Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][N:24]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1
Reactant: Clc1cnc(Nc2cnn(CC3CC3)c2)nc1NC1CC2CNCC2C1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CC2CC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 5-chloro-N2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (0.52 g, 1.40 mmol) and 2-cyanoacetic acid (136.9 mg, 1.61 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (821.4 mg, 2.16 mmol) and Et3N (0.33 g, 3.26 mmol). After addition, the reaction mixture was stirred at rt for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (357.2 mg, 58%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[C:20]([O:24][C:25]([NH:27][C:28](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])SC)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.CO.C1COCC1>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: NCCCCCCCCNCCCCCCCCN
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCCCCCCCNCCCCCCCCN)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,17-diamino-9-azaheptadecane 3 (4.9 g, 15.06 mmol) in THF/CH3OH 5/3 (80 mL) at 50° C., a solution of N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea (1.456 g, 5.02 mmol) in THF (25 mL) was added dropwise over 1 h. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (6% methanol, 4% triethylamine, 90% ethyl acetate), affording 12 as a pale yellow oil, 3.51 g (70%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(C)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CC(C)=O
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ncnc3ccccc23)c1
Yield: 16 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.48 g) and 4-chloroquinazoline (1.64 g) were stirred in acetone (30 ml) at room temperature for 7 days. The acetone was evaporated and the oily residue was dissolved in 2 Normal hydrochloric acid. The acidic solution was extracted with ethyl acetate. The aqueous solution was then basified to pH 9 and was extracted with ethyl acetate. A solid crystallised from the basic ethyl acetate extract and was collected and dissolved in chloroform. The chloroform solution was washed with water, dried and evaporated to dryness. The residue was recrystallised from ethyl acetate to yield the title compound (0.6 g), m.p. 111° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[N-:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[K+].C(O)(=O)C>O.C1COCC1>[CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[NH:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccn2c(=O)c(-c3nnn[n-]3)cnc12
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The free acid was prepared from pemirolast potassium (15.8 g; Chemtronica AB) by dissolution in a mixture of water (100 mL) and THF (80 mL) at room temperature and acidification with acetic acid (1 eq.; 17.5 g; 20% aq.). Firstly, ca. 1 mL of acetic acid was added and the obtained thin slurry was equilibrated for about 30 minutes. Thereafter the rest of the acetic acid was added slowly. The resultant thick slurry was diluted with water (50 mL) and equilibrated for 2 hours and then filtered and washed with water. The resultant solid was dried at 40° C. and under reduced pressure for 5-10 hours to yield 7.5 g of sub-title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:14][C:13]([C:15]([NH2:17])=[O:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[C:15]([C:13]1[S:14][C:10]([N+:7]([O-:9])=[O:8])=[C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=1)(=[O:16])[NH2:17]
Reactant: CCOC(=O)CCl
Reactant: NC(=O)c1ccc([N+](=O)[O-])s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(C(N)=O)sc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
Potassium tertiary-butoxide (1.96 g, 17.4 mmol) was dissolved in tetrahydrofuran (45 ml) and the solution cooled to −50° C. A solution of 5-nitrothiophene-2-carboxamide (1 g, 1.94 mmol) and ethyl chloroacetate (0.5 ml, 5.81 mmol) was added dropwise in dry tetrahydrofuran (12 ml) over 5 minutes. The reaction mixture was stirred at −50° C. for 16 hours then quenched with acetic acid (3 ml), then washed with water (20 ml). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed with saturated brine solution. The organic phase was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to give 610 mg of ethyl 5-carbamoyl-2-nitrothiophene-3-acetate as a yellow/brown oil. MS(ES): m/e 259 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.CCO.[NH2:19][NH2:20]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[O:2][CH:1]=[N:19][N:20]=1
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Product: FC(F)(F)c1cccc(Cc2nnco2)c1
Temperature: 135 °C

Procedure:
(3-Trifluoromethyl-phenyl)-acetic acid methyl ester (0.720 g, 3.30 mmol) was dissolved in hydrazine (7 mL) and EtOH (15 mL) and heated to 90° C. overnight. Analytical LCMS indicated complete reaction so the mixture was concentrated and azeotroped two time with toluene. The crude material was dissolved in triethylorthoformate and heated to 135° C. for 20 hours then allowed to cool. The reaction mixture was concentrated to afford the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13].O>C(O)(=O)C>[Br:1][CH2:12][C:10]([C:8]1[CH:7]=[CH:6][C:5]([F:13])=[C:4]([CH3:3])[CH:9]=1)=[O:11]
Reactant: CC(=O)c1ccc(F)c(C)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.1 mL bromine was added to 15 g 4-fluor-3-methylacetophenone in 80 mL concentrated acetic acid. The reaction was stirred 3 h at RT. The reaction was added to water. The precipitate was filtered and dried to give 20.6 g desired product. Rt: 1.37 min (method I), (M+H)+: 231
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of 2-amino-5-fluorobenzamide (2.00 g, 13.0 mmol) and triethylamine (1.45 g, 14.3 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.95 g, 14.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-fluorophenyl)amino)(oxo)acetate as a white powder (2.88 g, 87%).
Reaction SMILES: B(Cl)(Cl)[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:40]=1>C(Cl)Cl>[ClH:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:21]=3)=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:40]=1
Reactant: ClB(Cl)Cl
Agent: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Solvent: ClCCl
Product: Cl
Temperature: 22.5 °C
Reaction time: 1.42 h

Procedure:
A mixture of the compound prepared as described in Preparation 1 (8.46 grams) and the acid chloride prepared as described in Preparation 3 (10.0 grams) in methylene chloride (350 mL) was cooled to about 20-25° C. The cool mixture was treated with boron trichloride (2.6 mL), and the resulting mixture mechanically stirred. The reaction was monitored by HPLC using the assay described above. After 85 minutes, the in situ HPLC yield based on a 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene standard was 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1>CC(O)C.[Ni]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([OH:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Ni]
Solvent: CC(C)O
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A mixture of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (1.0 g, 0.0048 mol) in 2-propanol (40 mL) and Raney nickel (about 0.1 g) was shaken under hydrogen (37 psi) at 25° C. for 16 hours. Subsequent workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-ol (0.78 g) as a mixture of four diastereoisomers (ratio 8.1:20.6:57.8:7.8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.FC1C(OC)=C(F)C=C2C=1C=CN2C.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][CH2:17][C:16]([F:15])([F:29])[F:28])[CH:21]=1
Reactant: O=Cc1cccc(OCCC(F)(F)F)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: COc1c(F)cc2c(ccn2C)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(CCNCc3cccc(OCCC(F)(F)F)c3)c2c1

Procedure:
Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg 3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4 A molecular sieves in 35 mL EtOH and reflux overnight. Decant the liquid into a separate flask and treat with 209 mg (5.5 mmol) NaBH4. Stir the reaction at ambient temperature for 1 hour. Concentrate under vacuum, and partition between 50 mL 1 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 ml dichloromethane and combine the organic layers and concentrate to dryness. Purify the resulting oil by radial chromatography (SiO2; 1% MeOH in CHCl3 mixed with conc. NH4OH) to afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil. Conversion to it's HCl salt by stirring a solution of the compound in 50 mL 50/50 THF/EtOH with 1 g polyvinyl pyridine hydrochloride overnight, filtering and concentrating to a solid. Recrystallize the product from EtOAc: Analysis for C21H23F3N2O2 HCl: calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.42; H, 5.44; N, 6.51; ISMS 393 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:8]([C:7]3[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:9]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[NH:35]2)=[CH:30][CH:29]=1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2NC(C=Cc3ccc([N+](=O)[O-])cc3)=CC2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of bis (4-nitrobenzal)acetone (1.62 g; 0.005 m) and 4-methoxy-phenyl-hydrazine hydrochloride (0.87 g; 0.005 m) in dimethylformamide (25 ml.) was heated at 100° C. for 4 hours to give a dark red solution, which was drowned into water (100 ml.) The crude solid product was filtered, water washed and was recrystallised from butanol to give a dark red solid (1.0 g; 45% theory)
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([CH2:21][OH:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[OH:22][CH2:21][C:14]1[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:16][C:10]2[N:6]3[CH2:7][CH2:8][N:9]([C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=4)[C@H:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[N:12][C:11]=2[CH:13]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)[C@H]1NCCn2c1nc1cc(CO)c(S(C)(=O)=O)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (30 mg, 0.093 mmol) in CH2Cl2 (0.5 mL) and iPrOH (0.5 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (36 mg, 0.14 mmol) and DIEA (36 mg, 0.28 mmol). The mixture was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (42.0 mg, 83.7% yield) as a white solid. Analytical chiral HPLC: tR=9.927 min in 15 min chromatography, 96.74% ee (Method: OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1 [M+H]+. 1H NMR (CD3OD 300 MHz): δ 8.96 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 6.12-6.00 (m, 1H), 5.45-5.29 (m, 1H), 5.01 (s, 2H), 4.51-4.47 (m, 1H), 4.33-4.18 (m, 3H), 3.91 (t, J=10.8 Hz, 1H), 3.18 (s, 3H), 2.63-2.47 (m, 1H), 1.35-1.26 (m, 6H), 1.05 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][S:18][CH:19]=1.N[C@@H:21]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:18]1[CH:19]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH2:1][CH3:21])[C:9]2=[O:13])[CH:16]=[N:17]1
Reactant: Brc1cnsc1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1ccncc1N1CCN(c2cnsc2)C1=O
Yield: 172.2 %

Procedure:
Using the same reaction conditions as described in example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 4-bromo-isothiazole (166 mg, 1.016 mmol), 1,4-dioxane (15 mL), copper iodide (16.09 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.254 mmol) and potassium phosphate (540 mg, 2.541 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 120 mg of the product (54.54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].COCN[C:19]([C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1)=[O:20]>C1COCC1>[C:26]1([C:23]2[S:24][CH:25]=[C:21]([C:19]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[O:20])[N:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: COCNC(=O)c1csc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Yield: 27.3 %

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stirring continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1h. Yield: 27.3%. NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[C:16]2[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].CO>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:28][OH:29])=[C:16]2[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 53 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.64 g, 1.9 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol), methanol (25 mL) and pyridine (1 mL) was heated to reflux for 30 min. The mixture was cooled, the methanol removed by evaporation. The product was extracted into ethyl acetate (2×50 mL) and the organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated, and the product was purified by silica gel chromatography (25% ethyl acetate-hexanes) to provide a white solid (53%): mp 171-173° C.; 1H NMR (DMSO-d6): δ 2.31 (3H, s), 5.20 (2H, s), 6.94-7. J01 (1H, m), 7.10-7.14 (2H, m), 7.23 (2H, d, J=8.9 Hz), 7.37-7.47 (5H, m), 7.52 (2H, d, J=7.4 Hz), 8.01-8.03 (1H, m), 8.41 (1 H, s), 10.66 (1H, s); MS m/z (M+H)+357. Anal. for C23H20N2O2·0.5H2O: Calc'd: C, 75.60; H, 5.79; N, 7.67. Found: C, 75.12; H, 5.53; N, 7.34.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH-].[Na+].[NH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1>C1COCC1.O>[CH2:5]([O:4][C:2]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.5 %

Procedure:
Benzyl chloroformate (1.5 mL, 10.5 mmol) and sodium hydroxide (12.5 mL, 1N, 12.5 mmol) were added to a solution of trans-(4-aminomethylcyclohexyl)acetic acid (2.08 g, 10.0 mmol) in THF (32 mL) and H2O (16 mL). The reaction was stirred at RT for 17 hr. The reaction was quenched with 1N HCl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to yield 1.91 g (62%) of product which was carried to the next step without purification. ESI-MS m/z 306 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:15]3[C:20]([C:21](=[O:22])[C:9]4=[C:10]2[C:5](=[CH:6][CH:7]=[N:8]4)[CH:4]=1)=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3.[I:27][CH3:28]>CC(C)=O>[CH3:28][N+:8]1[CH:7]=[CH:6][C:5]2[C:10]3=[C:11]([C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]2[C:20]([C:21](=[O:22])[C:9]=13)=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2.[I-:27]
Reactant: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3ccnc(c13)C2=O
Reactant: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3cc[n+](C)c(c13)C2=O
Product: [I-]

Procedure:
Oxoglaucine methiodide was prepared from oxoglaucine in accordance with the process of Example V. A 31 mg sample of oxoglaucine was refluxed in 8 ml of acetone until it completely dissolved (approximately 30 minutes) and then 0.75 ml of iodomethane was added. The solution was refluxed until it became brown. The crystals were then collected by filtration to yield 15 mg of the methiodide salt, mp 255 d.