Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorothio phenol (1.5 g) were dissolved in ethanol (30 ml) and potassium carbonate (1.4 g) was added thereto, followed by stirring at 60° C. for five hours. Subsequently, the solvent was removed under reduced pressure and the residue was dissolved in water (50 ml). The resultant solution was subjected to extraction with ethyl acetate (30 ml×2). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was re-crystallized from diethyl ether, to thereby produce the target compound (2.1 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:13]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([CH3:1])=[N:3][C:4]=2[CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1nc2cc(CO)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a DMF solution (10 mL) of (2-methyl-1H-benzimidazol-5-yl)methanol (811 mg) were added tert-butyldimethylsilyl chloride (904 mg) and imidazole (680 mg), followed by 2 hours of stirring at room temperature. The reaction solution was concentrated, water was added thereto, the mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain 5-(tert-butyldimethylsilyloxymethyl)-2-methyl-1H-benzimidazole (1305 mg, 94%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([O:11][CH2:12][C:13]([F:21])([F:20])[CH:14]([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:22]([O:26]CCCC)(=[O:25])[CH:23]=[CH2:24].[CH2:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OC(C)COC)(=O)C>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([O:11][CH2:12][C:13]([F:20])([F:21])[CH:14]([F:19])[C:15]([F:17])([F:18])[F:16])(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:22]([O:26][C:33]([CH3:32])([CH3:34])[CH3:38])(=[O:25])[CH:23]=[CH2:24].[CH2:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=CC(=O)OCCCC
Agent: C=C(C)C(=O)OCC(F)(F)C(F)C(F)(F)F
Agent: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COCC(C)OC(C)=O
Solvent: C=Cc1ccccc1
Product: C=CC(=O)OC(C)(C)C

Procedure:
Acrylic acid (4.2 g), 2,2,3,4,4,4-hexafluorobutyl methacrylate (14 g), t -butyl acrylate (14 g) and styrene (8.26 g) were mixed with azobisisobutyronitrile (AIBN) (4 g) as a polymerization initiator and propyleneglycol methyl ether acetate (PGMEA) (145 g) as a polymerization solvent. The resulting mixture was reacted at approximately 67° C. for approximately 12 hours, and precipitated in normal hexane and dehydrated to obtain an organic polymer compound with yield of approximately 82% (see FIG. 3).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C@H:9]([CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[CH2:8]1.O1CCCC1>C(N(CC)CC)C.ClCCl.O>[N:26]1([CH2:25][C@@H:9]2[CH2:8][C@@H:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][N:10]2[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1ccnc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.40 ml) was added to a suspension of (2S,4R)-4-hydroxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.79g) in a mixture of triethylamine (0.80 ml), tetrahydrofuran (16 ml) and dichloromethane (24 ml) at 0-5° C., and the mixture was stirred at 0-5° C. for one hour. The reaction mixture was poured into a mixture of water (50 ml) and dichloromethane (20 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98, V/V) to give (2S,4R)-2-(imidazol-1-yl)methyl-4-methanesulfonyloxy1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.78 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36](F)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]>C(#N)C>[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
Methylpiperazine (10 ul, 116 umol; CAS Reg. No. 109-01-3) and DIEA (20 ul, 93 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 46 umol; example 388 g) in acetonitrile (400 ul) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 72 h, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (14 mg, 23 umol; 49%) as colorless oil. MS (ESI): m/z=618.2 [M−H]−.
Reaction SMILES: Cl.Cl.[O:3]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[NH:21][C:22]([NH2:25])=[N:23][N:24]=2)[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Br:28][CH:29]([CH:32]=O)[CH:30]=O>O>[Br:28][C:29]1[CH:30]=[N:25][C:22]2[N:23]([N:24]=[C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:19][CH2:18]3)[N:21]=2)[CH:32]=1
Reactant: Nc1nnc(N2CCN(CCCCOc3ccccc3)CC2)[nH]1
Reactant: O=CC(Br)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cnc2nc(N3CCN(CCCCOc4ccccc4)CC3)nn2c1

Procedure:
A 10.0 g (0.03 mole) amount of 5-[4-(4-phenoxybutyl)-1-piperazinyl]-4H-1,2,4-triazol-3-amine, dihydrochloride was partially dissolved in 20 ml of water, then 5N sodium hydroxide was added to adjust the pH to just greater than pH 7, resulting in formation of a solid. The solid was collected by filtration and washed with water. The colorless crystals, were transfered into a 125 ml round bottom flask and dissolved in 50 ml of ethanol. Then 7.5 g (0.05 moles) of bromomalonaldehyde was added and the mixture was heated at reflux for 7 hours. The reaction mixture was cooled and filtered. The filter was washed with ethanol/ether, then ether. The filtrate was evaporated in vacuo, combined with the filter cake, extracted with hot chloroform and filtered. The filtrate was passed through a pad of magnesium silicate and the pad was washed with chloroform. The combined chloroform filtrate and wash was evaporated to a syrup. Crystallization from ethanol gave 2.2 g of the desired product as pale yellow crystals, mp 122°-123° C.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=[C:15]([Cl:29])[N:14]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](Cl)(Cl)=[O:40].C1(C)C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:13]3=[N:14][C:15]([Cl:29])=[N:16][CH:17]=[C:18]3[CH2:19][N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[C:39]2=[O:40])[CH2:8]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: CCc1ccc(NCc2cnc(Cl)nc2N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (±)-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-{2-chloro-5-[(4-ethyl-phenylamino)-methyl]-pyrimidin-4-yl}-amine (270 mg, 0.58 mmol) (from Example 39a supra) and triethylamine (0.25 mL, 1.76 mmol) (Allied Signal) in dichloromethane (6 mL) was cooled to 0° C. A 20% phosgene in toluene solution (0.32 mL, 0.61 mmol) (Fluka) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The mixture was allowed to warm up to room temperature and 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) (Aldrich) was added. The reaction was stirred at room temperature overnight, heated at reflux for 4 hours, and then concentrated to dryness. The yellow residue was purified by flash chromatography (20% ethyl acetate in hexanes) to give (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 213 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC1C=CC=CC=1>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCc2cc(N)ccc2O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2cc(NS(C)(=O)=O)ccc2O1
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 40 parts of ethyl 6-amino-3,4-dihydro-2H-1-benzopyran-2-carboxylate, 86 parts of pyridine and 234 parts of methylbenzene was added dropwise a solution of 20.6 parts of methanesulfonyl chloride in 135 parts of methylbenzene. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the oily residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 210 parts of 2,2'-oxybispropane and 12 parts of acetonitrile, yielding 10.2 parts (18.9%) of ethyl 3,4-dihydro-6-[(methylsulfonyl)amino]-2H-1-benzopyran-2-carboxylate; mp. 111.1° C. (intermediate 25).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].O[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=N1.N1CCCCC1NC>O.CN(C=O)C.C(N(CC)CC)C>[NH:28]1[CH2:29][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:30][NH:26][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CNC1CCCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCC1CCCCN1
Temperature: 0 °C
Yield: 44.8 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were sequentially added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then piperidin-2-yl-methylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 117.8 g (448 mmol) of N-[(piperidin-2-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 44.8%, m.p. 107-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>C1COCC1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Yield: 34.3 %

Procedure:
A solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide (1.1 g, 2.8 mmol) and dimethylcarbamyl chloride (0.5 mL, 5.4 mmol) in THF (5 mL) was heated to reflux for 2 days. The solvent was removed in vacuo to give a solid, which was purified with prep HPLC to give (3R)-3-[7-(3,3-dimethyl-ureido)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (450 mg, 34% yield): mp 105-107° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.05 (dd, J=6, 16 Hz, 1H, CHH), 3.09 (s, 9H, 3 CH3), 3.46 (dd, J=9.15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.22 (d, J=17 Hz, 1H, NCHH), 4.41 (d, J=17 Hz, 1H, NCHH), 5.63 (dd, J=6, 9 Hz, 1H, NCH), 6.91-6.96 (m, 4H, Ar), 7.39 (t, J=8 Hz, 1H, Ar), 8.30 (d, J=8 Hz, 1H, Ar), 9.99 (s, 1H, NH); 13C NMR (CDCl3) δ 14.76, 35.57, 36.31, 36.38, 37.45, 48.70, 53.35, 55.97, 64.53, 111.46, 112.63, 115.07, 116.27, 117.57, 119.16, 131.90, 133.02, 139.61, 141.54, 148.55, 149.08, 155.49, 149.69, 170.15. Analy. Calculated for C25H32N4O5+1.2H2O: C, 61.26; H, 7.07; N, 11.43; H2O 4.41. Found: C, 60.89; H, 6.95; N, 11.10; H2O 4.04.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][CH2:16][C:12]1[N:11]([CH3:28])[C:10]([C:29]([OH:31])=[O:30])=[C:9]([OH:8])[C:14](=[O:15])[CH:13]=1)(=[O:20])=[O:19]
Reactant: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(O)c1C(=O)O
Yield: 37.2 %

Procedure:
6-[(2-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-03) (120.0 mg, 37.18%, purified by Prep-HPLC) was synthesized as a white solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (400.0 mg, 0.866 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:3]=1[C:9](=[O:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(OCc2ccccc2)cccc1OCc1ccccc1
Yield: 91.4 %

Procedure:
A suspension of (2′,6′-dihydroxy)acetophenone (25.0 g, 164 mmol), benzyl bromide (40 mL, 337 mmol), potassium carbonate (136 g, 986 mmol) and sodium iodide (2.5 g, 16 mmol) in acetone (500 mL) was stirred at reflux overnight. The mixture was concentrated under reduced pressure, and diluted with ethyl acetate (500 mL) and water (250 mL). The separated aqueous phase was extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexane, collected by filtration, washed with hexane and dried under reduced pressure to give 1-[2,6-bis(benzyloxy)phenyl]ethanone (24.9 g, yield; 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]=2)[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH2:12][CH2:11][C@@:10]4([CH2:16][CH2:15][NH:14][C:13]4=[O:17])[N:9]=3)[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCC[C@@]12CCC(c1cc(Br)ccn1)=N2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=C1NCC[C@@]12CCC(c1cc(-c3ccc(C(F)(F)F)cc3)ccn1)=N2
Temperature: 120 °C
Yield: 74.1 %

Procedure:
To a solution of (5S)-2-(4-bromo-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 19) (200 mg, 0.6800 mmol) in 1,2-dimethoxyethane (3 mL) and water (1 mL) was added [4-(trifluoromethyl)phenyl]-boronic acid (142.05 mg, 0.7500 mmol) and sodium carbonate (216.2 mg, 2.04 mmol). The reaction mixture was degassed with nitrogen and then treated with bis(triphenylphosphine)palladium (II) dichloride (23.86 mg, 0.0300 mmol). The reaction mixture was heated in the microwave at 120° C. for 50 minutes then cooled and diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography eluting with 0-20% methanol in ethyl acetate to give (5S)-2-[4-[4-(trifluoromethyl)-phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D20) as a pale yellow solid (181 mg);
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]12[CH2:12][N:9]([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=O.Br.O=C(C12CN(CC1)CC2)C=O.[CH3:25]/[C:26](/[NH2:29])=[N:27]/[NH2:28].Cl.N1C=CC=CC=1>CS(C)=O.CO>[CH3:25][C:26]1[N:27]=[N:28][CH:3]=[C:4]([C:6]23[CH2:12][N:9]([CH2:10][CH2:11]2)[CH2:8][CH2:7]3)[N:29]=1
Reactant: O=C(CBr)C12CCN(CC1)C2
Reactant: C/C(N)=N/N
Agent: Br
Agent: Cl
Agent: O=CC(=O)C12CCN(CC1)C2
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CO
Product: Cc1nncc(C23CCN(CC2)C3)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
A solution of 4-(α-bromoacetyl)-l-azabicyclo[2.2.1] heptane hydrobromide (EP-0366304, Description 19) (3.0 g, 10.0mmol) in dry dimethylsulphoxide (50 ml) was stirred overnight at room temperature. The reaction was concentrated in vacuo ensuring that the water bath temperature did not exceed 60° C. Co-distillation with successive portions of toluene was used to remove residual dimethylsulphoxide. The residue was placed in an oil bath at 120° C. for 5 min. A stream of nitrogen was passed through the reaction vessel during this period, and the dimethylsulphide which was generated was trapped in a solution of sodium hypochlorite. The resulting crude 2-oxo-2-(1-azabicyclo[2.2.1]hept-4-yl) ethanal hydrobromide was immediately treated with a solution of acetamidrazone hydrochloride (1.1 g, 10.0 mmol) in dry methanol (30 ml) containing pyridine (0.8 ml, 10.0 mmol). The mixture was stirred overnight at room temperature and then heated under reflux for 1 h. The reaction was concentrated in vacuo, and the residue was treated at ice temperature with a saturated solution of potassium carbonate (25 ml). After extraction with chloroform (3×25 ml) the combined organic layers were dried over sodium sulphate and concentrated in vacuo. The resulting crude product was purified on a neutral alumina column using 1% ethanol in chloroform as eluant to give the title compound (E3) as an oil (0.63 g, 33%) which was converted into the hydrochloride salt m.p. 222° C. (dec) (from methanol-ether) . Hydrochloride salt:
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[C:46]2[O:45][C:44]([C:47](=O)[CH3:48])=[CH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:47]([C:44]2[O:45][C:46]4[C:38]([OH:37])=[CH:39][CH:40]=[CH:41][C:42]=4[CH:43]=2)[CH:48]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc2cccc(O)c2o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc5cccc(O)c5o4)ccc3c1)n2C1CCCCC1
Yield: 20 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(7-hydroxy-benzofuran-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 20% yield). MS: 504.22 (M+H+); HPLC Procedure A, retention time=12.20 min.