Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([CH2:13][O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]3[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH2:13][O:14][CH2:15][C:16]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C3CC3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2(COCc3cc(C4CC4)cc4cn[nH]c34)CCNCC2)cc1

Procedure:
tert-Butyl 4-(((5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (34 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the product purified by reverse phase HPLC to afford 10 mg (48%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.96 (s, 1H), 7.42-7.47 (m, 5H), 7.31-7.34 (m, 1H), 7.01 (m, 1H), 4.71 (s, 2H), 3.51 (s, 2H), 3.24-3.28 (m, 2H), 2.89-2.95 (m, 2H), 2.46-2.49 (m, 2H), 2.16-2.21 (m, 2H), 1.98-2.02 (m, 2H); 13C-NMR (126 MHz, CD3OD) δ ppm 141.1, 138.1, 136.8, 133.5, 129.1, 127.2, 127.0, 125.6, 124.1, 120.1, 116.5, 78.9, 70.4, 41.1, 41.0, 28.9, 15.1, 8.1. Mass spec.: 362.22 (MH)+. Accurate mass spec.: m/z 362.2217 [MH]+, Δ=4.2 ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10].NC(N)=[S:19].[OH-].[Na+]>C(O)C>[SH:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: NC(N)=S
Reactant: O=c1[nH]c(=O)n(CCCCCCBr)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]c(=O)n(CCCCCCS)c(=O)[nH]1
Temperature: 25 °C

Procedure:
6-Mercaptohexyl isocyanuric acid (MH-ICA) was synthesized using methods and materials known in the art (see, e.g. Jogireddy et al., J. Synlett 2008, 1219-1221). Briefly, a solution of 6-bromohexyl isocyanuric acid (224 mg, 0.77 mmol) and thiourea (65 mg, 0.853 mmol) in ethanol (40 mL) was degassed (freeze, pump, thaw) thrice, and refluxed under an atmosphere of Ar for 24 h. After cooling down to room temperature, 2 mL NaOH (5 M) aqueous solution was added. The reaction solution was again degassed (freeze, pump, thaw) thrice and slowly heated to reflux. After refluxing for 24 h under Ar atmosphere and cooling down to room temperature, the mixture solution was acidified with 1 mL HCl (2 M) aqueous solution. The precipitate was filtered and extensively washed with deionized H2O to give the pure product, 6-mercaptohexyl isocyanuric acid (MH-ICA) in a yield of 85% (210 mg). 1H NMR (500 MHz, DMSO-d6) δ: 11.38 (s, 1H), 3.61 (t, 2H), 2.68 (s, 2H), 1.60 (m, 2H), 1.50 (m, 2H), 1.35 (m, 2H), 1.26 (m, 2H) ppm; 13C NMR (125 MHz, DMSO-d6) δ: 149.84, 148.64, 40.32, 37.71, 28.42, 27.41, 27.21, 25.70 ppm. ESI-MS (M+): 246.94 (calculated 246.09).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Temperature: 40 °C
Yield: 98 %

Procedure:
To a suspension of methyl (3S,4R)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 20 (15 g, 45 mmol) in ethanol (225 mL) at room temperature under dry nitrogen was added 10% palladium on carbon (Degussa type) (1.5 g), and the reaction mixture placed under 50 psi pressure of hydrogen, and heated to 40° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an orange oil (10.8 g, 98%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:20]([O:19][C:18](=[O:24])[N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=2[F:26])[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[CH3:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cccc(B(O)O)c1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere 100° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16]CCC.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccccc1)C1CCCCC1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
α-Cyclohexylstyrene was prepared from cyclohexyl phenyl ketone using standard Wittig chemistry (Gupta, P.; Fernandes, R. A.; Kumar, P. Tet. Lett. 2003, 44, 4231–4232.) Methyltriphenylphosphonium bromide (29.57 g, 82.77 mmol) was slurried in 600 mL THF in the glovebox. The mixture was cooled to 2° C., and nBuLi (1.6 M in hexanes, 52 mL) was added over 15 min. After 1 h, solid cyclohexyl phenyl ketone (15.18 g, 80.63 mmol) was added, and the solution was allowed to slowly warm to room temperature overnight. Water (200 mL) was added. The solution was extracted with Et2O (3×150 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give a tan liquid. Ph3PO crystallized upon standing and was removed by filtration and washed with hexane (200 mL). The hexane solution was filtered through a 2 in column of neutral alumina, washing with an additional 200 mL of hexane. The filtrate was evaporated to a colorless liquid which was distilled (46–49° C./0.1 mm Hg) to give 13.72 g of colorless liquid (89% yield).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH2:21][OH:22])[CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:20]=1)[CH2:21][O:22][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Imidazole (5.22 g) and tert-butyldimethylsilyl chloride (8.64 g) were added to a solution of (5-bromo-2-chlorophenyl)methanol (8.47 g) in DMF (80 ml). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed twice with water. The aqueous layer was again extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (12.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[Cu][C:11]#[N:12].[C-]#N.[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:11]#[N:12])=[CH:4][N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(N)ncc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)ncc1C#N
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-bromo-4-methylpyridine (4.0 g, 21.4 mmol) and copper(I) cyanide (2.2 g, 24.6 mmol) in N,N-dimethylformamide (5 mL) was stirred for 4 h at reflux temperature. The hot mixture was poured into a warm solution of sodium cyanide (4.3 g) in water (13 mL). After the mixture was vigorously shaken, the mixture was extracted with ethyl acetate. The organic extract was washed with 10% aqueous sodium cyanide, saturated brine solution and evaporated. The title compound was obtained as a solid after chromatography on silica gel (15% acetone/hexane); yield 1.81 g (64%).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:58][N:57]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56]1.C(N(CC)CC)C>CN(C)C=O>[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:56][N:57]([CH:59]2[CH2:64][CH2:63][N:62]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:61][CH2:60]2)[CH2:58]1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (116 mg) and triethylamine (0.168 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (57.5 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:22][CH2:23][NH:36][CH2:35][CH2:34][F:33])([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NCCF
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCNCCF)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using 2-fluoroethylamine in Step 2. LC-MS Method 2 tR=1.183 min, m/z=505.1; 1H NMR (CDCl3) 1.48 (d, 3H), 1.94-2.32 (m, 5H), 2.40 (m, 1H), 2.67-2.85 (m, 3H), 2.86 (m, 1H), 4.34 (t, 1H), 4.45 (t, 1H), 5.62 (m, 1H), 6.88-7.19 (m, 6H), 7.20 (m, 4H), 7.40 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:45]1([CH2:44][O:43][C:30]2[C:29]([CH:10]3[CH2:1][CH2:2]3)=[CH:41][C:33]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])=[C:32]([F:42])[CH:31]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.19 g, 14%): 1H NMR (300 MHz, CDCl3) δ8.77-8.66 (m, 1H), 7.61-7.52 (m, 1H), 6.62-6.52 (m, 1H), 3.86-3.78 (m, 2H), 3.41 (s, 3H), 2.12-1.99 (m, 1H), 1.95-1.66 (m, 6H), 1.40-1.03 (m, 5H), 0.99-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 368.3 (M−1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:47])=[C:41]([CH:46]=1)[C:42]([O:44]C)=[O:43]>>[C:42]([C:41]1[CH:46]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:47])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:44])=[O:43]
Reactant: COC(=O)c1cc(CCl)ccc1C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1

Procedure:
Analogously to Method D, 1.68 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.700 g of methyl 5-chloromethyl-2-methylbenzoate are reacted. The title compound is obtained as a white foam. Rf=0.07 (1:2 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH2:11][CH2:12][CH2:13][Cl:14]>C1COCC1>[Cl:14][CH2:13][CH2:12][CH2:11][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: ClCCCBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCN1CCCCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
Sodium hydride (60% suspension in oil, 26 mg, 0.65 mmol) was added to a solution of 2-piperidone (54 mg, 0.54 mmol) in dry THF (2 mL) under argon atmosphere. After 15 minutes stirring at rt the reaction mixture was cooled to 0° C. over 15 minutes. A solution of 1-bromo-3-chloropropane (160 μL, 1.62 mmol) was added dropwise to the cold mixture and stirring was continued overnight at rt. The mixture was partitioned between water and ethyl acetate, the organic layer dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue on silica gel column chromatography, eluting with a stepwise gradient of 60–80% ethyl acetate in n-heptane, afforded 1-(3-chloropropyl)-piperidin-2-one (33 mg, 35%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:4]=1.[SH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:22]([CH3:33])[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:33][C:22]1[CH:21]=[C:20]([S:19][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:4]=2)[CH:32]=[CH:31][C:23]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: FC(F)(F)c1ccc(-c2cccc(CBr)n2)cc1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Yield: 93.7 %

Procedure:
A solution of the 2-(bromomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine (238 mg, 0.75 mmol), ethyl (4-mercapto-2-methylphenoxy)acetate (84 mg, 0.37 mmol) and K2CO3 (57 mg, 0.41 mmol) in MeCN (5 mL) was stirred at rt, under nitrogen overnight. The mixture was then partitioned between water and EtOAc and the layers separated. The organic layer was then washed with water and brine, dried (MgSO4), filtered and reduced. Purification by SPE (silica, 2 g cartridge) eluting with CHCl3:cyclohexane (5:1) afforded the title compound (160 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](I)=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][C:34]=2[O:41][CH3:42])[CH3:31])=[CH:26][CH:25]=1>O1CCCC1>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:37]([C:36]2[CH:39]=[CH:40][C:33]([O:32][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH3:31])=[C:34]([O:41][CH3:42])[CH:35]=2)[OH:38])=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1OC(C)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C)(C)C(C)(C)C)c3ncccc23)ccc1OC(C)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (636, 647.0 mg, 1.81 mmol) was dissolved in tetrahydrofuran (10.0 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.98 mL) was added to the reaction. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzaldehyde(644, 420 mg, 1.4 mmol) in tetrahydrofuran (3.00 mL) was added. The reaction was stirred for 2 hours during which time the temperature rose to 10° C. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound, (645, 463 mg, 61%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:18])=[C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:27]=[O:28])[CH:11]=2)[N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8]1)([CH3:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Cc1cc2c(cc1Br)N(C(C)C)CCN2C(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)N(C(C)C)CCN2C(C)C
Temperature: 25 °C

Procedure:
A mixture of 7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (469 mg, 1.51 mmol), 2-methoxy-5-formylphenylboronic acid (407 mg, 2.26 mmol), potassium carbonate (834 mg, 6.03 mmol) and water (2.5 mL) in anhydrous 1,2-dimethoxyethane (30 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium (0) (349 mg, 0.30 mmol). The reaction mixture was heated under reflux for 8.5 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), saturated aqueous NH4Cl (100 mL), saturated aqueous NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40S cartridge, eluting with 10% ethyl acetate/90% hexane. The title compound was isolated as bright yellow solid (315 mg, 57%).
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][CH3:4].C[Si]([C:16]#[N:17])(C)C>>[Cl:11][C:7]1[CH:6]=[C:5]([CH:2]([CH2:3][CH3:4])[C:16]#[N:17])[CH:10]=[CH:9][CH:8]=1
Reactant: CCC(Br)c1cccc(Cl)c1
Reactant: C[Si](C)(C)C#N
Product: CCC(C#N)c1cccc(Cl)c1

Procedure:
rac-2-(3-chloro-phenyl)-butyronitrile was prepared from rac-1-(1-bromo-propyl)-3-chloro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:46]>O1CCCC1>[ClH:46].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(CN2CCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and pyrrolidine (0.11 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional pyrrolidine (011 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 6 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-(pyrrolidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.18 g, 42% yield) as a white solid.