Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[CH:7][C:6]=1[F:13])[CH3:2].[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:17]2[CH2:18][CH2:19][CH2:16][CH2:15]2)=[CH:7][C:6]=1[F:13])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCNC1
Product: CCOC(=O)c1cc(F)c(N2CCCC2)cc1F
Reaction time: 24 h
Yield: 97 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (5.25 g). MS CI: m/z 256 (MH+).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=1[OH:16].[N:22]1([C:28]2[NH:29][CH:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>N1C=CC=NC=1>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:14]=1[NH:13][C:36](=[O:37])[CH2:35][C:30]1[NH:31][C:32](=[O:34])[CH:33]=[C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:29]=1
Reactant: O=C([O-])CC1NC(=O)C=C(N2CCOCC2)N1
Reactant: Nc1c(O)cccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1cncnc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
1.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 946 mg of 2-aminoresorcinol are added to a solution of 1 g of sodium [4-(morpholin-4-yl)-6-oxo-dihydropyrimidin-2-yl]acetate in 8 ml of pyrimidine. The reaction mixture is stirred at ambient temperature for 18 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 904 mg of N-(2,6-dihydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-acetamide are obtained in the form of a red solid, which is used as it is in the next stage.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2.[O-:13][C:14]#[N:15].[K+]>O>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH:12][C:14]([NH2:15])=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2
Reactant: N#C[O-]
Reactant: NC1CCCCc2sccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCCCc2sccc21
Reaction time: 1 h

Procedure:
A mixture of 50 grams of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride in 100 ml. of water is stirred at about 15° C. and a solution of 23.1 grams of potassium cyanate in 100 ml. of water is added dropwise. After completion of the addition, the mixture is warmed slowly to 70°-75° C. and held there for one hour. The mixture is cooled and the white solid is collected by filtration and washed with water. The solid is air-dried, pulverized, and washed with acetonitrile. Upon drying, this crude product is treated with hot acetone whereby there is obtained 5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, m.p. 217° C. dec.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 3-nitrobenzylchloride (5 g, 29.14 mmol), N-methylpiperazine (3.9 mL, 34.97 mmol, 1.2 equiv), potassium carbonate (8 g, 58.28, 2 equiv), and acetone (100 ml) is stirred for 15 h at reflux. The reaction mixture is allowed to cool to RT, filtered and concentrated. The residue is purified by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) to afford the title compound as a brow oil: ESI-MS: 236.0 [MH]+; tR=1.40 min (purity: 100%, system 1); TLC: Rf=0.31 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[N:8]1([C:6]2[N:5]3[N:14]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[N:21][CH:22]=4)[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Reaction time: 6 h
Yield: 96 %

Procedure:
There was suspended, in 1,4-dioxane (1.0 mL), 5-chloro-7-morpholin-4-yl-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidine (20 mg, 2.4 mM) prepared in the preceding step 1, then hydrazine monohydrate (29 μL, 0.6 mM) was added to the suspension and the mixture was stirred for 6 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off to thus give a crude product of the title compound (18 mg, yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31][O:32]C3CCCCO3)[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11](=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31][OH:32])[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[C:11](=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(C(=O)N2CC(CCCO)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 11.5 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(#N)C.O>[CH3:13][C:5]1[C:6](=[O:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3](=[O:2])[C:4]=1[CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCCO)c2ccccc2)c1C
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(C(CCCCCCO)c2ccccc2)=C(C)C1=O
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
7-(2,5-Dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptanol (1.85 g, 5.0 mmole) was dissolved in a mixed solution of acetonitrile (12 ml) and water (6 ml), and a cooled solution of ceric ammonium nitrate (8.22 g, 5×3 mmole) in 50% aqueous acetonitrile (16 ml) was added dropwise to the solution, under ice cooling, over the 20-minutes period. After stirring was continued for another 20 minutes under ice cooling, acetonitrile was distilled off under reduced pressure, and isopropyl ether was added to the residue to conduct extraction. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate), and evaporated. The residual solution was chromatographed on a silica gel column, and purification was performed (elution with isopropyl ether) to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanol (1.53 g, 90%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 9, 10, 35, 36, 46 to 55 and 64 to 67 were prepared.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=O)[CH3:4]>C(O)C>[CH2:8]=[C:7]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:20]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at room temperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80 mL) and the whole was stirred at room temperature overnight, then concentrated by evaporation, thereafter water (14 mL) was added and then the mixture was acidified in an ice bath with concentrated hydrochloric acid (12.6 mL). Partitioning between water and ether was carried out, the organic phase was dried and the ether was distilled off. Then, pyridine (26 mL), piperidine (1.22 g) and paraformaldehyde (3.56 g) were added to the residue. The mixture was heated in an oil bath (130°) for 90 minutes, cooled, water (440 mL) were added and extration was carried out 3 times with n-hexane (150 mL). The combined organic phases were washed with water, 1N HCl, water, saturated NaHCO3 solution and brine. The solution was dried (MgSO4) and evaporated to give the title compound as colourless oil (26 g, 85% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure.
Reaction SMILES: [C:1]([NH:5][S:6]([NH:9][C:10]([CH2:13][C:14]([CH3:17])([CH3:16])C)([CH3:12])[CH3:11])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(N)(N)(=O)=O.ClO[C:25](C)([CH3:27])[CH3:26].[H-].[Na+].C(N=NC(CC(C)(C)C)(C)C)(C)(C)C>>[C:1]([NH:5][S:6]([NH:9][C:10]12[CH2:11][CH:26]3[CH2:25][CH:27]([CH2:16][CH:14]([CH2:17]3)[CH2:13]1)[CH2:12]2)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)NC(C)(C)C
Reactant: CC(C)(C)OCl
Agent: CC(C)(C)CC(C)(C)N=NC(C)(C)C
Agent: NS(N)(=O)=O
Agent: [H-]
Product: CC(C)(C)NS(=O)(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 45 %

Procedure:
Treatment of tertiary alcohols with chlorosulfonyl isocyanate gives monoalkyl sulfamyl chlorides (J. B. Hendrickson and J. Joffe, J. Am Chem. Soc., 95, 4084, 1973). Timberlake used this method to synthesize N-tert-butyl-N'-tert-octylsulfamide in 44% yield (J. W. Timberlake, M. L. Hodges and A. W. Garner, Tetrahedron Lett., 3843, 1973 and J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral and S. Szilagyi, J. Org. Chem., 46, 20282, 1981). The sulfamide was oxidized with tert-butyl hypochlorite and sodium hydride to tert-butyl tert-octyldiazene. N-tert-Butyl-N'-(adamant-1-y1 ) sulfamide was prepared in 45% yield by the same route. There is no evidence it was oxidized to the azo. Apparently, tert-butyl tert-2,2,4,6,6-pentamethyl-4-heptyldiazene was also prepared by this route (J. W. Timberlake and A. W. Garner, J. Org. Chem., 41, 1666, 1976).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.C(N(CC)CC)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
A mixture of t-Boc-Val-OSu (3.14 g, 10 mmol) and H-Lys(CBZ)-OCH3.HCl (3.31 g, 10 mmol) in THF (300 ml) was treated at room temperature with triethylamine (1.38 ml) and left stirring for 17 hr. The resulting solution was evaporated in vacuo and the residue was dissolved in EtOAc (500 ml). The organic solution was washed successively with water (2×200 ml), 5% citric acid (2×200 ml), water (2×200 ml) and dried over Na2SO4. The dried solution was filtered and evaporated in vacuo to give (VI) (4.9 g; 99%) as a foam. T.l.c. RfE4 =0.64.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][NH:18][CH3:19]>CCOCC>[CH3:17][N:18]([CH3:19])/[CH:1]=[CH:2]/[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC
Reactant: O=CC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CN(C)/C=C/Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 19.6 mL (20.0 grams, 149 mmol) of cinnamaldehyde, 40.6 grams (298 mmol) of potassium carbonate, and 150 mL of ether was cooled to −60° C. and treated with a prechilled (−78° C.) solution of 17.8 mL (13.5 grams, 300 mmol) of liquid dimethylamine, condensed from the gas at −78° C., in 20 mL of ether. After stirring for 0.5 hours at −60° C., the mixture was allowed to slowly warm to room temperature and then stirred for an additional 3 hours. The mixture was filtered, concentrated, and distilled to give 10.2 grams (42% yield) of the title compound as a yellow liquid, bp 95-100° C./2.8-3.0 Torr. The liquid slowly polymerized on standing and was used directly. 1H NMR (CDCl3) d 2.57 (6H, s), 3.30 (2H, d, J=7 Hz), 4.35 (1H, dt, J=7, 14 Hz), 5.99 (1H, dt, J=1, 14 Hz), 7.15-732 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F-].[K+].OC(C(F)(F)F)=O.[OH:21][C:22]([CH3:44])([CH3:43])[CH2:23][C@@:24]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:29][C:28](=[O:30])[N:27]([C@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:26][CH2:25]1.O=O>C(#N)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[OH:21][C:22]([CH3:44])([CH3:43])[CH2:23][C@@:24]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:29][C:28](=[O:30])[N:27]([C@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:32]2)[CH2:26][CH2:25]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(N2CCC[C@H](N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)C2)cn1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 56.9 %

Procedure:
A suspension of 6-methoxypyridin-3-ylboronic acid (4 mg, 1.5equiv), Cu(OAc)2 (1 mg, cat. amount), potassium fluoride (1.1 mg, 1.05 equiv), and powdered activated 4 Å Molecular Sieves (15 mg) in acetonitrile (1.5 mL) was stirred in a test tube at ambient conditions for 10 min. A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one TFA salt (6 mg, 0.018 mmol) in acetonitrile (1 mL) was added. The test tube was sealed with a septum and a balloon of oxygen gas was attached to maintain the oxygen atmosphere. The mixture was heated overnight at 85° C. LC-MS found the product peak. The mixture was filtered and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(6-methoxypyridin-3-yl)piperidin-3-yl)-6-phenyl-1,3-oxazinan-2-one (4.5 mg, 76% yield). LC-MS Method 1 tR=1.37 min, m/z=440(M+1); 1H NMR (CD3OD) 7.82(m, 2H), 7.43-7.29(m, 5H), 7.11(m, 1H), 4.14(m, 1H), 4.00(s, 3H), 3.56(t, 1H), 2.77(m, 3H), 2.52(m, 2H), 2.19(s, 2H), 1.23(s, 3H), 0.95(s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:21])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:21])[CH3:12])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: COC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.0 g) and 6-(dimethylamino)hex-4ynylamine (0.79 g) were reacted to give a solution of 3-methoxy-4-[6-dimethylaminohex-4-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia and purification as in Example 1 gave the title compound (0.62 g), m.p. 183°-5° C. (recrystallisation from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13])=[O:5].I[CH2:20]I>>[Cl:18][C:15]1[CH:16]=[CH:17][C:2]2[O:1][CH2:20][O:13][C:7]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=3[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O
Reactant: ICI
Product: O=C1c2cc(Cl)ccc2OCOc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared similarly as described in Journal of the American Chemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dry N,N-dimethylformamnide (226 ml). Dried and powdered potassium carbonate (8.3 g) was added and the mixture was heated at 105° C. for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate was collected by filtration after 0.5 h and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4 and evaporated in vacuo, affording 12 g (96%) of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:53]([O:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:22]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1)[CH3:54]
Reactant: CCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-ethoxyphenyl borate (115 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(2-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 119) (145 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCCl)c(=O)c2cc1OC

Procedure:
3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4(3H)-quinazolinone (1.65 g, 8 mmol). The quinazolinone was combined with 1-chloro-4-iodobutane (1.08 mL, 8.8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture was diluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 1.55 g (65%); gray solid; m.p. 117° C., MS: 296.8 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].[CH:17]([O:19][CH2:20]C)=O.[H-].[Na+].IC>COCCOC>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][C:8](=[CH:17][O:19][CH3:20])[C:9]#[N:10]
Reactant: CCOC=O
Reactant: COc1cc(C(C)C)c(OCC#N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: COC=C(C#N)Oc1cc(Cl)c(OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of (5-chloro-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (1.44 g, 6.0 mmol) and ethyl formate (2.2 g, 29.2 mmol) in 7 mL 1,2-dimethoxy ethane at 5° C. was added 95% NaH (0.15 g, 6.0 mmol) in one portion. The mixture was warmed to room temperature. After 1 hour 95% NaH (0.15 g, 6.0 mmol) was added in one portion. After 1 hour 10 mL iodomethane was added and the mixture was allowed to stir for 16 hour. The mixture was concentrated in vacuo, 1N HCl was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (85:15 hexane/ethyl acetate) afforded 2-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-3-methoxy-acrylonitrile (1.41 g, 84%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH2:30][CH2:31]Cl)=[CH:25][C:24]=1[Cl:33]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][C:26]3[CH:27]=[C:28]([Cl:29])[C:23]([NH2:22])=[C:24]([Cl:33])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: Nc1c(Cl)cc(CCCl)cc1Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-3,5-dichlorophenyl)-ethyl chloride.