Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:19][CH2:20][CH2:21][O:22][C:23]=4[CH:24]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+].CN1CCCC1=O>[Cu]Br.O>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4[C:15](=[CH:24][C:23]5[O:22][CH2:21][CH2:20][O:19][C:18]=5[CH:17]=4)[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:29][CH:28]=1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Reactant: COc1ccc(O)cc1
Agent: [Cu]Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Oc2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3C)cc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A 10 mL microwave reaction vessel was charged with 4′-bromo-1′-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one (0.19 g, 0.5 mmol), 4-methoxyphenol (0.12 g, 1.0 mmol), potassium tert-butoxide (0.11 g, 1.0 mmol), copper (I) bromide (0.012 g, 0.08 mmol) and anhydrous 1-methylpyrrolidin-2-one (2 mL). The reaction mixture was irradiated at 250° C. for 75 min in a microwave reactor and was allowed to cool to ambient temperature. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes afforded 4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.084 g, 39%) as an off-white solid: mp 55-58° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.27-7.14 (m, 1H), 6.78-6.59 (m, 5H), 6.44 (d, J=8.48 Hz, 1H), 6.31 (d, J=1.08 Hz, 1H), 6.22 (d, J=1.08 Hz, 1H), 4.86 (ABq, 2H), 4.16-4.03 (m, 4H), 3.74 (s, 3H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 155.8, 155.6, 154.3, 149.6, 144.8, 144.3, 137.7, 130.0, 120.2, 120.1, 119.5, 114.5, 112.7, 111.0, 103.1, 99.1, 64.4, 63.9, 57.4, 55.6, 27.0; MS (ES+) m/z 432.0 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].C(N(CC)CC)C>C(OCC)C>[CH2:2]([O:3][C:4]([C:6]1[CH:12]=[C:11]([C:10]([OH:14])=[O:13])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: C#CC(=O)O
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(=O)O)on1
Yield: 60.4 %

Procedure:
Ethyl chlorooximidoacetate (3.30 mmol, 0.5 g) and propiolic acid (33.0 mmol, 2.311 g) were dissolved in diethyl ether (10 ml) with stirring. Triethylamine (3.30 mmol, 0.334 g) dissolved in diethyl ether (5 ml) was added dropwise to the previous mixture. The reaction mixture was stirred for three days at RT during which more triethylamine (2×0.668 g dissolved in 5 ml diethyl ether) was added dropwise. The pH of the reaction mixture was adjusted to 2. The organic phase was washed twice with water. The organic phase was dried, filtered and evaporated. The residue was dried under vacuum. 369 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.44 (t, 3H), 4.49 (q, 2H), 7.41 (s, 1H), 10.59 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) according to the general procedure M. Obtained as an orange oil (238 mg).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.C(Cl)Cl.O=C1CCC(=O)N1[O:24][C:25](=O)[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:25](=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCBr
Reactant: O=C(C=CC=Cc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=CC=Cc1ccccc1)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (1.09 g, 5.0 mmol) in anhydrous methylene chloride triethylamine (0.61 g, 6.0 mmol) was added and the mixture was stirred at ambient temperature for 30 min. The mixture was cooled in the ice bath and a solution of 5-phenyl-penta-2,4-dienoic acid 2,5-dioxo-pyrrolidin-1-yl ester (10) (1.35 g, 5.0 mol) in methylene chloride (20 ml) was added. The reaction mixture was stirred at ice bath temperature for 1.5 hours and at ambient temperature for 2 hours. The solvent was removed and the residue was suspended in water. The precipitate was filtered and washed with water and hexane to give the title compound 11 (1.0 g, 68%). 1H NMR (CDCl3, HMDSO) δ: 1.92-2.32 (2H, m); 3.31-3.67 (4H, m); 6.00 (1H, d, J=15.0 Hz); 6.07 (1H, br s); 6.78-6.96 (2H, m); 7.22-7.61 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[NH2:1][C:2]1[N:3]([CH2:29][CH3:30])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (88 mg, 0.31 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 16 mg, 0.40 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of ethyl iodide (62 mg, 0.40 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 53 mg (55%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28]>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:27]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][N:21]=2)=[O:28])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(Cl)c1cnccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1C(=O)O)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 2.0 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1F
Temperature: 100 °C

Procedure:
A solution of methyl 2-bromo-4-nitrobenzoate (5.20 g), 2-fluorophenylboronic acid (3.92 g) and potassium carbonate (4.98 g) in a 10:1 mixture of DME:water (120 ml) was degassed by gently bubbling though nitrogen for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (2.32 g) was then added and the mixture was degassed for a further 10 minutes before being sealed under nitrogen. The reaction mixture was heated to 100° C. for 14 hours. The solvents were removed under vacuum. The residue obtained was redissolved in DCM and washed with water (2×). The organic phase was passed through a hydrophobic frit and then concentrated to dryness under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol containing increasing amounts of ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[S:23](=O)(=[O:26])([OH:25])[OH:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:13]=[C:12]([S:23]([OH:26])(=[O:25])=[O:24])[S:11][CH:10]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccsc2)cc1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(=O)c2csc(S(=O)(=O)O)c2)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
9.7 g (0.05 mol) of product from Step A was dissolved in 75 ml CH2Cl2 and cooled to -10° C. Then, 15.3 g (0.15 mol) acetic anhydride was added dropwise followed by the dropwise addition of 5.9 g (0.06 mol) concentrated sulfuric acid. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([CH3:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:24]=[C:25]([CH3:34])[C:26]([OH:32])=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:28]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(C)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.8 %

Procedure:
Boron trifluoride dimethyl sulfide (1.48 mL, 13.7 mmol) was added at 4° C. to a stirred solution of methyl-N-[3,5-dichloro-4-(5-isopropyl-4-methoxy-3-methylphenoxy)benzoyl]glycine (155 mg, 0.352 mmol) and dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 24 hours and then treated with ice-water (30 mL), extracted with ethyl acetate and concentrated. The residue was purified on column (MPLC, silica gel, chloroform/methanol/acetic acid, gradient elution from 1/0/0 to 95/5/0.5) to give 110 mg (76%) of N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-5-methylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 410.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.40 g), 8N aqueous sodium hydroxide solution (0.40 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.35 g, yield 91%) as colorless crystals. melting point>240° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.[O:13]1CCOCC1>>[ClH:1].[NH2:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:13]
Reactant: C1COCCO1
Reactant: O=C1NCc2ccc(Cl)cc21
Agent: Cl
Product: NCc1ccc(Cl)cc1C(=O)O
Temperature: 110 °C
Yield: 4 %

Procedure:
A mixture of 6-chloro-2,3-dihydro-isoindol-1-one (0.115 g, 0.68 mmol) and 6M hydrochloric acid (8 ml) in dioxan (1 ml) was heated to 110° C. for 18 hours. After cooling to room temperature the solid was filtered off and dried in vacuo to give the title compound (0.0055 g, 4%) as a beige solid.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.[C:30](Cl)(=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:30](=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: CC(C)(C)COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 2 with 100 mg (0.29 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A, 5 ml of pyridine and 43 mg (0.29 mmol) of neopentyl chlorocarbonate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)=[O:3]
Reactant: CC(=O)c1cccc(C)n1
Reactant: COC(OC)N(C)C
Product: Cc1cccc(C(=O)C=CN(C)C)n1

Procedure:
A mixture of 25.0 g of 2-acetyl-6-methylpyridine and 35 ml. of N,N-dimethylformamide dimethylacetal is refluxed for 16 hours. The mixture is cooled and filtered to give 3-dimethylamino-1-(6-methyl-2-pyridyl)-2-propen-1-one as crystals, m.p. 97°-98° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH2:9]1[C:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][CH2:8]1
Reactant: COC(=O)C1=CN(C(=O)OC(C)(C)C)CCc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=CNCCc2c1[nH]c1ccccc21
Yield: 49.5 %

Procedure:
To a solution of 1,6-dihydro-2H-azepino[4,5-b]indole-3,5-dicarboxylic acid 3-tert-butyl ester 5-methyl ester (0.293 g, 0.62 mmol) in MeOH (4 mL) was added 4 N NaOH (2 mL) and the mixture was heated for 5 hours under nitrogen. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with AcOH. Precipitate was collected by filtration and washed with water and ether and dried under high vacuum to give the title compound (70 mg); 1H-NMR (DMSO-d6): δ 11.40 (1H, s), 10.73 (1H, br s), 7.83 (1H, m), 7.73 (2H, d), 7.38 (1H, m), 7.25 (1H, m), 6.88 (2H, m), 3.45 (2H, t), 3.87 (3H, s), 3.2.98 (2H, t), MS (ES): 229 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2](=[O:4])(=[O:3])[NH:18][CH2:16][CH3:17])[CH:6]=1
Reactant: CCN
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Methyl 2-(3-chlorosulfonyl-phenyl)acetate (0.29 g, 1.17 mmol) was dissolved in THF (10 mL) and to this solution 1 mL (2 mmol) of 2M ethylamine in THF was added. Let stir at room temperature 30 minutes, diluted with ethyl acetate and the organic layer was washed with 10% citric acid, brine, dried over sodium sulfate and concentrated to afford (3-ethylsulfamoyl-phenyl)-acetic acid methyl ester as an oil (0.28 g, 1.09 mmol, 93% yield). 1H NMR (CDCl3) 7.72 ppm, 2H, m; 7.41 ppm, 2H, m; 4.32 ppm, 1H, t; 3.68 ppm, 3H, s; 3.67 ppm, 2H, s; 2.98 ppm, 2H, m; 1.07 ppm, 3H, t.
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N:23]1([C:29]2[O:30][C:31]3[C:36]([N:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:26]2[CH2:25][CH2:24][N:23]([C:29]3[O:30][C:31]4[C:36]([N:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: c1cnc2oc(N3CCNCC3)nc2c1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated, aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→2% methanol/chloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 7.25 (dd, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (app s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:14]([CH3:25])[NH:15][CH:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:10]2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(#N)C>[C:33]([N:15]1[CH:14]([CH3:25])[CH:11]2[CH:10]([C:9](=[O:26])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]2=[O:13])[CH:16]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)(=[O:35])[CH3:34]
Reactant: CC1NC(c2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C12
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1C(C)C2C(=O)N(Cc3ccccc3)C(=O)C2C1c1ccc(C#N)cc1
Reaction time: 1.5 h
Yield: 83 %

Procedure:
4.B)c) A solution of 3.46 g (10 mmol) of (1RS,3SR,3aRS,6aSR)-4-(5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile in acetonitrile (10 ml) was treated with pyridine (20 mmol). Acetic anhydride (20 mmol) was slowly added dropwise while cooling with ice. The cooling was removed and the reaction mixture was stirred for a further 1.5 hours. Thereafter, the reaction mixture was poured into saturated NaCl solution and extracted with dichloromethane. The solvent was removed and the residue was separated chromatographically (hexane:ethyl acetate=1:1). (1RS,3SR,3aRS,6aSR)-4-(2-Acetyl-5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (83%) was isolated as a colourless solid. M.p.: 107°-109° C. EI-MS: 387 ([M]+, 72); 344 (35); 320 (28); 254 (18); 183 (16); 169 (17); 158 (53); 91 (86); 43 (100).
Reaction SMILES: [N:1]([CH:4]([C:9]1[C:14]2[N:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:16]3=[N:17][C:13]=2[C:12]([Cl:30])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:30][C:12]1[C:13]2[N:17]=[C:16]3[N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[CH2:19][CH2:20][CH2:21][N:15]3[C:14]=2[C:9]([CH:4]([NH2:1])[C:5]([F:6])([F:7])[F:8])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Yield: 104.5 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Sn](Cl)(Cl)CCCC)CCC.[CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=O.C1([SiH3])C=CC=CC=1>C1COCC1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:27][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Reaction time: 72 h
Yield: 82.8 %

Procedure:
(Z)-5H-Dibenzo[b,f]azepine (100 mg, 0.52 mmol), dibutyltin dichloride (54 mg, 0.16 mmol) and methyl 4-formylbenzoate (260 mg, 1.60 mmol) were stirred in THF (2 mL) for 30 minutes. Phenylsilane was added and the reaction mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by flash chromatography (0% to 40% EtOAc in hexanes). The fractions containing some product were washed with Na2S2O4. The layers were split and the organic layer was evaporated to afford title compound 350 (147 mg, 83%) as a yellow solid.