Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:17]2[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([CH:12]=[CH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc(Br)cc1C=CCCOCc1ccccc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(-c2cccc(OCc3ccccc3)c2)cc1C=CCCOCc1ccccc1

Procedure:
10.3 g (31 mmol) of 2-(4-benzyloxybut-1-enyl)-4-bromophenol, 5.5 g (20 mmol) of sodium metaborate octahydrate and 0.6 g (0.84 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 20 ml of THF and 60 ml of water, and, after addition of 0.03 ml of hydrazine hydrate, a solution of 6.0 g (26 mmol) of 3-benzyloxybenzeneboronic acid in 40 ml of THF is added dropwise. The batch is heated under reflux overnight and subsequently extracted four times with dichloromethane. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is recrystallised once each from toluene and ethanol, giving 3′-benzyloxy-3-(4-benzyloxybut-1-enyl)biphenyl-4-ol as a colourless solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester using the procedure of Example 74. 1H NMR (400 MHz, CDCl3) δ 7.17-7.12 (m, 3H), 6.77 (d, 2H, J=8.99 Hz), 6.61-6.59 (m, 1H), 6.50-6.47 (m, 1H), 6.46 (t, 1H, J=2.35 Hz), 4.14 (t, 2H, J=6.06 Hz), 3.75 (s, 3H), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 3.00-2.94 (m, 3H), 2.33 (s, 3H), 2.05-2.01 (m, 2H), 1.83-1.80 (m, 2H), 1.75-1.69 (m, 1H), 1.58-1.54 (m, 2H), 1.44 (s, 3H), 1.37-1.26 (m, 3H); HRMS (ES+) m/z exact mass calcd for C29H36NO6 494.2543, found 494.2543.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][N:7]([CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:8]([NH:10][CH2:11][CH:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][N:14]1[CH2:19][CH2:18]N(C)[CH2:16][CH2:15]1)=[O:9])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].O1CC[CH2:44][CH2:43]1>>[C:1]([S:4][CH2:5][CH2:6][N:7]([CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:8]([NH:10][CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:15][CH2:16][CH:43]([CH3:44])[CH2:18][CH2:19]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCN(CCC1CCCCC1)C(=O)NCC(CN1CCN(C)CC1)O[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)NCC(O)CN1CCC(C)CC1
Temperature: 25 °C

Procedure:
1-[2-(Acetylthio) ethyl]-3-[(2RS)-2-(t-butyldimethyl siloxy)-3-(4-methyl-1-piperazinyl)propyl]-1-(2-cyclohexylethyl) urea (Compound 3-19, 748 mg) was dissolved in anhydrous tetrahydrofuran (1.4 ml) in the nitrogen gas atmosphere, followed by the addition of a 1M solution of fluorinated tetra-n-butyl ammonium fluoride in tetrahydrofuran (1.45 ml) to the resulting solution with stirring at room temperature and stirring the mixture over 2.5 days. Saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate and then saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting oily product was purified by the silica gel column chromatography to thus give the title compound (Compound 5-1, 89 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC.[CH:24](OCC)=[O:25].C(OCC)(=O)C>CCOCC>[CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([CH:24]=[O:25])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(I)cc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 22.4 %

Procedure:
To a solution of [Difluoro-(4-iodo-phenyl)-methyl]-phosphonic acid diethyl ester (1.6 g, 4.1 mmol) in anhydrous ether (40 mL) at -78° C. was added dropwise n-butyl lithium (2.5 M in hexanes, 2.5 mL, 6.1 mmol). The brown solution was stirred at -78° C. for 2 minutes. Ethyl formate (0.66 mL, 8.2 mmol) was then added, and the reaction was stirred for 10 minutes at -78° C. The mixture was then quenched with saturated ammonium chloride (10 mL) and warmed to room temperature. The reaction was then diluted with ether. The organic layers were washed with saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a yellow oil. Chromatography of the residue [3:7, ethyl acetate:hexanes] gradient to (1:1)] afforded the aldehyde (268 mg, 22%) as a clear oil. 1H NMR (400 MHz, DMSO): δ 10.28 (s, 1H), 8.25 (d, 2H), 7.97 (d, 2H), 4.42 (m, 4H), 1.40 (t, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:28]([NH:30][C@H:31]([C:50](O)=[O:51])[CH2:32][C:33]1[N:37](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:36]=[N:35][CH:34]=1)=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:28]([NH:30][C@@H:31]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[C:50]([NH:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([OH:5])[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:51])=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:20])[CH3:21]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1

Procedure:
In an analogous manner to that described in Example 13, by reacting (1RS,2R,3S)-3-amino-4-cyclohexyl-1-(2-furyl)-1,2-butanediol with N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there was obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-propionamide (1:1 mixture of epimers) as a pale yellow solid, MS: 657 (M+H)+. The more polar epimer (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-propionamide, MS: 657 (M+H)+, can be separated from the above mixture by chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4](=[O:21])[C:3]([C:22]#[N:23])=[C:2]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 46 (2.0 g, 6.04 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.56 g, 18.21 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 2.18 g (95%) yellow solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 2.84 (s, 1H), 2.94 (m, 4H), 3.54 (m, 4H), 5.45 (s, 2H), 7.15 (m, 2H), 7.27 (m, 2H), 7.44 (dd, J=4.4, 9.3 Hz, 1H), 7.53 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 381 (M+1).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:42][C:43]([F:53])([F:52])[O:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:28])[N:9]([CH3:27])[C:10]=3[N:17]=[CH:16][C:15]=2[O:51][C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([O:44][C:43]([F:42])([F:52])[F:53])[CH:46]=2)=[CH:25][CH:24]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)cnc21
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a mixture of 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 0.086 mmol), N,N-dimethylglycine (4.4 mg, 0.043 mmol), CuI (2.0 mg, 0.011 mmol), and Cs2CO3 (56 mg, 0.172 mmol) in dioxane (1 mL) was added 3-(trifluoromethoxy)phenol (23 mg, 0.130 mmol). The reaction was heated at 120° C. (MW) for 2 h, cooled to RT then diluted with EA (15 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (7 mg, 15% yield) as a white solid. 1H NMR (CDCl3) δ: 8.36 (s, 1H), 7.32 (t, J=8.3 Hz, 1H), 7.16 (s, 4H), 6.98 (d, J=8.3 Hz, 1H), 6.75 (dd, J=13.0, 4.7 Hz, 2H), 4.71 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.55 (t, J=5.5 Hz, 2H), 1.98-1.87 (m, 2H). LCMS: MH+ 536 and TR=3.320 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21](I)=[CH:22][C:13]=12.[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25]>C1C=CC=CC=1.C(N(CC)CC)C.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.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:25]#[C:24][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Reactant: C#Cc1cccnc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(Nc2c(C#N)cnc3sc(C#Cc4cccnc4)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile (220 mg, 0.50 mmol), 3-ethynylpyridine (72 mg, 0.7 mmol), 20 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide (6 mg, 0.22 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 5 hours. The reaction mixture is cooled to room temperature and a solid appears. The solid is triturated with hot ethyl acetate, filtered, washed with hexanes and dried under vacuum to provide 100 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 191° C. (decomposition); 1H NMR (DMSO-d6+TFA) δ 3.88 (s, 3H), 7.37 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 7.85 (bs, 1H), 8.16 (s, 1H), 8.39 (bs, 1H), 8.54 (s, 1H), 10.02 (bs, 1H); MS 451.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1.B(F)(F)F.CC[O:21]CC.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:21])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C=CCCCC(O)c1ccc(Br)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: OO
Solvent: COCCOCCOC
Solvent: O
Product: OCCCCCC(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
1-(4-Bromo-phenyl)-hex-5-en-1-ol (1 g) was dissolved in 0.5 M NaBH4 in diglyme (9 mL) and chilled in an ice bath. BF3.OEt2 (1 mL) in diglyme (4 mL) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 mL) was added. 3M NaOH (2 mL) was added followed by 30% H2O2 (3 mL). Anhydrous K2CO3 (5 g) was added and the solvent was decanted. The K2CO3 was washed with ethyl acetate and the combined organics were dried (Na2SO4) and evaporated. Distillation under vacuum removed most of the remaining diglyme. The residue was purified by column chromatography (light petroleum:diethyl ether 2:1) to give a clear oil which solidified to give the title compound as a white powder. 13C NMR (CDCl3): δ 25.4, 25.6, 32.5, 39.0, 62.7, 73.8, 121.2, 127.7, 131.5 and 143.9. 1H NMR (CDCl3): δ 1.40 (4H, m), 1.52 (2H, m), 1.74 (2H, m), 3.61 (2H, t, J=6.5 Hz), 4.74 (1H, t, J=6.5 Hz), 7.20 (2H, d, J=8.2 Hz) and 7.41 (2H, d, J=8.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(Cl)C=CC=2COOC(=O)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([Si](C)(C)OCC(O)CCC)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)OOCc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCC(O)CO[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxyoxymethyl)phenyl]benzenesulfonamide (13.7 g, 36.6 mmol), triphenylphosphine (21.1 g, 80.6 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy-2-pentanol (16.0 g, 73.3 mmol) in THF (130 mL) was added diisopropylazodicarboxylate (15.9 mL, 80.6 mmol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22° C. with stirring. Stirring was continued for a period of 12 h followed by the addition of 150 ml of H2O. The mixture was extracted with ether (3×100 mL). The combined organic extracts were washed with 1M NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 16.6 g of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)dimethylsilyl]oxy)butyl]benzenesulfonamide as a yellow oil in 79% yield.
Reaction SMILES: [C:1]([CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])#[N:2].C(NCC)C.C(=O)=O.[SH2:23]>>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[CH2:4][CH2:3][C:1]([NH2:2])=[S:23])[CH3:14]
Reactant: CCO[Si](CCC#N)(OCC)OCC
Reactant: S
Agent: O=C=O
Solvent: CCNCC
Product: CCO[Si](CCC(N)=S)(OCC)OCC
Temperature: 60 °C

Procedure:
Into a clean, dry 300 milliliter high pressure reaction vessel was added 200 grams (0.92 moles) of beta-cyanoethyltriethoxysilane and 10 grams of diethylamine. The reactor was cooled to the temperature of solid carbon dioxide, and 42.0 grams (1.3 moles) of hydrogen sulfide was added via a calibrated metering system. The reactor was placed in a rocker and with agitation was heated to 60° C. for 5 hours. The pressure of the system increased to a maximum of 140 psig and decreased to 70 psig when the reaction was terminated. The final pressure at ambient temperature was 30 psig. The yield of crude beta-triethoxysilylthiopropionamide product was 258.4 grams. Analysis of the product mixture indicated 19 mg/g or 16% unreacted beta-cyanoethyltriethoxysilane.
Reaction SMILES: C1(N(C2CCCCC2)C)CCCCC1.Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:19]#[N:20].[C:26]([O:30]C(C)(C)C)(=[O:29])[CH:27]=[CH2:28]>CN(C)C(=O)C.[Cl-].C([N+](CC)(CC)CC)C.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16](/[CH:28]=[CH:27]/[C:26]([OH:30])=[O:29])[CH:17]=1)#[N:20]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(C#N)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(C#N)cc1/C=C/C(=O)O
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a suspension of palladium(II)acetate (0.77 g, 3.42 mmol) in N,N-dimethylacetamide (375 ml) are added tetraethylammonium chloride (19.36 g, 114.5 mmol), dicyclohexyl methyl amine (35.1 g, 174.5 mmol), and 3-bromo-4-methoxybenzonitrile (25.51 g, 118.0 mmol) under a nitrogen atmosphere. The suspension is heated to 100-105° C. whereupon t-butyl acrylate (14.82 g, 114.5 mmol) is slowly added over a period of 45 min. After a further 30-60 min stirring at 100° C., the solution is cooled to room temperature and diluted with TBME (375 ml). The resulting biphasic mixture is stirred vigorously for 10 min. The (upper) TBME phase is successively washed with water (100 ml), 10% aq. citric acid (100 ml) and 25% aq. NaCl (100 ml). The combined aqueous phases are extracted with TBME (100 ml). After adding active charcoal (0.4 g), the combined TBME phases are stirred vigorously for 10 min and filtered. Anhydrous Na2SO4 (10 g) is added and the resulting suspension is stirred for another 10 min and filtered. The filtrate is concentrated to a volume of 50-70 ml under reduced pressure and, over a period of 25-30 min, added at room temperature to anhydrous trifluoroacetic acid (150 ml). The resulting solution is stirred at room temperature for 60 min (precipitation forms), cooled to 0-5° C. in an ice bath, and diluted with ethyl acetate (410 ml). After stirring vigorously at 0° C. for an additional 60 min, the suspension is filtered. The residue is dried under vacuum at 45-50° C. to give (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid as a crystalline solid, mp. 252-253° C. MS (ES): [M−H]−202.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([N+:22]([O-])=O)=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(#N)C.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[N:19]=[N:20][N:21]=[C:14]1[C:13]([NH2:22])=[C:12]2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccc(OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Reaction time: 5 h
Yield: 82.6 %

Procedure:
7-(Benzyloxy)-N-(2-methylpropyl)-4-nitrotetraazolo[1,5-α]quinolin-5-amine (10 g, 25.4 mmol) was shaken in 200 mL of acetonitrile with 5% platinum on carbon (1 g) under 50 psi (3.45×105 Pa) of hydrogen. After 5 hours, the mixture was filtered through CELITE filter agent. Some product was isolated as a solid on the top of the filter cake. This solid was collected, dissolved in warm DMF, and filtered again through fresh CELITE filter agent. The combined filtrates were cooled and allowed to sit overnight. The resulting precipitate was collected in 2 crops to yield 7.6 g of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-α]quinoline-4,5-diamine as a brown solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:22]/[C:23](=[O:25])[CH3:24])[CH2:17][CH2:16]2)[CH:10]=3)[CH2:3][CH2:2]1>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH2:17][CH2:16]2)[CH:10]=3)[CH2:3][CH2:2]1
Reactant: CC(=O)/C=C/[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Solvent: CCOC(C)=O
Product: CC(=O)CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (3E)-4-{trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexyl}but-3-en-2-one (2.85 g), palladium-activated carbon ethylenediamine complex (0.538 g) and ethyl acetate (100 mL) was stirred at room temperature for 15 hr under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.75 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(NC(=O)CCC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(NC(=O)CCC)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-butanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:19]#N)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[N:5](C2C=CC=CC=2)[CH2:4][NH:3]1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:27]1([N:5]2[C:6]3([CH2:7][CH2:8][N:9]([C:12]4([C:19]5[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=5)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:11]3)[C:2](=[O:1])[NH:3][CH2:4]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1NCN(c2ccccc2)C12CCN(C1(c3ccccc3)CCCCCC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
To a stirred solution of 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)cycloheptane-carbonitrile (323 mg, 0.916 mmol) in THF (6 ml) was added phenylmagnesium bromide (3M solution in diethyl ether, 3.05 ml, 9.16 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was poured into ice water, then extracted with CH2Cl2. The extracts combined were dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (CH2Cl2/MeOH:10/1 to give 70.5 mg (19.1%) of title compound.