Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[C:14]([O:18][C:19]([NH:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NC1(CCC(=O)O)CC=CO1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(CCC(=O)O)CC=CO1

Procedure:
5.0 pts. by wt. of 2-amino-furfurylacetic acid (Rohm and Haas, Netherlands Application No. 66,07754) in 100 pts. by vol. of 80 percent strength aqueous dioxane are brought to pH with 4 N sodium hydroxide solution. 8.0 pts. by wt. of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile are added and the mixture is warmed to 70° for 2 hrs. During this time, the above pH is maintained by adding 4 N sodium hydroxide solution. Thereafter, 80 pts. by vol. of water are added, the dioxane is stripped off and the reaction mixture is extracted several times with ethyl acetate. The aqueous phase is brought to pH 4 with 10 percent strength citric acid, and is saturated with sodium chloride and extracted by shaking with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and concentrated. The residue is recrystallized from a little abs. carbon tetrachloride. 4.3 pts. by wt. of 2-t-butoxycarbonylamino-furfurylacetic acid of melting point 99°-101° are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[S:15])[NH:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[C:17](OCC)(=[O:23])[C:18](OCC)=[O:19].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:18](=[O:19])[C:17](=[O:23])[NH:14][NH:13][C:12]1=[S:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCNC(=S)NN
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1c(=S)[nH][nH]c(=O)c1=O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
4-(2-tert.-Butoxycarbonylamino-ethyl)-thiosemicarbazide (9.37 g) is added to a solution of sodium (0.92 g) in methanol (40 cc) at 20° C., and diethyl oxalate (5.4 g) is then introduced dropwise in the course of 10 minutes. The mixture is heated under reflux for 3 hours. It is allowed to cool, water (100 cc) is added, concentrated hydrochloric acid (3 cc) is introduced dropwise, the mixture is extracted with ethyl acetate (2×100 cc) and the extract is washed with a saturated sodium chloride solution (2×50 cc), dried over sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is taken up in methylene chloride (65 cc), the crystallisation is started, the batch is left for 2 hours at 20° C. and then filtered, and white crystals (4.59 g) of 4-(2-tert.-butoxycarbonylamino-ethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine, melting at 160° C., are obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (19.1 mg, 0.0621 mmol, 1 eq), 1-piperidinepropanoic acid (24.5 mg, 0.156 mmol, 2.5 eq), 1-hydroxybenzotriazole (HOBt) (8.5 mg, 0.063 mmol, 1 eq), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (36.3 mg, 0.189 mmol, 3 eq) in anhydrous DMF (1.3 mL), DiPEA (64 μL, 0.37 mmol, 6 eq) was added and the reaction was stirred at rt, under N2, for 16 h. Solvent was concentrated in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on MDPS giving the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ=1.45-1.56 (s, br, 2H), 1.64 (sextet, J=5.6 Hz, 4H), 2.46-2.78 (m, 10H), 3.81 & 3.84 (t, J=5.6 Hz, rotamers, 2H), 4.29 & 4.33 (d, J=2.0 Hz, rotamers, 2H), 6.48 (s, br, 1H), 6.62 & 6.63 (s, rotamers, 1H), 8.50 (d, 1H). MS (ES+): m/z 373.99/376.00 (100/36) [MH+]. HPLC: tR=1.86 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Cl:24]>>[Cl:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Cl
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)s2)s1
Yield: 71.1 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl- 2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (Example 141C, 200 mg, 0.68 mmol) with 5-amino-4-chloro-3-methylisoxazole (91 mg, 0.68 mmol) yielded 188 mg of the final product (71% yield). A small portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a tan colored solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]/[C:10](/SC)=[CH:11]/[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:26]([O:28][C:29](=[O:33])[CH2:30][NH:31][NH2:32])[CH3:27].Cl.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][N:31]1[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[CH:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:32]1)[CH3:27]
Reactant: CCOC(=O)CNN
Reactant: CS/C(=C\C(=O)c1ccc2c(c1)OCCO2)Nc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1nc(Nc2ccc(F)c(F)c2)cc1-c1ccc2c(c1)OCCO2

Procedure:
A mixture of D16 (0.00138 mol), 2-hydrazinyl-acetic acid ethyl ester.monohydrochloride (1:1) (0.00276 mol) and K2CO3 (0.00206 mol) in t-BuOH (100 ml) was stirred at 85° C. overnight in a sealed reaction vessel. The reaction mixture was cooled, filtered and the filtrate's solvent evaporated in vacuo. Yield: 0.55 g of E10 (96.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:19].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:19])[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC)c2oc(CBr)cc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a well stirred solution of Methyl-2-bromomethyl-7-methoxybenzo[b]furan-4-carboxylate (step 6) (3.1 g, 10.36 mmol) in dimethyl sulfoxide (30.0 mL) was added powdered sodium carbonate (1.64 g, 15.55 mmol) at 90-95° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (2.9 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 2.2 g of pure product.
Reaction SMILES: [CH2:1]1[C:15](=[O:16])[C:14]2[C:5](=[C:6]([OH:20])[C:7]3[C:12]([C:13]=2[OH:17])=[C:11](O)[CH:10]=[CH:9][C:8]=3O)[C:3](=[O:4])[CH2:2]1.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:8]1[C:7]2[C:6](=[O:20])[C:5]3[C:14](=[C:15]([OH:16])[CH:1]=[CH:2][C:3]=3[OH:4])[C:13](=[O:17])[C:12]=2[C:11]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:10][CH:9]=1
Reactant: NCCCN
Reactant: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Product: NCCCNc1ccc(NCCCN)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 45 °C
Reaction time: 17 h

Procedure:
A suspension of 10.0 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in 120 ml. of de-aerated 1,3-diaminopropane is stirred and heated at 45° C. under nitrogen for one hour and then for 10 minutes as air is bubbled into the suspension. The mixture is then evaporated to dryness and the residue is extracted with 650 ml. of ethanol in a Soxhlet apparatus for 17 hours. The extract is filtered while hot, concentrated to 95 ml. and then diluted with 900 ml. of diethyl ether. The mixture is cooled and the solid is collected, washed with ethanol-diethyl ether, then diethyl ether giving the desired product as 9.57 g. of a blue solid, mp. 115°-130° C.
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1>CC#N.C(O)(C(F)(F)F)=O>[O:5]1[CH2:6][CH2:1][CH2:2][CH2:3][CH:4]1[NH:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1cnc(N)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1cnc(NC2CCCCO2)s1
Yield: 63.6 %

Procedure:
TFA (22 μL, 0.3 mmol) and DHP (3.9 mL, 43.5 mmol) were added to a suspension of ethyl 2-aminothiazole-5-carboxylate (5 g, 29 mmol) in CH3CN (40 mL) at RT. The resulting mixture was stirred at reflux overnight. The reaction mixture was concentrated and dissolved in AcOEt/PE and kept at 4 C overnight. The resultant white solid was filtrated and washed with PE, yielding ethyl 2-(tetrahydro-2H-pyran-2-ylamino)thiazole-5-carboxylate (4.73 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH2:29][OH:30]>>[OH:30][CH2:29][C:28]#[C:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OCC#CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 48.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 2.5 g (6.46 mmoL) of tert-butyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.667 g (7.752 mmol) of 2-butyne-1,4-diol gave 1.42 g of tert-butyl (3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[CH:29][CH:28]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccc(Oc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 2 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 10.7 mg (5%) colourless solid.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 32) (90 mg, 0.218 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.076 ml, 0.436 mmol) followed by ethyl 3-bromopropanoate (0.056 ml, 0.436 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography on silica, eluting with 60-70% ethyl acetate in cyclohexane to give the title compound as a brown oil (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][O:41]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(O)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a 0.2M solution of the tertiary alcohol of Step 4 in CH2Cl2 were added 5 equiv. of dihydropyran and 0.1 equiv. of triphenylphosphonium bromide and the mixture was stirred at reflux for 1 day. Then, the same amount of dihydropyran and triphenylphosphonium bromide were added and the mixture stirred at reflux another day. Toluene was added and the resulting solution was filtered through silica with EtOAc:toluene 0:100 to 2:98 to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Brc1cccs1
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Product: Clc1ccc(-c2cn(-c3cccs3)cn2)cc1
Yield: 7 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-(4-chlorophenyl)-1H-imidazole (125 mg, 0.595 mmol) and 2-bromothiophene, to prepare the desired 4-(4-chlorophenyl)-1-(thiophen-2-yl)-1H-imidazole (11 mg, 0.042 mmol, yield 7.0%) as a reddish sticky solid. The HPLC purity of the final product was 95.62%. LC-MS [M+H] 261 (C13H9ClN2S+1 expected 261.02). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[OH-].[Na+].Cl>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylate (166.8 mg, 0.34 mmol, 1.00 equiv, 80%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (84 mg, 2.10 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the aqueous solution was adjusted to 3-4 with 1N aqueous hydrogen chloride and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 35% in 8 min, up to 70% in 8 min, up to 100% in 1.5 min); Detector, uv 220&254 nm. This resulted in 40 mg (31%) of 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylic acid as a orange solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[OH:11][C@:12]1([CH3:35])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[O:31][CH2:32][C:33]#[CH:34])[CH2:13]1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:34]#[C:33][CH2:32][O:31][C@H:21]2[CH2:20][CH2:19][C@H:18]3[C@H:17]4[C@H:26]([CH2:25][CH2:24][C@:22]23[CH3:23])[C@:27]2([CH3:30])[C@H:14]([CH2:13][C@@:12]([OH:11])([CH3:35])[CH2:29][CH2:28]2)[CH2:15][CH2:16]4)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(C#CCO[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@](C)(O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
A solution of 4-iodoacetophenone (16 mg, 0.06 mmol), 3α-hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane (22 mg, 0.06 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (2 mg) and CuI (2 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1 hr. The TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (85:15) gave 17β-[3-(4-acetylphenyl)-2-propynyloxy]-3α-hydroxy-3β-methyl-5α-androstane (19 mg) as a colorless solid; mp 52-55° C.; TLC Rf (hexane:acetone 85:15)=0.15.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:6]=[CH:7][NH:8]3)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ccc23)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (1.1 equivalents) is added to a solution of 4-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]([C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: C=CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)N(CCC(=O)OCC)CC(=O)OCC
Reaction time: 18 h

Procedure:
To the product of Step A, 1-a, (5.10 g, 25.1 mmol) in CH2Cl2 (50 mL) was added pent-4-enoyl chloride (2.83 mL, 25.1 mmol, 98% purity) and NEt3 (4.20 mL, 30.1 mmol) at 5° C. The reaction stirred about 18 hours and was then diluted with CH2Cl2, washed with aq Na2CO3 (2 M) and brine, dried (Na2SO4), filtered and concentrated to afford the product, 1-b.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20]C=CC=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.[CH2:22](C1C=CC(C(C(OCC)=O)=O)=CC=1)C(C)C.C1C=CC([C@@H](N)CO)=CC=1.C(C1C=CC([C@@H](C)C(OC)=O)=CC=1)C(C)C>>[OH:13][C:9]1[C:10](=[O:12])[O:11][C@:7]([CH3:15])([C:4]2[CH:3]=[CH:2][C:1]([CH2:16][CH:21]([CH3:20])[CH3:22])=[CH:6][CH:5]=2)[C:8]=1[OH:14]
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Agent: COC(=O)[C@H](C)c1ccc(CC(C)C)cc1
Agent: N[C@@H](CO)c1ccccc1
Product: CC(C)Cc1ccc([C@@]2(C)OC(=O)C(O)=C2O)cc1
Yield: 15 %

Procedure:
(R)-(-)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (R)-(-)-Phenylglycinol was used to resolve the methyl (R)-(-)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g, (5 mmol) was converted into 190 mg (15% yield) of (R)-(-)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 180-181° C. dec. (CHCl3 /hexanes); [α]25D -137° (c=1.27; MeOH); 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4 : C, 68.68; H, 6.92. Found: C, 68.52; H, 7.01.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH:11]1([C:14]2([F:18])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][C:14]([CH:11]3[CH2:13][CH2:12]3)([F:18])[CH2:15]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: FC1(C2CC2)CNC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC1(C2CC2)CN(c2cc(Cl)nc(Cl)c2)C1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A solution of 2,4,6-trichloropyridine (3.0 g, 16.4 mmol), 3-cyclopropyl-3-fluoroazetidine hydrogen chloride (2.49 g, 16.4 mmol) and DIPEA (7.09 ml, 41.0 mmol) in ethanol (40 ml) was heated under reflux for 1 h. Reaction mixture cooled to room temperature then concentrated to dryness in vacuo. Crude product purified by flash chromatography on silica (0 to 100% EtOAc: petrol) to give title compound as a white solid (1.56 g, 36%). 1H NMR (CDCl3) 0.52-0.48 (2H, m), 0.72-0.67 (2H, m), 1.42-1.31 (1H, m), 3.91 (2H, ddd), 4.05 (2H, ddd), 6.20 (2H, s). ES+261.30.