Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH:14]=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH2:14][NH:19][CH:16]1[CH2:18][CH2:17]1
Reactant: CNC(=O)CCc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)CCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of 3-(4-chloro-3-formyl-phenyl)-N-methyl-propionamide (2.30 g, 10.2 mmol) and cyclopropylamine (1.09 mL, 15.3 mmol) in MeOH (109 mL) was stirred for 2 h. Cyclopropylamine (0.364 mL, 5.09 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool down to rt, and NaBH4 (771 mg, 20.4 mmol) was added by portion. The mixture was stirred for 2 h at rt. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc (500 mL). The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (2.05 g, 75%). LC-MS: tR=0.58 min; ES+: 267.39.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[C:37](O)(=[O:41])[C@H:38]([CH3:40])[OH:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:37](=[O:41])[C@@H:38]([OH:39])[CH3:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: C[C@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@H](C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), L-Lactic acid (17 μL, 0.22 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 2%) affording 723 as a white solid (27 mg, 29%). LCMS (method I): RT 2.90 min, [M+H]+ 562.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-8.00 (1 H, m), 7.78-7.74 (1 H, m), 7.35-7.25 (2 H, s), 4.46-4.43 (1 H, m), 4.34 (4 H, brd s), 4.06-3.94 (1 H, m), 3.91 (3 H, s), 3.86 (4 H, t, J=4.68 Hz), 3.76-3.75 (2 H, m), 3.50-3.48 (1 H, m), 3.37-3.35 (3 H, m), 3.24-3.22 (1 H, m), 2.59-2.53 (2 H, m), 1.45 (3 H, t, J=7.48 Hz), 1.34-1.30 (4 H, m), 1.26-1.15 (5 H, m)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][NH:5][N:4]=4)=[N:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CS(=O)(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NS(C)(=O)=O)[nH]c3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-methanesulfonamide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and Methansulfonylchloride (30 μl, 0.39 mmol). The title compound was obtained as off-white powder (30 mg, 24%).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][OH:8])=[O:2].C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O:8][CH2:7][CH2:6][C:5]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:4][NH:3][CH:1]=[O:2])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=CNCC(CCO)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(CNC=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a suspension of 4-formylamino-3,3-diphenylbutanol (21.5 g) in methylene chloride (250 ml) were added triethylamine (22 ml), 4-dimethylaminopyridine (catalyst amount) and tosyl chloride (15.3 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and dissolved in water-ethyl acetate. The ethyl acetate layer was washed with 1N-hydrochloric acid, further washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4:1~1:1) to provide the title compound (32 g) as colorless syrup.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:38]C1C=C(B(O)O)C=CC=1>>[Cl:38][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:2]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(Cl)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCOCc1ccccc1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a stirred solution of (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (209 g, 0.80 mol) in absolute CH2Cl2 (3 L) at 0° C. under N2 was added dropwise TiCl4 (92.2 mL, 0.84 mol) over 30 min. After 15 min, DIEA (0.864 mol) was added dropwise over 15 min, and stirring was continued for 1 h at 0° C. ((Chloromethoxy)methyl)benzene (222 mL, 1.60 mol) was added dropwise over 90 min at 0° C. After stirring for 20 h at 0° C., the reaction was quenched by addition of 10% aq NH4Cl (800 mL) and H2O (1 L). The aqueous phase was extracted with CH2Cl2 (2×1 L), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel to afford (R)-4-benzyl-3-((S)-2-(benzyloxymethyl)-3-methylbutanoyl)oxazolidin-2-one (152 g, 50%). 1H NMR (400 MHz, CDCl3): 0.99 (m, 6H), 2.05 (m, 1H), 2.67 (m, 1H), 3.23 (m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.14 (m, 3H), 4.52 (m, 2H), 4.72 (m, 1H), 7.26 (m, 10H).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 95 °C
Yield: 48.3 %

Procedure:
A mixture of intermediate 59 (5.0 g, 0.0136 mol), benzylamine (4.5 mL, 0.0407 mol) and MeOH (1 mL) is heated at 95° C. for 2 days. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-50:50) gives 2.81 g of the product 77. 1H NMR (CDCl3) δ 7.55-7.25 (m, 6 H), 7.10-6.85 (m, 8 H), 6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.14 (s, 9 H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[OH:12][CH:5]1[CH2:6][CH2:7][NH:8][C:9]2[N:10]=[CH:11][C:2]([C:25]3[CH:24]=[CH:23][C:22]([C:20]([N:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:21])=[CH:27][CH:26]=3)=[CH:3][C:4]1=2
Reactant: OC1CCNc2ncc(Br)cc21
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Yield: 49 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (300 mg) was reacted with (4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methanone (450 mg) as in General Procedure 13. Basic alumina chromatography using a gradient of 0-10% methanol/ethyl acetate as the eluting solvent gave the title compound as a white foam (49% yield). LCMS: m/z=353 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.78 (m, 1H), 2.19 (s, 3H), 2.32 (bs, 4H), 3.27 (m, 1H), 3.36 (m, 1H), 3.50 (bs, 4H), 4.65 (m, 1H), 5.27 (d, J=4.8 Hz, 1H), 6.81 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.71 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:15]=1[C:16]([O:18]CC)=O)C.C(O)(=O)C>O1CCCC1>[F:25][C:23]1[CH:24]=[C:14]2[C:15]([C:16]([OH:18])=[C:7]([C:6]#[N:8])[CH:12]=[N:13]2)=[CH:21][CH:22]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(F)cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cnc2cc(F)ccc2c1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
To a solution of 2.5 M n-butyl lithium in tetrahydrofuran (53.6 mL, 134 mmol) in 54 mL of tetrahydrofuran at −78° C. is added dropwise a solution of acetonitrile (7.1 mL, 136 mmol) in 100 mL of tetrahydrofuran. After stirring at −78° C. for 10 min, a solution of ethyl 2-{[(1E)-(dimethylamino)methylidene]amino}-4-fluorobenzoate (14.5 g, 60.9 mmol) in 100 mL of tetrahydrofuran is added over a period of 1.5 h. After stirring at −78° C. for 2 h, the reaction temperature is slowly allowed to warm to −10° C. The mixture is then cooled to −78° C. and acetic acid (18.3 g, 305 mmol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The precipitate is collected by filtration washing with tetrahydrofuran, water, diethyl ether, ethyl acetate and then additional diethyl ether to give 7.95 g of 7-fluoro-4-hydroxyquinoline-3-carbonitrile as an off-white solid, mp>250° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Cl.Cl.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH3:20]>ClC1C=CC=CC=1>[CH3:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[N:9]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2ccccc2c1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccc2ccccc2c1N1CCNCC1
Yield: 62 %

Procedure:
14.7 g (82.7 mM [sic]) of bis(2-chloroethyl)amine ×HCl were added to 13.0 g (82.7 mM [sic]) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene and refluxed under nitrogen for 90 h. The mixture was then concentrated and partitioned between methylene chloride and water at pH=9, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (silica gel, eluent/THF/methanol/ammonia 85/13/2. 11.6 g (62%) of product were isolated.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Reaction time: 1 h

Procedure:
A solution of 69.2 g of 15α-hydroxy-4-estrene-3,17-dione in 408 ml of pyridine is combined under ice cooling with 46.4 ml of benzoyl chloride and stirred for one hour under cooling. Then the mixture is combined with 5.7 ml of water and agitated for 3 hours at room temperature and precipitated into ice water. The thus-formed precipitate is filtered off, washed with water, and dried, thus yielding 98.7 g of 15α-benzoyloxy-4-estrene-3,17-dione.
Reaction SMILES: S(=O)(=O)(O)O.C([Si](C)(C)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([O:34]C3CCCCO3)[CH3:33])[CH:22]=2)=[CH:15][CH:14]=1)(C)(C)C>C1COCC1.O>[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([OH:34])[CH3:33])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(CO)cc2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.2 ml of concentrated sulphuric acid with 1 g (1.86 mmol) of tert-butyldimethyl-[4-(2-{3-[6-methyl-6-(tetrahydropyran-2-yloxy)heptyl]phenyl}vinyl)benzyloxy]silane in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 50-heptane 50), white crystals (m=350 mg; Y=56%) are obtained. m.p.=105-7° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (100 mg, 0.224 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.224 mmol), potassium carbonate (155 mg, 1.121 mmol) and Pd(Ph3P)4 (26 mg, 0.022 mmol) was added Dioxane (1120 μl) and Water (374 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material will be used as is for subsequent reactions. m/z (ESI) 504.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:11][CH:10]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reactant: OCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Oc2ccc(OCCCCCCCCCCCO)cc2)cc1
Temperature: 80 °C

Procedure:
9.3 g (0.042 mol) of 4-hydroxyphenyl 4-methylbenzoate are dissolved in 80 ml of absolute dimethylformamide (DMF), and 6.8 g (0.05 mol) of potassium carbonate are added. 11.3 g (0.045 mol) of 11-bromo-1-undecanol are then added, and the mixture is heated at 80° C. for 24 hours. During this time, a further 0.6 g of potassium carbonate is added. For work-up, the reaction mixture is poured into ice water and acidified by means of dilute hydrochloric acid, and the precipitate is filtered off with suction. The residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate and freed from solvent under reduced pressure. The product is purified by column chromatography (silica gel, eluent toluene/ethyl acetate 5:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:28]2[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CCN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In an ice bath under N2-atmosphere, 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster; 11.8 g, 50 mmol), CH2Cl2 (150 ml), a few drops of DMF and oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 3 h at rt. The resulting solution is concentrated in vacuo. The residue is dissolved in CH2Cl2 (170 ml) and added dropwise to an ice cooled solution of N-ethyl-piperazine (12.7 ml, 0.10 mol) in CH2Cl2 (100 ml). After stirring for 1 h at rt, the mixture is washed with a diluted solution of Na2CO3, 2 portions of water and finally brine. The aqueous layers are re-extracted twice with AcOEt, the combined organic phases dried (Na2SO4) and concentrated giving the title compound as an oil: MS: [M+1]+=332; 1H-NMR (CDCl3): 8.53 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 3.84 (m, 2H), 3.43 (m, 2H), 2.57 (m, 2H), 2.48 (q, 2H), 2.44 (m, 2H), 1.12 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
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: C1COCCO1
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
13.9 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1 mL of 1,4-dioxane, and 6.3 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of Na2CO3, and 0.2 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:ethanol=15:1) to obtain 3.2 mg (19.7% yield) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.C(O)(=O)C.[Zn]>[N:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:13][C:12]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:11][C:10]=2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2)c1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2)c1

Procedure:
To a solution of 4-[4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyridine in absolute ethanol (5 mL) and acetic acid (1 mL), zinc (300 mg) was added. The mixture was stirred and heated to reflux for 3 h. The mixture was dried up and treated with a small amount of 1 N HCl. After stirring for 1 h, the solution was brought to pH 14 using sodium hydroxide and extracted with DCM. The organic layer was dried with sodium sulfate and evaporated to driness. The solid material so obtained was purified by silica gel column chromatography eluting with ethyl acetate/hex/ammonium hydroxyde 8/2/0.1 yielding the title compound (52 mg, 59%).
Reaction SMILES: [C:1]([C:3]1(O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:25])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:3]1([F:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(F)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of phenylmethyl 3-cyano-3-hydroxy-1-pyrrolidinecarboxylate (1.8 g, 7.31 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.98 mL, 8.04 mmole). After 2 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (1.0 g, 55%) as a light orange oil: LC-MS (ES) m/e 249 (M+H)+.