Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[CH3:19][CH:20]([CH3:36])[CH2:21][C@H:22]([NH2:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:35][C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:21][CH:20]([CH3:36])[CH3:19])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. Then 2.38 g (11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33 mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml. The resulting solution is heated over the stem bath and petroleum ether is added in batches thereto (total of 55 ml) until the turbidity remains. It is cooled in ice, whereupon crystallisation takes place. It is suction filtered and dried at 75° C/4 torr. The product obtained (4.57 g; melting point 111°-112° C; ee=98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained. This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75° C./4 torr.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[OH:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[OH:29])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O.CN(C)C=O>[OH:21][C:15]1[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=2[OH:29])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][CH:4]=2)[N:13]=1
Reactant: Sc1ccccc1
Reactant: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stirrer, condenser, Dean-Stark trap and nitrogen atmosphere are charged 16.1 g (0.0394 mol) of 6-(p-chlorophenyl)-2,4-bis-(2,4-dihydroxyphenyl)-s-triazine, 2.72 g (0.0197 mol) of potassium carbonate, 600 mg of potassium iodide and 150 mL of N,N-dimethylformamide. A pre-heated oil bath (150° C.) is then applied to the stirred brown solution. Thiophenol (4.04 mL, 0.00394 mol) is added all at once through a syringe. The mixture is stirred at 150° C. for 4.5 hours and then allowed to cool to room temperature. The solution is diluted with water and extracted thrice with ethyl acetate. The combined organic layers are washed twice with 0.1N hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure to give a yellow product. There is some unsolubilized material found at the interface in the ethyl acetate extractions of the reaction mixture which is washed with water and triturated with heptane. Both crops of yellow solid are the title compound and are combined to afford the title compound in a yield of 17.5 g (92%); mp>250°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][NH:16][C:17]([C:19]1[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]2[C:25]3[NH:33][C:34]([C:36]([O:38]C)=[O:37])=[CH:35][C:24]=3[C:23]3(OCC[O:40]3)[C:22](=[O:44])[C:21]=2[N:20]=1)=[O:18])=[N+:2]=[N-:3].Cl.C(Cl)Cl.CO.[Li+].[OH-]>C1COCC1.C(Cl)Cl.CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][NH:16][C:17]([C:19]1[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]2[C:25]3[NH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:24]=3[C:23](=[O:40])[C:22](=[O:44])[C:21]=2[N:20]=1)=[O:18])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc2c([nH]1)-c1c(C(=O)OC)cc(C(=O)NOCCOCCOCCOCCN=[N+]=[N-])nc1C(=O)C21OCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=NCCOCCOCCOCCONC(=O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from EXAMPLE 5 (6, 250 mg, 0.4 mMol) in THF (36 mL) was treated with 1N HCl (0.4 mL) was kept at 45-47° C. in for 24 hours. The reaction mixture was cooled to room temperature. TLC (DCM-MeOH 95:5) shows no 4 (Rf=0.75) and one major product (Rf=0.45). The solution was concentrated on a rotary evaporator to remove THF. The resulting mixture was partitioned between EtOAc (100 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. The last two steps (standing and decanting) were repeated. The resulting EtOAc solution was then evaporated at reduced pressure to give an orange gum. The gum was dissolved in DCM (20 mL) and evaporated at reduced pressure twice to give an orange foam which was further dried in vacuo for 4 hours. The foam was dissolved in 0.5 M LiOH (3.4 mL, 1.7 mMol). The resulting black solution was stirred at room temperature for 24 hours. The reaction mixture was then acidified by dropwise addition of concentrated HCl (0.25 mL, 3 mMol) to give red solution. The solution was partitioned between EtOAc (50 mL), water (5 mL) and saturated aqueous NaCl (5 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. Evaporation of solvent at reduced pressure gave a red gum. The gum was triturated with DCM and the resulting slurry was evaporated at reduced pressure. The resulting solid was triturated with DCM-hexanes (1:1), the solvent was decanted from the red-brown solid, and the solid was dried in vacuo to afford 7 (94 mg 43%). MS (AP− taken from a MeOH solution) 577 (M+MeOH-1), 545 (M−1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(NCCN2CCCC2)c1
Temperature: 100 °C
Yield: 18.4 %

Procedure:
The mixture of 1-fluoro-3-nitrobenzene (420 mg, 3 mmol) in DMF (1.5 mL), N-(2-aminoethyl)-pyrrolidine (514 mg, 4.5 mmol) and Cs2CO3 (977 mg, 3 mmol) is heated at 100° C. under microwave radiation for 2.5 hours, then concentrated. The mixture is diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=1:99 to 10:90) to give 130 mg of the title compound as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:22]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=3)=[N:4][CH:3]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ncc(OC(=O)c3ccc(CCCCCCC)cc3)cn2)cc1

Procedure:
A mixture of 0.65 g of 5-methoxy-2-(4-n-octyl-phenyl)-pyrimidine [can be obtained by condensation of methyl β-hydroxy-α-methoxyacrylate with 4-n-octylbenzamidine hydrochloride, reaction of the 4-hydroxy-5-methoxypyrimidine obtained with P2S5 and reduction of the 4-mercaptopyrimidine obtained with a Raney nickel according to J. H. Chesterfield et al., J. Chem. Soc. 4590 (1960)] and 1.0 g of KOH in 15 ml of ethylene glycol are boiled for 10 hours. 10 ml of water are added to the cooled solution, which is then acidified using glacial acetic acid and extracted five times with ether. After conventional work-up, 5-hydroxy-2-(4-n-octylphenyl)-pyrimidine is obtained. (The other homologues can be obtained analogously). 0.26 g of the 5-hydroxy-2-(4-n-octylphenyl)pyrimidine obtained, 0.25 g of 4-n-heptylbenzoyl chloride and 0.15 g of potassium carbonate in 2.5 ml of dimethylformamide are subsequently heated at 100° C. for 12 hours with stirring. The salt is removed by filtration under suction, and the filtrate is concentrated to a residue, which is taken up in ether and washed with water until neutral. Conventional work-up gives 2-(4-n-octylphenyl)-pyrimidin-5-yl 4-n-heptylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: BrCC1CCCCO1
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 12 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved in N,N-dimethylformamide (5 mL). 2-Bromomethyl-tetrahydro-pyran (0.34 g, 1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and the reaction mixture is stirred at 60° C. for 12 hours under N2. The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid residue is triturated with diethyl ether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellow filtrate (mixture of N1 and N3 regioisomers by NMR). The solids are collected and washed with diethyl ether to yield 0.12 g (37%) of the pure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+) m/z 496, 498 (M+, Br pattern) detected.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:36]([NH:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:37].Cl>CS(C)=O.CCOCC.O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([N:38]([CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:36][CH3:37])=[O:23])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCNCCN(CC)CC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCN(CC)C(=O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 177.8 %

Procedure:
7.0 Grams (0.02 mole) of 2-[4-(7-chloro-4-quinolylamino)phenyl] acetic acid hydrochloride were dissolved in 150 milliliters of dimethyl sulphoxide by heating the stirred mixture to 50° C. under nitrogen. The solution was cooled to room temperature, 6.48 grams (0.04 mole) of carbonyl diimidazole were added and the mixture was stirred for 21/2 hours under nitrogen. 8.64 Grams (0.06 mole) of triethylethylene diamine was added, the solution was stirred for another 21/2 hrs. and poured into 500 milliliters of water. The mixture was refrigerated overnight and the resulting solid was broken up and stirred with water, but melted at room temperature. The gum was extracted with chloroform and the chloroform layer dried and evaporated to give a yellow oil, which was dissolved in ether. Addition of ethereal HCl gave 9.1 grams (89% yield) of 2-[4-(7-chloro-4-quinolylamino)phenyl]-N-(2-diethylaminoethyl)-N-ethyl acetamide dihydrochloride as a hygroscopic yellow solid, melting point 140°-142° C.
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:20]([O:32][CH3:33])[CH:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)=[CH:29][CH:30]=2)=[C:20]([O:32][CH3:33])[CH:19]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of DMF (5 ml), 1-bromomethyl-3-nitro-benzene (0.92 g, 4.2 mmol), and 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (1 g, 4.2 mmol) was added lithium bis(trimethylsilyl)amide (1M in THF, 4.4 ml). The reaction was stirred at room temperature overnight and was then diluted with ethyl acetate (200 mL), washed with water (200 mL), aqueous ammonium chloride (10%, 200 mL) and brine, dried over magnesium sulfate and concentrated to yield 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl as yellow solid (1.5 g, 95%). LC-MS (ES) calculated for C20H15F2NO4, 371.1; found m/z 370 [M−H]−.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:26]4=[N:27][O:28][C:24]5=[C:25]4[C:16]([C:17](=[O:29])[C:18]4[C:23]5=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:15]([NH:30][C:31]4[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=4)[CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:41]>CO>[CH:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:26]4=[N:27][O:28][C:24]5=[C:25]4[C:16]([C:17](=[O:29])[C:18]4[C:23]5=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:15]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:35]([O-:37])=[O:36])=[CH:38][CH:39]=4)[CH:14]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:41]
Reactant: O=C(O)c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Temperature: 40 °C
Yield: 45 %

Procedure:
Dissolving intermediate 6, 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid in sodium hydroxide in methanol solution. Raising temperature to about 40° C. and maintaining for 2-3 hours. Then lowering temperature and filtering solid to get Compound I, sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate. The compound was purified in sodium hydroxide in methanol solution and dried. It gave more than 99% (HPLC, area %) purity and about 45% yield. Mass spectra gave [M+1]=523.2. 1H-NMR (400 MHz, DMSO-d6, see also FIG. 3), ppm (δ): 11.79 (1H, s), 8.48 (1H, d), 8.20 (1H, d), 7.93 (2H, d), 7.84 (1H, t), 7.72 (1H, t), 7.35 (2H, d), 6.39 (1H, s), 3.85 (4H, m), 2.72-2.70 (4H, m), 2.28-2.265 (1H, m), 1.72-1.78 (4H, m), 1.55-1.58 (1H, m), 1.08-1.23 (5H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN1CCCC1=O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)CCc1nc(Cl)c2c(n1)sc1ccccc12
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1nc(NCc2ccc(OC)c(Cl)c2)c2c(n1)sc1ccccc12

Procedure:
Methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin-2-yl)propionate [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine] and 3-chloro-4-methoxybenzylamine (“A”) in N-methylpyrrolidone are stirred at 110° for 5 hours. The solvent is removed and the residue is worked up in the customary manner. Methyl 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno-[2,3-d]pyrimidin-2-yl]propionate is obtained as a colourless oil.
Reaction SMILES: [CH3:1][O-:2].[Na+:3].[NH:4]1[CH:8]=[N:7][CH:6]=[N:5]1.C[OH:10]>>[NH:4]1[CH:8]=[N:7][C:6]([C:1]([O-:10])=[O:2])=[N:5]1.[Na+:3]
Reactant: C[O-]
Reactant: c1nc[nH]n1
Reactant: CO
Agent: [Na+]
Product: O=C([O-])c1nc[nH]n1
Yield: 98 %

Procedure:
A three-necked-flask stirring apparatus with mechanical stirrer, internal thermometer and reflux condenser was charged under dry nitrogen with 200 ml of dry methanol and 45 ml of a 30% strength methanolic solution of sodium methoxide, corresponding to 0.25 mol of sodium methoxide. 17.4 g (0.25 mol) of 1,2,4-triazole was added thereto in portions at room temperature. After the end of addition of the 1,2,4-triazole the reaction mixture was stirred at reflux temperature for 4 h. The solvent was subsequently distilled off under reduced pressure and the oily residue which remained was admixed at room temperature with 200 ml of methylene chloride. The mixture was stirred at room temperature for 15 min and the precipitated solid product was filtered off. This gave 22.5 g of sodium 1,2–4-triazolate (yield: 98% of theory) in the form of a colourless powder. The product was pure according to its 1H-NMR spectrum and free of the 1,2,4-triazole used.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:14])[CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[NH2:7][CH2:8][CH:9]1[CH2:10][N:11]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:14])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCC1CN(C(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 28 (65 mg, 0.11 mmol) in DCM (7 mL) was treated with trifluoroacetic acid (3 mL) and stirred for 1 h at r.t. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in water (25 mL) and basified to pH 10 with sodium carbonate. The aqueous solution was extracted with 5% methanol in DCM (4×25 mL), and the extracts combined, then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (SiO2, 4:1 DCM/methanol) to give the title compound as a gummy solid, which was triturated from ether to give a cream-coloured powder (34 mg, 63%). δH (DMSO-d6) 8.31 (1H, m), 7.93 (1H, m), 7.72 (1H, dd, J 1.5, 10.5 Hz), 7.55 (1H, m), 7.37 (1H, dd, J 4.6, 8.1 Hz), 7.29-7.24 (1H, m), 4.88 (2H, br s), 4.03-3.97 (2H, m), 3.71-3.67 (2H, m), 2.65 (1H, m), 2.70-2.68 (2H, m). LCMS RT 2.93 minutes, (ES−) 481 (M−H)−, (ES+) 483 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1COCC1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:10](=[O:11])[NH:12]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
204 mg (1.0 mmol) N-[3-(trifluoromethyl)phenyl]urea, 142 mg (0.77 mmol) 4-bromobenzaldehyde, and 100 mg (0.77 mmol) ethyl 3-oxobutanoate are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][S:41]([C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.CO>O1CCOCC1.O>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][S:41]([C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=2)(=[O:42])=[O:43])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
4-(N—(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)sulfamoyl)benzoic acid (10 mg, 0.013 mmol) from Step 1 was dissolved in dioxane (1 ml) and MeOH (5 ml) sodium hydroxide (10.20 mg, 0.255 mmol) (powder) was added followed by 5 drops of water. The resulting suspension was stirred at 70° C. for 6 h. After the reaction was completed, all volatile material was removed in vacuo. The residue was re-dissolved in MeOH and purified by prep. HPLC to afford 4-(N—(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)sulfamoyl)benzoic acid as a white solid (1.8 mg, 18.4%). LCMS: m/e 728.2 (MH+), 2.11 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 8.24 (m, J=8.5 Hz, 2H), 8.01 (m, J=8.5 Hz, 2H), 7.94 (m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.31 (d, J=4.3 Hz, 1H), 4.70 (d, J=2.3 Hz, 1H), 4.59 (s, 1H), 3.05 (s, 1H), 2.62 (d, J=13.1 Hz, 1H), 2.37 (br. s., 1H), 2.11 (m, 1H), 1.76-2.01 (m, 4H), 1.65-1.76 (m, 6H), 1.53-1.65 (m, 4H), 1.44 (br. s., 5H), 1.31 (d, J=2.8 Hz, 6H), 1.03 (s, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H).