Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])/[CH:5]=[C:6](\[CH3:33])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH2:26][CH2:27][CH3:28])=[CH:23][C:22]2[C:21]([CH3:30])([CH3:29])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])C.[OH-].[Na+].CCO>CCOC(C)=O.CCCCCC>[F:12][C:11]([F:13])([F:14])/[C:10](/[C:15]1[C:24]([O:25][CH2:26][CH2:27][CH3:28])=[CH:23][C:22]2[C:21]([CH3:30])([CH3:29])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=2[CH:16]=1)=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:33])=[CH:5]\[C:4]([OH:34])=[O:3]
Reactant: CCCOc1cc2c(cc1/C(=C/C=C/C(C)=C/C(=O)OCC)C(F)(F)F)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCCOc1cc2c(cc1/C(=C/C=C/C(C)=C/C(=O)O)C(F)(F)F)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure B and using (2E,4E,6Z)-8,8,8-trifluoro-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester (Compound 3, 83 mg, 0.17 mmol), 1M NaOH (0.35 mL), and EtOH (3 mL) at 60° C. for 1.5 h followed by flash column chromatography on silica gel (30% EtOAc-hexane) and HPLC (15% EtOAc-hexane), the title compound was obtained as a white solid (60 mg, 77%).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2c(c1)CCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)CCO3)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.33 g-see Preparation 8), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.25 g-see Preparation 13), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (10 ml), the layers were separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to leave a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 8%). The product-containing fractions were combined and concentrated in vacuo to leave an oil which was crystallised from diisopropyl ether to give the title compound as a colourless powder, yield 0.17 g, m.p. 131°-132° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:11]([C:13]1[NH:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=1)[NH2:12])[CH3:10].[N:22]([O-])=O.[Na+]>C(O)(=O)C>[CH2:9]([N:11]1[C:13]2=[N:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[C:14]2=[N:22][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:12]1)[CH3:10]
Reactant: O=N[O-]
Reactant: CCN(N)c1cc(=O)n(C)c(=O)[nH]1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1nc(-c2ccccc2)nc2c(=O)n(C)c(=O)nc1-2
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 28.8 %

Procedure:
Benzaldehyde (55 μl, 0.54 mmol) is added to a solution of compound 3 (115 mg, 0.54 mmol) in glacial acetic acid (2 ml) and the mixture is stirred at 10° C. for 20 min. An aqueous solution of sodium nitrite (40 mg of NaNO2 in 100 μl of water) is then added and the mixture is stirred at 10° C. for a further 30 min. The mixture is poured onto ice water and the product is extracted with ethyl acetate (3×30 ml). The organic phases are dried (Na2SO4) and the solvent is distilled off in vacuo. The residue is purified by flash chromatography (7:3, toluene/ethyl acetate). 1-Ethyl-6-methyl-3-phenyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione (44 mg, 28.8%) and 1-ethyl-4-oxy-3-phenyl-6-propyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione (41 mg, 32%) are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13](Cl)[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28].C1C[O:39][CH2:38]C1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:13]([O:39][CH3:38])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(-n2nc(C(C)(C)C)cc2N)ccc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To a solution of 3-tert-butyl-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine (840 mg, 90% purity, 2.75 mmol) in dry THF (10 mL) under N2 was added imidazole (240 mg, 3.5 mmol) and chlorotriisopropylsilane (720 μL, 650 mg, 3.40 mmol) and the reaction mixture kept at RT for 18 hr. The resulting mixture was diluted with DCM (5.0 mL) and was treated with a second aliquot of chlorotriisopropylsilane (720 μL, 650 mg, 3.40 mmol) and after a further 5 hr with additional imidazole (240 mg, 3.50 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (360 μL, 330 mg, 1.70 mmol) and imidazole (120 mg, 1.8 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (50 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford a brown oil which comprised of a mixture of starting material and the desired product. This mixture was taken up into THF (1.0 mL) and was treated with chlorotriisopropylsilane (200 μL, 200 mg, 0.30 mmol) and imidazole (75 mg, 1.1 mmol) and was maintained at RT for 24 hr and then evaporated in vacuo. The residue was partitioned between EtOAc (10 mL) and water (10 mL) and the organic phase was separated and extracted brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate A16 as a yellow oil (510 mg, 37%); Rt 5.74 min (Method 1 basic); m/z 432 (M+H)+, (ES+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: Oc1cccnc1
Reactant: Cc1ccc(C#N)c(Cl)n1
Product: Cc1ccc(C#N)c(Oc2cccnc2)n1

Procedure:
2-chloro-6-methyl-nicotinonitrile was reacted with pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 212 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(OCC)=O)=[CH:5]2.[NH2:16][NH2:17].[CH2:18]([OH:20])C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:18]([NH:16][NH2:17])=[O:20]
Reactant: NN
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CCO
Product: NNC(=O)c1c[nH]c2ccc(O)cc12
Yield: 85 %

Procedure:
To a sample of ethyl 5-hydroxyindole-2-carboxylate (5 g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mL, 121 mmol). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3-carboxylic acid hydrazide in 85% yield.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([OH:37])[C:18]2[C:13](=[CH:14][C:15]([C:23](O)=[O:24])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)[C:11]1=[O:36].[CH3:38][NH2:39]>>[ClH:2].[CH3:38][NH:39][C:23]([C:15]1[CH:14]=[C:13]2[C:18]([C:10]([C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])([OH:37])[C:11](=[O:36])[N:12]2[CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=1)=[O:24]
Reactant: CN
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(=O)O)cc3C(F)(F)F)C1
Agent: Br
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(=O)NC)cc3C(F)(F)F)C1
Product: Cl

Procedure:
The compound of Example 8 (200 mg, 0.32 mmol) and excess amount of methylamine were reacted in a similar manner to Example 9 to give the titled compound (75.0 mg, 40%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:27]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 1.97 g (4.68 mmol) 2-[(2-Chloro-benzoyl)-(4-chloro-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 1.02 g (56%) of the title compound. MS (m/e): 393.1 (MH+, 100%)
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=2)=[N:6][CH:7]=1.C[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N-:31]Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O.O.O.[Na+].[C:37](#N)C>>[Br:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:19][CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([S:15]([CH3:16])=[N:31][S:28]([C:25]3[CH:24]=[CH:23][CH:22]=[CH:27][C:26]=3[CH3:37])(=[O:29])=[O:30])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CSc1cccc(Nc2ncc(Br)c(NC3CC3)n2)c1
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1S(=O)(=O)N=S(C)c1cccc(Nc2ncc(Br)c(NC3CC3)n2)c1

Procedure:
In analogy to Example 1, 0.19 g (0.54 mmol) of 5-bromo-N4-cyclopropyl-N2-(3-methylsulphanylphenyl)pyrimidine-2,4-diamine is reacted with 0.168 g (0.59 mmol) of chloramine-T trihydrate in 5.0 ml of acetonitrile (24 hours). Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%, then ethyl acetate/methanol with methanol 5-10%) results in 0.13 g (47% of theory) of the product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:22][C:34](=[O:35])[C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:37])=[O:26])[CH2:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition A); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].Cl[C:16](OC1C=CC=CC=1)=[O:17].C(N(CC)CC)C.[CH2:32]([C:34]1[N:35]=[C:36]([NH2:41])[S:37][C:38]=1[S:39][CH3:40])[CH3:33]>C(#N)C>[CH2:32]([C:34]1[N:35]=[C:36]([NH:41][C:16]([NH:13][S:10]([C:8]2[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:14])[CH:7]=2)(=[O:12])=[O:11])=[O:17])[S:37][C:38]=1[S:39][CH3:40])[CH3:33]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCc1sc(S(N)(=O)=O)cc1C
Reactant: CCc1nc(N)sc1SC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1nc(NC(=O)NS(=O)(=O)c2cc(C)c(CCOC)s2)sc1SC
Temperature: 60 °C
Yield: 68 %

Procedure:
5-(2-Methoxy-ethyl)-4-methyl-thiophene-2-sulfonic acid amide (0.235 g, 1.00 mmol) was dissolved in 6 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.157 g, 1.00 eq.) and triethylamine (0.348 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1. h. The above prepared 4-ethyl-5-methylsulfanyl-thiazol-2-ylamine (0.211 g, 1.00 eq. as hydrochloride) was then added, and the mixture heated to 60° C. over night. Cooling, pouring onto crashed ice, twofold extraction with ethyl acetate, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, ethyl acetate/MeOH=95/5) and trituration over heptane yielded 0.296 g of the title compound as light brown solid.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:8][S:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[OH:20])(=[O:11])=[O:10])[CH2:7][CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]1[CH2:7][CH2:6]1)(=[O:11])=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 42.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-cyclopropyl -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-chlorophenylisocyanate (155 mg, 1.01 mmol) were coupled to form the desired urea (150 mg, 43%). LC-MS (m/z) 416.2 (M+).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.CN(C=O)C.CC#N.[I-].[Na+].[CH3:45][S:46]([O-:48])=[O:47].[Na+]>Cl.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][S:46]([CH3:45])(=[O:48])=[O:47])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CS(=O)[O-]
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCS(C)(=O)=O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (800 mg, 1.67 mmol) in 1:4 DMF/CH3CN (8 mL) is added sodium iodide (2.50 g, 16.7 mmol). The resulting mixture was refluxed overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). Organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether and used without further purification. To 4 mL of a DMF solution containing the iodoethyl intermediate (0.56 mmol) was added the sodium methane sulfinate (113 mg, 1.11 mmol), and the reaction was stirred at room temperature overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. The mixture was purified over silica gel column (CH2Cl2) to provide 100 mg (35% yield) of {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester, as an off-white powder.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:16]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:15]=3[N:27]=2)=[C:6]([O:28][CH3:29])[CH:5]=1.Cl>O.CO.C(Cl)Cl>[CH:22]1([N:16]2[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:14]3[CH:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=4[O:28][CH3:29])=[N:27][C:15]2=3)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCCN3C)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCCN2C
Temperature: 25 °C
Yield: 99 %

Procedure:
Methyl4-[(9-cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoate (Intermediate 7; 250 mg, 0.61 mmol) and HCl (2 mL, concentrated aqueous) were suspended in water (4 mL) and heated at reflux for 24 h. The reaction mixture was then cooled to ambient temperature and the volatiles were removed under reduced pressure. The solid obtained was dissolved in MeOH:DCM (1:10, 40 mL) and washed with NaHCO3 (saturated aqueous, 40 mL). The organic layer was then dried (MgSO4), filtered and the volatiles removed under reduced pressure to afford the title compound (240 mg, 99%) as a solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11].[C:14]1(O)([CH3:23])[CH2:19][CH2:18][CH:17]([C:20]([CH3:22])=[CH2:21])[CH:16]=[CH:15]1>>[S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[C:9]2[CH:18]3[CH2:19][C:14]([CH3:23])=[CH:15][CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[O:11][C:10]=2[CH:12]=1
Reactant: Oc1cc(O)cc(C2SCCS2)c1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Product: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C

Procedure:
The compounds of formula I in which R is hydrogen can be prepared by reacting a 3,5 -dialkanoyloxybenzaldehyde (III) with 1,2-ethanedithiol to produce a 1,3-dialkanoyloxy-5-(1,3-dithiolan-2-yl)benzene (IV), hydrolyzing the 1,3-dialkanoyloxy ester to produce 5-(1,3-dithiolan-2-yl)resorcinol (V), reacting compound V with p-mentha-2,8-dien-1-ol to produce 3-(1,3-dithiolan-2-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) which is then subjected to oxidative cleavage conditions to produce a compound of formula I named 3-formyl-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol. This process can be represented as follows: ##STR9## wherein R5 represents a lower alkanoyl group, such as the acetyl, propionyl and butyryl groups.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:20])=[CH:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])C1C=C2C(C=CN2)=CC=1>>[I:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(F)cc21
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Product: FC(F)(F)c1ccc2c(I)c[nH]c2c1
Yield: 98 %

Procedure:
Following the general method as outlined in Intermediate 3, starting from 6-(trifluoromethyl)-1H-indole (0.97 g; 5.24 mmol), 1.60 g (98%) of the title compound was obtained as a red solid, which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)[C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc(CCl)n1CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1c2ccc(Br)cc2nc2n1CC1CCCCN1C2
Temperature: 25 °C

Procedure:
A solution of 7-bromo-2-(chloromethyl)-3-(piperidin-2-ylmethyl)quinazolin-4(3H)-one and K2CO3 (1 g, 7.2 mmol) in CH3CN was stirred at reflux for 1.5 h. After it was cooled to room temperature, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography to give the desired product. MS (ESI): 334, 336 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of p-chlorophenyl isocyanate (15.3 g, 0.10 mol) in toluene (50 ml) is metered at room temperature into a solution of methyl anthranilate (15.1 g, 0.10 mol) in toluene (100 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (1.4 ml, 1.0 g, 0.010 mol) is metered in and the mixture is stirred at 90° C. for a further 3 hours. After cooling, the product is filtered off with suction and washed with 3×20 ml of toluene and dried. 21.0 g of 3-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione (yield: 77.0% of theory) of melting point 288° to 290° C. are obtained. According to thin-layer chromatography, the product is contaminated with the intermediate ethyl N-(4-chlorophenylcarbamoyl)anthranilate.