Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=1B(O)O>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]4[CH:28]=[C:29]([CH:30]=[CH:31][C:26]=4[Cl:25])[C:32]#[N:33])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cc(C#N)ccc4Cl)cc32)N=C1N
Temperature: 120 °C
Yield: 18.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2-chloro-5-cyanophenylboronic acid (18.9 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar under microwave for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-4-chlorobenzonitrile (4.2 mg, 18%). 1H-NMR (MeOD): 2.38 (m, 1H), 2.52 (m, 1H), 3.15 (s, 3H), 5.18 & 5.76 (m, 1H), 7.03 & 7.18 (m, 1H), 7.26-7.64 (m, 10H).
Reaction SMILES: ClC1C=CC(C2N(CC3C=CC(CCC(O)=O)=CC=3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.C1([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([F:55])[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH2:63]C2C=CC(C3NN=NN=3)=CC=2F)CCCCC1.BrC[C:78]1[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=1[F:86]>>[F:54][C:52]1[C:51]([F:55])=[CH:50][C:49]2[N:45]([CH2:44][C:78]3[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=3[F:86])[C:46]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[O:62][CH3:63])=[N:47][C:48]=2[CH:53]=1
Reactant: Fc1cc2nc(-c3ccccc3OCc3ccc(-c4nnn[nH]4)cc3F)n(CC3CCCCC3)c2cc1F
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Product: COc1ccccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 5,6-difluoro-2-(2-methoxy-phenyl)-1H-benzoimidazole (Example 34, intermediate d) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Blue solid (32%). MS (Turbo Spray): m/z=394.4 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[NH:5][C:6]=1[CH3:7].[CH2:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>[Pt](=O)=O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[NH:5][C:6]=1[CH3:7]
Reactant: CC(C)CCN
Reactant: Cc1nc(C=O)[nH]c1C
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1nc(CNCCC(C)C)[nH]c1C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 3.35 g (27 mmol) of 4,5-dimethyl-2-imidazolecarboxaldehyde, 9.0 mL (77 mmol) of isoamylamine, 200 mL of ethanol, and 0.20 g of platinum dioxide is hydrogenated under 50 psi of pressure at 22° C. for 24 h. The solution is filtered, and the volatiles are evaporated under reduced pressure to give 5.17 g (98%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine. Mass Spec m/z (M++1) 196.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].Cl>CO>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: C=CC#N
Reactant: CC(C)C=O
Agent: Cl
Solvent: CO
Product: CC(C)(C=O)CCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Isobutyraldehyde (1 g, 13.9 mmol) and acrylonitrile (0.81 g, 15 mmol) were mixed thoroughly and cooled with an ice-bath. Triton B (40% in MeOH, 0.58 g, 1.4 mmol) was added. The mixture was stirred at room temperature overnight. It was then neutralized with 0.1 M HCl (14 cm3) and extracted with CH2Cl2 (100 cm3) The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give the product 4,4-dimethyl-5-oxopentanenitrile (0.8 g, 50.7%) as an oil, bp 125-130° C./20 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[CH:13]=1.P(Br)(Br)[Br:15].CN(C=O)C>CCOCC>[Br:15][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=2[C:7]=1[CH3:12]
Reactant: BrP(Br)Br
Reactant: Cc1c(CO)oc2ccc(Cl)cc12
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(CBr)oc2ccc(Cl)cc12
Reaction time: 3 h

Procedure:
A solution of 5-chloro-3-methyl benzofuran 2-methanol (18.3 mmol, 3.6 g) in ether (200 mL) was cooled to 0° C. To this was added drop wise phosphorus tribromide (29.3 mmol, 7.9 g) and then DMF (2 mL). After allowing the reaction mixture to come to room temperature over three hours, the reaction was quenched with ice water (100 mL). The ether layer was collected, dried, filtered and the filtrate was evaporated to a yellow solid: 2-bromomethyl-5-chloro-3-methyl benzofuran (88%, 4.2 g); mp 81° C.-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:19][OH:20])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Cl)C(=O)C1.C(=O)([O-])O.[K+].[Cl:34][C:35]1[CH:40]=[C:39]([C:41]([C:43]([F:46])([F:45])[F:44])=[CH2:42])[CH:38]=[C:37]([Cl:47])[CH:36]=1>CN(C=O)C.ClCCl.CCCCCC.C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH2:42][C:41]([C:39]4[CH:38]=[C:37]([Cl:47])[CH:36]=[C:35]([Cl:34])[CH:40]=4)([C:43]([F:44])([F:46])[F:45])[O:20][N:19]=3)=[CH:16][CH:17]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C=NO)cc2)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[4-(Hydroxyimino-methyl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester (Preparation 39, 1 g, 3.62 mmol, 1.0 equivalents) in DMF (6.0 mL) was added NCS (725.26 mg, 5.43 mmol, 1.5 equivalents) and heated to 50° C. for 1 hour. Progress of the reaction was monitored by TLC using 5% methanol in dichloromethane. After complete consumption of starting material, reaction was cooled to 0° C. followed by the addition of potassium hydrogen carbonate (543.18 mg, 5.43 mmol, 1.5 equivalents) and pre-dissolved solution of 1,3-Dichloro-5-(1-trifluoromethyl-vinyl)-benzene (1.04 g, 4.345 mmol, 1.2 equivalents) in DMF (4.0 mL). Resulting reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Progress of the reaction was monitored by TLC using 20% ethyl acetate in hexane and visualized in UV light (254 nm). Reference of required product was 0.6 and 0.5 for starting material. After consumption of starting material, reaction mixture was quenched with water (40 mL) extracted with diethyl ether (3×50 mL). Combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulphate and concentrated in vacuo to afford (1.50 g, crude). Further purification by column chromatography (on neutral alumina) using 10% ethyl acetate in hexane as eluent afforded off white solid 1.3 g (69.84%). 1H NMR and LC-MS were consistent. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 3.84 (m, 3H), 4.25-4.38 (m, 4H), 7.47 (d, J=8 Hz, 2H), 7.62 (d, J=1 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.81 (t, J=2 Hz, 1H). LC-MS (m/z):=513 (M−H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.076 mmol), β-alanine (896 mg, 10.1 mmol) and NaOMe solution (15 mL, 7.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 29 mg of the title compound as a pale yellow solid. MS: (+) m/z 521.34 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([S:27][CH2:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:30](=[O:31])[CH:29]([CH3:33])[CH2:28][S:27][C:24](=[O:26])[CH3:25])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CNC1CCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCCCC1
Yield: 98.7 %

Procedure:
To a stirred and chilled (0°-5° C.) solution of N-cycloheptylglycine t-butyl ester (32.9 g, 0.12 mol) and triethyl amine (13.2 g, 0.13 mol) in methylene chloride (150 ml) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (21.6 g, 0.12 mol) dissolved in 50 ml methylene chloride. The reaction mixture was stirred overnight. Filtration of the reaction mixture followed by washing the filtrate with saturated sodium bicarbonate (500 ml), brine (500 ml), 5% HCL (4×500 ml), brine (500 ml), saturated aqueous sodium bicarbonate (3×500 ml), brine (500 ml); drying the organic layer over Na2SO4 and MgSO4 ; filtration; and solvent evaporation afforded a nearly quantitative yield of the desired compound (44 g, crude).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11]([S:21]([CH3:24])(=[O:23])=[O:22])[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.C1C([N+]([O-])=O)=CC=C([Cl-][C:42]([O-:44])=[O:43])C=1.Cl>C1COCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH2:7][C:5]3[N:4]=[CH:3][N:2]([C:42]([O:44][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:43])[CH:6]=3)[CH2:9][C@@H:10]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:11]([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:12][C:13]=2[CH:18]=1)#[N:20]
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reaction time: 8 h
Yield: 116 %

Procedure:
To a solution of Compound C of Example 248 (200 mg, 0.76 mmol) in THF (20 mL) under argon was added 4-nitrophenylchloroformate (0.88 mL, 0.76 mmol). The solution was stirred for 8 hours, poured into aqueous hydrochloric acid (150 mL, 1N), extracted with ethyl acetate (2×150 mL), dried (MgSO4), and concentrated to an oil which was purified using flash chromatography (50 g silica, 2:1 hexane:ethyl acetate) to provide Compound A (230 mg, 70%) as a clear oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2].[H-].[Na+].Cl.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][N:8]1[C:9]2[C:4](=[C:3]([CH2:1][CH3:2])[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=2)[CH:5]=[CH:6][C:7]1=[O:15]
Reactant: CN(C)CCCl
Reactant: CCc1cc(CC)c2ccc(=O)[nH]c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(CC)c2ccc(=O)n(CCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5,7-diethyl-1,8-naphthyridin-2(1H)-one (4.04 g., 0.02 mole) in 25 ml. of dry dimethylformamide under nitrogen atmosphere is added a 57% suspension of sodium hydride in mineral oil (0.84 g., 0.02 mole). This mixture is stirred at room temperature for 0.5 hours. Then a mixture of 2-dimethylaminoethyl chloride hydrochloride (3.17 g., 0.022 mole) and a 57% suspension of sodium hydride in mineral oil (0.93 g., 0.022 mole) in 25 ml. of dry dimethylformamide is added to the above suspension. The mixture is stirred at steam bath temperature overnight (16 hours). After the mixture is cooled to room temperature it is filtered to remove salt (2.6 g., theory 2.45 g.). Removal of the solvent under reduced pressure gives a pale tan waxy solid (4.8 g.). Several recrystallizations from hexane gives 1-(2-dimethylaminoethyl)-5,7-diethyl-1,8-naphthyridin-2(1H)-one melting at 59.5°-61° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:21][C:22]([NH:24][C:25]1([C:42]2[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:43]=2[F:49])[CH:29]([CH2:30]O)[CH2:28][N:27]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:26]1)=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O>[C:13]([NH:21][C:22]1[S:23][CH2:30][CH:29]2[CH2:28][N:27]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[CH2:26][C:25]2([C:42]2[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:43]=2[F:49])[N:24]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC(=S)NC1(c2cc(Br)ccc2F)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1=NC2(c3cc(Br)ccc3F)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
1,1′-carbonyldiimidazole (2.87 g, 17.7 mmol) is added to a solution of benzyl 3-(benzoylcarbamothioylamino)-3-(5-bromo-2-fluoro-phenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (5.198 g, 8.86 mmol) in tetrahydrofuran (52 mL). The mixture is stirred for 1.5 hours at room temperature and then the reaction is heated at reflux overnight under nitrogen. The reaction is cooled, diluted with water, and extracted with ethyl acetate (3×). The organic layers are combined, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (2.93 g, 58%). ES/MS (m/e): (79Br/81Br). 568/570 (M+H)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[C:6]1([CH:2]([O:1][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C(O)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(O)C(OC1CCCCO1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred solution of hydroxy-phenyl-acetic acid (2 g, 13.4 mmol) in DCM (30 mL) was added PTSA (51.2 mg, 0.27 mmol) at 0° C. followed by the addition of 3,4-dihydro-2H-pyran (1.55 g, 18.4 mmol). The mixture was stirred at 0° C. for another 15 min and then gradually warmed up to room temperature and stirred for a further 1.5 hours. The reaction mixture was diluted with DCM (100 mL). The organic phase was washed with saturated aq. Na2CO3 (2×20 mL), water (20 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 48% yield, 1.5 g. LCMS (system 10): Rt=1.82 min; m/z 237 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14]
Reactant: [I-]
Reactant: O=c1sc2ccccc2n1CCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1sc2ccccc2n1CCCI
Reaction time: 60 h
Yield: 96 %

Procedure:
To a solution of 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 12.56 mmol) in acetone (50 mL), was added sodium iodide (3.77 g, 25.12 mmol). After refuxing for 60 hours, the reaction mixture was filtered. The filtrate was washed with water and dried to obtain the title compound (3.85 g, 83%); 1H NMR (DMSO-d6): δ 2.13-2.16 (m, 2H), 3.28 (t, 2H, J=6.8 Hz), 4.05 (t, 2H, J=6.8 Hz), 7.18-7.22 (m, 1H), 7.38-7.39 (m, 2H), 7.66 (dt, 1H, J=7.6 and 0.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+].[I-]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1
Temperature: 120 °C

Procedure:
A suspension of 3-nitrophenol (837 mg, 6.02 mmole), 1-chloro-3-[imidazo-1-yl]-propane (871 mg, 1 eq), KCO3 (3.3 μm, 4 eq) and NaI (1.0 μm, 1.1 eq) in DMF was heated at 120° C. for 6 hr. After cooling to RT, the reaction was filtered and the filter cake was washed with DMF. The solvent was removed from the filtrate and the residue was chromatographed (radial chromatography; 4 mm silica gel plate that was eluted with a step gradient of DCM containing 0, 1, 2.5, 5, 7.5% MeOH) to afford 400 mg of 3-[3-imidazo-1-ylpropyloxy]]-nitrobenzene. This was treated with 10% palladium on charcoal (400 mg) in EtOH under a hydrogen atmosphere for 4 hr. Removal of the catalyst and the solvent left 3-[3-imidazo-1-ylpropyloxy]]-aniline was then coupled with 319A as described for 570 to afford 576 (HPLC retention time (YMC ODS S5 4.6×30 mm): 1.33 min). Beginning with 4-nitrophenol and 1-chloro-3-[imidazo-1-yl]-propane 577 (HPLC retention time (YMC ODS S5 4.6×30 mm): 1.42 min) was prepared in a similar manner as 576.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCCCCC)=C=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:2]([C:1]([NH2:8])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCN=C=O
Agent: CN(C)c1ccncc1
Agent: O=C1CN(Cc2ccccc2)C(=O)N1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCC(N)=O
Temperature: 115 °C
Reaction time: 6 h

Procedure:
1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatohexane (80.3 mg, 0.63 mmol) and, if required, a catalytic amount of 4-dimethylaminopyridine were dissolved in 10 ml of toluene and 0.5 ml of pyridine and stirred at 115° C. for 6 h. Then a further 80 mg of 1-isocyanatohexane were added, and the mixture was stirred at 115° C. for a further 6 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and H2O, and the org. phases were washed twice with water, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 11.3 mg (7%), M+H+:318.14.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([CH:22]2[C:24]3([C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[O:26][C:25]3([CH3:33])[CH3:32])[O:23]2)[CH:15]=1>ClCCCl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([CH:22]2[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[O:26][C:25]([CH3:33])([CH3:32])[C:24]2=[O:23])[CH:15]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of concentrated sulphuric acid (6 ml) is added a second solution of 2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (1.90 g, 0.0045 mol) in 1,2-dichloroethane (6 ml) dropwise over 5 mins. This biphasic mixture is stirred vigorously for 2 hours at 0° C., then is poured into ice and extracted with diethyl ether. All organics are combined, washed with brine, dried over magnesium sulfate then concentrated in vacuo. The crude product is purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione as a yellow gum.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].Br[C:11]1[CH:12]=[C:13]2[C:26]3[C:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:25]=1)[CH2:22][C@H:21]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20][N:19]4[CH2:35]CC)=[CH:15][N:14]2[Si](C(C)(C)C)(C)C>>[CH2:30]([N:29]([CH2:32][CH3:33])[C:28]([NH:27][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][CH:16]3[C:26]4[C:13](=[CH:12][C:11]([OH:2])=[CH:25][C:24]2=4)[NH:14][CH2:15]3)[N:19]([CH3:35])[CH2:20]1)=[O:34])[CH3:31]
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]21
Reactant: O=[N+]([O-])c1ccccc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(O)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With nitrobenzene and 3-(13-bromo-1-tert-butyldimethylsilyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:37]1[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (273 mg, 1 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (311 mg, 1 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (146 mg).
Reaction SMILES: CO.C(C1C=C[C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:13]([OH:32])[C:12]2=[O:33])=CC=1)=O.[CH2:34]([OH:37])[CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[O:36]1[CH2:35][CH2:34][O:37][CH:8]1[N:11]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]([C:22](=[O:31])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:13]([OH:32])[C:12]1=[O:33]
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C(=O)C2=C(O)C(=O)N(C3OCCO3)C2c2ccccc2)cc1
Yield: 10 %

Procedure:
The 0.1M methanol solution of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (1 mL, 0.1 mmol) was concentrated under reduced pressure. Toluene (1 mL), ethylene glycol (0.033 mL, 0.6 mmol) and p-toluenesulfonic acid monohydrate (3.8 mg, 0.02 mmol) was added to the residue. The mixture was heated under azeotropic dehydration for 3 hr. Water (100 mL) was added to the mixture, which was then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to give 1-(1,3-dioxolan-2-yl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (3.8 mg, 8%) as pale yellow crystals.