Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43]O.O>CN(C=O)C>[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: CN(C)C(=O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid (0.15 g, 0.42 mmol) [See Ex. 9 above] in DMF(10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at rt, N,N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3 h at rt. The reaction mixture was poured into H2O extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solvent gradient of 2% MeOH/CHCl3 to afford the title compound: CIMS (NH3,m/z): 445 (M++H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH:10]=[O:11].O>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of sodium borohydride (322 mg, 8.5 mmol) in anhydrous methanol (10 mL) was added a solution of 3,5-dichloropyridine-4-carbaldehyde (1.0 g, 5.7 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3,5-dichloropyridin-4-yl)methanol was obtained (940 mg, 93% yield) and used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 2.23 (t, J=7.1 Hz, 1H), 4.94 (d, J=7.1 Hz, 2H), 8.52 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:11](O)=[O:12].O>CN(C)C=O>[OH:17][CH2:16][CH2:15][CH2:14][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: Nc1ccccc1S
Reactant: O=C(O)C(Br)CCCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2SC1CCCO
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 6.26 g of 2-aminothiophenol in 50 ml of dimethylformamide was added 9.85 g of 2-bromo 5-hydroxyvaleric acid. The mixture was stirred at room temperature for 2 hours and at 100° C. for 1 hour. The reaction solution was cooled, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure. The concentrate was subjected to a column chromatography on silica-gel (200 g). From the eluate with hexane-acetone (2:1, v/v) was obtained 3.7 g (31.6%) of 2-(3-hydroxypropyl)-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate-hexane gave prisms, m.p. 59°-60° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:1][CH:2]1[C:3](=[O:29])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=2[NH:7][C:8]1=[O:9]
Reactant: COc1ccc(CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a stirred solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione (0.50 g) in acetonitrile/H2O (9:1, 12 ml) at ambient temperature was added cerric ammonium nitrate (1.84 g) portionwise over a ten minute period. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resultant solid partitioned between saturated aqueous potassium carbonate (40 ml) and ethanol (60 ml). The phases were separated and the aqueous phase extracted with ethanol (4×50 ml). The ethanol portions were combined, dried over sodium sulfate and concentrated in vacuo to a tan solid. This solid was extracted exhaustively with boiling CH2Cl2 (10×60 ml), the organics combined, dried over sodium sulfate, filtered and concentrated to give the title compound (0.30 g) as a tan solid. 1H (300 MHz, DMSO-d6): d 1.98 (br s, 2H), 4.08 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.11-7.46 (m, 8H), 10.78 (br s, 1H); 13C (75.429 MHz, DMSO-d6): d 56.98, 123.41, 126.22, 126.51, 127.34, 128.30, 128.89, 130.15, 132.29, 134.42, 142.36, 168.13, 169.39. MS (FAB): m/z=268.10 (MH+); TLC (CH2Cl2 /CH3OH,15:1): Rf =0.21
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)CC(=O)CCl
Product: Cc1cn2c(=O)cc(CCl)nc2s1
Yield: 63.9 %

Procedure:
This compound was synthesized from 2-amino-5-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 6.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.58 (s, 2H), 6.39 (s, 1H), 7.87 (s, 1H); ESI-MS (m/z) 215.37 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[NH4+:18].[Cl-]>CN(C=O)C>[CH3:9][CH:14]1[CH2:13][CH2:12][N:18]([CH2:4][CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[C:15]1=[O:16]
Reactant: [NH4+]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1=O
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To an ice-cold solution of NaH (0.505 g, 12.6 mmol) in DMF (20 mL) 5-methyl-pyrrolidin-2-one (1.0 g, 10.1 mmol) in DMF (10.0 mL) was added slowly. This was stirred for 30 min at 0-25° C. 2-(3-Bromo-propyl)-isoindole-1,3-dione (2.47 g, 9.0 mmol) was added and the reaction was stirred at room temperature for 16 h. A solution of saturated NH4Cl (10.0 mL) was added and extracted with ethyl acetate. Organic layer was washed with LiCl solution and concentrated. The crude was purified on silica gel using CH2Cl2/MeOH (10%) as eluent to give 2-[3-(3-methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (1.2 g, 41%).
Reaction SMILES: ClC1C=CC([N+:8]([O-:10])=[O:9])=CC=1C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:8]([O-:10])=[O:9])[C:14]=1[CH3:19]
Reactant: Cc1ccccc1Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Product: Cc1c(Cl)cccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
2-Chloro-5-nitrotoluene, which is required as a starting product, is accessible by nitrating o-chlorotoluene (Rec. Trav. Chim. Pays-Bas 32, (1913) 244 et seq.). It can be isolated from the resulting mixture of isomers by distillation in 43% yield (Loc. cit. 286). This distillation gives pure 2-chloro-6-nitrotoluene as first runnings the other isomers can be separated in a known way. Since all isomers, by virtue of their reactive groups, are intermediates which can be put to many uses and for which there is adequate demand, no undesirable by-products are obtained in this reaction. Thus, even if this preliminary stage is included, this invention represents a very favorable procedure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[CH:10](O)=[O:11]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[O:11])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=CO
Product: O=CNc1ccc(Br)c(Cl)c1

Procedure:
A mixture of 60.7 g of 4-bromo-3-chloroaniline and 300 ml of 97% formic acid was refluxed for four hours. The resulting mixture was poured over ice and filtered. The solid was washed with water and recrystallized from 3/1 v/v ether/hexane to give N-(4-bromo-3-chlorophenyl)formamide (4A), as a tan solid, mp: 110°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][O:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(O)cc(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)cc(OCCBr)c1

Procedure:
Preparation according to Preparation 2: 3-chloro-5-methylsulfonyl-phenol (2.8 g, 13.5 mmol), 1.2-dibromoethane (12 ml, 135 mmol), potassium carbonate (3.7 g, 27.1 mmol), acetonitrile (15 ml) Yield: 2.1 g, 50%). MS m/z (relative intensity, 70 eV 314 (M+, 35), 312 (M+, 25), 206 (7), 126 (9), 109 (98), 107 (bp).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH3:17])=[O:13])=[N:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1>[Br:1][C:2]1[C:7]([C:8](=[S:27])[NH2:10])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH3:17])=[O:13])=[N:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A suspended mixture of 5-bromo-2-(3-propylureido)isonicotinamide (Intermediate 43, 123 g, 407 mmol), Lawesson's Reagent (131.6 g, 326 mmol), and tetrahydrofuran (1.55 L) was stirred at 70° C. for 18 h. Stirring was stopped and a bright yellow precipitate was allowed to settle. The precipitate was then vacuum filtered and washed with methyl tert-butyl ether (2×500 L). This solid was then dried in the vacuum oven at 50° C. for 12 hours to give 50 g of product solid. The mother liquor was concentrated and the residue was suspended in toluene (300 mL). The solid thus obtained was filtered and combined with the previous solid. The combined totaled 110 g (85%) of 5-bromo-2-(3-propylureido)pyridine -4-carbothioamide as an off white solid
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH2:29]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH:29][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: NCCCc1ccc(F)cc1F
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4F)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(2,4-difluorophenyl)-1-propylamine, using the method given in Example 1, gave (a) 6-{trans-4-[3-(2,4-difluorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one and (0.75 g, 37%), isolated as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.84 (br s, 2H), 7.40 (ddd, J=9, 9, 7 Hz, 1H), 7.22-7.18 (m, 2H), 7.05 (ddd, J=8, 8, 2 Hz, 1H), 7.01 (dd, J=8, 1 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 3.11-3.02 (m, 1H), 2.98-2.92 (m, 2H), 2.70 (t, J=8 Hz, 2H), 2.56-2.49 (m, 1H), 2.18-2.11 (m, 2H), 1.96-1.86 (m, 4H), 1.51 (m, 4H), and
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1.[O:29]([C:31]#[N:32])[Na]>O.CCO>[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:31]([NH2:32])=[O:29])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:26])[F:27])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCN)cc2)cc1
Reactant: N#CO[Na]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reaction time: 5 h
Yield: 53.8 %

Procedure:
To a suspension of (2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride (7.5 g) in H2O (150 ml) and EtOH (75 ml) was added NaOCN (2.27 g) at room temperature. pH was adjusted to 6.3 with 1NHCl . The mixture was stirred for 5 hours under the condition of pH 6.0–7.0. The reaction mixture was extracted with EtOAc and washed with dil. NaCl (twice), dried over MgSO4, filtered and evaporated. The residue was column chromatographed on silica gel (CH2Cl2/MeOH) and evaporated. The residue was crytalized from IPE/EtOH. Recrystalized from EtOH/H2O (50 ml–50 ml Final) and dried to give 4.10 g (54%) of N-(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:44])[CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)[C:13]2=[O:45])=[CH:4][CH:3]=1.[Si:46](Cl)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CN=C1>>[Si:46]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:44])[CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)[C:13]2=[O:45])=[CH:4][CH:3]=1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N[C@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=O)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-N-[1-(7-hydroxynaphthalen-1-yl)-2-oxopyrrolidin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step C, (6.50 g, 11.0 mmol), tert-butyldiphenylsilyl chloride (4.55 g, 16.6 mol), and imidazole (1.87 g, 27.5 mol) in dry, degassed DMF (100 mL) was stirred, under argon, at 50° C. for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (125 mL). The aqueous layer was extracted further with CH2Cl2 (125 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—1% MeOH—0.1% NH4OH to yield the desired product as a pale solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Reaction time: 72 h
Yield: 90.9 %

Procedure:
Lit. J. Org. Chem., 44:975 (1979). To a stirred solution of 5.0 g (45.0 mmol) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol) triethylamine in 100 ml DMF was added dropwise 26 ml (225 mmol) benzyl bromide and stirring continued for 72 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed twice with saturated sodium bicarbonate solution and twice with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (25% EtOAc in hexane) afforded 8.23 g (90%) of the title compound as a yellow oil. MS m/e (%): 201 (M+, 33), 94 ([M−OBn]+, 22), 91 (Bn+, 100).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Yield: 76.8 %

Procedure:
The hydrolysis procedure described for 191 was followed. A solution of ethyl({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate (220) (0.280 g, 0.66 mmol) in THF/EtOH (1:1, 10 mL) was treated with 1 N NaOH (5 ml, excess) at 70° C. for 1 h. Acid work-up and purification afforded 0.20 g (77%) of the title compound 221. mp 163-164° C. 1H NMR (300 MHz, CD3OD): δ 7.05 (d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 4.46 (s, 2H), 2.99 (d, J=4.8 Hz, 4H), 1.30 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 393 (M−H)−.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:21]1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: OB(O)c1ccsc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccsc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 2 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and thiophene-3-boronic acid. The title compound (118 mg) was obtained as a pale solid, m/z 347 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([NH:30][C:31]([NH2:33])=[O:32])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:28][C:27]3[C:22]([CH3:21])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:30][C:31]([NH2:33])=[O:32])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH2:12][C:13]#[CH:14]
Reactant: C#CCc1c(C)nc2c(O)cccn12
Reactant: Cc1cccc(NC(N)=O)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(N)=O)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl) imidazo-[1,2-a]pyridine (0.571 g) and potassium carbonate (0.424 g) in N,N-dimethylformamide (11.5 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 6-methyl-2-ureidobenzyl chloride (0.6 g) was added. After being stirred for 2.5 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (25 g) with a mixture of chloroform and methanol (100:1 to 100:4) as eluents to give 2-methyl-8-(6-methyl-2-ureidobenzyloxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>CS(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:30])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CN3CCOCC3)cc2c1O
Agent: [Li+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-cinnolinecarboxamide [Preparation 12] (200 mg) in dry DMSO (15 mL) is added lithium bis(trimethylsilyl)amide (0.51 mL of a 1 M solution in hexanes). The mixture is stirred for 15 min over which time everything dissolves. Methyl iodide (0.032 mL) is then added and the reaction is stirred for an additional 2 h. The mixture is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (gradient CH2Cl2, 1% MeOH/CH2Cl2, 2% MeOH/CH2Cl2, 3% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The residue from the column is dissolved in CH2Cl2. Hexanes are added to precipitate the product. The resulting solid is collected and dried to yield 0.079 g (39%) of the title compound as a white solid. Physical characteristics are the same as reported above.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[Se:9][C:5]=2[C:4](=[O:14])[NH:3][N:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:15][N:3]1[C:4](=[O:14])[C:5]2[Se:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:1]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nnc2c1[se]c1ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2c([se]c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3H-benzo[b]1,2,3-triazino[4,5-d]selenophen-4-one (200 mg, 0.8 mmol) in acetone (50 mL) was added sequentially potassium carbonate (400 mg, 1.6 mmol), iodomethane (0.1 mL, 0.9 mmol) and a catalytic amount of PEG-400 was added at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using hexane-chloroform (70:30) as eluents to give the product as a off-white solid (120 mg, 47%), mp 190-192° C. IR (neat) νmax 3431, 1673, 1220, 1021 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56-8.58 (1H, m, H-9), 7.98-8.01 (1H, m, H-6), 7.58-7.66 (2H, m, H-7,8), 4.13 (3H, s, —NCH3); 13C NMR (100 MHz, CDCl3): δ 155.5, 152.8, 142.3, 135.3, 130.4, 129.8, 126.4, 126.2, 126.0, 37.8; LC-MS (positive ion mode): m/z 286, 288 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nnn1-c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCn1nnn(-c2ccc(Br)cc2)c1=O

Procedure:
Compound 53a was treated with SEMCl as described in Example 51, Step C to obtain compound 53b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C13H19BrN4O2Si: 371.0 (M+H). Found 371.1.