Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[Mg]Br.CO>C1COCC1.C(Cl)Cl>[CH3:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:15]=1)=[O:9]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: COc1ccc([Mg]Br)c(C)c1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Yield: 54.9 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.6 g, 3.6 mmol) in THF (12 mL) was treated with a 0.65 M THF solution of 2-methyl-4-methoxyphenylmagnesium bromide (20 mL, 13.0 mmol) (prepared from 4-bromo-3-methylanisole, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 1.02 g (55%) of the title compound as a dark oil: 1H NMR d 1.46 (m, 2H), 1.63 (m, 4H), 2.26 (s, 3H), 2.54 (m, 4H), 2.79 (t, J=5.8 Hz, 2H), 3.47 (s, 3H), 3.89 (s, 3H), 4.12 (t, J=5.8 Hz, 2H), 6.60 (m, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.98 (dd, J=2.4, 8.9 Hz, 1H), 7.19 (d, J=9.3 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.69 (d, J=8.8 Hz, 2H); MS (FD) m/e 515 (M+); Anal. calc'd. for C31H33N1O4S1 : C, 72.20; H, 6.45; N, 2.72. Found: C, 72.50; H, 6.56; N, 2.80.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CC(O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: C1CCNC1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Yield: 45 %

Procedure:
To a suspension of 52 (444 mg, 0.98 mmol, crude material from the previous step) in iPrOH (10 ml) was added pyrrolidine (210 mg, 2.96 mmol) and the reaction mixture was refluxed for 4 hrs. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the resultant oil was purified by column chromatography (eluents EtOAc to 30% MeOH in EtOAc), to afford title compound 53 (200 mg, 45% yield) as an orange solid. MS (m/z): 450.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH:21]([NH2:24])([CH3:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:24][CH:21]([CH3:23])[CH3:22])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-(3,4-Dichloro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea intermediate (0.3 mmol) was taken up in tetrahydrofuran (5 ml) and isopropyl amine (20 eq.) was added. The reaction was stirred overnight at room temperature. Added a saturated solution of NaSO3 (40 ml). Extracted this with EtOAc twice. The combined organic extracts were dried over Na2SO4, filtered and solvent removed in vacuo. The crude 1-(3,4-dichlorobenzyl)-3-(4-((isopropylamino)methyl)thiazol-2-yl)urea was used as is.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C(OC)=O)=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Oc1c(C(=O)OC)ccc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of methyl 3-chloro-2-[(methoxycarbonyl)oxy]-4-(trifluoromethyl)benzoate (6.00 g) in methanol (60.0 mL) was added potassium carbonate (8.00 g), and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was filtered, the filtrate was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.50 g).
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]=1[NH2:29])([O-:16])=[O:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]=1[NH:29][C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-:16])=[O:15]
Reactant: Nc1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCC(=O)Nc1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of methyl 8-chloro-8-oxooctanoate (200 mg, 0.97 mmol) in DMF at 0° C. was added a solution of 4-nitrobiphenyl-3-amine (207 mg, 0.97 mmol) and triethylamine (0.46 mL, 3.3 mmol) in DMF drop-wise. The reaction was stirred overnight at room temperature, diluted with ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The separated organic layer was concentrated and purified by biotage column chromatography to give methyl 8-(4-nitrobiphenyl-3-ylamino)-8-oxooctanoate (279 mg)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.8 %

Procedure:
To a suspension of NaH (240 mg, 60–72%) in tetrahydrofuran (5 ml) was added 2,2,2-trifluoroethanol (500 mg, 5 mmol) at 0° C. After the mixture was stirred for 45 minutes at room temperature, t-butyl bromoacetate (0.9 ml, 6 mmol) was added and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude t-Butyl 2,2,2-trifluoroethoxyacetate (1.08 g, quant.).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CC(=O)N1CCN(Cc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2)CC1
Temperature: 140 °C
Yield: 96.3 %

Procedure:
In a microwave vial, 4-[(4-acetylpiperazin-1-yl)methyl]phenol (1.0 g, 4.3 mmol)—see EP 50298—, tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.0 g, 4.0 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) together with DMF (10 mL) was added. The mixture was heated in a microwave oven at 140° C. for 60 minutes. Water (40 mL) was added and the suspension was extracted with twice with EtOAc (50 mL). The combined organic phases were washed with brine, dried (Na2CO3) and the solvent was removed by evaporation. The residue was co-evaporated with toluene. There was obtained 1.5 g (68%) of 23A.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[I:21])[CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([C:15]2[CH:20]=[CH:19][N+:18]([O-:9])=[CH:17][C:16]=2[I:21])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Ic1cnccc1C1CC1
Solvent: ClCCl
Product: [O-][n+]1ccc(C2CC2)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
m-Chloroperbenzoic acid (408 mg, 2.36 mmol) was added to the solution of 4-cyclopropyl-3-iodopyridine (I-30a: 200 mg. 0.816 mmol) in DCM (10 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The reaction mixture was quenched with ice and diluted with DCM. The organic layer was washed with dilute NaOH solution, water and brine solution, dried over sodium sulphate and concentrated to afford 200 mg of the product (94.7% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)(=[O:15])[CH3:14].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])(=[O:15])[CH3:14]
Reactant: CC(=O)OCCCCCCCl
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
A mixture of 50 g (300 mmol) of 5-hydroxy-2-nitrobenzaldehyde, 59 g (330 mmol) 6-chlorohexanol acetate, 5 g of potassium iodide, and 50 g of potassium carbonate in 500 ml of dry DMF was heated to 100° C. under dry nitrogen for 3 h. The reaction was cooled, filtered and evaporated to a dark oil. The crude product was dissolved in 500 ml of ethyl acetate, and the organic layer was washed twice with 300 ml of saturated sodium carbonate, and twice with 300 ml of brine, dried filtered and evaporated. Distillation (180° C., 0.2 mm) gave a yellow oil which solidified on cooling, to yield 81.5 g (263 mmol, 88%) of 5-(6-acetoxyhexyl)oxy-2-nitrobenzaldehyde, m.p. 42°-43° C.
Reaction SMILES: COC(=O)[NH:4][CH2:5][CH:6]=[CH:7][C:8]1[NH:9][CH:10]([NH2:13])[NH:11][CH:12]=1>[OH-].[Na+]>[NH:9]1[C:8]2[C:12](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:11]=[C:10]1[NH2:13]
Reactant: COC(=O)NCC=CC1=CNC(N)N1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ncccc2[nH]1
Reaction time: 48 h
Yield: 29.8 %

Procedure:
20 mg (0.1 mmol) of the cis allyl amine 16 are dissolved in a 1M NaOH solution (2 ml). The mixture is left at ambient temperature for 48 h. This solution is extracted with BuOH (3×20 ml). The butanol phases are combined and evaporated to dryness. The residue is taken up in the minimum amount of methanol and then purified on preparative silica gel plates using the DCM/MeOH(NH3), 8/2, mixture as eluent. Compound 17 (4 mg) is obtained with a yield of 31%.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[NH2:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl (14R,18R)-14-(((9H-fluoren-9-yl)methoxy)carbonylamino)-18-(dodecyloxy)-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].CI.[C:15](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Reaction time: 12 h
Yield: 35.3 %

Procedure:
6.5 g of 4-nitroindazole (Chem. Ber. (1904), 37, 2583), 1.9 ml of methyl iodide and 14.4 g of cesium carbonate in 110 ml of DMF are stirred for 2 hours at 0° C. and then for 12 hours at room temperature. It is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. The residue is recrystallized from ethyl acetate/hexane. 2.49 g of 1-methyl-4-nitroindazole is obtained. The latter is hydrogenated in 70 ml of THF with 420 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 2.1 g of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH2:8]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]2[CH2:24][O:23]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+].[Cl-]>CN(C=O)C>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)=[CH:25][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: c1cc[nH]c1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.048 g (1.200 mmol) sodium hydride as 60% dispersion in mineral oil is suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and admixed with 0.077 g (1.15 mmol) pyrrole. Having stirred for one hour, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane (Kuliev et al. Uch. Zap. Azerb. Gos. Univ. Ser. Khim Nauk. 1964, 4, 97; Chem. Abstr. 1966, 65, 640c) in 10 ml absolute DMF is added drop-wise. The mixture is stirred for 19 hours, hydrolyzed with a semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator and washed three times with saturated NaCl solution. Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a red oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[C:8]([CH:10]=O)[O:9][C:5]=2[CH:4]=1.[CH3:14]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:10]([C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]=2[CH:7]=1)#[CH:14]
Reactant: COc1ccc2cc(C=O)oc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2ccc(OC)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A mixture of 6-methoxybenzofuran-2-carbaldehyde (0.21 g, 1.19 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.27 g, 1.43 mmol) and K2CO3 (0.33 g, 2.4 mmol) in anhydrous MeOH (5 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was taken in EtOAc (50 ml), washed with H2O and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the crude product (0.18 g; 88%), which was used in the next step without purification. 1H-NMR (CDCl3) 1.53 (s, 1H); 3.82 (s, 3H); 6.87 (dd, 1H, J=2.25, 8.58 Hz), 6.92 (s, 1H); 6.95 (d, 1H, J=2.01 Hz); 7.39 (d, 1H, J=8.61 Hz).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:25]4[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: OC1CCNCC1
Product: OC1CCN(Cc2ccc(N3CCC(CN4CCCC4)CC3)cc2)CC1

Procedure:
Prepared from the product of Example 9 and 4-hydroxypiperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)=[N:11][C:10]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([S:30]([CH3:29])(=[O:32])=[O:31])[C:12]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][O:23][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:20][CH2:21]2)=[N:11][C:10]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(N2CCC(CO)CC2)[nH]c(=O)c1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N2CCC(COS(C)(=O)=O)CC2)n(S(C)(=O)=O)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a solution of ethyl 5-(benzyloxy)-2-(4-(hydroxymethyl)piperidin-1-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.814 g, 2.1 mmol) in THF (20 mL) was added methanesulfonyl chloride (0.327 mL, 4.20 mmol) followed by Et3N (0.732 mL, 5.25 mmol). The resulting mixture was stirred at room temperature for 2.5 h (white solids precipitated out over the reaction time). The mixture was diluted with ethyl acetate (50 mL) and washed with water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to give the title compound as an amber oil (1.1320 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ: 7.44 (2H, d, J=7.32 Hz), 7.39-7.32 (3H, m), 4.98 (2H, s), 4.67-4.64 (2H, m), 4.35 (2H, q, J=7.1 Hz), 4.09 (2H, d, J=6.4 Hz), 3.46 (3H, s), 3.02 (3H, s), 2.91 (2H, td, J=12.9, 2.4 Hz), 2.08-2.00 (1H, m), 1.86-1.84 (2H, m), 1.35-1.28 (5H, m). LCMS (M+H) calcd for C22H30N3O9S2: 544.14; found: 544.30.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[CH3:10][C:11]1[CH2:15][C:14]2([CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[O:13][N:12]=1.O.O[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2N=N1.[C:35](NC1C=CC=CC=1)([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([C:33]1[CH:32]=[CH:31][C:30]([NH:26][C:21]([CH:18]2[CH2:17][CH2:16][C:14]3([O:13][N:12]=[C:11]([CH3:10])[CH2:15]3)[CH2:20][CH2:19]2)=[O:23])=[CH:29][CH:34]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)Nc1ccccc1
Reactant: CC1=NOC2(CCC(C(=O)O)CC2)C1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: O
Product: CC1=NOC2(CCC(C(=O)Nc3ccc(C(C)(C)C)cc3)CC2)C1
Reaction time: 8 h

Procedure:
N,N′-diisopropylcarbodiimide (96 mg, 0.76 mmol) was added to a solution of 3-methyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (150 mg, 0.76 mmol) in DCM (40 ml). The reaction mixture was mixed after 30 minutes with 1-hydroxybenzotriazole hydrate (HOBt, 101 mg, 0.76 mmol) and tert-butylaniline (113 mg, 0.76 mmol), stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc. The organic phase was washed successively with diluted aq. citric acid solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The desired product N-(4-tert-butylphenyl)-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxamide was obtained after purification by column chromatography (SiO2, hexane/EtOAc 1:1) as a diastereomer mixture in a yield of 66 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:38])([F:37])[F:36])[CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+].[C:47]1(B(O)O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>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.O>[CH3:32][N:31]([CH3:33])[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([NH:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:3][C:4]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:10])=[O:9])[CH2:14][CH2:15]2)[N:30]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reactant: OB(O)c1ccccc1
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: O
Solvent: CO
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(-c4ccccc4)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 130 °C
Reaction time: 10 h

Procedure:
To a solution of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide obtained in step H of example 1 (122 mg, 0.198 mmol) in toluene (2.7 mL) were added MeOH (0.9 mL), 2 M aqueous K2CO3 (0.9 mL), phenylboronic acid (29.0 mg, 0.237 mmol), and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol). The reaction mixture was stirred at 130° C. for 10 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography H-silica gel, 25% EtOAc in hexane and silica gel, 9% MeOH in CHCl3) to give trans-3-trifluoromethoxy-biphenyl-4-sulfonic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide (77 mg, 0.125 mmol) as a white solid.