Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][C:29]1[C:30]([NH:44][CH3:45])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[CH:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([NH:44][CH3:45])=[C:29]([CH2:28][O:27][CH3:26])[CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1)([CH3:22])[CH3:21]
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COC
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cc1COC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and [3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (Stage 248.1.1) to give the title compound as a yellowish foam. (HPLC: tR 2.24 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.20 (s, 1H), 8.15-8.13 (m, 1H), 8.05-8.02 (m, 1H), 7.85-7.81 (m, 1H), 7.48-7.45 (m, 1H), 7.43-7.41 (m, 1H), 6.13 (q, 1H), 4.55 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 2.86 (d, 3H), 1.96 (s, 3H), 1.49-1.45 (m, 6H))
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][N:33]=1>>[ClH:30].[ClH:1].[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][N:33]=3)[CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: COc1ccc(CCl)nc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3ccccc32)cn1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4ccccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 73.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 334 using N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.95 g) and 2-chloromethyl-5-methoxypyridine (0.83 g) as starting materials, N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.97 g) was obtained.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([N+:23]([O-:25])=[O:24])=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[CH:16]3[O:21][CH:15]3[C:14]=2[CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)C>[C:1]([NH:9][C:10]1[C:11]([N+:23]([O-:25])=[O:24])=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[C@@H:16]([OH:21])[C@H:15]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]=2[CH:22]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2[C@@H](N2CCCC2)[C@@H]1O
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of an ethanol (5 mL) solution of a 6-(benzoylamino)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (II-1) (147 mg, 0.43 mmol) was added with a pyrrolidine (0.07 mL) and heated under reflux for two hours. After the mixture was cooled to room temperature, the mixture was concentrated and the obtained residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the intended product (40.3 mg, 23%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.C(Cl)(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2c(OCCCBr)cccc21
Yield: 57 %

Procedure:
32.43 g (0.2 mol) 5-hydroxy-1-oxotetraline and 120.14 g (0.6 mol) 1,3-dibromopropane were, while stirring, heated to the boil in 200 ml anhydrous isopropanol and thereafter 41.46 g (0.3 mol) pulverized anhydrous potassium carbonate were added thereto over the course of about three hours. Subsequently, the reaction mixture was vigorously stirred for six hours at reflux temperature, then filtered with suction and the filter cake washed out with isopropanol. The filtrate was evaporated in a vacuum and excess 1,3-dibromopropane was substantially stripped off. The oily evaporation residue obtained was taken up in chloroform, the chloroform solution was extracted several times with a dilute aqueous solution of sodium hydroxide, then shaken with water until neutral and dried. After distilling off the chloroform, the oily residue was distilled at oil pump vacuum. Between 145°-155°C/0.05 mm Hg, there were obtained 32.3 g (57.1% of theory) 5-(3-bromopropoxy)-1-oxotetraline, which was then further worked up.
Reaction SMILES: [NH3:1].[CH:2]([S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH3:20])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5])=[CH2:3]>C(#N)C>[NH2:1][CH2:3][CH2:2][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH3:20])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: C=CS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OCCC)c1OCCC
Reactant: N
Solvent: CC#N
Product: CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(S(=O)(=O)CCN)c1OCCC
Temperature: 65 °C

Procedure:
Ammonia was bubbled into a solution of trans-2-(3-vinylsulfonyl-4,5-dipropoxyphenyl)-5-(3,4,5-trimethoxy-phenyl)tetrahydrofuran (30 mg, 0.06 mmol) at 0.5° C. for 3 min in acetonitrile (3 mL). The solution was then heated at 65° C. in a pressure bottle overnight, cooled, and evaporated to dryness. Purification by preparative TLC (CHCl3 -MeOH; 95:5, v/v) gave the title compound MS, m/z 538 (M+1)+. ; Rf 0.27; NMR (CDCl3) δ 1.05 & 1.09 (2 t J=7.5 Hz, 2 CH2CH2CH3), 3.58 (bt, SO2CH2CH2), 4.02 & 4.14 (2 t, J=6.5 Hz, 2 CH2CH2CH3), 5.16-5.28 (m, H-2 & H-5), 6.63 (s, 2 H, C5ArH), 7.27 & 7.48 (2 d, J=1.5 Hz, 2 H, C2ArH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 (2.4 g, 11.8 mmol) in 60 ml of ethyl acetate was added 60 ml of saturated K2CO3. To this biphasic solution was added benzyl chloroformate (2.03 ml, 14.23 mmol) dropwise. After stirring at room temperature for 3 hours the layers were separated and the organic layer dried over MgSO4, filtered, and the solvents removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCN)CCCC3
Reactant: O=C(Cl)N1CCOCC1
Product: COCCc1nc2c(N)nc3c(c2n1CCCNC(=O)N1CCOCC1)CCCC3
Yield: 44.4 %

Procedure:
Using the general method of Example 167, 1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.59 mmol) was reacted with 4-morpholinecarbonyl chloride (1.08 g, 7.25 mmol) to provide 1.22 g of N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 171.8-173.2° C. Analysis: Calculated for C21H32N6O3: % C, 60.56; % H, 7.74; % N, 20.18. Found: % C, 60.30; % H, 7.72; % N, 20.11.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)OS(C)(=O)=O.[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reactant: Nc1cnc2ccccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Temperature: 60 °C

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate (123 mg, 0.347 mmol) in acetonitrile (1.74 mL) was added 3-amino quinoline (60.6 mg, 0.416 mmol), followed by potassium phosphate (155 mg, 0.694 mmol). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 2 H), 7.92 (d, J=7.8 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.44-7.35 (m, 2 H), 6.81 (d, J=2.5 Hz, 1 H), 4.62-4.54 (m, 1 H), 4.44-4.33 (m, 3 H), 2.36-2.10 (m, 4 H), 1.38 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CO>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: O
Solvent: CO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 75 °C
Yield: 74 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and methanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated under nitrogen to reflux (75° C.) and kept at this temperature overnight. The reaction mixture was allowed to cool to below 50° C. and water (15 mL, 3 vol) was added. The precipitated light yellow solid was isolated by filtration, then was washed twice with water (5 mL) and dried to provide olanzapine in 74% yield (4.35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C#N)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C(=O)Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methoxy-4-cyanobenzoic acid (Tetrahedron Letters, 1986, 27(49), 5997–6000) (1 g, 5.6 mmol) was dissolved in CH2Cl2 (20 ml). Oxalyl chloride (1.5 ml, 8.2 mmol) was rapidly introduced into the solution and a drop of DMF was added. A vigorous reaction took place with the abundant evolution of gaseous products. The solution was stirred for 1 h then allowed to stand over night. Solvent was removed using a rotary evaporator to leave 1.1 g of an off white solid (5.6 mmol, yield 99%) that was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1>CN(C=O)C.O>[CH2:2]([CH:3]([O:6][C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-pentanol (0.093 ml, 0.86 mmol) in DMF (2 ml) was added sodium hydride (60% in oil, 34 mg, 0.86 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (64.8 mg, 0.20 mmol). The mixture was stirred at 60° C. for 1.5 hours, then diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 52 mg (69%) of the title compound as crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16].S>C(O)C.C(OC(C)C)(C)C>[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(C)CCN
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methylbutylamine (8.5 cc) is added to a solution of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (5.86 g) in absolute ethanol (135 cc). The mixture is saturated with hydrogen sulphide and then brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is diluted with ethyl acetate (150 cc), washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. before being purified by chromatography on a column (height: 32 cm; diameter: 4 cm) of silica gel (0.06-0.2 mm), eluting with pure ethyl acetate (1000 cc), collecting 60-cc fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is dissolved in isopropyl ether (80 cc). Crystallization is primed by scratching, and the mixture is stirred for 12 hours at 25° C. The crystals are filtered off to give 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (4.3 g) in the form of yellow crystals, m.p. 140° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:23])[C:7](=[O:20])[C:8]([F:18])([F:19])[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (2.4 g, 7.95 mmol) was dissolved in DMA (20 mL) and cooled in an ice bath. Sodium hydride (348 mg of 65% in mineral oil, 8.75 mmol) was added slowly and left to stir for 10 minutes. Methyl iodide (0.546 mL, 8.75 mmol) was then added and then after 10 minutes the solution removed from the bath. After 30 minutes the reaction was deemed complete by LCMS, poured into ice water (300 mL), the solution acidified with 1N HCl, the product filtered off as a yellow solid (2.36 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-2.00 (m, 8 H) 3.34 (s, 3 H) 4.15 (t, J=13.26 Hz, 2 H) 4.80 (q, 1 H) 8.35 (s, 1 H). [M+H] calc'd for C13H15ClF2N4O, 317; found 317.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:51])[NH:10][CH:11]([CH3:50])[CH2:12][C:13]([NH:15][CH:16]([C:29](=[O:49])[N:30]([CH2:41][CH:42](OCC)OCC)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][N:38]=[CH:37]2)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C(C)(C)C)=[CH:20][CH:19]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([NH:8][C:9]([N:10]1[CH:11]([CH3:50])[CH2:12][C:13](=[O:14])[N:15]2[CH:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:29](=[O:49])[N:30]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:40]=3[NH:39][N:38]=[CH:37]4)[CH2:41][CH:42]12)=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Solvent: O=CO
Product: CC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4cn[nH]c34)CC2N1C(=O)NCc1ccccc1
Yield: 33.7 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-N-{2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(1H-indazol-7-ylmethyl)-carbamoyl]-ethyl}-butyramide (3.46 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 6-(4-Hydroxy-benzyl)-8-(1H-indazol-7-ylmethyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (0.923 g, 3 step yield: 29%). 1H NMR (CDCl3, 300 MHz) δ 8.30 (s, 1H), 7.4-7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.45 (m, 3H) MS ESI 553 (M+H), 575 (M+Na).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11])([CH3:8])[C:3](OCC)=[O:4].Cl.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][C:2]1([CH3:8])[O:9][C:10](=[O:11])[N:23]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:26][CH2:25]2)[C:3]1=[O:4]
Reactant: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N([C@H]2CC[C@H](C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of the compound (1.3 g) obtained in step 1, benzyl trans-4-aminocyclohexanecarboxylate monohydrochloride (1.1 g), potassium carbonate (0.88 g) and DMF (30 mL) was stirred at 60° C. for 6 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→25% ethyl acetate/hexane) to give benzyl trans-4-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)cyclohexanecarboxylate (1.2 g, 81%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:23][C:21]1[C:22]2[C:18](=[N:17][C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:8]=2[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:19][N:20]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: Cc1ccc(C(=O)Cc2ccncc2)cn1
Product: Cc1ccc(-c2nc3[nH]nc(C)c3c(-c3ccc(C)nc3)c2-c2ccncc2)cn1
Yield: 24 %

Procedure:
Following a similar procedure to that described in example 1 method A, but using 1-(6-methylpyridin-3-yl)-2-(4-pyridyl)ethanone (obtained in reference example 13) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, the title compound was obtained (yield: 24%).
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[N:26][CH:27]=1.CC(C)([O-])C.[Na+].O>CS(C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:3]2[C:2]([O:35][C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:25]4[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=4)=[CH:34][CH:33]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)CC1
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Nc2ccc(Oc3nccnc3C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (9.55 mL, 3.73 mmol), 4-(5-methylpyridin-2-ylamino)phenol (0.747 g, 3.73 mmol), and sodium tert-butoxide (1.07 g, 11.20 mmol) in DMSO (15 mL) was stirred at RT in 24 h. Water was added, and the reaction mixture was extracted with ether (3×), dried over MgSO4, concentrated and purified by ISCO (0-60% EtOAc/Hexanes) to give the light brown oil. MS (ESI, pos. ion) m/z: 462.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 76.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 5 g 3-methoxyphenylboronic acid, 5 g 5-bromo-2-fluoronitrobenzene and 11 mL of 2 M sodium carbonate solution in 100 mL of toluene. The mixture was refluxed for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and brine and then dried and concentrated to give an oily solid. The solid was chromatographed on silica gel (ethyl acetate:hexane (1:6)) to give 4.3 g (77% yield) of 4-fluoro-3'-methoxy-3-nitrobiphenyl.