Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccc(Cl)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 3-chloro-N2-phenylbenzene-1,2-diamine (495 mg, 2.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (470 mg, 2.48 mmol), HOAt (338 mg, 2.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (477 mg, 2.48 mmol) and 4-methylmorpholine (0.550 mL, 4.97 mmol) in anhydrous DCM (15 mL) was stirred at RT for 19 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 22 h. After cooling to RT, volatiles were removed in vacuo and the residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as pale yellow oil (quantitative). LCMS: RT 3.83 min [M+H-tBu]+ 316.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=3[F:19])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:19][C:12]1[C:13]([F:18])=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[C:3]2[CH:10]=[N:9]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)c(F)c1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle under N2 was added Intermediate 70A (169.2 mg, 0.451 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (217 mg, 0.855 mmol), potassium acetate (206 mg, 2.099 mmol) and anhydrous DMSO (4.5 mL). The reaction mixture was flushed with argon, then treated with PdCl2(dppf).CH2Cl2 (28.3 mg, 0.039 mmol). The reaction mixture was again flushed with argon, securely capped and heated at 85° C. for 1 h to give complete conversion to the desired product. LC/MS (Condition B): ret. T=3.3 min, (M+H)+ 294.03.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:33]2[N:34]([C:16]3[N:15]=[C:14]4[C:19]([N:20]=[C:12]([CH2:11][N:8]5[CH2:9][CH2:10][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]5)[N:13]4[CH3:28])=[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:17]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: c1ccc2[nH]c(N3CCC3)nc2c1
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCC4)nc4ccccc43)nc21

Procedure:
4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (75 mg) was reacted with 2-(azetidin-1-yl)-1H-benzo[d]imidazole (33 mg) via General Procedure for Buchwald coupling to give 36.1 mg 454 following reverse phase purification. MS (Q1) 545.4 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C.C([O-])(O)=O.[Na+]>[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:15]2[C:14]([F:24])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:8]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:9]=3)[N:16]=2)[CH2:19]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(Cc5ncc[nH]5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.16 g, 0.32 mmol) in 1,2-dichloroethane (2 mL) was added 1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops of acetic acid and Na(OAc)3BH (0.10 g, 0.49 mmol). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled to room temperature and diluted with aqueous saturated NaHCO3 solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH/CH2Cl2) to afford the product, 4a.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1-c1nc2ccccc2s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1-c1nc2ccccc2s1
Temperature: 70 °C

Procedure:
A mixture of 0.65 g (0.00223 mol) of 2-(2′-nitro-5′-chlorophenyl)benzothiazole OF31A and 2.52 g (0.01118 mol) of SnCl2.2H2O in 100 ml of ethanol was heated at 70° C. for 2 hours. A verification step using thin layer chromatography showed that the mixture no longer contained any starting reactant.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:28]=[CH:27][C:26]2[N:25](S(C3C=CC=CC=3)(=O)=O)[C:24]3[CH2:38][CH2:39][N:40]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][C:48]=4[CH3:49])[C:41](=[O:42])[C:23]=3[C:22]=2[CH:21]=1.CO>C1COCC1.C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][C:26]2[NH:25][C:24]3[CH2:38][CH2:39][N:40]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][C:48]=4[CH3:49])[C:41](=[O:42])[C:23]=3[C:22]=2[CH:21]=1
Reactant: Cc1ccncc1N1CCc2c(c3cc(F)ccc3n2S(=O)(=O)c2ccccc2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCc2[nH]c3ccc(F)cc3c2C1=O
Yield: 49.4 %

Procedure:
1M TBAF (0.3 mL, 0.274 mmol) was added to a solution of 8-fluoro-2-(4-methylpyridin-3-yl)-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-60b: 60 mg, 0.137 mmol) in THF (5 mL) at 0° C. and the resulting reaction mass was refluxed for 1 hour. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was concentrated under reduced pressure and the crude residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by preparative HPLC afforded 20 mg of the product (52% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([C:49]1[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=1)=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccncc1)C2=O
Reaction time: 0.17 h
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (74%).
Reaction SMILES: [BrH:1].Br.N1CCNCC1.Br.Br.OC1C=CC(N2CCNCC2)=CC=1.C[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[BrH:1].[BrH:1].[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Agent: Br
Agent: C1CNCCN1
Agent: Oc1ccc(N2CCNCC2)cc1
Product: Oc1ccccc1N1CCNCC1

Procedure:
4-(=- 1)piperazine dihydrobromide may be prepared in the following manner: the experiment is carried out as in Example 8 for the preparation of 4-(4hydroxyphenyl)piperazine dihydrobromide, starting with 4-(2-methoxypheny)piperazine (25 g) and 47% aqueous solution of hydrdromic acid (360 cc). The mixture is heated at boiling point for 9 hours, the cooled to a temperature close to 20° C. Stirring is maintained for 15 hours at this temperature, then the mixture is concentrated at 40° C underreduced pressure (20 mm g; 2.7 kPa). The residual oil is redissolved in acetonitrile (40 cc) and isopropyl oxide (40 cc); the precipitate formed is separated by filtration, washed with oxide (2×50 cc). 4-(2-Hydroxyphenyl)piperazine dihydrobromide (m.p.: 235° C.) (18g) is obtained, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[N:13]=[C:14]2[C:23]=1[C:22]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=1[N:16]=[C:15]2[NH2:24].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl>[NH2:24][C:15]1[C:14]2=[N:13][N:12]([CH3:25])[C:11]([CH2:10][CH2:9][NH:8][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:33])=[C:23]2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc2c(N)nc3c(c2c1CCNC(=O)N1CCOCC1)CCCC3
Temperature: 4 °C

Procedure:
Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 50) (1.0 g, 4.08 mmol) in dichloromethane (50 mL) and cooled to 4° C. 4-Morpholinecarbonyl chloride (0.61 g, 4.08 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed sequentially with water (50 mL), 4% sodium bicarbonate (2×50 mL), water (50 mL), and brine (50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with mixtures of chloroform and CMA). The material was crystallized from acetonitrile to provide N-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]morpholine-4-carboxamide as orange needles, mp 187-188° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([C:15]1[N:19]([CH3:20])[C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:15]1[N:19]([CH3:20])[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)#[N:14]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 25.4 %

Procedure:
4-Bromo-N-methylbenzenesulfonamide (100 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. The reaction mixture was filtered through silica and rinsed with ethyl acetate. The solvent was concentrated in vacuo to provide the crude product. The crude product was pre-adsorbed onto the Celite® reagent and purified via Isco chromatography (the Redisep™ column, silica, gradient 5-50% ethyl acetate in hexane) to afford 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide (28 mg, 25%). MS (ESI) m/z 275. HPLC purity 100.0% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a suspension of 7-hydroxy-1-tetralone (1.0 g, 0.0061 mol) and K2CO3 (5.5 g) in DMF (20 mL) under an argon atmosphere was added benzyl bromide (0.725 mL, 0.0061 mol) at room temperature. The reaction mixture was then stirred at room temperature for 18 h before being poured onto ice. The aqueous solution was extracted with ethyl acetate, washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (15%) as eluent to give compound 7-benzyloxy-1-tetralone (1.395 g, 90%): thick oil, 1H NMR (500 MHz, CDCl3): δ 2.09-2.14 (m, 2H), 2.63 (d, J=6.5 Hz, 2H), 2.90 (d, J=6.0 Hz, 2H), 5.75 (s, 2H), 7.11-7.13 (dd, J=3.0 and 8.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.31-7.45 (m, 5H), 7.62 (d, J=3.0 Hz, 1H). HFABMS m/z 253.1231 (calc for C17H16O2, MH+, 253.1229).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:5]=[N:6][C:7]=1[Cl:8].C([Sn](CCCC)(CCCC)[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>C1(C)C=CC=CC=1>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:22]=[N:27][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CN1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 49.9 %

Procedure:
To the solution of 5-bromo-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)-pyridine (390 mg, 1.27 mmol) in toluene (15 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.57 g, 1.53 mmol). The mixture was stirred and heated under reflux for 6 h. Solvent was evaporated and the residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.3 to 10:1) to afford an oil (193 mg, 50%): 1H NMR (CDCl3, 300 MHz) δ 1.62 (m, 1H), 1.68-1.90 (m, 2H), 2.02 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.12 (m, 1H), 3.98-4.06 (m, 2H), 7.25 (m, 1H), 8.18 (d, 1H, J=3.0 Hz), 8.87 (s, 2H), 9.29 (s, 1H); MS (CI/NH3) m/z 305 (M+H)+.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](C2CCCC(=O)C=2)=[CH:4][CH:3]=1.C[N:20](C=O)C>>[CH:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([NH2:20])[CH:9]=[CH:10][C:11]=2[CH:2]=1
Reactant: Nc1ccc(C2=CC(=O)CCC2)c2ccccc12
Reactant: CN(C)C=O
Product: Nc1ccc2ccccc2c1

Procedure:
To a tube containing a solution of 2.0 g of 1-amino-4-bromonaphthalene (9.0 mmol, 1 equiv.) in 70 mL DMF were added 1.75 mL of 2-cyclohexen-1-one (18.0 mmol, 2.0 equiv.), 2.3 g of sodium bicarbonate (27.0 mmol, 3.0 equiv.) and 186 mg of 1,3-bis-(diphenylphosphino)propane (dppp, 0.45 mmol, 0.05 equiv.). A stream of dry nitrogen gas was bubbled through the mixture for 15 min, then 316 mg of bis-(triphenylphosphino)palladium(II) chloride (0.45 mmol, 0.05 equiv.) was added and the tube was sealed. The mixture was heated at 150° C. for 8 h, then cooled to ambient temperature, diluted with EtOAc (150 mL) and filtered through diatomaceous earth. The mixture was washed with water, then brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude oil was purified by column chromatography on SiO2 using 10 to 50% EtOAc in hexane mixtures as eluents to give 2.0 g of a thick liquid consisting of 3-(4-aminonaphthalen-1-yl)cyclohex-2-enone and DMF (molar ratio 1:2 respectively, 5.22 mmol of naphthylamine, 58% of theoretical yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S)-1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][N:4]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6](/[CH:7]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cn1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(/C=N/[S@](=O)C(C)(C)C)cn1
Temperature: 65 °C

Procedure:
6-Methoxynicotinaldehyde, (a-1), (20.0 g, 146 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide, (a-2), (21.2 g, 175 mmol) were dissolved in chloroform (140 mL) and PPTS (1.8 g, 7.3 mmol), magnesium sulfate (17.6 g, 146 mmol) and copper(II)sulfate (46.6 g, 292 mmol) were added. The mixture was heated to 65° C. overnight. The material was allowed to cool and was filtered through a Solka Floc pad and concentrated under vacuum. The material was purified by flash chromatography on silica gel gradient eluted with 0-40% EtOAc in hexane affording the product (1-A). HPLC/MS: 241.0 (M+1); Rt=2.84 min.
Reaction SMILES: C(C[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:18]([CH2:19][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([OH:21])=[O:20]
Reactant: CC(=O)CCc1ccccc1CCCC#N
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)CCc1ccccc1CCCC(=O)O

Procedure:
A solution of 50 g (0.23 mol) of 4-[2-(3-cyanopropyl)phenyl]-2-butanone, 8 in 125 ml glacial acetic acid and 125 ml concentrated HCl was refluxed overnight. The solution was evaporated and the residue diluted with H2O. The precipitate was recrystallized from benzene-petroleum ether to give 42.5 g of the keto acid 9, mp 59°-61° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](=S)(OC2C=CC(C)=CC=2)=O)=[CH:12][CH:11]=1.Cl>C1COCC1>[OH:7][C:2]1[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[S:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: O=C1CCCCC1=O
Reactant: Cc1ccc(OS(=O)(=S)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(SC2=C(O)C(=O)CCC2)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A 1.0M solution of lithium bis(trimethyl)silylamide in THF (28.7 mL, 28.77 mmol) was added to 30 mL of dry THF stirring under N2, and the solution was cooled to -10° C. A solution of 1.54 g (13.7 mmol) 1,2-cyclohexanedione in 7 mL of THF was added in a slow stream via syringe. The reaction mixture turned darkreddish brown. The reaction mixture was stirred for 15 min at -10° C. and then cooled to -50° C. A solution of 4-methylphenyl 4-methyl-benzenethiosulfonate (3.5 g, 14.2 mmol) in 10 mL of THF at -50° C. was added in one portion via syringe. The reaction mixture was stirred for 2 h at -50° C. and allowed to warm at ambient temperature until approximately 0° C., and then 100 mL of 0.1 N HCl was added. The mixture was extracted with 300 mL and then 100 mL of diethyl ether, and the combined organic extracts were dried over anhydrous sodium sulfate. Concentration in vacuo provided a yellow solid which was purified by flash chromatography over silica gel using CH2Cl2, 10% EtOAc/Hexane, and then 3% MeOH/CH2Cl2 as eluent. The desired product, 2-hydroxy-3-[(4-methylphenyl)thio]-2-cyclohexenone [Compound Iy], was isolated as a white solid (1.939 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[Br:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Br:18][C:19]1[C:24]([C:25]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(O)c1cccnc1Br
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Product: Cc1nc(N2CC3CN(C(=O)c4cccnc4Br)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 1 utilizing Intermediate 42 and 2-bromopyridine-3-carboxylic acid. MS (ESI): mass calculated for C19H22BrN5O, 415.10; m/z found 416.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.44 (dd, J=4.7, 1.6, 1H), 7.33 (dd, J=7.6, 4.7, 1H), 6.38-6.24 (m, 1H), 3.94-3.90 (m, 2H), 3.88-3.84 (m, 1H), 3.74-3.50 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.23 (m, 6H), 2.12-2.06 (m, 3H).