Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[O:20])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (0.895 g) was added to a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine (0.993 g) and pyridine (0.6 g) in methylene chloride (10 ml) and stirred at 4° C. for 16 hours under an atmosphere of nitrogen. The reaction mixture was washed with aqueous citric acid (1.0 M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine as a yellow gum (0.685 g); 1H NMR Spectrum: (DMSO d6) 1.30-1.36 (s, 9H), 1.98-2.07 (m, 1H); 2.37-2.48 (m, 1H); 2.83 (s, 3H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 4.70 (m, 1H), 5.23 (m, 1H), 8.21 (d, 2H), 8.47 (d, 2H).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:23])=[CH:20][CH:19]=1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a suspension of 508 mg of 4-carbamoylimidazolium-5-olate and 486 mg of triethylamine in 6 ml of anhydrous dimethylformamide was added 770 mg of p-chlorobenzoyl chloride in 3 ml of anhydrous dimethylformamide at a temperature below 5° C. The mixture was stirred under ice cooling for 4 hours. The insoluble crystals were filtered off, then the filtrate were concentrated to a residue under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-carbamoyl-1H-imidazol-4-yl p-chlorobenzoate. The crude solid was washed with ethyl acetate to give 340 mg of pure product, m.p. 220° C. (charred).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:43]=[CH:42][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:28]([C:37](OCC)=[O:38])=[CH:27]2)=[CH:23][CH:22]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:28]([CH2:37][OH:38])=[CH:27]2)=[CH:42][CH:43]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccn3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Lithium aluminium hydride (0.25 g) was added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)pyrrole-3-carboxylate (2.40 g) in tetrahydrofuran (30 ml) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. After sodium sulfate decahydrate (2.13 g) and hexane (30 ml) were added to the reaction mixture, the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]methanol (2.09 g, yield: 95%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][CH:18]1[CH2:17][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:6][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=4)=[O:49])[CH2:8]3)[O:10][CH:11]=2)=[O:15])[CH2:19]1
Reactant: COC1CN(C(=O)c2coc(N3CC(SC(C)=O)C3)n2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC1CN(C(=O)c2coc(N3CC(SC4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)C3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 3-acetylthio-1-(4-(3-methoxyazetidine-I-carbonyl)-1,3-oxazol-2-yl)azetidine (330 mg, 1.06 mmol) (obtained as described in Reference Example 73) in dimethylformamide (17 ml) was added hydrazine acetate (117 mg, 1.27 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (630 mg, 1.06 mmol) in acetonitrile (32 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (739 μl, 4.24 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate:methanol (95:5→9:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (550 mg, yield 85%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([NH2:13])=[N:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[C:10](=[NH:11])[NH2:13])[CH3:2]
Reactant: CCOc1cccc2onc(N)c12
Agent: [Pd]
Solvent: CO
Product: CCOc1cccc(O)c1C(=N)N
Reaction time: 16 h

Procedure:
3.65 g [20.48 mmol] of 4-ethoxy-3-amino-1,2-benzisoxazole are hydrogenated in 40 ml of methanol and in the presence of 0.39 g of palladium (loading: 10, support: activated carbon) at room temperature and pressure 1 bar for 16 hours, analogously to the method from WO 2007/030582. The reaction mixture is filtered through silica gel, and rinsed through repeatedly with methanol. The combined filtrates are concentrated under reduced pressure. This leaves 1.9 g of product as a beige solid; the purity according to LC-MS is 100%.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1SC=CN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: NCCSCc1nccs1
Reactant: CSC(=NCCSCc1nccs1)NC#N
Agent: CCN
Product: CCNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 2-[(2-aminoethyl)thiomethyl]thiazole by the procedure of Example 3(c)(i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO>[NH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: NN
Solvent: CO
Product: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To a suspension of 2-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]-1H-isoindole-1,3(2H)-dione (20.0 g, 44.0 mmol) in methanol (400 mL) was added hydrazine (8.00 mL). The mixture was stirred at ambient temperature for 48 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with ethyl acetate/methanol/ammonia (10/1/0.2) to afford the crude product which was recrystalized from ethyl acetate to yield the title compound (8.0 g) in 56% yield as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 1H), 7.17 (dd, 1H), 7.06 (dd, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 5.89-5.82-(ABq, 2H), 4.93 (d, 1H), 4.66 (d, 1H), 3.95-3.74-(m, 2H), 3.06 (t, 2H), 1.59-1.35-(br, 2H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.9, 148.8, 142.3, 132.4, 128.9, 124.0, 123.4, 119.5, 108.6, 103.1, 101.5, 93.6, 80.5, 58.2, 43.4, 39.8; MS (ES+) m/z 325 (M+1), 308 (M−16).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Brc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc2c(Br)cccc2c1
Yield: 4.2 %

Procedure:
1-bromonaphthalene (0.42 g), acryloyl chloride (0.31 g), and aluminium chloride (0.27 g) were treated in the same manner as described in Example 1 to obtain the title compound (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:9]([O-])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[SH-].C(O)C>O.C1(C)C=CC=CC=1>[NH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccnc1N
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 70.4 %

Procedure:
Then, a reaction flask was loaded with this 3-methoxy-2-nitropyridine (9.0 g), sodium sulfide enneahydrate (64 g), ethanol (93 ml) and water (46 ml) and they were mixed, followed by stirring at 70° C. for 2.5 hours. Then, the mixture was cooled to room temperature. To this, toluene and water were added, followed by stirring. The organic layer was collected and washed with a saline solution, and then dried with sodium sulfate. This was filtrated and the filtrate was condensed to give 2-amino-3-methoxypyridine (5.1 g).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([CH2:21][C:22]#[N:23])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.O=[Pt]=O>[NH2:23][CH2:22][CH2:21][C:19]1[N:18]=[CH:17][N:16]([C:13]2[N:12]=[CH:11][C:10]3[N:9]([CH3:24])[C:8](=[O:25])[C@@H:7]([CH2:26][CH3:27])[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:15]=3[N:14]=2)[CH:20]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(CC#N)c3)nc2N1C1CCCC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(CCN)c3)nc2N1C1CCCC1
Reaction time: 18 h
Yield: 42.2 %

Procedure:
(R)-2-(1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazol-4-yl)acetonitrile (Example 35, 0.08 g, 0.218 mmol) and PtO2 (40 mg) were suspended in 2 mL of EtOAc and the resulting mixture was stirred under an atmosphere of hydrogen (1 atm, balloon) for 18 h. The resulting solution was filtered through Celite, concentrated, then purified by preparative HPLC to give the title compound (34 mg). LCMS: 370.1 m/z (M+H)+; ret. Time: 4.09 (Analytical Method C).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1.CCOC(C)=O.[NH4+:19].[OH-]>CO>[NH2:19][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1
Reactant: [NH4+]
Reactant: Cc1nc2ccc(CO)cc2[nH]1
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(CN)cc2[nH]1

Procedure:
The title compound was prepared from 5-(hydroxymethyl)-2-methylbenzimidazole: Rf (8:1:1 EtOAc:MeOH:NH4OH)=0.15. 1H NMR (300 MHz, CD3OD): δ7.45 (m, 2H), 7.20 (d, J=8.1 Hz, 1H), 3.90 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]([Mg]Br)([CH3:20])=[CH2:19]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:18]([CH3:20])=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (793 mg) in THF (5 mL) at −78° C. was added isopropenyl magnesium bromide (12.3 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 5 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orange gum. The orange gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a peach-colored solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[S:12][C:11]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>O>[N:1]1([CH2:6][CH2:7][C:8]2[S:12][C:11]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(CCn2ccnc2)s1
Solvent: O
Product: O=C1CCC(c2ccc(CCn3ccnc3)s2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4.2 g of 4-{5-[2-(1-imidazolyl)-ethyl]-thien-2-yl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.8 g of hydrazine hydrate are added and the mixture is stirred at 90° C. for 2 hours. After the mixture has been cooled, it is extracted with chloroform. The chloroform phase is washed with water, dried over Na2SO4 and concentrated to dryness.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].[Cl-].[Na+]>O1CCCC1.O>[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:19][CH2:20][C:21](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=C3SCCCS3)CC2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 272 %

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0° C. under an argon atmosphere was added rapidly n-butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78° C. and a solution of 4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p. 115°-116° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[CH2:19][C:20]1[CH:21]=[C:22]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:32]([O:31][C:29]([N:28]=[S:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH:21]=1)([CH3:34])=[O:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CBr)c1
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (65 mg, 0.21 mmol) and (RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (102 mg, 0.27 mmol) are suspended in 14 ml of acetone. After addition of caesium carbonate (2427 mg, 0.74 mmol), the reaction mixture is stirred at reflux for 3 hours. After cooling, the batch is concentrated, the residue is taken up in ethyl acetate, and the organic phase is washed with water and dried over sodium sulphate. After removal of the solvent, the residue (144 mg, 97% of theory) is employed in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][N:9]2[Si:12]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][CH:4]=1.C([Li])(C)(C)C.[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>CCOCC>[Cl:34][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:10]2[C:6]=1[C:7]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][N:9]2[Si:12]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:13]([CH3:14])([CH3:15])[CH3:16])[C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(Cl)c2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
To a stirred solution of (6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethylamine (0.2 g, 0.56 mmol) in anhydrous ether (20 ml) at −78° C. was added tert-butyllithium (43 mg, 0.67 mmol, 1.7M in pentane) dropwise. After being stirred for 20 min, the mixture was allowed to warm to 0° C. and was stirred for one hour. The mixture was then re-cooled to −78° C., and a solution of hexachloroethane (0.2 g, 0.84 mmol) in anhydrous ether (10 ml) was added over 10 min. The reaction mixture was warmed to room temperature and stirring was continued for another 1.5 hour before quenching with saturated ammonium chloride solution. After extracting into ether, the ether extract was dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give (4-Chloro-6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethylamine as an oil (0.217 g, 98.6%). 1H NMR (CDCl3) δ:1.12 (d, 18H, J=7.52 Hz), 1.66 (m, 3H), 2.30 (s, 6H), 3.75 (s, 2H), 3.80 (s, 3H), 6.78 (d, 1H, J=2.2 Hz), 6.88 (d, 1H, J=2.2 Hz), 7.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:16]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Yield: 60 %

Procedure:
2,4 dichloropyrimidine and 3-formyl phenyl boronic acid were coupled following procedure A. The yield was 60%. LC-MS showed the product was >95% pure and had the expected M+H+ of 219. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 610.1 (s, 1H) 8.7 (d, 1H) 8.6 (m, 1H) 8.4 (m, 1H) 8.1 (m, 1H) 7.7 (m, 2H).
Reaction SMILES: O.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([NH:18][C:19](=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])SC)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:26]([O:25][C:23]([NH:22][C:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[N:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: NCc1ccc(O)cc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(=NCc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
4-hydroxybenzylamine hydrate, prepared as above (5.33 g) and N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (10.96 g) were combined in 150 mL THF, and stirred at reflux for 4 hr. The mixture was concentrated, and the crude product chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization from methanol-water provided the title compound as a white solid, mp 187°-189° C. (10 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:21])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:24][N:25]([CH3:26])[CH3:27])[C:14](=[O:20])[CH:13]3[CH3:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (500 mg, 1.52 mmol) in DMF (1 mL,) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.2 min, Method [1], MS(ESI) 356 (M−NMe2+OH+H).