Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].C([Li])CCC.CSC.[C:24]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.N1C=CN=CC1>O1CCCC1>[CH2:11]([O:10][C:7]1[C@@H:8]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24](=[O:31])[CH2:25]2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C@H:5]([CH:13]([CH3:14])[CH3:15])[N:6]=1)[CH3:12]
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1
Reactant: O=C1C=CCCCC1
Agent: C1=CNCC=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC1=N[C@H](C2CCCCC(=O)C2)C(OCC)=N[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of (S)-3,6-diethoxy-2-isopropyl-2,5-dihydro-pyrazine (6.0 g, 28.3 mmol) in tetrahydrofuran (58 mL) is cooled to −78° C. n-butyllithium (1.6 M in hexane, 21.4 mL, 34.2 mmol) is added slowly via syringe, and the reaction is allowed to stir at −78° C. for 30 minutes. The reaction mixture is then transferred via canula to a solution of CuBr-Me2S (3.35 g, 16.3 mmol) in tetrahydrofuran:dimethylsulfide (90 mL, [2:1]) at −50° C. The reaction is warmed to −30° C. and stirred further for 30 minutes. The reaction is then cooled to −78° C. and cyclohept-2-eneone (5.23 mL, 46.9 mmol) is added dropwise over 10 minutes. The reaction is maintained at −78° C. until the disappearance of the dihydropyrazine is confirmed by TLC and quenched by the addition of a saturated aqueous solution of ammonium chloride at −78° C. The reaction is allowed to warm to ambient temperature, diluted with water, and extracted with diethyl ether. The organic extracts were washed with ammonium chloride, dilute ammonium hydroxide, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by column chromatography eluting with a gradient of hexane in ether (20-25%) to afford the title compound (6.52 g, 72% yield), slightly contaminated with cyclohept-2-enone. LCMS (m/z): 323.13 (M+1).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of t-butyl isocyanate (400 mg, 4.04 mmol) in toluene, the 2-amino-5-nitrophenol (622 mg, 4.04 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (864 mg, 85%). m.p: 99.0-101.1° C.; EI-MS m/z 254 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.C(=O)(O)[O-].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][CH:2]3[CH:7]4[CH:3]3[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]4)=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
tert-Butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 1.0 eq.) was added to a solution of sodium bicarbonate (0.84 g, 2.0 eq.) in water (5 ml) at 5° C. FMOC—Cl (1.56 g, 1.2 eq.) in 1,4-dioxane (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, transferred into iced water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 1.9 g of tert-butyl 6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[S:23][C:13]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccncc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2c(c1)N(C)C(=O)CS2
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)N(C)C(=O)CS4)nc2c1
Yield: 58.8 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-4-methyl-3-oxo-3,4-dihyro-2H-1,4-benzothiazine (1.9 g) was prepared in the substantially same manner as that of Example 4 from 6-(2-bromopropionyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (3.14 g) and 2-amino-4-methyl-pyridine (3.24 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CC([O-])=O.[Na+].BrBr.[NH2:18][C:19]([NH2:21])=[S:20]>CC(O)=O>[NH2:21][C:19]1[S:20][C:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]=2[N:18]=1
Reactant: NC(N)=S
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2sc(N)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
5,5-Dimethyl-cyclohexane-1,3-dione (201 g, 1.43 mol) and NaOAc (176 g, 2.14 mol) are suspended in AcOH (2 L) and Br2 (229 g, 1.43 mol) is added in dropwise while maintaining the reaction temperature between 15 and 20° C. After complete addition, the reaction is stirred at RT overnight. Thiourea (109 g, 1.43 mol) is added in portions and the reaction mixture is heated at 100° C. for 1 h. After cooling to RT, the AcOH is removed in vacuo and the resulting crude product is diluted with water (1 L) and neutralized with an aqueous saturated NaHCO3 solution. The resulting mixture is extracted with ethyl acetate (4×500 mL). The organic layer is washed with brine (500 mL), dried over anhydrous Na2SO4 and the solvent is evaporated in vacuo to give crude product. The crude product is washed with water (1.5 L) to yield 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (211 g, 75% yield).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[N:21][C:20]=1[NH2:26].O>CN(C)C=O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:26][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1ccc(-c2cc(C)nnc2N)c(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)OC
Temperature: 140 °C

Procedure:
Methyl 2-chloro-3-oxopentanoate (7 mL) was added to a solution of the resulting 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine in N,N-dimethylformamide (60 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([S:15][CH:12]([CH3:14])[CH3:13])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CC(C)S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)C(SC(C)C)CC1=O
Reaction time: 5 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), isopropylmercaptan (20 g), triethylamine (1 g) and toluene (45 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was washed with an acid, an alkali and water in order. The organic layer was separated and concentrated to give 2-allyl-3-methyl-4-isopropylthio-2-cyclopentenone (20.2 g). Yield, 96.3%. The product was purified by silica gel chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.5196.
Reaction SMILES: I[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.O.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>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][N:10]=[CH:11][C:2]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27]
Reactant: CNC(=O)c1ccncc1I
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a suspension of 450 mg (1.7 mmol) 3-iodo-N-methyl-isonicotinamide in 10 ml toluene were added successively 60 mg (0.05 mmol) tetrakis(triphenylphosphine)palladium(0), 2.5 ml 2 M sodium carbonate solution in water and 342 mg (2.5 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 20 h. The aqueous layer was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 341 mg (87%) of the title compound as a light yellow solid. M.p. 90-92° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H) 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25H2O.0.16MeOH: C, 56.34; H, 4.17; N, 11.49. Found C, 56.32; H, 4.45; N, 11.70.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH2:14]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:2]([CH2:3][OH:4])[C:5]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Yield: 88.9 %

Procedure:
D-serine (10.5 g, 0.1 mol) was stirred with potassium carbonate (69 g, 0.5 mol), benzyl bromide (64.8 g, 0.375 mol) and water (10 mL) in acetonitrile (250 mL) at 55° C. for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20% ethyl acetate in hexanes to give benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (33.36 g, 88%) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): (ppm) 7.20-7.44 (m, 15H), 5.27 (q, 2H), 3.91 (d, 2H), 3.80 (m, 2H), 3.67 (d, 2H), 3.63 (m, 1H) and 2.52 (dd, 1H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[CH3:29]>>[CH3:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(Cc3cnc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 46.5 %

Procedure:
A solution of 0.95 g (0.00494 mol) of 1-(4-methoxy-phenyl)-piperazine in 30 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.00164 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol (1:1 ), digested in diethyl ether and subsequently filtered off under suction. 0.24 g (47%) of 5-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[CH:17](OS(C)(=O)=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]CC)=[O:25])[C:15]=2[CH3:23])[S:10](=[O:30])(=[O:29])[CH2:9]1>CO.C(OCC)(=O)C>[CH3:7][C:8]1([CH3:31])[CH:17]([S:6][CH2:4][CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[C:15]=2[CH3:23])[S:10](=[O:29])(=[O:30])[CH2:9]1
Reactant: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCSC1c2c(ccc(C(=O)O)c2C)S(=O)(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A methanolic solution of 0.8 g (4 mmol, 3 eq.) containing about 28 wt % sodium methoxide was diluted with 5 ml of anhydrous methanol, and 0.5 ml (6.8 mmol, 1.5 eq.) of ethanethiol was added. The mixture was stirred at room temperature for 5 minutes, and then 0.5 g (1.3 mmol) of 3,3,5-trimethyl-4-methanesulfonyloxy-6-ethoxycarbonylthiochroman-1,1-dioxide was added. The mixture was refluxed for 8 hours, and allowed to stand at room temperature for 5 days. The reaction mixture was diluted with 100 ml of ethyl acetate and washed with 50 ml of water twice, and an aqueous layer was separated and cooled in an ice bath. The aqueous layer was acidified with 5 wt % hydrochloric acid and extracted with 100 ml of ethyl acetate, and an organic layer was dried over sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to give 0.32 g (yield 75%) of a yellowish solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:19]1[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 105.8 %

Procedure:
Benzyl bromide (696 mg, 4.01 mmol) was added to ethyl 5-phenyl-1H-pyrazole-3-carboxylate (880 mg, 4.1 mmol) and potassium carbonate (562 mg, 4.01) in DMF (8 mL). The reaction was stirred for several h and then diluted with water. The mixture was washed several times with ethyl acetate and the combine extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on ISCO using 0-100% ethyl acetate/hexane gradient to give ethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (1.3 g, quantitative). MS (ESI) m/z: Calculated for C19H18N2O2: 306.14. found: 307.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8])=[O:4].C[SiH](C)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C@@H:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4]
Reactant: COC(=O)N[C@@H](C)C(=O)c1cc(OC)ccc1OC
Agent: C[SiH](C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@@H](C)[C@H](O)c1cc(OC)ccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm3) at 0° C. in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm3). The solution was stirred at 0° C. for 1 h and then quenched by the addition of sodium hydroxide (500 cm3, 1 N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%). 1H NMR (250 MHz; C2HCl3) 1.03 (3H, d, J7.0, CH3), 3.04 (1H, d, J4.3, OH), 3.68 (3H, s, COCH3), 3.78 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.94-3.99 (1H, m, H-2), 5.05-5.15 (2H, m, H-1 and NH), 6.72-6.85 (2H, m, ArH) 6.97 (1H, d, J 2.0, ArH).
Reaction SMILES: [C:1]([CH:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[C:1]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([C:12]#[N:13])[CH3:16])#[N:2]
Reactant: COc1ccc(C(C#N)C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)(C#N)C#N)cc1
Reaction time: 22 h
Yield: 268.5 %

Procedure:
To a mixture of Compound 35 (1.0 g, 6.0 mmol) and NaH (280 mg, 7.0 mmol) in DMF (12 ml) was added MeI (1.0 g, 7.0 mmol) at room temperature. After the mixture was stirred for 22 hours, the mixture was poured into H2O (30 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil (3 g), which was purified by a column chromatography on silica gel to give Compound 35 as a colorless solid (900 mg, 81%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)C>CO>[CH3:13][O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 17 h
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid hydrate (620 mg, 3.26 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (1.10 g, 3.08 mmol) in MeOH (10 mL). After 17 h at rt, the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40% EtOAc/CH2Cl2→60% EtOAc/CH2Cl2, gradient, then 7% MeOH/CH2Cl2) afforded 538 mg (64%) of [(Z)-4((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]([CH3:61])([CH3:60])[C:57](Cl)=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:57](=[O:58])[C:56]([CH3:61])([CH3:60])[CH3:55])[CH2:49][CH2:48]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,2-dimethylpropanoyl chloride as starting materials in 32% yield. LCMS for C29H35ClN7O2 (M+H)+: m/z=548.2.