Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[N:29]([CH3:31])[CH:28]=[C:27]2[CH:32]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[N:29]([CH3:31])[CH:28]=[C:27]2[CH2:32][NH:6][CH3:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cn1cc(C=O)c2cccc(OCc3ccccc3)c21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(OCc3ccccc3)cccc12
Yield: 88 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-benzyloxy-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (3.7 g, 88%) was obtained as an oil: MS (ES) m/e 281.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:6][C@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C@@H:3]([CH:2]=[O:1])[CH2:4]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: OC[C@H]1CNC[C@@H]1c1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.4 g (13.1 mmol) of 3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine, 6.8 mL (39 mmol) of diisopropylethylamine, and 4.1 g (23.4 mmol) of 2,4-dichlorobenzaldehyde (Aldrich) in 60 mL of CH2Cl2 at rt was added 5.5 g (26 mmol) of sodium triacetoxyborohydride in several small portions and the reaction mixture was stirred at rt for 3 h. To the reaction was added 50 mL of sat'd NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 4:1) to give the title compound. Mass Spectrum (ESI) m/e=342 (M+1 35Cl, 35Cl), 344 (M+1 35Cl, 37Cl), and 346 (M+1 37Cl, 37Cl). 1H-NMR (CDCl3, 500 MHz): 7.38 (m, 2H), 7.30 (m, 1H), 7.23 (m, 1H), 7.03 (m, 2H), 3.65-3.77 (m, 3H), 3.34 (m, 1H), 3.21 (t, J=8.5 Hz, 1H), 2.82 (m, 2H), 2.70 (m, 1H), 2.52 (t, J=8 Hz, 1H), 2.38 (m, 1H). 13C-NMR (CDCl3, 125 MHz): 145.0, 134.7, 134.6, 133.3, 131.3, 129.3, 127.0, 126.9, 126.0, 119.8, 66.2, 61.7, 57.8, 56.1, 48.0, 41.7.). [α]D=+3.0 (c=1.75, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:18])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cn1
Yield: 89 %

Procedure:
5-Nitropyridine-2-carboxylic acid (100 g, 0.60 mol) was heated at reflux in methanol (1 L) and sulfuric acid (57 mL) for 5 hours. The reaction mixture was cooled, reduced to half volume in vacuo, and the residue neutralized with a solution of sodium carbonate. The resulting precipitate was filtered to give methyl 5-nitropyridine-2-carboxylate (yield 89%, 98
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].C([O:18][C:19](=[O:64])[CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:32](Br)=[C:31]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:30]3[N:51]=[CH:52][C:53]([C:54]4[CH:55]=[N:56][C:57]5[C:62]([CH:63]=4)=[CH:61][CH:60]=[CH:59][CH:58]=5)=[C:29]3[N:28]=2)[CH2:23][CH2:22]1)C.Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:31]1[N:30]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:29]2[N:28]=[C:27]([CH:24]2[CH2:23][CH2:22][CH:21]([CH2:20][C:19]([OH:18])=[O:64])[CH2:26][CH2:25]2)[C:32]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1c(-c2ccncc2)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 100 °C
Reaction time: 18 h
Yield: 9.6 %

Procedure:
4-Pyridine boronic acid (0.156 mmol, 20 mg), K2CO3 (0.234 mmol, 33 mg), and Pd(PPh3)4 (0.008 mmol, 10 mg) was added to a solution of (4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexyl)-acetic acid ethyl ester (0.078 mmol, 60 mg) in dioxane (1 mL). To this suspension was added distilled H2O (0.2 mL). The resulting reaction mixture was stirred at 100° C. under argon for 18 hours. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in 2:1 MeOH:H2O (1.5 mL) and was treated with 2N NaOH(aq) (0.5 mL). The resulting reaction mixture was stirred at room temperature for 18 hours. Aqueous hydrochloride solution (1.0 N, 2 ml) was added to the reaction mixture and the resulting solution was stirred at 65° C. for 2 h. The solution was concentrated in vacuo and purified by prep-LC to afford the title compound (3.6 mg) as a mixture of cis and trans isomers: LC/MS RT=2.84 min. Mass calculated for, M+H 479.21, observed 479.21.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])[CH3:2].[Se](=O)=[O:16]>>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[C:9]2=[O:14])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cccc2c1CCCC2=O
Product: CCOc1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-ethoxy-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-ethoxy-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described to yield the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN(C)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-dimethylaminobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]aniline.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:26](O)[CH2:27][OH:28].O>C1C=CC=CC=1>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(COCC2CC3(C2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluene sulphonic acid (2.0 gm) was added to a solution of 3-[(benzyloxy)methyl]cyclobutanone (25.0 gm, 131.6 mmol) (step b) and 1,2-ethanediol (8.98 gm, 144.7 mmol) in benzene and the reaction mixture was refluxed with removal of water through dean-stark apparatus. After about 6 hours, the reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution, followed by water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=5)[CH:25]=4)(=[O:31])=[O:30])[CH2:37][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cn1
Agent: Cl
Product: Nc1ncc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cn1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-amino-5-pyrimidyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl]sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.[Cl-].[CH3:18][C:19]1[C:25](=O)NC(=O)N([C@@H]2O[C@@H]3COP(O)(O[C@H]3C2)=O)[CH:20]=1.ClCl>>[C:19]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH3:25])([CH3:20])[CH3:18]
Reactant: Oc1ccccc1
Reactant: Cc1cn([C@H]2C[C@@H]3OP(=O)(O)OC[C@H]3O2)c(=O)[nH]c1=O
Agent: ClCl
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(O)cc1

Procedure:
To a solution of phenol, 1 molar in hexanes, at 40°-45° C. stirred in a three neck flask fitted with condenser, pressure-equalized dropping funnels, magnetic stirrer and dry-nitrogen inlet/outlet, was added freshly distilled undiluted boron trifluoride etherate (0.07 mole). Subsequently olefin or tert.-chloride (0.2 molar in hexanes) was added dropwise. The olefins used were the model compound TMP, or the olefin telechelic PIB; the tert.-chlorides used were CTMP, or the tert.-chloride telechelic PIB. The olefin end group concentration of the olefin telechelic PIB was determined by 1H NMR and it was assumed that the precursor, i.e., the tert.-chlorine telechelic PIB, contained the same concentration of end groups. After the addition was complete (8-10 hours) the temperature was raised to 50°-55° C. and stirring was continued for ~30 hours. It was observed that in the presence of more than 10% of the catalyst based on the total quantity of phenol, and at a relatively high temperature of ~60° C., cracking of TMP occurred and p-tert.-butyl phenol was obtained. The reactor was cooled to room temperature and the brown oily layer (if any) was removed. Approximately 200 ml water were slowly added and the content of the flask was transferred to a separatory funnel. The aqueous layer was removed and the organic layer washed 8-10 times with hot water (40°-50° C.) followed by washing with 50% aqueous solution of methanol. The methanol was removed by washing with cold water. Great care must be taken to remove even traces of free phenol. The presence of phenol in the washing water was monitored by its UV absorption. Washing was continued until the aqueous and the organic layer were free of phenol (GPC technique, UV detector). The organic layer was dried over anhydrous Na2SO4, the solvent then removed by rotary evaporation and the product was dried at 60° C. under vacuum.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:58])[C@@H:14]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:59].O1CCOCC1>CO>[ClH:59].[C:1]1([CH2:11][NH:12][C:13](=[O:58])[C@@H:14]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:42][NH:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCN[C@H]2CCCc3cccnc32)C(=O)NCc2cccc3ccccc23)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCN[C@H]1CCCc2cccnc21)C(=O)NCc1cccc2ccccc12)c1ccc(CNCc2ccccn2)c2ccccc12

Procedure:
The compound obtained in Example 90-2 (14.2 mg) was dissolved in methanol (0.3 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.3 ml) was added to the solution. After the reaction for 3.5 hours, the reaction solution was concentrated. The residue obtained was purified by silica gel column chromatography (0.5 g, chloroform/methanol/water=7/3/0.5) and treated with hydrochloric acid to obtain hydrochloride of the title compound (8.1 mg) as a white solid.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride 1.6 g. (10 mmoles) of p-trifluoromethylaniline and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a mixture of methylene chloride-hexane to obtain the product of this Example, m.p. 189°-193°C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:7]([CH:8]=[CH:9][CH:10]=[C:11]4[CH:12]=[CH:13]2)=[C:6](C#CCO)[CH:5]=[C:4]3C=1C.[OH-].[Na+].[C:25]1(C)C=CC=C[CH:26]=1>>[C:6]1([C:25]#[CH:26])[C:5]2[C:12]3=[C:13]4[C:14](=[CH:16][CH:4]=2)[CH:15]=[CH:2][CH:1]=[C:8]4[CH:9]=[CH:10][C:11]3=[CH:17][CH:7]=1
Reactant: Cc1cc2ccc3cccc4c(C#CCO)cc(c1C)c2c34
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1ccc2ccc3cccc4ccc1c2c34
Temperature: 120 °C
Yield: 58 %

Procedure:
1.5 g (5.28 mmol) of Dimethylhydroxymethyl-9-pyrenylacetylene and 222 mg (5.54 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 26 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.67 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to give 1-pyrenylethyne as an orange-color solid (0.69 g, yield: 58%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Mg].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([Cl:9])[CH:11]=1)[OH:14]
Reactant: O=Cc1cccc(Cl)c1
Reactant: ClCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCCCBr)c1cccc(Cl)c1

Procedure:
A solution (30 ml) of 1-bromo-5-chloropentane (7.0 g) in tetrahydrofuran was gently added dropwise under refluxing to a suspension (30 ml) of magnesium (0.92 g) in tetrahydrofuran. After confirmation of disappearance of magnesium, a solution (30 ml) of 3-chlorobenzaldehyde (5.3 g) in tetrahydrofuran was dropwise added. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanol, which was dissolved in chloroform (50 ml). Thereto was added 15 equivalents of manganese dioxide, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was filtered, and the residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanone.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][NH:40][CH3:41]>CCOCC.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:40]([CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH3:41])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CNCCN(C)C
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N(C)CCN(C)C)cc3C)cc12
Reaction time: 8 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and triethylamine (2.5 eq.) in ether (0.05 M) was added N1,N1,N2-trimethylethane-1,2-diamine (5.0 eq.). The reaction mixture was stirred for overnight. Then the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-N,3-dimethylbenzamide as a white solid. 1H NMR (CDCl3): δ 8.66 (s, 1H), 8.37 (s, 1H), 8.07 (d, 1H), 7.63 (s, 1H), 7.09-7.30 (m, 4H), 3.90 (br, 2H), 3.01-3.19 (m, 4H), 3.08 (s, 6H), 2.72 (br, 5H), 2.52 (s, 3H), 2.33 (s, 3H). LRMS [M+H]=456.3.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:8][CH2:7][C:6]4[CH:15]=[CH:2][CH:3]=[CH:4][CH:5]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CO
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)CC(=O)CCc5ccccc5)c4c(c23)C1=O
Temperature: 20 °C
Yield: 53 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 95 mg of the compound of example 21 were added. The mixture was refluxed during 4.5 hours and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 81 mg (yield: 53%) of the desired product (formula below) as a red powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:14])/[CH:11]=[CH:12]\[CH3:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13]
Reactant: C/C=C\C(O)C1=C(C)CCCC1(C)C
Solvent: c1ccncc1
Product: C/C=C/C(=O)C1=C(C)CCCC1(C)C
Reaction time: 0.17 h
Yield: 25.5 %

Procedure:
When the addition of the bromine derivative was completed, the mixture was refluxed for 45 minutes; then cooled to -10°, at which temperature 110 g. of β-cyclocitral dissolved in 410 ml. of tetrahydrofuran were introduced dropwise within 45 minutes. Stirring was continued for 1 hour at -5°, then overnight at room temperature under nitrogen. The reaction mixture was poured into a suspension of 0.5 kg. of crushed ice in 1.5 l. of a saturated ammonium chloride solution. It was extracted 3 times with ether, the extract were combined and washed 3 times with water and then with a concentrated NaCl solution. After drying over anhydrous Na2SO4 the volatile portions were evaporated and the residue distilled. There were thus obtained 91 g. (65.2 %) of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene. B.p. 64°-68° /0.01 Torr. By replacing in the above procedure the β-cyclocitral by its analogue α, cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]2-cyclohexene was obtained. 1700 ml. of absolute pyridine were cooled to 0°-5° and 154 g. of CrO3 were added portionwise within 30 minutes while stirring vigorously. Stirring was continued for 10 minutes at 5° and then 95 g. of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene dissolved in 300 ml. of pyridine were added dropwise within 20 minutes, while maintaining the temperature below 10°. When the addition was completed stirring was continued for 20 minutes, then the mixture was allowed to stand for 15 hours at room temperature. The reaction mixture was diluted with 5 l. of water and extracted with 6 portions of 800 ml. of ether each. The extracts were combined and successively washed with: 4 portions of water, 8 portions of 10 % HCl at 0° , 3 portions of water, 2 portions of 5 % Na2CO3, 2 portions of water. Moreover, each washing portion was extracted with ether before being discarded, and the extract was added to the main extract after washing. The ethereal solution was dried over anhydrous Na2SO4, concentrated in vacuo and the residue distilled. There were thus obtained 57 g. of a liquid fraction, b.p. 75°-85° /0.001 Torr, which fraction was redistilled by means of a spinning band column and yielded 24 g, (25.5 %) of pure trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene.
Reaction SMILES: [CH2:1]([C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C(C)C.C(O)(=O)CC(C)C.C(O)(=O)CCCC.C(O)(=O)CCC>C(O)(=O)C.C(O)=O>[CH3:9][C:8]1[CH2:7][C:5](=[O:6])[CH2:1][C:2]([CH3:4])([CH3:3])[CH:10]=1
Reactant: CC(C)CC(=O)CC(C)C
Solvent: CCCC(=O)O
Solvent: CCCCC(=O)O
Solvent: CC(C)CC(=O)O
Product: CC1=CC(C)(C)CC(=O)C1

Procedure:
The source of the acid component cannot be determined exactly, but it may be ascribed to something decomposed in the oxidation reaction procedure. For example, the acid component may be ascribed to the solvent (e.g., diisobutyl ketone) decomposed in the oxidation reaction (e.g., decomposed into a C1-10carboxylic acid, such as formic acid, acetic acid, isobutyric acid, isovaleric acid), or to a by-product (e.g., valeric acid, butyric acid) produced in the step of forming the starting material β-isophorone derivative (isomerization step of α-isophorone).