Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:30][C:31]1[C:32]([N:59]2[CH2:64][CH2:63][CH:62]([C:65](O)=[O:66])[CH2:61][CH2:60]2)=[N:33][CH:34]=[C:35]([C:37](=[O:58])[NH:38][C:39]2[S:40][C:41]([CH2:50][N:51]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH3:52])=[C:42]([C:44]3[S:45][CH:46]=[C:47]([Cl:49])[CH:48]=3)[N:43]=2)[CH:36]=1>C(Cl)(Cl)Cl.C1COCC1.C(N(CC)CC)C>[ClH:30].[Cl:30][C:31]1[C:32]([N:59]2[CH2:60][CH2:61][CH:62]([C:65]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:66])[CH2:63][CH2:64]2)=[N:33][CH:34]=[C:35]([CH:36]=1)[C:37]([NH:38][C:39]1[S:40][C:41]([CH2:50][N:51]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH3:52])=[C:42]([C:44]2[S:45][CH:46]=[C:47]([Cl:49])[CH:48]=2)[N:43]=1)=[O:58]
Reactant: COCCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)O)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)N4CCOCC4)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 μl of triethylamine, 30 μl of morpholine, 45 mg of WSC.HCl and 30 mg of HOBt were added to 2 ml of a THF solution of 52 mg of 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid hydrochloride, and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform:MeOH=100:1 to 50:1, hexane:EtOAc=2:1, then chloroform:MeOH=20:1), and suspended in 2 ml of diethyl ether. 2 ml of 4M HCl-EtOAc was added, and the precipitate was collected by filtration to obtain 25 mg of 5-chloro-N-(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)-6-[4-(morpholinocarbonyl)piperidino]nicotinamide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](C(Cl)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 41.6 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoic acid (1.00 g, 3.76 mmol) in DCM (10 mL) was added TEA (0.974 mL, 7.52 mmol) and DMAP (23 mg, 0.188 mmol) and the reaction mixture was cooled to 0° C. and BnCOCl (635 mL, 4.51 mmol) was added via an addition funnel over 20 min. The mixture was allowed to warm to ambient temperature overnight at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-50% ethyl acetate/hexanes+1% TEA) provided (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate (0.558 g, 42%) as a light brown solid. MS (EI) for C20H24N2O4, found 257.2 [M-Boc]+.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:14]2[CH2:13][CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[CH:25]=1
Reactant: CCOC(=O)N1CCN(C2Cc3ccc(OC)cc3Sc3ccc(SC)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2

Procedure:
61 G. of 1-carbethoxy-4-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine, 600 ml. of ethylene glycol, 25 g. of potassium hydroxide and 2.7 ml. of water are heated at 160° C. for a period of 2 hours. Then, the mixture is poured on to water and extracted with benzene. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 1-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.C(N(C(C)C)CC)(C)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:27](=[O:28])C1.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]2=[O:59])[CH2:45][CH2:44]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:14][C:27]([N:43]1[CH2:44][CH2:45][CH:46]([N:49]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]2=[O:59])[CH2:47][CH2:48]1)=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(N)Cc1ccc(OC)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(OC)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-3-(6-methoxy-pyridin-3-yl)-propionic acid methyl ester (130 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0° C.) was added N,N′-disuccinimidyl carbonate (158 mg). After 30 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (1 mL) was added via canula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep HPLC to give 160 mg (55%). Mass spec.: 468.19 (MH)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C[N:18]=[C:19]=[O:20].Cl[CH2:22]Cl>>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([N:1]([CH3:22])[C:19]([NH2:18])=[O:20])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CN=C=O
Reactant: ClCCl
Product: CN(C(N)=O)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
Trans-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (2.00 g) in dichloromethane (30 ml) was added dropwise to a stirred solution of methyl isocyanate (0.54 ml) in dichloromethane (15 ml), the temperature being maintained at below 10° C. After 15 min a white precipitate formed and the reaction mixture was allowed to reach room temperature. The solid was filtered and recrystallised from dichloromethane to give the title compound (1.30 g) as crystals of m.p. 143°-146° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([OH:15])=[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][N:31]2[CH2:32][CH2:33][N:34]([CH2:2][C:3]3[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([OH:15])=[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=3)[CH2:35][CH2:36]2)=[CH:25][CH:24]=1
Reactant: CCCCCOc1cc(CO)cc(OCCCCC)c1O
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1cc(CN2CCN(CC(=O)c3ccc(F)cc3)CC2)cc(OCCCCC)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To the solution of 4-hydroxymethyl-2,6-bis-pentyloxyphenol (525 mg, 1.62 mmol), 1-(4-fluorophenyl)-2-piperazine-1-yl-ethanone (432 mg, 1.94 mmol) and PPh3 (509 mg, 1.94 mmol) in drying THF (10 ml) was dropped diethyl azodicarboxylate (0.38 ml, 2.43 mmol) at 0° C. and then was stirred 15 minutes at room temperature. The solution was added with H2O, then CH2Cl2 was evaporated in vacuo and was washed with brine. The obtained organic solution was dried over anhydrous magnesium sulfate and filtered. The obtained filterate was vacuum concentrated to give the residue, which was purified by column chromatography (Hexane:EtOAc=1:10), yielding 129 mg (15%) of 1-(4-fluorophenyl)-2-[4-(4-hydroxy -3,5-bis-pentyloxybenzyl)piperizine-1-yl]ethanone as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (29 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[ClH:1].[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])=[CH:17][CH:16]=3)=[O:20])[CH:32]=[CH:31][C:29]=2[N:30]=1.[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])=[CH:13][CH:14]=3)=[O:19])[CH:32]=[CH:31][C:29]=2[N:30]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: CC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)c(Cl)c1
Product: CC(C)Oc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c(Cl)c1
Product: Cl

Procedure:
The title compound is prepared by following Method A, using 2′-chloro-4′-isopropoxy-biphenyl-4-carboxylic acid (0.35 g, 1.21 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.23 g, 0.93 mmol) to afford 2′-chloro-4′-isopropoxy-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.23 g, 48%). The material is dissolved in EtOH and treated with 1.0 M HCl in EtOH (0.44 mL). Organic solvent is removed in vacuo, the residue is dissolved in i-PrOH, heptane is added and the resulting precipitate is collected to give 0.24 g (96%) of the hydrochloride salt. LC/MS, Retention time=5.73 min; (m/z): calcd for C28H31ClN4O2S: 523.1; found: 523.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[OH:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@H]3CO)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@H]3CO)c2)cc1

Procedure:
To a mixture of (S)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (65 mg, 0.16 mmol), p-tolylboronic acid (24 mg, 0.18 mmol), toluene (4 mL), cesium carbonate (57 mg, 0.18 mmol), and water (0.2 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (9.2 mg, 0.0080 mmol). The reaction mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-80% CH3CN/water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[Br:1][C:2]1[C:3]([NH:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 mole) in ethanol 80 mL was added Hunig's base 3.0 mL followed by the addition of a solution of N-(tert-butoxycarbonyl)-1,2-diaminoethane 2.5 g (0.0156 mole) in 20 mL ethanol. The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) was added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0-60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[N:3]=1.Cl.[NH2:19][OH:20].[C:21](=O)([O-])O.[Na+]>CCO.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:21])[CH:10]=2)[N:5]=[C:4]([C:16]([NH:19][OH:20])=[NH:17])[N:3]=1
Reactant: O=C([O-])O
Reactant: NO
Reactant: CN(c1ccccc1)c1nc(N)nc(C#N)n1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of 4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazine-2-carbonitrile (Intermediate 2, 138 mg, 0.6 mmol) in EtOH (4 mL) was added to a solution of hydroxylamine hydrochloride (51 mg, 0.7 mmol) and sodium hydrogencarbonate (61 mg, 0.73 mmol) in water (2 mL). The mixture was heated at 70 C for 2 h, allowed to cool to room temperature and the solvent evaporated. The crude solid residue was slurried with water (4 mL) before filtering under reduced pressure to afford Intermediate 1 (95 mg, 60%). Method C HPLC-MS: MH+ requires m/z=260. Found: m/z=260, Rt=0.88 min (98%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:23])[CH2:21][NH:20][C:19](=[O:22])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH3:16][C:17]1([CH3:23])[CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:22])[CH2:18]1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: CC1(C)CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)nn2)C1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 9.8 %

Procedure:
To a solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (180 mg, 839 mmol) and 4,4-dimethylpyrrolidin-2-one (CAS 66899-02-3) (142 mg, 1.26 mmol, 1.5 equiv.) in 2 ml of DMF were added cesium carbonate (546 mg, 1.68 mmol, 2 equiv.). The suspension was heated 16 hours at 120° C. and then allowed to cool to room temperature. Ethyl acetate (10 ml) were added and the unsoluble salts were filtered off. After concentration in vaccuo, the residue was dissolved in 10 ml of ethyl acetate. Silicagel (4 g) were added and the suspension was evaporated to dryness. The silicagel with the adsorbed crude mixture was loaded onto a 20 g silicagel flash chromatography column and eluted three min. with heptane followed by a heptane to 45% ethyl acetate/heptane gradient over 25 min to yield 36 mg (15% yield) of the title compound as a cristalline yellow solid, MS: m/e=292.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Br:18])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(N)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (5.0 g, 21.5 mmol) in MeOH (20 mL) and DCM (40 mL) was added tetrabutylammonium tribromide (10.9 g, 22.6 mmol) portionwise and the resulting reaction mixture was stirred for 0.5 h at 25° C. The reaction was quenched by addition of saturated aqueous sodium thiosulphate (10 mL). The mixture was neutralized by the addition of saturated aqueous NaHCO3, diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layer was concentrated, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluting with 5% MeOH in DCM) to give 6-amino-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (3.0 g, 46%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 7.02 (s, 1H), 6.68 (s, 1H), 4.98 (brs, 2H), 4.50 (m, 3H), 1.31 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[CH:11]([C:13]1[CH:14]=[C:15]([CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([CH2:11][NH:10][CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1C=O
Reactant: NCCc1ccccc1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(CNCCc2ccccc2F)c1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-(2-Fluorophenyl)ethylamine (180 mg) in dichloromethane (5 mL) was added to (3-formyl-4-methoxy-phenyl)-acetic acid (260 mg). After 30 minutes, sodium triacetoxyborohydride (0.5 g) was added. After a further 2.5 hours, the reaction mixture was evaporated and the residue loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (50 mL) and then eluted with a mixture of methanol/0.880 ammonia solution [4:1] (50 mL). The elution fraction was concentrated, the residue was dissolved in methanol (100 mL) and tri-methylchlorosilane (2 mL) added. After 18 hours, the reaction mixture was evaporated and the residue purified on silica, eluting iso-hexane/ethyl acetate [4:1 to 1:1 to 0:1]+1% triethylamine, to give the subtitle compound as an oil (0.30 g).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)nc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-5-methyl-pyridine (5.40 g, 19.4 mmol) described in Manufacturing Example 44-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 8.73 mL, 23.3 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (2.99 mL, 38.8 mmol) was then added dropwise thereto, which was stirred for 10 minutes at −78° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:6→1:4) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: CCCCCCCC/C=C/CCCCCCCC(OCC(OC(CCCCCCC/C=C/CCCCCCCC)=O)COP(OCCNC(CCC(OCCOC)=O)=O)(O)=O)=O.CC(CCC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@H](CC2)O)=CC3)CC1)C)C.[CH3:91][C@@H:92]1[O:97][C@@H:96]([O:98][C@@H:99]2[C:104]3=[C:105]([OH:122])[C:106]4[C:118](=[O:119])[C:117]5[C:112](=[CH:113][CH:114]=[CH:115][C:116]=5[O:120][CH3:121])[C:110](=[O:111])[C:107]=4[C:108]([OH:109])=[C:103]3[CH2:102][C@@:101]([OH:127])([C:123]([CH2:125][OH:126])=[O:124])[CH2:100]2)[CH2:95][C@H:94]([NH2:128])[C@H:93]1[OH:129].C(Cl)(Cl)[Cl:131]>>[CH3:91][C@@H:92]1[O:97][C@@H:96]([O:98][C@@H:99]2[C:104]3=[C:105]([OH:122])[C:106]4[C:118](=[O:119])[C:117]5[C:112](=[CH:113][CH:114]=[CH:115][C:116]=5[O:120][CH3:121])[C:110](=[O:111])[C:107]=4[C:108]([OH:109])=[C:103]3[CH2:102][C@@:101]([OH:127])([C:123]([CH2:125][OH:126])=[O:124])[CH2:100]2)[CH2:95][C@H:94]([NH2:128])[C@H:93]1[OH:129].[ClH:131].[CH3:91][C@@H:92]1[O:97][C@@H:96]([O:98][C@@H:99]2[C:104]3=[C:105]([OH:122])[C:106]4[C:118](=[O:119])[C:117]5[C:112](=[CH:113][CH:114]=[CH:115][C:116]=5[O:120][CH3:121])[C:110](=[O:111])[C:107]=4[C:108]([OH:109])=[C:103]3[CH2:102][C@@:101]([OH:127])([C:123]([CH2:125][OH:126])=[O:124])[CH2:100]2)[CH2:95][C@H:94]([NH2:128])[C@@H:93]1[OH:129].[ClH:131]
Reactant: ClC(Cl)Cl
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCCCCC/C=C/CCCCCCCC(=O)OCC(COP(=O)(O)OCCNC(=O)CCC(=O)OCCOC)OC(=O)CCCCCCC/C=C/CCCCCCCC
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Product: Cl

Procedure:
Vesicle-forming lipids containing PEG-PE, PG, PHEPC, and cholesterol and α-TC in a mole ratio of 0.15: 0.3: 1.85: 1: 0.2 were dissolved in chloroform to a final lipid concentration of 25 μmol phospholipid/ml. The lipid mixture was dried into a thin film under reduced pressure. The film was hydrated with a solution of 0.125 M ammonium sulfate to form MLVs. The MLV suspension was frozen in a dry ice acetone bath and thawed three times and sized to 80-100 nm by extrusion as detailed above. An ammonium ion gradient was created substantially as described in Example 10. The liposomes were loaded with epirubicin, and free (unbound drug) removed also as described in Example 10 for doxorubicin. The final concentration of entrapped drug was about 50-100 μg drug/μmol lipid. Epirubicin HCl and doxorubicin HCL, the commercial products, were obtained from the hospital pharmacy.