Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]1([CH2:4][O:5][N:26]2[C:27](=[O:36])[C:28]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]3[C:30]2=[O:31])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Reaction time: 15 h
Yield: 86.4 %

Procedure:
To a suspension of cyclopropyl methanol (562 μl, 6.93 mmol), triphenylphosphine (2.02 g, 7.63 mmol) and N-hydroxyphthalimide (1.28 g, 7.63 mmol) in THF (10 mL) at 0° C. was added dropwise diethylazodicarboxylate (1.20 mL, 7.63 mmol) in THF (10 mL). The reaction mixture was allowed to stir for 15 h after which the solvent was removed under vacuum to dryness. Et2O (15 mL) was added to triturate the triphenylphosphine oxide and diethylhydrazinedicarboxylate, which was filtered off and washed with a little Et2O. The ethereal solution was concentrated under vacuum to give a residue which was filtered through a pad of silica (eluting with EtOAc/PE, 3:7). Removal of the solvent under reduced pressure afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-(cyclopropylmethoxy)phthalimide (1.30 g, 86%), as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Si:19]([O:36][CH2:37][CH2:38][CH:39]([OH:41])[CH3:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:41][CH:39]([CH3:40])[CH2:38][CH2:37][O:36][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Triethylamine (4.64 mL), p-toluenesulfonyl chloride (4.66 g) and DMAP (271 mg) were added to a solution of 4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS #114079-44-6) in 1,2-dichloroethane (80 mL) at 0° C., and the reaction solution was stirred at 60° C. for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 6.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.COC(=O)CC1C=CC([O:27][CH2:28]/[CH:29]=[C:30](/[C:32]2[CH:44]=[CH:43][C:42]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][C:34]=3[CH:33]=2)\[CH3:31])=CC=1>C1COCC1>[CH:33]1[C:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[CH:44][C:32]=1/[C:30](/[CH3:31])=[CH:29]/[CH2:28][OH:27]
Reactant: COC(=O)Cc1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of DIBAL-H in toluene (15 ml, 15 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of (E)-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester (2.0 g, 7.2 mmol) in dry THF (100 ml) and stirred for 30 min. The mixture was warmed to room temperature, and stirred for 1.5 h. The mixture quenched with methanol (2 mL), added 1N HCl (30 ml) and the product extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude (E)-3-(9H-fluoren-2-yl)-but-2-en-1-ol.
Reaction SMILES: [CH:1]1([N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[Cl:44])[C:5](=[O:35])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[C:31]([Cl:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[Cl:34])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]2[C:27]([Cl:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=2[Cl:32])=[CH:19][CH:18]=1)[C:5]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=1[Cl:44])=[O:35]
Reactant: Cc1cc(Cl)c(OCCc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCc2ccc(CC(CN)C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.06 M) of tert-butyl (3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethyl]benzyl}-3-oxopropyl)carbamate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 14 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 97:3 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 578.9.
Reaction SMILES: CS[C:3]([S:14][CH3:15])=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CCO>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:21][C:3]([S:14][CH3:15])=[C:4]2[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]2=[O:13])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Reactant: COc1ccc(N)cc1OC
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.O.Cl.C(CCP(CCC(O)=O)CCC(O)=O)(O)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Br)ccc1S
Yield: 99.9 %

Procedure:
To as solution of 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride (4.85 g) in dioxane (29 ml) was added at 22° C. water (6.5 ml) and tris-(2-carboxyethyl)phosphine hydrochloride (17.3 g) and the mixture was heated to reflux temperature for 6 h. The cooled mixture was partitioned between water and dichloromethane, the organic layer was washed with water, dried and evaporated give pure 4-bromo-2-trifluoromethyl-benzenethiol (3.85 g) as a colorless liquid. MS: 257.2 and 255.1 [M−H]−.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cccc(F)c1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cccc(F)c4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 41.4 mg (0.269 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 76.4 mg (58% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(Cl)ccc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
A mixture of 2.55 g of 4-chloro-1-nitro-2-(propan-2-yloxy)benzene in 40 ml of acetic acid is heated at 50° C., and then 7 ml of water and 2.64 g of iron powder are added. The mixture is stirred for 1 h at 50° C., and then cooled to ambient temperature and filtered on Celite. The Celite is rinsed three times with 20 ml of methanol, and the filtrate is concentrated under reduced pressure. The residue is taken up in 50 ml of 1N sodium hydroxide and 50 ml of dichloromethane. The aqueous phase is extracted twice with 50 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 2.25 g of 4-chloro-2-(propan-2-yloxy)aniline in the form of a green oil.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Yield: 99 %

Procedure:
Into a 1000 mL three-neck flask were put 24 g (100 mmol) of 9-phenylcarbazole, 18 g (100 mmol) of N-bromosuccinimide, 450 mL of toluene, and 200 mL of ethyl acetate, and the mixture was stirred for 45 hours at room temperature. This suspending solution was washed with water, and magnesium sulfate was added therein, so that moisture was removed. Then, the suspending solution was filtered to provide a filtrate was obtained. The obtained filtrate was concentrated and dried, whereby 32 g of a caramel-like solid of 3-bromo-9-phenyl-9H-carbazole, which was the object of the synthesis, was obtained in a yield of 99% (synthesis scheme (a-6)).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[C:5]1=[O:11].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CN(C)C=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[C:6](=[O:10])[C:5]1=[O:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCNC(=O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C=O)cc2)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
0.34 g of 60% sodium hydride was added to a solution of 1.00 g of 1-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50° C. Then, 0.88 mL of 4-fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120° C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-piperazinyl)benzaldehyde as white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:10][OH:11].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.O>[CH3:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:10][O:11][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCCBr
Reactant: CC(C)CCCC(C)CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCC(C)CCOCCCCBr
Temperature: 25 °C
Yield: 67.5 %

Procedure:
1,4-Dibromobutane (22.7 g, 105 mmol), 3,7-dimethyloctanol (4.99 g, 31.5 mmol) and tetrabutylammonium bromide (585 mg, 1.81 mmol) were dissolved in hexane (40 mL). Sodium hydroxide solution (50% w/v, 40 mL) was added to the reaction mixture and then the whole was heated at reflux for 2 d. The reaction mixture was cooled to room temperature, diluted with hexane (40 mL) and water (40 mL) and transferred to a separatory funnel. The product was extracted into the organic layer and the aqueous layer was further extracted with ether (3×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure. The dibromobutane in the crude product was removed under reduced pressure and heating at 120° C. under high vacuum (Kugelrohr). This gave the product as a honey-coloured oil (6.24 g, 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:16]1[CH2:15][CH2:14][N:13]([C:5]2[C:6]3[S:12][CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:3]([N:2]([CH3:19])[CH3:1])[N:4]=2)[CH2:18][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)c1nc2c(c(N3CCNCC3)n1)SCCC2
Reactant: BrCc1ccccc1
Product: CN(C)c1nc2c(c(N3CCN(Cc4ccccc4)CC3)n1)SCCC2

Procedure:
2-Dimethylamino-4-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine obtained in Example 11 was reacted with benzyl bromide in the same manner as described in Example 3 to obtain 4-(N-benzylpiperazino)-2-dimethylamino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine which was then recrystallized from dichloromethane-diethyl ether. Colorless prisms. Melting point: 106° to 108° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[OH:15])([CH2:3][CH3:4])[CH3:2].[CH2:16]1[O:18][CH2:17]1>[OH-].[Na+]>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[O:15][CH2:16][CH2:17][OH:18])([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)c1cccc(C(C)CC)c1O
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)c1cccc(C(C)CC)c1OCCO

Procedure:
2,6-di-sec-butylphenol (103 parts) is ethoxylated with ethylene oxide (29 parts) using sodium hydroxide (0.5 part) as catalyst at 150° C. in a method similar to that used in Example 12 to give 2-(2,6-di-sec-butylphenoxy)-ethanol (70 parts) b.p. 132°-136° C./0.9 mm.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li][CH2:22]CCC.CI.[Cl-].[NH4+].N.Cl>C(OCC)C>[CH3:22][C:18]1[Se:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CCCC1CCC(c2ccc(-c3ccc[se]3)cc2)CC1
Reactant: [Li]CCCC
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CI
Solvent: CCOCC
Product: CCCC1CCC(c2ccc(-c3ccc(C)[se]3)cc2)CC1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
3.4 g (10.3 mmol) of 2-[4-(4-propylcyclohexyl)phenyl]selenophene are initially introduced in 100 ml of diethyl ether, and 9.0 ml (14.3 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −78° C. 1.60 ml (25.7 mmol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The mixture is acidified using hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=25:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-Methyl-5-[4-(4-propylcyclohexyl)phenyl]selenophene is obtained as a colourless solid (m.p. 98° C.).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OCC)(=[O:18])[CH2:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.[Na]>P(=O)(O)(O)O>[C:13]([C:11]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:9](=[O:18])[CH:10]=1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: O=P(O)(O)O
Agent: [Na]
Product: CCOC(=O)c1cc(=O)oc2cc(O)ccc12
Yield: 80 %

Procedure:
0.10 mole resorcinol and 0.12 mole sodium diethyl oxalacetate is heated to 80° C. for 1 hour in 60 ml concentrated phosphoric acid. 4-Carbethoxy-7-hydroxy-coumarin is thus obtained at an 80% yield in the form of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH:12][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]=1[Cl:1])=[O:18]
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)c3cc(Cl)cc(Cl)c3)ccc2s1
Yield: 60 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3,5-dichlorobenzoyl chloride (122 mg, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave 3,5-Dichloro-N-(4-chloro-2-methyl-benzothiazol-5-yl)-benzamide (66 mg, 0.15 mmol, 60% yield) as a off-white powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH2:32][CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH2:32][CH3:33])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CCCBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 22.1 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.745 mmol) and propyl bromide (91 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>C1(C)C=CC=CC=1>[C:18]([CH2:20][C:21]([NH:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:22])([OH:19])=[O:17]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)CC(=O)O)c(C(=O)O)cc1OC
Yield: 98.9 %

Procedure:
4,5-Dimethoxyanthranilic acid (0.50 g, 2.5 mmol) was added to a solution of Meldrum's acid (0.42 g, 2.9 mmol) in toluene (5.0 mL) and treated according to Procedure 1. 2-[(Carboxyacetyl)amino]-4,5-dimethoxybenzoic acid (0.70 g, 97%) was obtained as a brown solid; δH (400 MHz, DMSO-d6) 3.43 (br s, 2H, CH2), 3.75 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 7.42 (s, 1H, H3), 8.24 (s, 1H, H6), 11.40 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]([CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH2:28][CH2:29][N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:6][CH:7]=3)[CH2:18][CH2:19]2)=[CH:22][CH:23]=1
Reactant: CCCCOC(=O)CCc1ccc(N)cc1
Reactant: ClCCN(CCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)CCc1ccc(N2CCN(c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 12.3 g. (55 mmole) n-butyl 3-(4-aminophenyl)-propionate, 16.0 g. (55 mmole) N,N-bis-(2-chloroethyl)-4-chloroaniline and 50 ml. n-butanol is maintained at reflux temperature for 48 hours, then 3.8 g. (27 mmole) pulverised anhydrous potassium carbonate are added thereto and stirring continued for 1 week at reflux temperature. Thereafter, it is suction filtered hot, the filtrate is evaporated in a vacuum and the residue is stirred with ligroin and suction filtered. The product is now taken up in diethyl ether, filtered and mixed with hydrogen chloride-containing diethyl ether. Since the hydrochloride is difficult to suction filter, the ether phase is evaporated in a vacuum and the residue recrystallised from n-butanol. Yield 9.5 g. (39% of theory) of hydrochloride; m.p. 179°-183° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1)CCC>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:6]=[CH:7][C:2]([C:38]6[CH:43]=[N:42][CH:41]=[CH:40][N:39]=6)=[CH:3][CH:4]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cnccn4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 135 °C
Yield: 35 %

Procedure:
According to the procedure described in example 8, (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 2-tributylstannylpyrazine were heated in a microwave at 135° C. (150 W, 25 minutes) to give the title compound (35% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.84-2.86 (m, 24H), 4.47 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.30-7.34 (m, 2H), 7.92-7.96 (m, 2H), 8.49 (d, J=3 Hz, 1H), 8.61 (dd, J=3 and 1 Hz, 1H), 9.01 (d, J=1 Hz, 1H).