Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16]2[CH:21]=[C:20]([CH:22]=[CH2:23])[CH:19]=[CH:18][C:17]=2[O:24]COC)[C:13]([CH2:28][CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(S)CCCCCCCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Zn+2].[Br-].[Br-]>[Si:1]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16]2[CH:21]=[C:20]([CH:22]=[CH2:23])[CH:19]=[CH:18][C:17]=2[OH:24])[C:13]([CH2:28][CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(OCOC)c(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCCCCCCCCCCS
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: C=Cc1ccc(O)c(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2O[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a solution of 20 (1.3 g, 2.4 mmol) in CH2Cl2 (25 mL) at 0° C. was added ZnBr2 (0.59 g, 2.6 mmol) followed by 1-dodecane thiol (1.1 mL, 4.8 mmol). Then the reaction mixture was stirred for 10 minutes, diluted with CH2Cl2 (60 mL), then NaHCO3 (sat) solution was added dropwise and the mixture was filtered through a pad of celite. The aqueous layer was separated and further extracted with CH2Cl2. The combined organic solution was dried with Na2SO4, volatiles were removed in vacuo to provide crude product and column chromatography on silica gel using [hexane/EtOAc (90:10)] provided 21 (1.12 g, 2.22 mmol, 93%) as a clear liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])=[C:11](I)[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:4].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28](/[CH:29]=[CH:30]/[C:11]1[CH:12]=[C:13]2[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:7][C:8]2=[N:9][C:10]=1[N:15]([CH3:16])[S:17]([CH3:20])(=[O:19])=[O:18])#[N:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(/C=C/C#N)cc12
Yield: 70 %

Procedure:
2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (10 mg, 0.020 mmol), acrylonitrile (1.371 mg, 0.026 mmol), palladium(II) acetate (0.446 mg, 1.987 μmol) and triethylamine (2.77 μl, 0.020 mmol) in DMF (1 ml) were heated under microwave irradiation at 120° C. for 40 min. After LCMS showed predominant conversion to product, the reaction mixture was concentrated to dryness, taken up in DMF, filtered and purified by HPLC to afford the title compound (6 mg, 0.014 mmol, 70.5% yield). MS (ESI) m/z 429.3 (M+1). NMR (400 MHz, CD3CN) δ 8.51 (s, 1H), 8.06-8.03 (m, 2H), 7.94-7.89 (d, 1H, J=17 Hz), 7.34-7.30 (m, 2H), 6.91 (br s, 1H), 6.30-6.26 (d, 1H, J=17 Hz) (s, 1H), 3.31 (s, 3H), 3.12 (s, 3H), 2.91-2.89 (d, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)[OH:10].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(O)c1

Procedure:
In these examples and comparative examples, ethylbenzene was sulfonated with sulfuric acid in the presence of anhydrous sodium sulfate, isomerized, hydrolyzed (desulfonated), separated from excess sulfuric acid, neutralized and fused with an alkali to give m-ethylphenol. The composition of the reaction mixture in each step was examined, and the relationship with the quantity of sodium sulfate was investigated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10](I)=[C:9]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:8]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=2[N:7]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCCCCC.C(OCC)(=O)C>O1CCOCC1.O.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[N:3]=[CH:4][C:5]2[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])=[C:9]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:8]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=2[N:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(OCC)c1c(I)c2cnc(Cl)nc2n1CCNC(=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=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1c(-c2ccccc2C)c2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 64.6 %

Procedure:
To tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate (0.1 g, 0.19 mmole) in dioxane (3 mL) was added 2-Methylphenylboronic acid (28 mg), tetrakis(triphenylphosphine)palladium (25 mg) and 250 mg potassium phosphate in 0.3 mL water. Heat in a CEM Discovery microwave at 90° C. for 3 hrs. The crude reaction was loaded onto silica gel and columned using hexane/ethyl acetate (0-30%) to afford tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate (0.06 g). LCMS (ESI) 489 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1[CH:58]=[C:57](C)[CH:56]=[C:55](C(C)(C)C)[C:54]=1[OH:64])(C)(C)C>CN(C=O)C.[Pd].CO.ClCCl.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>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([CH:56]4[CH2:57][CH2:58][O:64][CH2:54][CH2:55]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with tri-n-butyl-(3,6-dihydro-2H-pyrin-4-yl)-stannane, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-methylphenol in DMF. Then hydrogenation using palladium on charcoal in methanol and dichloromethane. ES-MS m/e (%): 477 (M+Na+, 16), 455 (M+H+, 100).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+].O>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@H:6]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
In acetonitrile was dissolved 3 g of 2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide, and 2.88 g of dry sodium azide was added to the solution. The mixture was stirred at 60° C. for 4 hours. Water was added to the reaction and the mixture was extracted with chloroform. The chloroform layer was washed with water, dehydrated and subjected to silica gel column chromatography with a solvent system of chloroform-acetone (100:1) to obtain 1.36 g of 2,3,4-tri-O-acetyl-1-azido-1-deoxy-β-D-xylopyranose.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccncc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccncc1

Procedure:
Ethyl (E)-3-pyridin-4-ylprop-2-enoate (Method 8; 102.3 g, 576 mmol) in MeOH (300 ml) was hydrogenated using palladium on carbon 5% (9.0 g) under atmospheric pressure hydrogen for 72 hours. The catalyst was filtered off through diatomaceous earth and the filtrate concentrated to give a yellow oil. Yield 103.1 g (99%). NMR (300 MHz, CDCl3) 8.50 (d, 2H), 7.15 (d, 2H), 4.12 (q, 2H), 2.95 (t, 2.64 (t, 2H), 1.21 (t, 3H); m/z 180.4.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1ccccc1B(O)O
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccccc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (25 mg, 0.068 mmol), (2-methylphenyl)boronic acid (11.97 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.91 mg, 3.39 μmol) in ethanol (1 mL) and toluene (1 mL) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 30 min before being cooled to room temperature. The mixture was filtered through celite and the insoluble washed with EtOH. Most of the solvent was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 30 to 60% AcOEt in hexanes) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(2-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (24 mg, 0.063 mmol, 93%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCO
Reactant: FCc1cccc(Br)n1
Product: OCCC#Cc1cccc(CF)n1
Yield: 80.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(A), from 2-bromo-6-(fluoromethyl)pyridine (compound 190(E), 3.50 g, 18 mmol) and 3-butyn-1-ol (1.3 g, 18 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 2.60 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol as an orange solid (Yield: 79%).
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[C:22](Cl)([CH:24]=[CH2:25])=[O:23]>C1(C)C=CC=CC=1>[C:22]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])(=[O:23])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(c1ccccc1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1ccccc1C(C)(C)c1ccccc1
Reaction time: 2 h
Yield: 84 %

Procedure:
Cumylphenyl acrylate was prepared in the apparatus described in Example A. One mole of cumylphenol and 2 moles of calcium carbonate were slurried in the presence of 1 liter of toluene solvent. During a period of 2 hours, one mole of acryl chloride was added to the solution while the temperature was maintained at 40° to 50° C. The reaction mixture was filtered and the filtrate distilled at 5 mm Hg. to produce a pale yellow oil boiling at 198° to 203° C. The yield was 84%. Gas chromatographic assay indicated that less than 3% of unreacted cumyl phenol was retained in the product.
Reaction SMILES: ONC(=O)C=CC1C=CN(S(CC2C=CC=CC=2)(=O)=O)C=1.[CH3:22][N:23]([CH3:50])[C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:42][O:43]C3CCCCO3)=[O:41])=[CH:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>CO.O>[CH3:50][N:23]([CH3:22])[C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:42][OH:43])=[O:41])=[CH:34]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: O=C(C=Cc1ccn(S(=O)(=O)Cc2ccccc2)c1)NO
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 2. Starting materials: (E)-3-[1-(4-dimethylamino-benzene sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (compound A4) (0.200 g), methanol/water 3/2 (50 ml), amberlyst IR15 (0.402 g).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCNC(=O)c2ccc(Br)cc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
50 g of 4-bromo-N-[2-(3-methoxy-phenyl)-ethyl]-benzamide are dissolved in 750 ml of acetonitrile and treated under argon with 55 ml of phosphorus oxychloride. After heating to 80° C. the majority of the solvent is removed and the residue is adjusted to pH >12 with concentrated ammonia solution and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried and concentrated. There are obtained 46.4 g of 1-(4-bromo-phenyl)-6-methoxy-3,4-dihydro-isoquinoline, MS: m/e 314 (M+, 1 Br).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][NH:15][NH2:16]>CC(O)C>[CH3:14][N:15]1[C:2]2[C:3](=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)[C:4]([NH2:5])=[N:16]1
Reactant: CNN
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Solvent: CC(C)O
Product: Cn1nc(N)c2cc(C(F)(F)F)ccc21

Procedure:
2-Fluoro-5-trifluoromethyl-benzonitrile (Matrix, 6.5 g, 34.4 mmol) and methylhydrazine (Aldrich, 2.72 mL, 51.6 mmol) in IPA (10 mL) were heated to reflux for 2 hours. The solvent was removed to afford the title compound as white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]([CH2:15][OH:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:30][S:31]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[OH:16][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][S:31]([CH3:30])(=[O:32])=[O:33])=[CH:40][CH:39]=2)[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]=1[C:18]([F:21])([F:20])[F:19])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)CC(CO)NC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Product: CC(C)CC(CO)NC(=O)c1cc(-c2ccc(NS(C)(=O)=O)cc2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(1-hydroxymethyl-3-methyl-butyl)-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinamide and 4-methanesulfonylaminophenylboronic acid as starting materials, MS (ISP) 567.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:17])[CH:5]=[N:4]1.[CH3:24]N(C)C=O.[H-].[Na+].CI>C(OCC)C.O>[CH3:1][O:2][C:3]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]([CH3:24])[C:6](=[O:17])[CH:5]=[N:4]1
Reactant: CN(C)C=O
Reactant: COC1(c2ccccc2)N=CC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: COC1(c2ccccc2)N=CC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-methoxy-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (920 mg) and dry dimethylformamide (8 ml), sodium hydride (50% suspension in a mineral oil; 156 mg) is added under cooling at -30° C. for 15 minutes. Methyl iodide (842 mg) is added to the mixture, which is stirred at room temperature for 10 minutes. The reaction mixture is poured into icy water, and shaken with diethyl ether. The organic layer is dried over sodium sulfate and evaporated to remove the solvent. The residue is recrystallized from methylene chloride/isopropyl ether to give 5-methoxy-1methyl-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (708 mg) as fine prisms melting at 163 to 164° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:6]=1[O:17][CH3:18].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:23])[C:8]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:7][C:6]=1[O:17][CH3:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)Cc1ccc(C2CCCCC2)cc1OC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Cl)c(C2CCCCC2)cc1OC
Reaction time: 60 h

Procedure:
The (4-cyclohexyl-2-methyoxyphenyl)-acetic acid methylester obtained as above is dissolved in 500 ml of methylene chloride, and 5.5 ml of sulphuryl chloride and 200 mg of silica gel are added. After stirring at 22° for 60 hours, there is substantial evaporation, and the residue is chromatographed on 300 g of silica gel. A homogeneous product is extracted with methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)OC(C)(C)C
Product: COc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Following the general procedure using 4-methoxyiodobenzene (117 mg, 0.50 mmol) and tert-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred for 4 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil (113 mg, 97%).
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[Li]C(C)(C)C.[I:15][C:16]1[C:24]2[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=2)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:17]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[I:15][C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:3]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH2:4])=[CH:22][CH:23]=2)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:17]=1
Reactant: C=CC1(Br)C=CC=CC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccc2c(I)nn(COCC[Si](C)(C)C)c2c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 69.5 %

Procedure:
1-Bromostyrene (26 μL, 0.20 mmol, 2.0 equiv) was dissolved in THF (0.75 mL), cooled to −78° C. and was treated with t-BuLi (235 μL, 0.40 mmol, 1.70 M, 4.0 equiv). The mixture was allowed to warm to −42° C. for 10 min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol, 2.5 equiv). The resulting solution was allowed to warm to 23° C. with stirring for 25 min. This mix was added to a mixture of neat 3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (50 mg, 0.10 mmol, 1 equiv) and Pd(PPh3)4 (5 mg, 0.004 mmol, 0.04 equiv). After 10 min the reaction was determined to be complete by TLC monitoring and was quenched with saturated sodium bicarbonate. Organic material was extracted into ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (5:95 ethyl acetate-hexane) provided 3-Iodo-6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (33.1 mg, 70%): Rf sm 0.39, p 0.36 (ethyl acetate-hexane 1:9); 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, J=1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J=1.0 Hz), 5.57 (d, 1H, J=1.0 Hz), 3.58 (t, 2H, J=8.2 Hz), 0.88 (t, 2H, J=8.2 Hz), −0.09 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 477.0859. found 477.0866.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](C(O)=O)[S:8][C:7]=2[CH:14]=1)#[N:2].N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]1=2
Reactant: N#Cc1ccc2cc(C(=O)O)sc2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc2ccsc2c1

Procedure:
A microwave vial was charged with 6-cyanobenzo[b]thiophene-2-carboxylic acid (1.90 g, 9.35 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol) and N,N-dimethylacetamide (15 mL) and the reaction was subjected to microwave irradiation at 190° C. for 1 hour. After cooling, the reaction mixture was poured into 1N aq. HCl and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to get the product as light brown solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: O=Cc1ccccc1Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(Cc4ccccc4Cl)C3)cc1-2
Yield: 51 %

Procedure:
Following the procedure for 372, a mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) and 2-chlorobenzaldehyde gave 373 (123 mg, 51%). LCMS: RT=8.80 min, [M+H]+=492/494. 1H NMR δ (ppm) (CDCl3): 8.34 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.43 (1H, d, J=7.55 Hz), 7.33 (1H, dd, J=7.76, 1.47 Hz), 7.24-7.13 (3H, m), 7.01 (1H, d, J=8.25 Hz), 5.95-5.82 (1H, m), 4.40-4.34 (2H, m), 3.90-3.83 (2H, m), 3.85-3.76 (3H, m), 3.42-3.36 (2H, m), 3.35-3.28 (2H, m), 1.60 (6H, d, J=6.65 Hz)