Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37](=[O:41])[C:38]([OH:40])=[O:39])([O-:29])=[O:28].C(N(CC)CC)C.C(O)=O>C(N(CC)CC)C.CO>[OH:41][C@H:37]([CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N+:27]([O-:29])=[O:28])[C:38]([OH:40])=[O:39]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 133.2 %

Procedure:
Into 120 ml of methanol were dissolved 293 mg (0.5 mmol) of [RuCl2(p-cymene)]2 and 360 mg (1.0 mmol) of (1R,2R)—N-tosyl-diphenylethylenediamine (hereinafter referred to as (R,R)-TsDPEN) to prepare a solution, and 0.27 ml (2.0 mmol) of triethylamine was dropwise added to the solution, followed by stirring for 0.5 hour at room temperature. To the reaction solution was dropwise added a solution prepared by dissolving 20 g (96 mmol) of o-nitrophenyl pyruvic acid into 80 ml of methanol, and 38.7 g (383 mmol) of triethylamine was furthermore dropwise added thereto. The bath was heated up to a temperature of 40° C., and then 13.2 g (278 mmol) of formic acid was dropwise added over 1 hour, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 40 ml of water, and then 22.6 g of concentrated hydrochloric acid was gradually dropwise added under ice cooling; thus, pH of the solution was adjusted to 2. Extraction was performed twice with 200 ml of ethyl acetate, and then the organic layer was washed with 20 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 27.0 g (yield 97%, 97% ee) of (2R)-hydroxy-3-(o-nitrophenyl)propanoic acid was obtained.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].C(OCC)(=O)C>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CO)co2)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (4.95 g, 11.3 mmol) (obtained as described in Reference Example 70(8)) in anhydrous tetrahydrofuran (100 ml) was added dropwise a suspension of lithium aluminium hydride (1.29 g, 33.9 mmol) in anhydrous tetrahydrofuran (250 ml) in an ice bath under an atmosphere of nitrogen and the mixture was stirred in an ice bath for 5 minutes. After checking the completion of the reaction, magnesium sulfate decahydrate was gradually added to the reaction mixture in an ice bath. After termination of foaming, the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate was gradually added to the reaction mixture. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-oxazol-2-yl)azetidine (3.88 g, yield 84%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
5-Methoxy-1H-indole (5.6 g, 21.5 mmol) was reacted with 1.0 g (25 mmol) of 60% sodium hydride and then 3.0 mL (25 mmol) of benzyl bromide by the method described in Example 12, Part D to give crude 5-methoxy-1-(phenylmethyl)-1H-indole. This material was dissolved in 250 mL of methylene chloride, cooled to -5° C., 50 mL of 1M BBr3 /CH2Cl2 added, the cooling bath removed and the mixture stirred for 1.75 hours. Ice water was added and the mixture stirred. The organic layer was separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% ether/hexane→ether to give 870 mg (19% overall yield) of crude 5-hydroxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:12][C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1)#[N:2].Cl.NC1C2CCCCC=2C(C#N)=CC=1.[OH:30][C@H:31]1[C@@H]2[N:34]([C:35](=[O:52])N(C3C4CCCCC=4C(C#N)=CC=3)C2=O)[CH2:33][CH2:32]1>>[OH:30][C@H:31]1[C@@H:14]2[N:34]([C:35](=[O:52])[N:12]([C:6]3[C:7]4[CH2:8][CH2:9][O:10][C:11]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:33][CH2:32]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: CC(=O)Nc1ccc(C#N)c2c1CCO2
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1OCC2

Procedure:
The title compound as a white solid was prepared from compound 4B by procedures analogous to those described in Example 2 (from 2D to 2F). HPLC: 100% at 3.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4). Flow rate at 2.5 mL/min. UV detection at 220 nm.). Chiral HPLC: retention time=13.69 min (100%); Conditions: OD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min. MS (ES) m/z 300 [M+1]+.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[Cl-].[Na+]>CCCCCC.CN(C)C=O>[Cl:11][C:9]1[CH:8]=[C:7]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:4][CH2:5][N:6]2[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cn1CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)C1CCn2cc(Cl)cc21
Reaction time: 2 h

Procedure:
In an atmosphere of argon, 2.52 g of 50% sodium hydride in mineral oil (0.053 moles) is washed free of the carrier with dry hexane (2×20 ml.). Thereafter 150 ml of anhydrous dimethylformamide is added and the mixture is cooled to 0°. To this mixture is added, with stirring, 16.4 g. of methyl 1-(2-iodoethyl)-4-chloropyrrol-2-acetate (0.05 moles) dissolved in 50 ml dimethylformamide. The reaction mixture is left at room temperature for 2 hours, when saturated aqueous sodium chloride solution is added and the product extracted into benzene (3×200 ml). The organic extract is washed with water (2×100 ml), dried over sodium sulphate and evaporated in vacuo. The crude product (8.52 g) is purified by column chromatography on silica gel (245 g) using hexane-ethyl acetate (90:10) as the eluting solvent, to yield methyl 6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, an oil having the following physical constants:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[C:8]2=[O:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17]([Cl:24])=[O:18])[C:8]2=[O:20])[CH:3]=1
Reactant: Cc1cc(-n2c(=O)c(C(=O)O)cc3cccnc32)no1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-n2c(=O)c(C(=O)Cl)cc3cccnc32)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g (6.3 mmol) of 1-(5-methyl-3-isoxazolyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 3.0 mL (36 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(5-methyl-3-isoxazolyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (50 mL), and 0.77 g (6.9 mmol) of 1,3-cyclohexanedione and 1.1 mL (7.5 mmol) of triethylamine were added to the above solution under ice cooling. The mixture was stirred for 30 minutes under ice cooling. 0.97 mL (6.9 mmol) of triethylamine and 0.59 g (6.9 mmol) of acetone cyanohydrin were added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:1 to 9:1), and thus 0.27 g (yield: 12%) of the title compound was obtained as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Clc1ncccn1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)n(-c2ncccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NaH (0.594 g, 14.84 mmol) was suspended in THF (10 mL), and 3,5-dimethylpyrazole (1.091 g, 11.35 mmol) was slowly added and stirred for one hour at room temperature. 2-Chloropyrimidine (1 g, 8.73 mmol) was slowly added to the mixture and refluxed for three hours. Completion of the reaction was confirmed by TLC, and then water (5 mL) was added to the mixture. The solvent was distilled off and the residue was extracted with ethyl acetate twice. The organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate) to give 1.05 g of the title compound (yield 69%).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C=O.CN(C)C(=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(F)F)cn4n3)ccc2C)n(C)n1
Yield: 72.7 %

Procedure:
In the same manner as in Example 259 and using 2,2-difluorocyclopropanecarboxylic acid (88 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (74 μL, 0.86 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (250 mg, 0.60 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (210 mg, 73%) was obtained as a white solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(OCC)(=O)C>O1CCCC1>[C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=[S:26])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=S)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
A solution of Example 120A (0.5 g, 2.2 mmol) in tetrahydrofuran (10 mL) was added Lawesson's reagent (0.53 g, 1.3 mmol). After stirring at room temperature for 5 hours, the reaction mixture was poured into ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Analogix® Intelliflash280™, SiO2, 0-100% of ethyl acetate in hexanes) to obtain 0.33 g of the title compound. MS (ESI+) M/Z 245 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:37]4[CH2:40][CH:39]([F:41])[CH2:38]4)[N:20]=3)[C@H:13]2[CH3:42])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:51]1(B(O)O)[CH2:53][CH2:52]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:51]1([C:2]2[CH:3]=[C:4]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]4[C:24]([C:25]5[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([F:34])=[CH:27][C:26]=5[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:37]5[CH2:38][CH:39]([F:41])[CH2:40]5)[N:20]=4)[C@H:13]3[CH3:42])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[CH2:53][CH2:52]1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C3CC3)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 140 °C
Yield: 46.8 %

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (0.031 g, 0.047 mmol) in dioxane (0.5 mL) was added tripotassium phosphate (0.071 mL, 0.142 mmol), cyclopropylboronic acid (6.10 mg, 0.071 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.47 mg, 4.74 μmol). The system was flushed with nitrogen and was sealed before heating at 140° C. by microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc, washed with sat. aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered, concentrated and the crude was purified by column chromatography to yield (4S,5R)-5-[3-cyclopropyl-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (13.3 mg, 0.022 mmol) as white solid. LCMS calc.=617.3. found=617.5.1H NMR (CDCl3, 500 MHz) δ 8.15 (s, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.69 (d, J=12 Hz, 1H), 5.54˜5.33 (br m, 2H), 4.74 (d, J=17 Hz, 1H), 4.50 (m, 2H), 4.33 (m, 3H), 4.16˜4.15 (br m, 1H), 3.97˜3.94 (br m, 1H), 3.79 (s, 3H), 3.25˜3.19 (m, 1H), 1.31˜1.26 (m, 6H), 1.07 (m, 2H), 0.76 (m, 2H), 0.69 (m, 3H). RTA=98 nM.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6](C(O)=O)[C:5]=1[CH3:15])([O-:3])=[O:2].Cl.[CH2:17]([OH:19])[CH3:18].C([OH:22])C>>[N+:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([C:11]([O:19][CH2:17][CH3:18])=[O:22])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1

Procedure:
To a solution of 4-nitromesitylenecarboxylic acid (13 g) in ethanol (50 ml) was added a solution of 28% hydrochloric acid-ethanol (50 ml) and the mixture was refluxed under heating for 2 hr. There action mixture was concentrated and ethyl acetate was added. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give the title compound (7.7 g) as pale-brown crystals.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.CN(C)C=O>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([S:7][CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:6]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CSc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 4-biphenylthiol (2.79 g., 0.015 mole) in dry tetrahydrofuran (30 ml) and dimethylformamide (6 ml) was added portionwise sodium hydride (0.37 g., 0.015 mole) with stirring under a nitrogen atmosphere. The resulting solution was added dropwise over 45 min. to ethyl bromopyruvate (3.0 g, 0.015 mole) in dry tetrahydrofuran (30 ml) with stirring under nitrogen at -7° to -10° C. After 1 hr. at 25° C. ice-water (250 ml) was added. Extraction with methylene chloride (3×50 ml) followed by evaporation of the extract, and recrystallization of the residue from carbon tetrachloride gave 1.56 g (35%) of ethyl 3-(4-biphenylylthio)-2-oxopropionate, m.p. 154.5°-156° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[CH2:13]([O:20][C:21]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48]Br)=[CH:42][C:22]=1[C:23]([NH:25][C:26]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:20][C:21]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][N:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:42][C:22]=1[C:23]([NH:25][C:26]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCSCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.0 g) and thiomorpholine (1.1 mL) were added to an acetone (20 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (2.0 g), followed by heating to reflux for 4 hours. The reaction mixture was cooled to room temperature, and thiomorpholine (0.55 mL) was added thereto, followed by heating to reflux for 2 hours and 30 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-40% hexane/ethyl acetate] to obtain 1.9 g of methyl 2-(2-(benzyloxy)-5-(2-(thiomorpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O>[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(C)cc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C#N)cc(CBr)c1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a stirred solution of carbon tetrachloride (270 mL), was added 3,5-dimethylbenzonitrile (37 g, 0.282M), N-bromo succinimide (NBS) (50 g, 0.282 M), and benzoyl peroxide (3.4 g, 14 mmol). The mixture was then refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered, evaporated, and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:10)) to give 48 g (81%) of 3-(bromomethyl)-5-methylbenzonitrile as a white solid. m.p. 80-81° C. 1H NMR (200 MHz, CDCl3) δ 2.39 (3H, s), 4.43 (2H, s), 7.39 (1H, s), 7.43 (1H, s), 7.48 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[N:6]=[C:5]([C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH:4]=1.[Cl-].[NH+]1C=CC=CC=1>O>[CH3:23][C:21]1[N:22]=[C:18]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=3)[N:6]=2)[S:19][CH:20]=1
Reactant: COc1cc(-c2nc(C)cs2)nc(-c2nc(C(F)(F)F)cs2)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: Cc1csc(-c2cc(O)cc(-c3nc(C(F)(F)F)cs3)n2)n1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of compound 22 (1.68 mmol) and pyridinium chloride (5 g/mmol) was heated at 200° C. with stirring. After 30 min, the reaction mixture was cooled down to room temperature and H2O was added. The solid was collected, washed with H2O, and dried to give compound 23 as a grey solid in 72% yield. MS (ESI, EI+): m/z=343.85 (MH+
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(O)C>[N:14]1[CH:15]=[CH:16][C:11]([C:3]2[NH:4][C:5]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:2]=2[C:25]2[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:13]=1
Reactant: Brc1c(-c2ccncc2)[nH]c2cccnc12
Reactant: Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2c(-c3ccncc3)[nH]c3cccnc23)c1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 52.6 %

Procedure:
To a solution of 274 mg (1 mmole) of 3-Bromo-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine in 1.8 mL of toluene under nitrogen is added a 0.6 mL of a 2N solution of sodium carbonate, 170 mg (1.25 mmole) of m-tolylboronic acid and 1.2 mL of ethanol. To the reaction mixture is finally added 45 mg of tetrakistriphenylphosphine palladium. The reaction mixture is sealed in a microwave vessel and stirred under microwave conditions at 180° C. for 2 min. The cooled reaction mixture is then poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into hexane to afford 150 mg of 2-Pyridin-4-yl-3-m-tolyl-1H-pyrrolo[3,2-b]pyridine as white crystals.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CCO>[CH3:7][C:2]([NH:1][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(N)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CC(=O)O)Nc1ccccc1[N+](=O)[O-]
Yield: 78.5 %

Procedure:
A round bottomed flask was charged with 3-amino-3-methylbutanoic acid (1.452 g, 12.39 mmol), potassium carbonate (2.57 g, 18.59 mmol), and a stirbar. EtOH (20 mL, 0.5 M) was added, followed by 1-fluoro-2-nitrobenzene (2.84 ml, 15.49 mmol), and the solution was stirred at reflux overnight. The mixture was cooled, concentrated with celite, and purified by silica gel chromatography (eluting with methylene chloride/methanol/ammonium hydroxide) to yield 3-methyl-3-(2-nitrophenylamino)butanoic acid as a red solid (2.32 g, 9.73 mmol, 79%).