Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[CH3:14][NH2:15]>CO>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:15][CH3:14]
Reactant: CN
Reactant: COc1cccc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cccc(OC)c1
Temperature: 100 °C

Procedure:
Crude 3-chloro-1-(3-methoxyphenoxy)propane (1.27 g, 6.33 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation, and saturated NaCl solution (50 mL) was added. The mixture was acidified to pH 1 with 10% HCl solution, and extracted with CHCl3 (4×25 mL) to remove impurities. The pH of the aqueous phase was adjusted to 7 with 10% NaOH solution, and the mixture was extracted with ether (4×30 mL) to remove impurities. The aqueous phase was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give a residue. The residue was briefly dried under high vacuum producing a light-brown oil (0.11 g). The oil was purified by column chromatography on silica gel (10 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2, v/v/v) to collect the product (Rf 0.27). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3, and the CHCl3 solution was dried (MgSO4), filtered and concentrated by rotary evaporation to a residue. The residue was dried briefly under vacuum to give 0.021 g (1.7%) of a light-brown oil. The compound exhibits a Ki of 5300 nM.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]1[N:25]=[C:24]([C:26]#[N:27])[C:23]([C:28](OC)=[O:29])=[C:22]([NH:32][C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)[N:21]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CCOC(C)=O>[O:29]=[C:28]1[C:23]2[C:22]([NH:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[N:21][C:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]3[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:25][C:24]=2[C:26]2([CH2:2][CH2:1]2)[NH:27]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1c(C#N)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC32CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethylmagnesium bromide (0.069 mL, 0.208 mmol) was added at RT to a solution of methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (50 mg, 0.104 mmol) and tetraisopropylorthotitanate (0.091 mL, 0.312 mmol) in Et2O (5 mL). The reaction mixture was stirred at RT for 20 h and was subsequently diluted with EtOAc. The organic phase was washed with saturated aq NaHCO3, brine and water, was dried then concentrated to give a pink residue, which was purified by reverse phase preparative HPLC. The fractions were collected and concentrated to a residue, which was used in next step. [M+H] calc'd for C26H34N6O3, 479. found, 479.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH2:22]C)=[CH:19][CH:18]=[C:17](C[N+]([O-])=O)[C:10]=1[CH:11]=[CH:12][CH2:13][N+]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=C(C[N+]([O-])=O)C=1C=CC[N+:41]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:10]=1[CH:11]=[C:12]([CH3:13])[NH:41]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Reactant: CCOc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Product: COc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Yield: 40 %

Procedure:
This compound is obtained according to the operating method described in Example 2b, in which the 2-benzyloxy-3-ethoxy-6,β-dinitromethylstyrene is replaced with 2-benzyloxy-3-methoxy-6,β-dinitromethylstyrene. A pale yellow powder (yield=40%, m.p.=74°-75° C.) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[N:17]=1>>[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:20][CH:19]=2)[N:17]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)cs1
Product: Cc1nc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)cs1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (27 mg, 0.19 mmol) and 4-(2-methylthiazol-4-yl)-benzoic acid (D87) (50 mg, 0.23 mmol) as a solid. MS(ES): MH+ 346, M-H+ 344
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12]2=[O:18].[N-:22]=[N+]=[N-].[Na+]>CO>[CH3:6][C:7]1[C:8]2[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12](=[O:18])[NH:22][C:13]=2[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: COC1=CC(=O)c2c(C)cc(C)cc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c(C)cc(C)cc2[nH]c1=O
Yield: 93.4 %

Procedure:
To stirred, ice bath cold, coned H2SO4 (14 mL, Baker), there was added 5,7-dimethyl-2-methoxynaphthalene-1,4-dione (1.00 g, 4.63 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (601 mg, 9.24 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (100 mL) to give a brown suspension. A solution of 30% MeOH/70% CHCl3 (90 mL) was added and vigorously stirred until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (~1 g). Crystallization from 95% EtOH (dissolved in 40 mL, hot filtered, concd to 25 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (678 mg, 63%, pure by 1H NMR); mp 237°-238° C.; 1H NMR (DMSO-d6) δ2.25 (s, 3H), 2.29 (s, 3H), 3.70 (s, 3H), 6.28 (s, 1H), 6.90 (s, 1H), 6.94 (s, 1H), 10.94 (s, 1H); 13C NMR (DMSO-d6) δ20.66, 56.04, 113.58, 118.69, 127.47, 128.10, 135.44, 137.45, 141.20, 153.83, 160.10, 190.53; IR (KBr) 3207 (m), 3003 (m), 2920 (m), 1682 (s), 1645 (s), 1619 (s), 1241 (m), 1224 (m), 855 (m); MS (m/z) 231 (M+, 100).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[OH-].[Na+]>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:17]
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1Cl
Yield: 87 %

Procedure:
To 0.97 g (˜0.01 mole) of freshly prepared N-methyl-aniline (b.p. 196° C.) is added 1.94 g (˜0.01 mole) of 2-chlorobenzenesulfonyl chloride (98 w/w %). The mixture is stirred until it becomes hot, and then ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. 2-chloro-N-methylbenzenesulfonanilide is formed as a viscous yellow liquid. It is washed with water several times until the wash water is neutral to litmus paper, and the viscous yellow liquid extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of a yellow oil is 2.2 g (87% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:21][C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:25][Si:24]([CH3:27])([CH3:26])[C:23]#[C:22][CH2:21][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: C[Si](C)(C)C#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCc1ccc2ccccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solution of LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at −78° C. and the reaction mixture was stirred for 1 hour at −78° C. Then (3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added to the reaction mixture, the solution was stirred for 18 hours at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%) of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[F:30])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Br[C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=[O:38]>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:15]([F:30])=[CH:16][C:17]([C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH:37]=[O:38])=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1ccccc1Br
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2C=O)cc1F

Procedure:
In analogy to example 262.2, (RS)-N-(4-cyano-benzyl)-2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-ethoxy-acetamide (example 262.1) was reacted with 2-bromobenzaldehyde to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-formyl-biphenyl-4-yl)-2-ethoxy-acetamide. Off-white solid. MS 435.0 ([M+H]+)
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:4]1[O:5][C:6]2[C:7](=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc2cc(C(C)=O)oc12
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12

Procedure:
reacting 2-acetyl-7-methoxybenzofuran with chlorosulfonic acid to produce 2-acetyl-7-methoxybenzofuran-4-sulfonyl chloride;
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Yield: 96.6 %

Procedure:
To a toluene (100 mL) solution of 6-bromo-pyridine-3-carbaldehyde (5.0 g, 27 mmol) described in Manufacturing Example 154-1-1 were added ethylene glycol (3.0 mL, 54 mmol) and p-toluenesulfonic acid monohydrate (512 mg, 2.7 mmol), which was refluxed for 3 hours and 40 minutes under nitrogen atmosphere. Sodium hydrogencarbonate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (6.0 g, 97%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1.[CH3:32][Sn:33]([N:36]=[N+:37]=[N-:38])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:36]([Sn:33]([CH3:35])([CH3:34])[CH3:32])[N:37]=[N:38][N:12]=3)=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C#N)cc34)cc3cccnc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnnn5[Sn](C)(C)C)cc34)cc3cccnc32)cc1
Yield: 84.3 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carbonitrile [100 mg, Reference Example 13(c)] in toluene (10 mL) was treated with trimethyltin azide (56 mg, 0.28 mmol) then heated under reflux for 14 hours. The white precipitate was collected by filtration washed with toluene (10 mL) and then dried to give the title compound (125 mg) as a colourless solid, m.p. 240–243° C. (with decomposition). MS: 633(MH+).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(N(CC)CC)C>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1csc(C2CCNC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)C1
Reaction time: 0.33 h

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-pyrrolidin-3-yl-thiophen-3-yl)-methanone (CC-177) (0.065 g, 0.19 mmol) was dissolved in triethylamine (2 mL) and acetic anhydride was added and the resulting mixture stirred for 20 minutes. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.029 g). LCMS m/z 361.20[M+H]+ RT=9.24 min (Analytical Method 2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[I-:39].[K+]>CC(C)=O>[I:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: ICc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 94.5 %

Procedure:
A mixture of 4.0 g of 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 2.2 g of potassium iodide in 50 ml of acetone is heated at reflux for 50 minutes. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with cold water and the resulting solid collected by filtration, washed with water and air dried to give 4.1 g of the desired product as a solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C@H:11]1[C@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(COCCOCCOCCO)OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 mL of CH2Cl2 and treated with 63 g of 4 Angstrom molecular sieves. After 1 h trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 ml, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate/AcOH/MeOH/water=60/3/3/2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M−H]−.
Reaction SMILES: [C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3](Cl)[CH3:4].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3]([O:21][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])[CH3:4]
Reactant: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Reactant: C=C(C)C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOC(=O)OC(C)OC(=O)C(=C)C
Yield: 76.8 %

Procedure:
1-Chloroethyl 2-methacryloyloxyethyl carbonate (1.183 g, 5.00 mmol) prepared as described in Example 7 is added to a suspension of freeze dried potassium methacrylate (0.683 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g (77%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.63 (3H, d, J=5 Hz, CH3 --CH), 1.98 (6H, s, 2×CH3), 4.42 (4H, s, 0--CH2 --CH2 --O), 5.62 (2H, m, CH=), 6.15 (2H, m, CH=), 6.84 (1H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1.Cl[C:45]1[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[C:28]([CH2:27][O:26][CH:14]3[CH:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:45]5[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=5)=[CH:8][CH:9]=4)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]3)[CH:37]=2)[CH2:32][CH2:33][C:34]1=[O:43]
Reactant: COc1cncnc1Cl
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCNc4ncncc4OC)cc3)cc21
Temperature: 90 °C
Reaction time: 20 h

Procedure:
The mixture of 0.200 g of tert-butyl 4-[4-(4-aminobutoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate, 0.058 g of 4-chloro-5-methoxypyrimidine, 0.0064 g of (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl, 0.387 g of sodium tert-butoxide and 0.0028 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex in 10 ml of toluene is stirred under argon at 90° C. over 20 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=4.60.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[C:21]([O:25][C:26](=[O:47])[NH:27][CH:28](S(C1C=CC=CC=1)(=O)=O)[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[Br:37])([CH3:24])([CH3:23])[CH3:22]>CC1CCCO1>[C:21]([O:25][C:26](=[O:47])[NH:27][CH:28]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[Br:37])[C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=1[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(c1ccc(C#N)cc1Br)S(=O)(=O)c1ccccc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)NC(C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(3-Trifluoromethyl-phenylamino)-cyclohex-2-enone (INTERMEDIATE 3, 10.7 g, 42 mmol) is suspended in 2-methyl-tetrahydrofurane (150 mL) and sodium hydride (60% in mineral oil) (1.76 g, 43.9 mmol) is added in portions. The mixture is stirred at room temperature for 20 min and [benzenesulfonyl-(2-bromo-4-cyano-phenyl)-methyl]-carbamic acid tert-butyl ester (INTERMEDIATE 19, 16.5 g, 36.6 mmol) is added. The mixture is stirred for 1 h at room temperature. The organic phase is washed with water, dried over MgSO4 and concentrated. The product is precipitated from cyclohexane. Yield: 20.6 g. ESI mass spectrum: [M+H]+=564 (bromine isotope pattern); Retention time HPLC: 0.81 min (X012_S02).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([C:25](O)(O)[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21](/[C:25](=[N:39]/[CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)/[C:26]([F:27])([F:29])[F:28])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C/N=C(/c2cc(C)c(-c3ccc4cc(NC(=O)[C@@H]5C[C@@H]5F)ncc4c3)cn2)C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
To a mixture of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (113.8 mg; 0.2614 mmol) and toluene (2 mL) was added a scoop of oven-dried 4 angstrom molecular sieves and a premixed solution of 4-methoxybenzylamine (54 μL; 0.393 mmol) and acetic acid (23 μL; 0.401 mmol) in toluene (1 mL). The reaction mixture was then heated at 100° C. for 3 days. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 99.7 mg of a 1:1 mixture of the title compound and unreacted starting material. LCMS (ESI): M +H=419.2.