Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5]O)(C)(C)C.[CH2:7]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C(CC(C)(C)C)(C)C>[CH2:7]([O:14][CH2:15][C@H:16]1[O:5][C@H:17]1[CH2:18][OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC/C=C\COCc1ccccc1
Reactant: CC(C)(C)OO
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: OC[C@@H]1O[C@@H]1COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 5.0 g of powdered 4A molecular sieves in 400 ml of dry CH2Cl2 was added 2.09 g (8.42 mmole) of Ti(Oi-Pr)4 and 2.76 g (11.8 mmole) of L(+)diisopropyl tartrate at O'C under argon. The mixture was allowed to stir for 10 min, cooled to -20° C., and 22.5 ml of 3.8M tert-butyl hydroperoxide in isooctane is added slowly at -20° C. The catalyst was allowed to "age" for 30 min. A solution of 7.50 g (42.1 mmole) of Z-4-(benzyloxy)-2-buten-1-ol in 15 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min and then added to the mixture at -20° C. over 10 min. The mixture was allowed to stand in a refrigerator at 2° C. for 8 days. The reaction mixture was removed from the refrigerator and 40 ml of H2O was added with stirring. After stirring for 30 min, 15 ml of 30% NaOH in saturated brine was added and the mixture was allowed to stir 60 min longer. The organic layer was separated and the aqueous layer washed twice with 50 ml of CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and evaporated to afford a milky, pale yellow oil. Distillation yielded 4.80 g of a clear viscous oil, bp 132°-5° C. (0.2 mm Hg). 1H NMR, δ7.4-7.2 (m, 5), 4.58 (dd, 2, J=12, 20 Hz), 3.7 (m, 4), 3.27 (ddd, 2, J=5, 10, 15 Hz), 1.98 (t, 1, J=6 Hz). Mass Spectra; EI; M+, Calc. 194.0942, Found 194.0929.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Br)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O-:13].[Na+].CO.Cl>CN(C)C=O.[Cu]Br>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Cu]Br
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Br)cc(C(=O)O)c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
A 3-necked flask was charged with 3,5-dibromobenzoic acid (1.0 g, 3.6 mmol), 4 M sodium methoxide solution in methanol (1.2 mL, 4.8 mmol), N,N-dimethylformamide (1.2 mL). The mixture was heated at 110° C. and then copper(I) bromide (51 mg, 0.36 mmol) was added. The mixture was stirred at 110° C. over 4 days. After cooling, the mixture was poured into 1N aq. HCl and adjusted to low pH, extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated to dryness. The crude product was used for the next step reaction without further purification. LC-MS: 231.2 [M−1]−.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]([Cu])#[N:21].CN(C)C=O.C(OCC)(=O)C>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]#[N:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1.621 g, 5 mmol; prepared as shown in Scheme 2, according to US 2004/0254215 A1; 1H NMR (200 MHz, CD3OD) δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4.49 (t, J=7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2 Hz, 3H)), CuCN (905 mg, 10 mmol) and dimethylformamide (20 mL) was refluxed with stirring under nitrogen for 5 min. After cooling to ambient temperature the mixture was diluted with water (300 mL). Then ethyl acetate (150 mL) was added and the mixture was shaken thoroughly for 5 min before it was filtered through a pad of celite. The organic phase of the filtrate was separated, and dried over MgSO4 before silica gel was added. The mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with dichloromethane gave the title compound as a yellowish solid (627 mg); MS-(−)-ion: M−1=269.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 27.4 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.50 g, 0.12 mmol), isobutyryl chloride (0.017 g, 0.15 mmol), TEA (0.042 g, 0.41 mmol) and DCM (10 mL) to afford 0.015 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.14-1.21 (m, 6H), 2.47 (m, 1H), 4.47 (s, 2H), 7.32-7.54 (m, 1H), 7.72 (d, J=8.7 Hz, 2H), 8.09 (br s, 1H), 8.18 (d, J=7.8 Hz, 2H), 8.70 (s, 1H); MS (m/z): 456.14 (M+H)+.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(C)C(O)/C=C/Br
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCC(C)(C)C(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 1.88 g. (8 moles) of 1-bromo-4,4-dimethyl-trans-1-octen-3-ol (Example 1174) with 2.58 g. (8 moles) of triphenylmethyl bromide in 20 ml. of pyridine and purification of Florisil, all as described in Example 728 gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)=[O:10])[C:3]=1[NH2:4].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:11]2[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=2)[OH:10])[C:3]=1[NH2:4]
Reactant: COc1cc(OC)nc(C(=O)c2cccc(F)c2N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(C(O)c2cccc(F)c2N)n1
Temperature: 5 °C
Yield: 98.5 %

Procedure:
2-Fluoro-6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]aniline 2.68 g (9.67 mmol) was dissolved in methanol 80 ml and, after cooling it to 5° C., sodium borohydride 0.73 g (19.33 mmol) was added thereto while stirring. Then the solution was stirred at room temperature for 2 hours. The reaction solution was distilled off under reduced pressure and the obtained crystals were dissolved in water and dichloromethane. The organic layer was separated and the water layer was further extracted three times with dichloromethane. After the organic layer had been washed with water and dried, dichloromethane was distilled off under reduced pressure to obtain the objective 2-fluoro-6-[(4,6-dimethoxypyrimidin-2-yl)hydroxymethyl]aniline 2.66 g (yield 98%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25](S(C3C=CC=CC=3)(=O)=O)[CH:24]=2)[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[NH:25][CH:24]=2)[CH:3]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3)c2c1
Temperature: 100 °C

Procedure:
A solution of Example 213d (0.500 g, 0.817 mmol) in dioxane (3.0 mL) was treated with 20% NaOH. The reaction mixture was heated at 100° C. for an hour. The solvent was evaporated and the residue was treated with water, sonicated, filtered, washed with water again, and oven-dried to give 0.289 g (75%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1([C:14]([F:17])([F:16])[F:15])[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:5][CH3:6].[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[O:29][CH3:30])=[CH:21][C:20]=1F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[O:29][CH3:30])=[CH:21][C:20]=1[O:13][CH:10]1[CH2:11][CH2:12][C:7]([CH:4]([NH2:3])[CH2:5][CH3:6])([C:14]([F:15])([F:16])[F:17])[CH2:8][CH2:9]1
Reactant: CCC(N)C1(C(F)(F)F)CCC(O)CC1
Reactant: COc1nccc2cc(F)c(Cl)cc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)C1(C(F)(F)F)CCC(Oc2cc3ccnc(OC)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
160 mg (4.00 mmol) of NaH were suspended using 3 ml of DMA and a solution of 300 mg (1.33 mmol) of 4-(1-Amino-propyl)-4-trifluoromethyl-cyclohexanol (74) in 3 ml of DMA added. The mixture was stirred for 1 h at ambient temperature. Afterwards, a solution of 282 mg (1.33 mmol) of 7-chloro-6-fluoro-1-methoxy-isoquinoline in 4 ml of DMA was added and the mixture was stirred for 3 h at ambient temperature. The mixture was then poured into 100 ml of a saturated aqueous solution of NaHCO3 and extracted three times using 50 ml of ethyl acetate each. The organic layer was washed twice using 50 ml of water, dried using MgSO4 and evaporated. Chromatography on silica gel using ethyl acetate/n-heptane, followed by chromatography on silica gel using t-butylmethyl ether/n-heptane 1:1+1% acetic acid yielded 162 mg of the desired product as the acetate. Rt=0.77 min (Method P).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B(F)(F)F.CSC.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COc1cc(Br)cc(CO)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of acid 56 (10.1 g, 38.0 mmol) in THF (100 mL) was added borontrifluoride-dimethylsulfide (14.4 mL, 152 mmol) dropwise at 0° C. under an atmosphere of nitrogen. The mixture was stirred at room temperature for 18 hours. MeOH was added to the reaction mixture dropwise at 0° C. The mixture was extracted with EtOAc/H2O (150 mL/150 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the crude alcohol 57 (9.50 g, 100%) as yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)(O)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:29]=1.[OH-].[Na+]>>[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:29]=1
Reactant: CSc1ccc2c(c1)CCc1cccnc1C2(O)C1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CSc1ccc2c(c1)CCc1cccnc1C2=C1CCN(C)CC1
Yield: 61.4 %

Procedure:
Thionyl chloride (6 ml) was added to 1.03 g of 8-methylthio-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol and the resulting mixture was refluxed for 1 hour. After the completion of the reaction, the reaction mixture was added with a 10% sodium hydroxide solution and then extracted with chloroform. The resultant extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1), 0.6 g of 8-methylthio-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 61%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([B:13]([OH:15])[OH:14])[C:9]([F:12])=[N:10][CH:11]=1.S([O-])([O-])(=O)=O.[Mg+2].O[C:23]([C:26](O)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([B:13]2[O:15][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:14]2)[C:9]([F:12])=[N:10][CH:11]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cc(C3OCCO3)cnc2F)OC1(C)C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (14.56 g, 68.4 mmol) was suspended in PhMe (300 mL) and anhydrous magnesium sulfate (41.223 g, 342 mmol) and pinacol (8.27 g, 70.0 mmol) were added. The reaction was stirred under nitrogen at room temperature over the weekend. The suspension was filtered, and the solid was washed with EtOAc. The filtrate was washed with brine (2×200 mL), and the organic phase was dried over sodium sulfate, filtered, concentrated and dried to give 19.19 g of 5-(1,3-dioxolan-2-yl)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a light yellow powder. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=2.54 Hz, 1H); 8.28 (dd, J=8.02 Hz, 2.54 Hz, 1H); 5.84 (s, 1H); 4.17-4.04 (m, 4H); 1.37 (s, 12H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1Cl)[CH3:10]>CS(C)=O>[CH3:10][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[CH3:8]
Reactant: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCNCCO
Solvent: CS(C)=O
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1N(CCO)CCO
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 41.5 %

Procedure:
Diethanolamine (5 g; 48.6 mmol) was added to a solution of 5 g (18.4 mmol) of N-[(N,N-dimethylamino)ethyl]-2-chloro-5-nitrobenzamide in 10 ml of DMSO, followed by stirring at 150° C. for 3.5 hours. After the resulting mixture was cooled to room temperature, it was extracted with ethyl acetate. Magnesium sulfate was added to the extract to dry the same, and the solvent was then distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate/methanol=1/0→1/1), whereby 2.6 g of the title compound were obtained as a colorless oil (yield: 38%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]2[C:5]([CH2:6][C:7]3[NH:8][C:9]4[C:14]([C:15]=32)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:17]=[C:16]2[C:5]([CH2:6][C@@H:7]3[C@H:15]2[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)-c1c([nH]c3ccccc13)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)[C@@H]1c3ccccc3N[C@@H]1C2
Temperature: 0 °C

Procedure:
5,6-Dihydro-9-fluoroindeno[2,1-b]indole (0.55 g, 2.5 mM) in glacial acetic acid (25 cm3) was stirred and treated with sodium cyanoborohydride (2.1 g, 36.5 mM) in small portions over 10 hours, maintaining the temperature below 18° C. The amount of the reducing agent appears crucial since mixtures form if more is added. The reaction mixture was then added to ice-water (100 cm3) and the yellow oil which was formed was separated from the aqueous phase. The pH of the aqueous phase was then adjusted to 6 by the addition of sodium carbonate (30 g), and the colourless oil which was liberated was extracted into diethyl ether (4×20 cm3). The combined extracts were dried and evaporated to yield an oil which was extracted with hot 60°-80° C. petroleum ether (6×10 cm3) and the residue triturated with ethanol (1 cm3). This treatment caused the compound to crystallise as a colourless prisms which recrystallised from ethanol to give the title compound. Yield: 60 mg, 11% M.p. 116°-117° C.; 1H NMR (CDCl3) δ: 3.06 (1H, dd, J=16.5 and 1.5 Hz), 3.31 (1H, dd, J=16.5 and 6.0 Hz), 3.67 (1H, br.s), 4.70 (1H, d, J=8.0 Hz), 4.82 (1H, ddd, J=8.0, 6.0 and 1.5 Hz), 6.43 (1H, dd, J=8.5 and 4.0 Hz), 6.70 (1H, ddd, J=8.5, 8.5 and 2.5 Hz), 7.07 (1H, dd, J=8.5 and 2.5 Hz), 7.16-7.25 (3H, m), 7.33 (1H, m).
Reaction SMILES: [Cl:1][C:2]1C=CC(SCCl)=CC=1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[CH3:12].CC(C)([O-])C.[K+].C1CCCCC=1>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][N:14]([C:11](=[O:13])[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCSc1ccc(Cl)cc1
Reactant: CC(=O)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1=CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N(CCl)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-Chloro-1-(chloromethylthio)benzene (30 mmol) was added to a mixture of acetanilide (30 mmol) and potassium tert-butoxide (30 mmol) in DMF (75 ml). The mixture was stirred at 80° C. for 2 hours before the solvent was distilled off, the residue dissolved in chloroform and washed three times with water. The dried solution (MgSO4) was evaporated and the residue dissolved in ether. Remaining acetanilide was precipitated by adding Pet. ether and the solution evaporated. Yield 3.0 g. (43%). The crude product (13 mmol) was dissolved in CH2Cl2 (40 ml) and SO2Cl2 (13 mmol) in CH2Cl2 (10 ml) was added with stirring at 5° C. over 5 minutes. The mixture was stirred for 10 minutes before cyclohexene (14 mmol in CH2Cl2 (10 ml) was added. After stirring for 10 minutes at 5° C. the mixture was evaporated and the residue washed with Pet. ether and dried. Yield 0.70 g (29%). The product was used in Example 32 without purification. 1H NMR (CDCl3, δ): 1.92 (CH3), 5.50 (--SCH2), 7.1-7.7 (Ph).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C@H:13](O)[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:26]([O:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:26]([O:29][N:30]([C@H:13]1[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[C:15]([CH3:16])=[C:14]1[CH3:17])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC1=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 110.5 %

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3,4-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 191, 1.73 g, 4.66 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 1.26 g, 4.89 mmol) following the procedure described for Intermediate 10. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as an off-white solid (3.15 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:8])[C:6]=1[Cl:7].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+].ClCCl>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].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.O1CCOCC1>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[CH:3]=[N:4][N:5]([CH3:8])[C:6]=3[Cl:7])[CH:28]=2)[NH:23][CH:22]=1)[CH3:20]
Reactant: Cn1ncc(Br)c1Cl
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C)c3Cl)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-5-chloro-1-methyl-1H-pyrazole (10.2 mg, 0.0522 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15 mg, 0.035 mmol), potassium carbonate (14.4 mg, 0.104 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (1.42 mg, 0.00174 mmol) in previously degassed 4:1 dioxane:water (1.0 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. The reaction was then charged with an additional 4-bromo-5-chloro-1-methyl-1H-pyrazole (10.2 mg, 0.0522 mmol) and charged with Pd(PPh3)4 (2.01 mg, 0.00174 mmol) and evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. A small water layer was removed from MW vial and the crude sample was purified by HPLC resulting the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 3.64 (br. s., 3H), 3.88 (s, 3H), 5.11 (d, J=6.8 Hz, 1H), 6.89 (dd, J=4.0, 8.6 Hz, 1H), 7.08 (dd, J=8.8, 8.8 Hz, 1H), 7.35 (s, 1H), 7.65-7.73 (m, 2H), 8.22-8.29 (m, 1H). MS (ES+): m/z 419.05, 421.03 (76/24) [MH+]. HPLC: tR=3.70 min (polar—5 min, ZQ3).
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([C:12]2[C:16](S(C3C=CC=CC=3)(=O)=O)=[N:15][O:14][N+:13]=2[O-:26])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C1COCC1>[O-:26][N+:13]1[O:14][N:15]=[C:16]([O:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]=1[S:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(c1ccccc1)c1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Aqueous 50% NaOH solution (6.4 g-80 mmol) is added in the course of 15 minutes to a solution, cooled to 15° C., of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (16 g-44 mmol) and tert-butyl 3-hydroxypropionate (10 g-68 mmol) in 200 ml of anhydrous THF. After stirring for 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is decanted off, washed with saturated NaCl solution, dried with sodium sulphate and evaporated.