Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:29])[O:7][C@@H:8]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=1[OH:10])[CH:2]=[CH2:3]>CO>[OH:10][C:9]1[C@H:8]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:7][C:6](=[O:29])[C:5]=1[O:4]/[CH:1]=[CH:2]/[CH3:3]
Reactant: C=CCOC1=C(O)[C@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O
Solvent: CO
Product: C/C=C/OC1=C(O)[C@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O
Reaction time: 0.08 h

Procedure:
To a flame-dried, three-necked 250 mL round bottom flask under argon was added 0.172 g (0.20 mmol) of [bis(methyldiphenylphosphine)](1,5-cyclooctadiene)iridium(1) hexafluorophosphate suspended in 35 mL of freshly distilled peroxide free anhydrous tetrahydrofuran. The flask as evacuated and the argon displaced with hydrogen. The red suspension turned to a colorless solution after 5 minutes. The flask was evacuated, and the hydrogen replaced with argon. (S)-3-allyloxy-4 -hydroxy-5-[(Z)-3-octadecenyl]-2(5H)-furanone (0.415 g, 1.02 mmol) was dissolved in 25 mL of peroxide free tetrahydrofuran and added to the activated catalyst. On completion (TLC; approximately 3 hours) the solvent was evaporated in vacuo and purified over silica gel using 10% methanol in chloroform as eluant to provide 0.33g (79%) of white waxy solid: mp 42°-45° C.; [α]D25 -13.0°(c=0.3, CH3OH); IR (neat, cm-1) 3079 (br), 3004, 2919, 1739, 1681, 1658, 738, 721; 1H NMR (CD3COCD3 δ 6.43-6.36 (m, 1H), 5.49-5.31 (m, 2H), 5.05-4.91 (m, 1H), 4.77 (dd, J=3.5, 7.8 Hz, 1H), 2.24-1.62 (m, 6H), 1.51 (dd, J=1.7, 6.9 Hz, 3H), 1.44-1.24 (m, 24H), 0.87 (t, J=6.8 Hz, 3H); HRMS calculated for C25H42O4 (M+) 406.3083, found 406.3083.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[N:18]([CH3:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[N:18]([CH3:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CCOC(=O)c1c(C)nc(-n2ccc(OCc3ccccc3)cc2=O)n1C
Yield: 24 %

Procedure:
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-phenylpyridin-2-ol to react with ethyl 2-bromo-1,4-dimethyl-1H-imidazole-5-carboxylate in place of ethyl 2-bromo-4-methylthiazole-5-carboxylate at 125° C. for 64 hours, the title compound was obtained as a colorless solid in 24% yield: 1H NMR (300 MHz, CDCl3) δ 7.44-7.36 (m, 5H), 7.22 (d, J=7.7 Hz, 1H), 6.09 (dd, J=7.7, 2.5 Hz, 1H) 5.98 (d, J=2.5 Hz, 1H), 5.04 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.69 (s, 3H), 2.49 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1ccc(CO)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A mixed solution of (5-methyl-pyridine-2-yl)-methanol (500 mg, 4.1 mmol) described in Manufacturing Example 11-1-1, thionyl chloride (0.59 mL, 8.1 mmol) and methylene chloride (10 mL) was stirred for 5 minutes under reflux. The reaction solution was cooled to room temperature and concentrated under a reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was separated and passed through a glass filter lined with silica gel (eluted with ethyl acetate). The eluate was concentrated to obtain the title compound (440 mg, 76%) as a crude product. The resulting compound was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH2:9]1[O:13][C:12]2[CH:14]=[C:15]([Cl:20])[C:16]([CH2:18]Cl)=[CH:17][C:11]=2[O:10]1>CN(C)C=O>[Cl:20][C:15]1[C:16]([CH2:18][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:17][C:11]2[O:10][CH2:9][O:13][C:12]=2[CH:14]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 1 of Example 11 starting with 12.3 g of 2-methyl-1H-imidazole, 7.92 g of sodium hydride with 50% oil, 150 ml of N dimethylformamide and 33.8 g of 6-chloropiperonyl chloride.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:12]=[C:13]([NH:22][C:23]2[N:28]3[N:29]=[CH:30][C:31]([C:32](OCC)=[O:33])=[C:27]3[N:26]=[C:25]([CH3:37])[CH:24]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C.O>CCOCC.C1COCC1>[C:7]([C:11]1[CH:12]=[C:13]([NH:22][C:23]2[N:28]3[N:29]=[CH:30][C:31]([CH2:32][OH:33])=[C:27]3[N:26]=[C:25]([CH3:37])[CH:24]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc(C)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n2ncc(CO)c2n1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of LiAlH4 (840 mg) in anhydrous ether (50 ml) is added dropwise a solution of 7-(3,5-di-t-butyl-4-hydroxyphenyl)amino-3-ethoxycarbonyl-5-methyl-pyrazolo[1,5-a]pyrimidine (3.5 g) prepared in Example 10 in dry THF (50 ml) with ice-cooling, and the mixture is stirred at the same temperature for 30 minutes, and further stirred at room temperature for one hour. To the mixture are added ethyl acetate and water to decompose excess LiAlH4, and the mixture is filtered with celite. The filtrate is diluted with ethyl acetate, and washed with a saturated aqueous Na2S2 O4 solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; ethyl acetate/dichloroethane=2:1→chloroform/methanol=8:1). The obtained crystal is washed with ethyl ether to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)amino-3-hydroxymethyl-5-methylpyrazolo[1,5-a]pyrimidine (2.3 g) as colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16]([C:19]1[C:24]([O:25][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=1)(=O)[CH3:17].[BH4-].[Na+].O>CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:16]([C:19]2[C:24]([O:25][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=2)[CH3:17])[CH2:10][CH2:11]1
Reactant: Fc1ccccc1OCC1CCNCC1
Reactant: COc1nccnc1C(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1nccnc1C(C)N1CCC(COc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
After dissolving 1.09 g of 4-(2-fluorophenoxymethyl)piperidine in 15 ml of methanol, 1.53 ml of titanium (IV) tetraisopropoxide and 400 mg of 2-acetyl-3-methoxypyrazine [CAS No. 56343-40-9] were added and the mixture was stirred overnight at room temperature. The reaction solution was cooled on ice, 148 mg of sodium borohydride was added and the mixture was stirred for 5 hours at room temperature. Water and ethyl acetate were added to the reaction solution and the mixture was filtered with celite. The filtrate was extracted with ethyl acetate and the extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (100 mg, 11% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:30][CH:31]=[CH2:32].S(O)(C(F)(F)F)(=O)=O>C1CCCCC1.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:32][CH:31]=[CH2:30])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (200 mg, 0.58 mmol) and allyl 2,2,2-trichloroacetimidate (0.18 mL, 1.16 mmol) in cyclohexane (0.7 mL) was added TfOH (29 □L), whereupon the solution became hot and stirring was continued at 23° C. for 1 h. The reaction mixture was poured on ice, diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over MgSO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (31 mg, 14%) as a yellow oil. 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.03-2.26 (3H, m), 2.32 (1H, dd, J=12, 7 Hz), 3.58 (1H, dd, J=9, 7 Hz), 3.92 (1H, m), 4.02 (1H, m), 4.13 (2H, q, J=7.1 Hz), 5.10-5.22 (2H, m), 5.25 (1H, d,J=12 Hz), 5.34 (1H, d,J=12 Hz), 5.75 (1H, m), 7.30-7.42 (5H, m);MS[EI] 284 [(M-CO2Et-N2)+ ]; □D20 17.85° (c=0.50, CHCl3).
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Br:3])[N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Br)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
86.0 g (0.3 mol) of phosphorus oxybromide was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol)of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 200 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 200 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 11.1 g (0.052 mol) of a pale yellow crystal of 2-amino-6-bromopurine (yield 52%). Its properties are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH3:21][O:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13]([NH:23][O:22][CH3:21])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: CON
Reactant: CSC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Solvent: CCO
Product: CONC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 63.4 %

Procedure:
To a solution of 0.95 g of the compound synthesized in Example 1 above in 30 ml of ethanol was added O-methylhydroxylamine (0.16 g), and the mixture was heated under reflux for 1 hour. The ethanol was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methoxyamino-2-nitrovinyl)ethylenediamine (0.6 g) having an nD20 of 1.5466.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Ba+2]>[Pd].C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)C=Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1

Procedure:
Hydrogenation of 50 g (190 mmol) of 1-(4-benzyloxy-phenyl)-4-methyl-pent-1-en-3-one prepared in Example B was effected as described in General Method 3 using 1.08 g 5% Pd over BaSO4 and 1000 mL of THF under hydrogen atmosphere.
Reaction SMILES: Br[C@@H:2]1[C@@H:7]([OH:8])[CH2:6][C@H:5]2[C@@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C:17]1[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=1[CH2:11][CH2:10]3.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@@H:9]([C@H:5]4[C@@:3]([CH2:20][CH2:19]3)([CH3:4])[CH2:2][C@@H:7]([OH:8])[CH2:6]4)[CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)[C@H](Br)[C@@H](O)C[C@@H]12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)C[C@@H](O)C[C@@H]12

Procedure:
A solution of 3.50 g (9.60 mmol) of 17α-bromo-3-methoxy-8α-estra-1,3,5(10)-trien-16β-ol, 3.50 g (12.03 mmol) of tributyl tin hydride and 50 mg of azobisisobutyronitrile in 30 ml of dry tetrahydrofuran is refluxed for 2 hours while being stirred in an argon atmosphere. For working-up, it is allowed to cool, concentrated by evaporation in a vacuum in a Rotavapor, and the residue is taken up in ethyl acetate (300 ml). After the organic phase is washed with aqueous hydrochloric acid, water and brine, it is dried on sodium sulfate. The residue is chromatographed on silica gel (dichloromethane/ethyl acetate, 9:1), yield 2.70 g (98%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:14]1[C:15](=[O:16])[N:11]([O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)=[O:9])[C:12](=[O:17])[CH2:13]1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 0 °C

Procedure:
The title compound is prepared in known a manner from 30.8 g of nicotinic acid, 34.5 g of N-hydroxysuccinimide and 55 g of dicyclohexyl carbodiimide in 800 ml of dimethyl formamide. When the reaction is terminated, the mixture is concentrated in vacuo to one third of its volume, cooled to 0° C., filtered and the filtrate is evaporated to dryness in vacuo. The residue is recrystallized from 200 ml of isopropanol. Yield 49.0 g, melting point 137° to 138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1.[CH3:23][CH:24]([O:26][C:27](=[O:52])[NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([C:48](=[O:50])[CH3:49])[C@@H:31]([CH3:51])[CH2:30]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:48]([N:32]1[C:33]2[C:38](=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]4=[O:22])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[C@H:29]([NH:28][C:27]([O:26][CH:24]([CH3:25])[CH3:23])=[O:52])[CH2:30][C@@H:31]1[CH3:51])(=[O:50])[CH3:49]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)C(=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A flask was charged with 1,1-dimethylethyl 4-[(4-bromophenyl)methyl]-3-oxo-1-piperazinecarboxylate (for a preparation, see Intermediate 72) (111 mg, 0.3 mmol), 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (250 mg, 0.600 mmol), potassium carbonate (124 mg, 0.900 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.95 mg, 0.030 mmol) then filled with 1,4-dioxane (3 mL) and water (1 mL) and flushed with nitrogen. The resulting mixture was stirred under microwave irradiation at 120° C. for 30 min then cooled to room temperature. Most of the 1,4-dioxane was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 5 to 25% (10% MeOH in DCM) in DCM) gave 1,1-dimethylethyl 4-({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)-3-oxo-1-piperazinecarboxylate (180 mg, 0.311 mmol, 104% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=1.Cl>CCO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cccc(CCN)c1
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
A solution of 3-cyanomethyl-benzoic acid methyl ester (1.36 g) in EtOH (25 mL) was saturated with HCl (g) and PtO2 (200 mg) was added. The reaction was hydrogenated on a Parr shaker at 50 psi for 2.5 h. The catalyst was removed via filtration through Celite and the solvent was removed in vacuo. The resulting solid was stirred in Et2O and the mixture was filtered to yield the title compound as a white solid (1.18 g). MS 180 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[N:13]2)=[C:8]([OH:22])[CH:7]=1)=[O:5])[CH3:2].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[N:13]2)=[C:8]([O:22][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(O)c1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCCCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of ethyl 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxylate (0.30 g) obtained in Example 133c) in DMF (10 ml) were added (3-bromopropyl)benzene (0.18 ml) and potassium carbonate (0.14 g), and the mixture was stirred overnight at 75° C. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow powder (0.25 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 59.1 %

Procedure:
Beginning with 11.6 gm (86.0 mMol) 6-fluoro-1H-indole and 26.5 gm (172 mMol) 4-piperidone hydrochloride monohydrate, 11.0 gm (59%) of the title compound were recovered as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)C(O)=O.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:36])C=CC=CC=1.C(O)(C)(C)C.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(F)cc2F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(CC(=O)c2ccc(F)cc2F)cc1
Temperature: 0 °C
Yield: 77.1 %

Procedure:
A solution of the acid from Step 1 (3.11 g, 10.2 mmol) and triethylamine (1.23 g, 10.8 mmol) dissolved in 15 mL of anhydrous toluene, was cooled to 0° C. and treated with diphenylphosphoryl azide (2.98 g, 10.8 mmol). The solution was maintained at 0° C. for twenty minutes and warmed to room temperature for 1 hour. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was diluted with an additional 10 mL of toluene and heated to 90° C. for 1.5 hours. tert-Butyl alcohol (4 mL, 42 mmol) was added to the reaction mixture. After an additional twenty minutes, concentrated hydrochloric acid (4 mL) was cautiously added and the reaction maintained at 90° C. overnight (16 hours). After cooling the solution to room temperature, the mixture was poured into a separatory funnel, diluted with ethyl acetate, and washed with water. The organic layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid. The crude solid was crystallized from a mixture of ethyl acetate and hexane to provide the desired ketone (2.19 g, 77%): mp 82°-88.5° C. 1H NMR (CDCl3) 300 MHz 7.91 (q, J=6.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.82-6.97 (m, 2H), 4.21 (d, J=2.6 Hz, 2H), 2.46 (s, 3H); 19F NMR (CDCl3) -101.74 (m), -104.15 (m). Mass spectrum: M+ =278.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(O)(=O)=[O:35].C(=O)(O)[O-].[Na+]>O>[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH2:30])=[O:29])=[CH:31][CH:32]=2)=[O:35])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc(Sc2ccc(CNCCc3ccccc3)cc2)cc1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: NC(=O)c1ccc(S(=O)c2ccc(CNCCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
Sodium periodate (43 mg) was added to a solution of 4-[4-(phenethylamino-methyl)-phenylsulfanyl]-benzamide (73 mg, 0.2 mmol), water (10 mL), and methane sulfonic acid (39 mg, 0.4 mmol) while stirring at room temperature. After 1 and 2 hours, and an additional equivalent of sodium periodate (43 mg) and continue to stir at room temperature. Pour the reaction into saturated aqueous sodium bicarbonate solution then extract with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (60 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide (26 mg): 1H NMR (DMSO-D6, 300.00 MHz): 8.98 (d, 1H, J=1.3 Hz), 8.46 (dd, 1H, J=7.9, 2.2 Hz), 8.23 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75-7.66 (m, 4H), 7.49 (d, 2H, J=8.3 Hz), 7.30-7.15 (m, 5H), 3.76 (s, 2H), 2.75-2.70 (m, 4H); m/z=380.04 (M+1); HPLC=100% (5.67 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.