Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>C(Cl)Cl.O>[Br:30][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[NH:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)ncn2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(NCC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.45 g, 1.37 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (314 mg, yield 56%). MS (m/z): 406 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:13])[C:9]#[C:10][CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O1CCOCC1>[OH:12][CH2:11][C:10]#[C:9][CH2:8][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#CCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC#CCO)cc1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At 10° C., a solution of triethylamine (17.5 ml, 128.0 mmol) in absolute dioxane (60 ml) is added dropwise to a solution of but-2-yne-1,4-diol (10 g, 116.1 mmol) and 4-toluenesulfonyl chloride (24.4 g, 128.0 mmol) in absolute dioxane (230 ml), and the mixture is stirred for 2 h. The mixture is then stirred at RT overnight. The reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8.5:1.5)] on a silica gel column. This gives the title compound (7.5 g) as a light yellow oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.49.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CC(O)=O.C(Cl)Cl>[C:12]([O:15][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: Clc1cc(Cl)c(I)c(CBr)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OCc1cc(Cl)cc(Cl)c1I
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(bromomethyl)-3,5-dichloro-2-iodobenzene (1.29 mmol) [WO2011/027156] and sodium acetate (9.91 mmol) in 4 mL AcOH was heated to 100° C. for 1 h and then to 80° C. for 20 h. The mixture was diluted with DCM and extracted with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (9/1) gives the desired compound as white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Yield: 87.6 %

Procedure:
110 mg of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.28 mmol) and 122 mg of morpholine (1.4 mmol) are dissolved in 3.0 ml of THF and 182 mg of cesium carbonate (0.56 mmol) is added. The mixture is put in 4 ml vial with a Teflon® lined cap and heated at 110 C overnight. The reaction mixture is concentrated and applied to a silica-gel column chromatography column with hexane:EtOAc=3:1 eluent to give 98 mg of the title compound (88%). mass spectrum (m/e): 400 (M+1); 1H-NMR (CDCl3): δ 6.70 (s, 1H), 3.87 (t, 4H, J=4.8 Hz), 3.56 (t, 4H, J=4.8 Hz), 3.35 (m, 1H) 2.56 (s, 3H), 2.46 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.6 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].O>CN(C=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (10.8 g) in DMF (50 ml) cooled to 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 2.0 g, 50 mmol). The mixture was stirred for 30 min at 0° C. and then 2-bromoacetophenone (9.9 g, 50 mmol) was carefully added. After stirring for an additional 15 h at 0° C., the mixture was poured into water (500 ml) and extracted with diethyl ether (500 ml×2). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:5) to afford 11.8 g (72%) of the title compound as a brown amorphous solid.
Reaction SMILES: C(N1[CH2:13][CH2:12][NH:11][CH2:10]C1)(OC(C)(C)C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:22]=O)=[CH:17][CH:16]=1>>[N:11]1([CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:10][CH2:13][CH2:12]1
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Clc1ccc(C(CN2CCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33B but replacing bis-(4-chloro-phenyl)-acetaldehyde and N—BOC-piperazine with (4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde and anticline, the title compound was obtained. LC/MS: (PS-B3) Rt 2.99 [M+H]+ 338.09. 1H NMR (Me-d3-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).
Reaction SMILES: [C:1]([CH:3]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>[Ni].C(OCC)(=O)C>[C:25]([NH:2][CH2:1][CH:3]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C#N)c1cn(C(=O)OCC)c2ccc(OC)cc12
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CNC(C)=O)c1cn(C(=O)OCC)c2ccc(OC)cc12
Reaction time: 20 h

Procedure:
A solution of Compound 1A, prepared above, (7.4 g, 0.022 mole) in 150 ml of acetic anhydride was hydrogenated for 20 hours at 50 psi, using about 10 g of Raney nickel as a catalyst. The catalyst was then removed by filtration, and the solvent was evaporated in vacuo to leave a thick syrup. This syrup was dissolved in 200 ml of ethyl acetate which was then washed five times with 6% aqueous potassium carbonate solution and dried over MgSO4. The solvent was then evaporated in vacuo, and the syrup which remained was crystallized from ethyl acetate:petroleum ether. One recrystallization from the same solvent pair yielded 4.6 g (56% theory) of product, mp. 88°-90° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[NH:16]1[CH2:21][CH2:20][C:19]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22]2)[CH2:18][CH2:17]1>>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([N:16]1[CH2:17][CH2:18][C:19]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22]2)[CH2:20][CH2:21]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCNCC2)C1
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and tert-butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate. LC-MS Method 1 tR=2.18, min, m/z=503
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([NH2:21])=[O:18])=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cnc(C2CCC3(CC2)OCCO3)s1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1cnc(C2CCC3(CC2)OCCO3)s1

Procedure:
A solution of 2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-thiazole-5-carboxylic acid (as prepared in Example 52, Step C, 700 mg, 2.60 mmol), EDCI (600 mg, 3.12 mmol), HOBT (420 mg, 3.12 mmol) and TEA (490 μL, 3.50 mmol) in DCM (10 mL) were treated with 2N NH3 in dioxane (2 mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by a CombiFlash® system using hexanes and ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:14]([C:5]1[CH:4]=[C:3]([CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:8]=[CH:7][C:6]=1[CH2:9][NH:10][C:11](=[O:13])[CH3:12])([O-:16])=[O:15]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NCc1ccc(CCl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1[N+](=O)[O-]

Procedure:
A solution of N-(4-chloromethyl-2-nitrophenylmethyl)acetamide (1.4 g), phenylpiperazine (0.8 ml) and potassium carbonate (0.6 g) in dimethylformamide (20 ml) was stirred at 60° C. for 4 hr. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid. The obtained pale-yellow solid was crystallized from ethyl acetate to give the title compound (1.3 g) as pale-yellow white crystals, m.p.=135-136° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9](I)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[Li]CCCC.CN([CH:22]=[O:23])C>O1CCCC1>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:22]=[O:23])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc(C)c(I)cc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C)c(C=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a stirred solution of 2-ethyl-5-iodo-4-methylbenzoic acid (compound 211.3, 5.00 g, 17.2 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) at −78° C. under nitrogen was added dropwise n-BuLi (17 mL, 2 M in THF, 2.00 equiv). After 1 h at −78° C., DMF (7.00 g, 95.8 mmol, 3.00 equiv) was added dropwise at −78° C. The resulting solution was slowly warmed up to 25° C., then carefully quenched with water followed by the addition of 10 mL of HCl (aq., 6 M). The aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (2:1) as eluent to furnish 450 mg (14%) of 2-ethyl-5-formyl-4-methylbenzoic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][C:38]([F:42])([F:41])[CH2:39][NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 (1 eq) and triethylamine (3 eq) in tetrahydrofuran (0.08M) at 0° C. was added isobutyl chloroformate (1.8 eq). After stirring at 0° C. for 2 hours, 2,2,2-trifluoroethylamine (5 eq) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-(2,2,2-trifluoroethyl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>C(Cl)Cl>[Cl:26][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=Cc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of methyl 4-(hydroxymethyl)cinnamate (4.1 g), triethylamine (3.1 ml) and methylene chloride (50 ml) was added dropwise under ice cooling methanesulfonyl chloride (1.7 ml), and the mixture was stirred at room temperature for 1.5 hours. Evaporation of the reaction solution gave a residue, which was then chromatographed on silica gel column (eluent: methylene chloride) to give methyl 4-(chloromethyl)cinnamate (2.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH2:22]>C(OCC)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(O)cc1
Reactant: C=COC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=Cc1ccc(OC(C)OC(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
12.02 g (100 mmol) of 4-hydroxystyrene, 0.09 g of p-toluenesulfonic acid and 100 ml of diethyl ether are introduced under a nitrogen atmosphere into a 250 ml three-neck flask. The mixture is cooled to between 0° and 5° C., and 11.02 g (110 mmol) of tert-butyl vinyl ether are added dropwise at this temperature over the course of 15 minutes. The mixture is then stirred at 10° C. for 2 hours. The reaction mixture is washed three times with 150 ml of 1N NaOH and three times with demineralized water. Stripping off of the solvent gives 16 g (72% of theory) of the desired product in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:15][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(4-nitrophenoxy)pyridin-2-amine [US Pat Appl 2008319188, Production Example 53] (0.60 g, 2.60 mmol) and DIPEA (0.680 μL, 3.89 mmol) in DCM (15.0 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (225 μL, 3.89 mmol) dropwise over 5 min. The reaction was maintained at RT for 16 hr and was quenched by the addition of a 1% solution of NH3 in MeOH (10 mL). The mixture was evaporated in vacuo and the residue was taken up into DCM (50 mL) and was washed with water (25 mL) and brine (25 mL), and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in DCM, 0-30%, gradient elution) to afford 2-methoxy-N-(4-(4-nitrophenoxy)pyridin-2-yl)acetamide as a white solid (0.73 g, 92%); Rt 1.88 min (Method 2); m/z 304 (M+H)+ (ES+).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[C:11]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:22][C:20](=[O:21])[C:19]([NH:18][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:24])[CH3:23]
Reactant: O=c1oc(CBr)c(CBr)o1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (188 mg, 0.69 mmol) was dissolved in acetonitrile (5.0 mL). Thereto were added 2-(N-Boc-amino)isobutyric acid (70 mg, 0.35 mmol) and potassium carbonate (48 mg, 0.35 mmol). This mixture was stirred at 25° C. for 18 hours. After the ordinary post-treatment, the reaction product was purified by thin-layer chromatography (developed with chloroform) to obtain Compound S-33 (50 mg, yield 18%).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:7](=O)[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:7](=[N:21][C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)C1(C)COCCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)COCCC1=N[C@H](C)c1ccccc1

Procedure:
Methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate (2.33 g, 13.53 mmol) was dissolved in toluene (150 mL) and treated with R-(+)-α-methylbenzylamine (3.96 mL, 2.3 eq) and ytterbium (III) trifluoromethanesulfonate (252 mg, 0.03 eq). The mixture was heated to reflux under Dean-Stark conditions overnight, and then concentrated to provide crude methyl 3-methyl-4-((R)-1-phenylethylimino)-tetrahydro-2H-pyran-3-carboxylate that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:5].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>O1CCCC1>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][C:25]2[CH:26]=[C:2]3[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]4[CH2:12][CH:13]=[C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:15][CH2:16]4)[C:35](=[O:36])[NH:1]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c(N)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3c(=O)n(CCCCN4CC=C(c5ccccc5)CC4)c(=O)[nH]c3c2)CC1
Yield: 60.6 %

Procedure:
A mixture of 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]benzamide (0.25 g), carbonyldiimidazole (0.45 g) and dry tetrahydrofuran (10 ml) was stirred under reflux for 14 hours. After evaporation of the solvent, the crude residue was taken up with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to give crystals. Recrystallization from ethanol afforded 7-(4-methylpiperazin-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccc1
Temperature: 80 °C

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 5.23 mmol) from step 2 was dissolved in excess benzylamine (5 mL) and heated to 80° C. for 4 hours. The mixture was then diluted in diethyl ether and washed several times with (0.5 N) HCl. The organic layer was concentrated in vacuo to give 2-benzyl-5-nitro-2H-isoquinolin-1-one as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])#[N:2].Cl.C(O)(=[O:26])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(=[O:26])[NH2:2]
Reactant: CC(=O)O
Reactant: CN(C)CCC=C1c2ccccc2C=Cn2cc(C#N)cc21
Agent: Cl
Product: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(N)=O)cc21
Temperature: 25 °C

Procedure:
2-Cyano-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 2-carbamoyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].Cl[CH2:10][CH:11]([OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[NH:13][CH2:12][CH:11]([OH:22])[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)CNc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
19.9 Grams (0.293 mol) of imidazole and 54.7 g (0.304 mol) of sodium methylate solution (30% in methanol) are mixed and concentrated to dryness at 50° C./12 Torr. 80 Ml of dimethylformamide are added to the thus-formed imidazole sodium salt. The mixture is heated to 110° C. and a solution of 50 g (0.197 mol) of N-(3-chloro-2-hydroxypropyl)-3,4-dichloroaniline in 100 ml of dimethylformamide is added dropwise at this temperature over a period of 30 minutes. This addition finished, the reaction solution is further heated and refluxed for 2 hours. The solution is then cooled to 90° C. and 650 ml of water are added. The reaction mixture is left standing for 12 hours. The solid precipitant is filtered off, washed with water and dried at 50° C./12 Torr. For purification the substance is recrystallized under filtration with active charcoal from 100 ml ethyl acetate to yield 22 g of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole, M.P. 98°-100° C.