Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12]C)=O.[CH2:14]([N:17]=[C:18]=[S:19])[CH2:15][CH3:16]>C(N(CC)CC)C>[CH2:14]([N:17]1[C:10](=[O:12])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[NH:4][C:18]1=[S:19])[CH2:15][CH3:16]
Reactant: CCCN=C=S
Reactant: COC(=O)c1sccc1N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCn1c(=S)[nH]c2ccsc2c1=O
Temperature: 25 °C

Procedure:
To a suspension of 150 mL of ethanol containing 9.5 g of methyl 3-amino-2-thiophenecarboxylate was added dropwise 9.3 mL of n-propyl isothiocyanate with stirring. To this reaction mixture was added 12.64 mL of triethylamine. The reaction mixture was heated at reflux for 3 h, allowed to cool to room temperature and then stirred for approximately 24 h. The mixture was then heated at reflux for an additional 32 h, cooled to approximately 5° C. and filtered to obtain 5.5 g of the title compound of Step A as an off-white solid melting at 246-249° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[Br:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Nc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Temperature: 110 °C

Procedure:
To a mixture of 2-[3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]acetamide (36.6 mg, 0.1388 mmol) in IpOH (1 ml) were added DIEA (27 μl, 0.1527 mmol) and 3-bromoaniline (26.3 mg, 0.1527 mmol). The mix was heated at 100-120° C. for 18 h. The solution was cooled to RT and sonicated. The precipitate was filtered and dried under reduced pressure, giving 2-{3-[4-(3-bromophenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH:6]2[NH:11][CH2:10][CH2:9][N:8]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:7]23)[CH2:4][CH2:3]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29]([N:11]1[CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:14]=[C:7]2[CH:6]1[CH2:5][CH:2]1[CH2:4][CH2:3]1)=[O:30])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: FC(F)(F)c1nc2n(n1)CCNC2CC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1CC1CC1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 35 mg portion of 8-(cyclopropylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D, with the following exception. The reaction mixture was stirred at ambient temperature for 24 h and then concentrated. The residue was purified by preparative TLC (silica gel, 10% methanol/dichloromethane) to provide 54 mg of the title compound as a mixture of diastereomers. The diastereomers were separated by HPLC (OD chiralcel column, 7% ethanol/hexane) to give the faster eluting diastereomer and the slower eluting diastereomer.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(O)C>[C:21]([C:20]1[CH:19]=[C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 76 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.04 g (25.8 mmol) 3-aminobenzonitrile was heated to reflux. Removed heat at 3.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and air dried. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Boiled in large volume ethyl acetate, collected solids and dried in vacuo, giving 5.15 g of yellow-brown solid: mass spectrum (electrospray m/e): 316.0.
Reaction SMILES: OC[C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.N1CCC[C@@H]1C[OH:44]>>[OH:44][C@H:6]1[CH2:7][CH2:3][N:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=3)[NH:19][CH:18]=[C:17]4[CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[CH:10]=2)[CH2:5]1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Reactant: OC[C@H]1CCCN1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CC[C@H](O)C5)c4)cc23)CC1
Yield: 53.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting (3S)-3-pyrrolidinol (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 12.8 mg of the title compound (53.1%).
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:6][CH:5]=1.[CH2:20]([N:22]([CH2:33][C:34](O)=[O:35])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:20]([N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:33][C:34]([NH:17][CH2:16][CH:12]1[O:13][CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:18])[F:19])=[CH:9][CH:8]=2)[CH2:11]1)=[O:35])[CH3:21]
Reactant: CCN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
(4-(4-(Trifluoromethyl)phenyl)morpholin-2-yl)methylamine hydrochloride (99 mg, 0.34 mmol), [ethyl-(4-fluoro-benzenesulfonyl)-amino]-acetic acid (87.2 mg, 0.34 mmol), BOP reagent (148 mg, 0.34 mmol) and TEA (0.2 mL) were combined in 5 mL of dichloromethane. The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was washed with sodium bicarbonate solution and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (11 g silica gel, ethyl acetate in hexanes 0% to 60%) to give the desired compound as a white solid (125 mg, 74%). [MH]+=504.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=[O:9])[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH3:18])=[O:9])[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxylic acid (7.55 g, 33 mmol) was dissolved in dichlormethane (145 ml) and oxalyl chloride (4.1 ml, 46 mmol) was added via syringe over about 10 minutes, resulting in vigorous bubbling. After stirring at room temperature for about 30 minutes, the reaction was cautiously quenched with MeOH (100 ml). The methanol was added slowly at first as vigorous gas evolution was observed. The reaction was stirred at room temperature for 1 hour, concentrated, and then partitioned between dichlormethane (125 ml) and saturated sodium bicarbonate (125 ml). More dichlormethane and saturated sodium bicarbonate were added, and the layers of the biphasic, homogeneous solution were separated. The aqueous phase was extracted with dichlormethane (3×100 ml), and the organic phases were collected, dried over sodium sulfate, filtered, and concentrated to give desired methyl 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (7.82 g, 79% purity by HPLC, 25 mmol, 77% yield). MS (ESI pos. ion) m/z: 247 (MH+). Calc'd exact mass for C13H14N2O3: 246.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20]CC)=[O:19])[CH:12]1[CH2:11][CH2:10]2)(C)C.[OH-].[Na+]>CO.O>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([OH:20])=[O:19])[CH:12]1[CH2:11][CH2:10]2)#[CH:5]
Reactant: CCOC(=O)C1C2CCc3cc(C#C[Si](C)(C)C)ccc3C21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)CCC1C(C(=O)O)C21
Temperature: 65 °C
Yield: 88.3 %

Procedure:
Ethyl 5-[(trimethylsilyl)ethynyl]-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.64 mmol) was dissolved in 4 ml of methanol and the solution of sodium hydroxide (0.05 g, 1.2 mmol) in 2 ml of water was added to the reaction mixture and stirred at heating at 65° C. for 6 h. The extraction of basic reaction mixture into hexane showed that no starting material present. The reaction mixture was acidified with excess of 3M HCl solution (pH=1), and extracted into ethylacetate (3×15 ml). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated by rotary evaporation to give 0.12 g of mixture of cis/trans:acids (85:15) as white solid. Yield 88%.7
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,3-dibromopropane (2.2 mL, 22.0) in THF (35 mL) was added 60% NaH (356 mg, 8.82 mmol), and the resultant mixture was refluxed for 1 h and stirred at room temperature overnight. The mixture was quenched with H2O (25 mL) and diluted with CH2Cl2 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) provided 1-(3-Bromo-propyl)-1H-imidazole (410 mg, 30%) as a colorless oil. 1H NMR (CDCl3) δ 2.20-2.34 (m, 2H), 3.31 (t, 2H, J=6.3 Hz), 4.16 (t, 2H, J=6.2 Hz), 6.93 (s, 1H), 7.08 (s, 1H), 7.51 (s, 1H).
Reaction SMILES: [C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[C:17](B5OC(C)(C)C(C)(C)O5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.Cl[C:36]1[CH:37]=[CH:38][C:39]2[O:52][CH2:51][N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=4[CH:49]=[C:41]3[C:40]=2[N:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:17]([C:36]5[CH:37]=[CH:38][C:39]6[O:52][CH2:51][N:42]7[C:43]8[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=8[CH:49]=[C:41]7[C:40]=6[N:53]=5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a degassed solution of 2-(bicyclo[3.1.0]hexan-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.20 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (67 mg, 0.24 mmol), K3PO4 (109 mg, 0.41 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg), X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extracted with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.46 (s, 2H), 7.21 (s, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.86 (q, J=8.0 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.67 (s, 3H), 2.14˜2.22 (m, 2H), 2.11˜2.16 (m, 2H), 2.01˜2.09 (m, 2H), 1.91˜1.98 (m, 1H), 1.84 (d, J=4.0 Hz, 2H). MS (M+H)+: 601.
Reaction SMILES: [CH3:1][S:2][C@H:3]1[CH2:7][NH:6][C@@H:5]2[C@@H:8]([OH:11])[CH2:9][O:10][C@H:4]12.C(=O)([O-])[O-].[Na+].[Na+].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCOCC1.O>[OH:11][C@@H:8]1[C@H:5]2[N:6]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:7][C@H:3]([S:2][CH3:1])[C@H:4]2[O:10][CH2:9]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CS[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of (3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (5 mL) was added whilst stirring to a solution of sodium carbonate (123 mg, 1.16 mmol) in water (1.5 mL) at 0° C. A solution of 9-fluorenylmethoxycarbonyl chloride (150 mg, 0.58 mmol) in 1,4-dioxane (1.5 mL) was added dropwise over 5 minutes then the mixture allowed to warm to ambient temperature over 2 hours. Water (20 mL) was added and the product extracted into dichloromethane (3×10 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 2:1 gave alcohol (55) as a white solid (130 mg, 60%). TLC (Rf=0.19, Et2O:pentane 2:1); HPLC-MS 398.2 [M+H]+, 420.1 [M+Na]+, 817.3 [2M+H]+; analytical HPLC single main peak, Rt=16.096 min., [α]D17 −59.4° (c=2.78, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 4:3; 1.06 (0.57H, d, J=3.63 Hz, OH major), 2.04 (1.71H, s, SCH3 major), 2.14 (1.29H, s, SCH3 minor), 2.57 (0.43H, d, J=2.83 Hz, OH minor), 3.10 (0.57H, d, J=5.40 Hz, FmocNCH2 major), 3.21-3.24 (0.43H, m, FmocNCH2 minor), 3.41 (0.57H, dd, J=12.18 and 5.57 Hz, OCH2CHOH major), 3.52-3.82 (4.43H, m, FmocNCH, CHSCH3 OCH2CHOH minor, 1×FmocNCH2 and 1 ×OCH2CHOH), 3.92 (0.43H, dd, J=9.85 and 4.41 Hz, OCH2CHOH minor), 4.23-4.84 (4.57H, m, Fmoc CH, OCHCHSCH3, Fmoc CH2 minor and 1×OCH2CHOH major), 7.28-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 14.574/14.768 (SCH3), 47.234, 47.445, 48.069 and 48.826 (Fmoc CH and CHSCH3), 50.417/50.633 (FmocNCH2), 65.752/67.282 (Fmoc CH2), 68.555/69.282 (FmocNCH), 74.361/74.600 (OCH2CHOH), 75.774/76.148 (OCH2CHOH), 85.505/86.026 (OCHCHOCH3), 119.848, 120.003, 120.029, 124.512, 124.593, 124.946, 127.030, 127.063, 127.427, 127.507, 127.755, 127.771 and 127.892 (Fmoc aromatic CH), 141.196, 141.320, 141.378, 141.428, 143.581, 143.818, 143.890 and 143.964 (Fmoc quaternary), 154.115/154.849 (Fmoc C═O).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10](O)[CH3:11]>OS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: CCO
Reactant: O=C(O)c1csc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(Br)c1

Procedure:
5-bromo-thiophene-3-carboxylic acid (18.2 g, 0.09 mol) was dissolved in absolute ethanol (150 ml) and H2SO4 (5 ml), and the mixture was refluxed for 5 hours. The mixture was concentrated under vacuum to give a yellow oil, then diluted with a mixture of ethyl acetate (100 ml) and saturated brine (200 ml), and mixed, let standing for layer separation. The aqueous layer was washed with ethyl acetate (25 ml twice). The extract and the organic layer was adjusted with Na2CO3 (10%) to pH=8, and the organic phase was separated and washed with saturated brine to pH=7□ dried over anhydrous Na2SO4 over night. The organic layer was concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as yellow oil (15 g).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:40])[CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:29][CH2:28]4)=[CH:21][CH:20]=3)[C:12]=2[CH2:11]C1>C(Cl)(Cl)Cl>[C:5]([O:4][CH:1]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:40])[CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)[C:12]=2[CH2:11][CH2:2]1)(=[O:7])[CH3:6]
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCc2c(Nc3ccc(C(=O)CC4CCN(Cc5ccccc5)CC4)cc3)ncnc21

Procedure:
20 ml of chloroform and 0.65 ml of acetic anhydride were added to 0.35 g of N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline, and the mixture was refluxed under heating for 4 hours. Then, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.16 g of the title compound as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>O1CCOCC1>[Cl:8][C:7]1[C:6]([N:15]([C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH:11]([F:10])[F:20])[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: Nc1ccccc1OC(F)F
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: C1COCCO1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccccc1OC(F)F
Yield: 89.9 %

Procedure:
16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride is dissolved in 100 ml of dioxane, and a solution of 15.9 g (0.1 mole) of o-difluoromethoxyaniline in 30 ml of dioxane is added dropwise to it at room temperature over 20 minutes with stirring. Thereafter, the resulting solution is stirred at 70°-80° C. for 2 hours and the dioxane is then distilled off under a reduced pressure. Water is added to the residue to precipitate crystals. The precipitated crystals are filtered off and recrystallized from ethanol to give 27.7 g (yield: 90%) of 2,3-dichloro-N-(o-difluoromethoxyphenyl)maleimide melting at 103.5°-104° C. in the form of light yellow crystals.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[I:16][CH2:17][C:18]([OH:20])=[O:19].[CH:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:35][C:34]=2O)=[CH:27][C:26]=1[O:46][CH3:47])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:16][CH2:17][C:18]([O:20][C:29]1[CH:30]=[C:25]([O:24][CH:21]([CH3:22])[CH3:23])[C:26]([O:46][CH3:47])=[CH:27][C:28]=1[C:31]#[C:32][C:33]1[CH:34]=[CH:35][C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([O:39][CH3:40])[CH:38]=1)=[O:19]
Reactant: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2O)ccc1OC(C)C
Reactant: O=C(O)CI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2OC(=O)CI)ccc1OC(C)C
Temperature: 18 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
DCC (1.60 g, 7.75 mmol) was added to a solution of 2-iodoacetic acid (1.44 g, 7.74 mmol), 2-[(4-isopropoxy-3-methoxy-phenyl)ethynyl]-5-isopropoxy-4-methoxyphenol (2.6 g, 7.03 mmol)and DMAP (43 mg, 0.35 mmol) in CH2Cl2 (30 mL) and the solution thereby obtained was stirred at 18° C. for 3 h. The resulting suspension was filtered (CH2Cl2 rinse) and the filtrate concentrated under reduced pressure. The residue was suspended in ether (30 mL) at 0° C. with rapid stirring then filtered [rinsing with Et2O (20 mL) pre-cooled at 0° C.] giving the title compound (3.67 g, 97%) as a cream solid mp 127-8° C. IR (KBr disc, cm−1) 2969, 2930, 2833, 1755, 1611, 1575, 1516, 1467, 1416, 1402, 1385, 1365, 1320, 1252, 1236, 1212, 1135, 1108. 1H NMR (300 MHz, CDCl3) δ 7.08 (dd, J=1.8, 8.4 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 7.01 (s, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 4.53 (septet, J=6.0 Hz, 2 Hz), 3.95 (s, 2H), 3.85 (s, 6H), 1.38 (d, J=6.0 Hz, 6H), 1.37 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 167.3 (C), 150.0 (C), 148.4 (C), 148.3 (C), 148.2 (C), 145.1 (C), 125.2 (CH), 115.6 (C), 115.3 (CH), 115.2 (CH), 115.0 (CH), 108.8 (CH), 93.6 (C), 82.7 (C), 72.0 (CH), 71.6 (CH), 56.5 (CH3), 56.3 (CH3), 22.3 (CH3), 22.0 (CH3), −6.2 (CH2). MS (70 eV) m/z (%): 538 (80, M+·), 496 (10, M+·-CH2CHCH3), 370 (10, M+·-CH2ICO), 328 (34), 286 (100); HRMS calcd for C24H27O6I 538.0852. Found 538.0854.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:12][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)COc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(Br)Oc1ccccc1

Procedure:
Phenoxy-2-propanone (0.10 mol), N-bromosuccinimide (0.10 mol) and a catalytic amount of 2,2'-azobis(2-methylpropionitrile) were stirred together in tetrachloromethane (100 ml) at 80° C. for 61/2 hours. The solvent was distilled off and the residue distilled under vacuum to give (1-bromo-2-oxopropyl) oxybenzene. Yield: 10.4 g (45%), b.p. 66°-68° C./0.01 mm Hg. 1H NMR (CDCl3, δ): 2.50 (s, CH3) 6.40 (s, --CHBr--), 6.9-7.5 (5H, Ph).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1F)([O-:14])=[O:13]>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Solvent: CCN(CC)CC
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
15.7 Grams (0.1 mole) of 1-methyl-2-hydroxymethyl-5-nitro-imidazole and 21.0 g (0.1 mole) of 2-nitro-4-trifluoromethylfluoro-benzene dissolved in 100 ml of butanone-2 were mixed with 15 g of triethylamine and were heated for 2 hours on a steam bath. The crystals obtained when the solution had been cooled were suction-filtered, were washed with water and were recrystallized from a little isopropanol, while adding charcoal. As a result, 25 g (= 72% of the theory) of 1-methyl-2-(4-trifluoromethyl-2-nitrophenoxymethyl)-5-nitro-imidazole were obtained in the form of yellowish crystals having a melting point of 126° C.