F)CC2)C1
Product: Cl
Reaction time: 8 h
Yield: 112.6 %

Procedure:
A mixture of 4.8 g of 4-(chloroacetyl)-7-(3-chlorophenyl)-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 3 g of 2-fluorobenzylpiperazine and 3.4 g of triethylamine in 200 ml of tetrahydrofuran was stirred under reflux for 18 hours, then cooled and treated with 750 ml of water. The resulting oil was extracted into dichloromethane, dried filtered and concentrated to a red-orange viscous oil. This oil was dissolved in 50 ml of acetonitrile and an excess of ether and 18 ml of 3.74N ethanolic hydrochloric acid added. After standing overnight the solid was collected, washed with ethanol and ether, dried and recrystallized from ethanol, giving 4.5 g of the desired product, mp 192°-194° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2[C:12](=[O:19])[CH:13]3[CH:17]([CH:18]=2)[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:1]([C:8]1[CH:7]=[CH:6][C:5]([C:11]2[C:12](=[O:19])[CH:13]3[CH:17]([CH:18]=2)[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1C(c2ccccc2)=CC2CCCC12
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(C2=CC3CCCC3C2=O)cc1

Procedure:
A solution of Perrier complex was prepared from acetyl chloride (663mg, 8.45 mmol) and aluminimum chloride (1.13 g, 8.45 mmol) in dichloromethane (5 ml) and 4,5,6,6a-tetrahydro-2-phenyl-1(3aH)pentalenone (335 mg, 1.69mmol) in dichloromethane (95 ml) was added at 0° C. The mixture was heated under reflux for 48 h, then poured onto ice, extracted with dichloromethane and the extract washed with aqueous potassium carbonate and dried (MgSO4). After removal of solvent the residue was chromatographed. Ethyl acetate—n-hexane (1:2) eluted unreacted starting ketone (17 mg) followed by the title product (277 mg, 68%), yellowish crystals, m.p. 76-77° C.