Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2.[BH4-].[Na+]>CO>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
Add isovaleraldehyde (64.5 mg, 0.750 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (intermediate 21, 148 mg, 0.500 mmol) dissolved in MeOH (5 mL) and stir at ambient temperature for 1.5 hours before adding NaBH4 (38 mg, 1.00 mmol). After stirring for an additional two hours, concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 123 mg of the title compound as a white foam. Mass spectrum (ion spray): m/z=368 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.25 (d, 1H), 6.94 (d, 1H), 6.89 (d, 1H), 6.85 (s, 1H), 5.82 (br. s, 2H), 2.97 (m, 1H), 2.84 (m, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 1.85 (m, 3H), 1.74 (m 1H), 1.62 (m, 1H), 1.41 (m, 2H), 0.90 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:23]2[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: Cc1c(Cl)nnc(C(=O)c2ccncc2)c1C
Reactant: C[C@@H]1CNCCN1
Product: Cc1c(C(=O)c2ccncc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 82.5 %

Procedure:
According to the protocol described below, (6-chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-4-yl-methanone (750 mg, 3.03 mmol) and (R)-2-methyl-piperazine (364 mg, 3.63 mmol) afforded the title compound as a beige solid (778 mg, 83%).
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:20][CH2:19]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C2c3ccccc3-c3[nH]c(=O)c(=O)[nH]c32)CC1
Reaction time: 20 h
Yield: 38.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.50 g, 6.39 mmol) was suspended in 15 ml of dry tetrahydrofuran, while cooling in an ice bath. N-Methylpiperazine (1.42 ml, 12.78 mmol) dissolved in 3 ml of dry tetrahydrofuran was added over 20 min, and the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran and dried to give 2.42 g of a remanence, which was dissolved in 100 ml of boiling ethanol, and treated with 300 mg of activated carbon. The mixture was filtered and concentrated to 10 ml. The precipitate was filtered off, washed with ethanol and dried to give 0.65 g of the crude product. From the filtrate another crop of 0.57 g could be isolated. Recrystallization from 6M HCl afforded 0.73 g (30%) of the title compound as a dihydrochloride. M.p. 263°-265° C. 1H-NMR (DMSO-dd6, δ): 2.6 (m, 1H), 2.73 (s, 3H), 2.78-3.52 (m, 7H), 4.84 (s, 1H), 5.9-7.0 (broad, 2H), 7.2 (t, 1H), 7.35 (t, 1H), 7.48 (d, 1H), 7.58 (d, 1H), 10.92 (s, 1H), 11.76 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.C(Cl)CCl.[NH2:25][C@@H:26]([CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:25][C@@H:26]([CH2:35][N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)[C@H:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:28])=[O:13]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: O=C(O)CCCCCCCCCO
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCCCO)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Methylene chloride (20 ml), 10-hydroxydecanoic acid (377 mg, 2.0 mmol), triethylamine (0.70 ml, 5.0 mmol) and EDC (580 mg, 3.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (472.0 mg, 2.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=20:1) to obtain the title compound (508 mg, yield 62%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:1][C:2]1([CH2:15][NH:16][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)C2CCCCC2)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(2.6 g, described in Example 3), triethylamine (1.34 g), cyclohexylcarbonyl chloride (1.94 g) and dry tetrahydrofuran (60 ml) is stirred at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (3.8 g); mp 174°-175° C.; nmr (CDCl3) δ0.85-2.25(m), 1.55(s), 2.81(m), 3.79(m), 4.00(m), 5.96(t), 6.9-7.2(m) and 9.71(s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14])([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH:13]=[O:14])=[CH:8]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C=O)c2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
5-Nitroindole-3-carboxaldehyde (2 g) was dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (4.0 g) and methyl iodide (5 ml) were added thereto, followed by stirring at 60° C. for 24 hours. The reaction solution was subjected to partitioning with chloroform, methanol and water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was rinsed with ethyl acetate to give 1-methyl-5-nitroindole-3-carboxaldehyde (Compound III-2, 1.99 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][C:16]([CH3:18])=[O:17].[OH-].[Na+]>O.Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:15]/[C:16](=[O:17])[CH3:18]
Reactant: CC(C)=O
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(/C=C/C(C)=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 19.6 g (0.1 mol) of 2,3,4-trimethoxybenzaldehyde in 21 ml (0.28 mol) of acetone and 10.5 ml of water was treated with 2.5 ml of 3N sodium hydroxide solution, whereby the temperature of the reaction mixture should not exceed 30°. The mixture was stirred at room temperature for 20 hours, diluted with water, and 3N hydrochloric acid was added to produce a strongly acidic reaction. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent ether/hexane 10:1). There was obtained (E)-4-(2,3,4-trimethoxyphenyl)but-3-en-2-one as a yellow oil. MS: 236 (M+), 205 (base peak) m/e.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>CN1CCN(C)C1=O>[CH2:17]([NH:20][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2ccc(Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: C=CCNc1nc(NCC=C)c2cc(Cl)ccc2n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 87.3 %

Procedure:
In 1 ml of 1,3-dimethyl-2-imidazolidinone was dissolved 300 mg (1.18 mmol) of 4-allylamino-2,6-dichloroquinazoline, and after 110 mg (1.87 mmol) of allylamine was added to the resulting solution, the mixture was stirred in a sealed tube at 100° C. for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 283 mg (yield: 87.3%) of the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[OH-].[Na+].[OH:10][C:11]1[CH2:19][CH2:18][N:17]2[C:13](=[N:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=32)[C:12]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[H-].[Na+]>CN(C=O)C.CCOCC>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][N:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[N:17]2[CH2:18][CH2:19][C:11](=[O:10])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]12
Reactant: CN(C)CCCl
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C2N(CCC1=O)c1ccccc1N2CCN(C)C
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
2-Dimethylaminoethylchloride hydrochloride is stirred with 10M aqueous NaOH (4 mL) and ether (20 mL) for one hour. The ether layer is decanted and the aqueous layer is washed with ether (10 ml). The combined ether layers are dried over Na2SO4, decanted, and treated with molecular sieves overnight. To a suspension of ethyl 1,2-dihydro-3-hydroxy-pyrido[1,2-a]benzimidazole-4-carboxylate (1.3 g , 5 mmol) in DMF (25 mL) is added in one portion the ethereal solution. The reaction mixture is stirred for 15 min, then a suspension of sodium hydride (0.6 g, 15 mmol, 60% in oil) in DMF (5 mL) is added in one portion. After stirring at ambient temperature for 15 min, the mixture is heated at 110° C. for 2 h. The mixture is cooled, concentrated, and water is added (20 mL). The resulting mixture is extracted 2X with chloroform (100 mL). The combined organic layers are dried and concentrated to afford ethyl 5-(2-dimethylaminoethyl)-3-oxo-1,2,3,5-tetrahydropyrido [1,2-a]benzimidazole-4-carboxylate.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl-].[Cl-].[Ca+2:68].Cl.[C:70]([OH:77])(=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74]>CO>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([OH:54])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:55][C@@H:56]2[O:61][C@H:60]([CH3:62])[C@@H:59]([OH:63])[C@H:58]([NH2:64])[C@@H:57]2[OH:65])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[Ca:68].[C:70]([OH:77])(=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74]
Reactant: [Ca+2]
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: Cl
Solvent: CO
Product: [Ca]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.66 g amphotericin B (938γ/mg of activity-equivalent to 10 g of chemical activity) suspended in 2.5 liters of anhydrous methanol containing 11.1 ml of 5% CaCl2 in methanol (equivalent to 200 mg Ca ion) is solubilized by means of 1.8 ml of 5.8 N HCl (pH 3.9). To the resulting solution are added 100 ml of methanol containing 10 g of reagent grade succinic acid to form a mixture of pH 3.2. The pH of the mixture is adjusted to about 7 by the addition of 7.7 ml concentrated NH 4 OH. The mixture is then heated to 45°-50° C and slurried for one hour and thereafter is cooled to room temperature, filtered and the wet cake dried overnight under vacuum at 45° C to yield 9.1 g of crystalline complex.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:6]=1[CH:7]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:5][C:6]=1[CH2:7][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: NC(=O)C1CC1
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CC1
Yield: 86.4 %

Procedure:
A mixture of 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carbaldehyde (250 mg, Example 3, step I), cyclopropanecarboxylic acid amide (160 mg), trifluoroacetic acid (0.142 ml) and triethylsilane (0.301 ml) in toluene (4 ml) is refluxed overnight. After 23 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (251 mg, compound 2.2 in Table 2) as a yellowish foam. MS (HPLC/MS): 495 (MH+). Retention time: 2.02 min.
Reaction SMILES: [CH:1]1([CH:7]([O:27][CH3:28])[C:8]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:9]=2[CH2:10][O:11][Si](C(C)(C)C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH:7]([O:27][CH3:28])[C:8]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:9]=2[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (1.13 g, 2.4 mmol) in THF (5 mL) at room temperature was added TBAF in THF (1.0 M, 4.8 mL, 4.8 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (633.9 mg, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.27 (m, 6H) 1.63-1.70 (m, 3H) 1.72-1.81 (m, 1H) 2.07 (d, J=12.86 Hz, 1H) 2.33-2.42 (m, 1H) 3.18 (s, 3H) 4.10 (d, J=7.88 Hz, 1H) 4.78 (dd, J=5.81, 3.32 Hz, 2H) 7.43 (d, J=7.88 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.69 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[O:12][CH:10]1[CH2:11][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[N:7]=2)[CH2:9]1
Reactant: Clc1ccc(OC2CN(c3ccnc(Cl)n3)C2)c(Cl)c1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(Nc2nccc(N3CC(Oc4ccc(Cl)cc4Cl)C3)n2)cc1
Yield: 28.6 %

Procedure:
To a solution of 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidine (0.200 g, 609 mmoL) and 4-amino-N-methylbenzamide (0.109 g, 0.731 mmoL) in dimethyl acetamide (5 mL) was added cesium carbonate (300 mg, 9.14 mmol) and the reaction mixture was degassed for 15 min. Tris(dibenzylideneacetone)dipalladium (0) [Pd2(dba)3](0.030 g, 0.03 mmoL) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [BINAP] (0.020 g, 0.03 mmoL) were added and the mixture was irradiated in the microwave at 120° C. for 1 h. Then the reaction was quenched with water and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 4-(4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (0.077 g, 29%) as solid. Observed mass (M+1): 443.9.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:21][C:20]4[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1SC.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCOCC>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:21][C:20]4[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c(=O)n1C
Agent: Cl
Solvent: CCOCC
Product: Cn1c(Nc2ccccc2)nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c1=O
Temperature: 150 °C
Yield: 4.2 %

Procedure:
A suspension of 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (34.0 mg, 0.100 mmol), aniline (0.5 mL, 5.49 mmol), and HCl (conc.) (20 μl, 0.240 mmol) was heated by microwave in a sealed flask at 150° C. for 10 min. The mixture was diluted with Et2O (5 mL) and the precipitated solid was collected by vacuum filtration, washed with Et2O (5 mL), and dried in vacuo. Purification of the residue by revered-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) followed by supercritical-fluid chromatography (Chiralcel OD-H (250×21 mm, 5 μm), 50% liquid CO2/50% MeOH, 55 mL/min) afforded 3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-(phenylamino)quinazolin-4(3H)-one (1.6 mg, 4.15 μmol) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.15 (1H, m), 7.95-8.04 (1H, m), 7.81 (1H, d, J=7.6 Hz), 7.41-7.53 (5H, m), 7.23-7.33 (1H, m), 7.08-7.18 (1H, m), 6.89 (1H, s), 6.82 (1H, s), 3.61 (3H, s), 3.28 (2H, obsc. m), 2.33 (2H, m). m/z (ESI, +ve) 386.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].S([O:26][CH3:27])(OC)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:26][CH3:27])=[C:4]([CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][C:7]([OH:12])=[O:8])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CC(c2ccccc2)c2cc(Cl)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1C(CC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
6-Chloro-4-phenyl-3,4-dihydrocoumarin (435 g, 1.68 mol. Preparation: T. Manimaran & V. T. Ramakrishnan, Ind. J. Chem. B 18 (1979) 328) is added to a hot solution of sodium hydroxide (140 g, 3.5 mol) in water (500 ml). The solution is chilled to 25° C. and dimethyl sulphate (442 g, 3.5 mol) is added dropwise during 1 h with stirring and cooling at 25°-35° C. The mixture is stirred for an additional 2 h whereupon a solution of 100 g of sodium hydroxide in 500 ml of water is added and the mixture is stirred until a clear solution is obtained. An excess of concentrated hydrochloric acid is added to precipitate the methoxy acid, which separates as an oil which slowly crystallizes. It is filtered off, washed with water and dried. Crystallization from 2-propanol gives colourless crystals of 3-(5-chloro-2-methoxyphenyl)-3-phenyl propionic acid, m.p. 144° C. Yield 455 g.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.Cl.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(I)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O[C@H]1CC[C@H](Nc2ncc(I)cc2F)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in dioxane (3 ml) and trans-4-aminocyclohexanol hydrochloride (227 mg, 1.49 mmol, 1.2 equiv.) and Cs2CO3 (1.01 g, 3.11 mmol, 2.5 equiv.) were added at room temperature. The mixture was stirred for 3 hours at 100° C. The reaction mixture was evaporated and treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 0:100). The desired trans-4-(3-fluoro-5-iodopyridin-2-ylamino)cyclohexanol (65 mg, 16% yield) was obtained as a white solid, MS: m/e=337.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:33]2[C:32](=[O:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:35])[C:24]=2[CH:23]=[CH:22][CH:21]=1.OS(O)(=O)=O.[K]>O>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[C:15]([C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[C:2]([NH:1][C:23]1[CH:22]=[CH:21][C:20]([NH2:19])=[C:33]2[C:32]([C:31]4[C:26]([C:25](=[O:35])[C:24]=12)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:34])[CH:3]=[CH:4][C:5]=3[NH2:18])=[O:17]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: O
Product: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)c2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of 52.0 g of 1,4-diaminoanthraquinone (92% pure) and 47.0 g of 1-aminoanthraquinone (98% pure) in 410 g of 96% strength H2SO4 is added dropwise to 410 g of water. 95.0 g of potassium peroxodisulphate is introduced into the red-orange paste at 40°-50° C. within 1 hour, the mixture is stirred for approximately a further 30 minutes and the solid is filtered off with suction. The filter cake is washed to neutrality and then stirred briefly in a mixture of 100 ml of 40% strength NaHSO3 solution and 400 ml of water. The solid is then filtered off with suction, washed with water and dried at 100° C. 96.5 g of 4,4'-diamino-1,1'-dianthrimide (84% pure), corresponding to 88% of theory, are isolated.