Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10](C2CCC(CC(OCC)=O)CC2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC#N)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C([CH:90]2[CH2:95][CH2:94][CH:93]([CH2:96][C:97]([O:99][CH2:100][CH3:101])=[O:98])[CH2:92][CH2:91]2)C=1>>[CH3:1][Si:2]([CH3:38])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:95]2[CH2:90][CH2:91][CH2:92][CH:93]([CH2:96][C:97]([O:99][CH2:100][CH3:101])=[O:98])[CH2:94]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2ccnn12
Product: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:9]=1.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[OH:44].[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:44][C:38]3[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=3[F:36])=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[N:9]=1
Reactant: CN(C)S(=O)(=O)Cc1nc(S(C)(=O)=O)nc2c1c(-c1ccccc1Cl)nn2COCC[Si](C)(C)C
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Product: CN(C)S(=O)(=O)Cc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COCC[Si](C)(C)C

Procedure:
C-[3-(2-Chloro-phenyl)-6-methylsulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide (398 mg) was treated with 2,4-difluorophenol in the presence of KOH using the procedure of step 6 of Example 4 to afford 287 mg of C-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide. Mass Spec. M+H=610.
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[N:23]=[N:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(c2ccccc2)C(=O)N=N1
Yield: 33.9 %

Procedure:
Phenylmaleic anhydride (20 g, 115 mmol), sodium acetate trihydrate (18.75 g, 138 mmol), hydrazine monohydrate (6.68 ml, 133 mmol) and 40% aqueous acetic acid (400 ml) were heated at reflux for 15 h then allowed to cool. The reaction mixture was left to cool in the fridge for 1h. The solid produced was filtered and washed with water and diethyl ether before drying in a vacuum oven at 40° C. to give the required product (7.26 g). 1H NMR (250 MHz, DMSO) 8 3.43 (2H, broad peak), 7.17 (1H, s), 7.44 (3H, m), 7.81 (2H, m); MS (ES+) m/e 189 [MH+].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[H-].[Na+].[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:40]I)[CH3:24].O>CC(OC)(C)C>[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)=[N:27][C:26]=1[CH2:40][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)[CH3:24]
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](CO)C1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
300 mg of tert-butyl 2-((1R,3S)-3-hydroxymethylcyclohexylmethoxy)-2-methylpropionate are dissolved in 10 ml of MTBE, and 50 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 600 mg of 5-ethyl-4-iodomethyl-2-(4-trifluoromethylphenyl)oxazole are added, and the suspension is heated under reflux overnight. After addition of water and MTBE, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue is purified by preparative HPLC, resulting in 190 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]-cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][C:40](O)=[O:41])[C:34](=[O:43])[C:33]2=[O:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([O:29][CH3:28])=[CH:38][CH:37]=2)[C:33](=[O:44])[C:34]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.2 g, 0.476 mmol), 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.18635 g, 0.292 mmol, 61% yield). MS/ESI+ 637.19 [MH]+; [αD]=+60.39 c=0.155 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.41 (s, 2H), 7.22 (dd, 1H), 7.19-7.21 (m, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.89-6.98 (m, 2H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.62 (d, 1H), 4.54 (d, 1H), 3.89 (d, 2H), 3.81 (s, 3H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.09-1.37 (m, 1H), 0.51-0.67 (m, 2H), 0.28-0.47 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.C(Br)C#C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:41][C:37]#[CH:38])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: C#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C#CCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 30.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), propargyl bromide (0.111 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061 g (25%) of the title compound as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(=O)([O-])O.[Na+]>ClCCl>[CH:26]([NH:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCCCN(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
tert-Butyl (3-hydroxypropyl)methylcarbamate (430 mg, 2.27 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.633 mL, 4.55 mmol) and methanesulfonyl chloride (0.262 mL, 3.41 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Isopropylamine (1.3 g, 23 mmol) was further added, and then the mixture was stirred overnight at room temperature. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=9:1→1:1, v/v) to give the title compound (362 mg; yield, 73%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([OH:24])=[O:23].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([C:20]1[CH:19]=[C:18]([C:22]([OH:24])=[O:23])[NH:17][CH:21]=1)=[O:5]
Reactant: O=C(O)c1ccc[nH]1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a 120 mL DCM solution of 2,4,6-trifluorobenzoyl chloride (4.3 g, 0.022 mol) was added AlCl3 (8.8 g, 0.066 mol) under N2 at room temperature. After stirring for 15 min, 1H-pyrrole-2-carboxylic acid (2.4 g, 0.022 mol) was added in small portions over a 10 min period. After stirring at room temperature for 1 hr, the reaction mixture was treated with dropwise addition of ice-water (20 mL) and 1N HCl to adjust pH to 1, stirred for another 30 min, extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (5.8g, 97% yield). 1H-NMR (500 MHz, CDCl3): δ 12.48 (br.s, 1H), 7.48 (s, 1H), 7.28-7.38 (m, 2H), 6.83 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:31]1([C:37]2[S:41][CH:40]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[NH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:39]1[N:38]=[C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[S:41][C@@H:40]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(OCc1ccccc1)C1NN=C(c2ccccc2)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (3.1 g) and 1-hydroxybenzotriazole (1.7g) in dichloromethane (100ml) was treated with a solution of the product of step (a) (6.85g) in dichloromethane (25ml). A solution of dicyclohexylcarbodiimide (2.26g) in dichloromethane (20ml) was added over 20 minutes and the mixture was stirred at room temperature for 2 days under nitrogen.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][C@H:27]12>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:30][CH2:29][N:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]5[CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN5CCC[C@@H]5C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-octahydropyrrolo[1,2-a]pyrazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 4H) 2.33 (d, J=2.53 Hz, 3H) 2.81-4.24 (m, 9H) 7.64 (br. s., 1H) 7.75 (t, J=7.45 Hz, 1H) 7.95-8.83 (m, 4H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH:13]=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:12]=1[CH:13]=[O:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.10 mmol) and 2-fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2CO3 (46.62 g, 143.1 mmol) and the reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3×150 ml). The organics were combined, washed with water, brine (2×), dried over Na2SO4, filtered and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25° C. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off white solid. 1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CN1C(=O)CCC1>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:25][CH2:26]1)[CH3:15]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Cc1ccc2nc(Cl)nc(N)c2c1
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3nc(N)c4cc(C)ccc4n3)CC2)ccc1OC
Yield: 47 %

Procedure:
A solution of 2-chloro-6-methyl-quinazolin-4-ylamine (29.1 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 220° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 29.7 mg (39%) of the title compound. MS (ISP): 422.5 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(Br)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To chlorosulphonic acid (140 mL, 2 mol), cooled to 0-5° C., there added dropwise 35 ml (0.279 mol) of 4-bromoanisole. The solution is stirred for 30 minutes at 0° C. and then for about 16 hours at ambient temperature; it is poured slowly onto ice and is then stirred for a few more minutes. The white precipitate formed is filtered off and then washed with copious amounts of water.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][NH2:69]>CN(C=O)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:69][O:68][CH:63]3[CH2:64][CH2:65][CH2:66][CH2:67][O:62]3)=[O:39])=[CH:32]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reaction time: 1.5 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBtH2O (171 mg, 1.16 mmol) and triethylamine (2 ml) is dissolved in DMF (100 ml) at room temperature. After addition of EDC.HCl (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then it is added O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and addition of 200 ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.O.[OH-].[Li+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A mixture of 300 mg of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 66 mg of lithium hydroxide monohydrate, 2 ml of water and 6 ml of methanol was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 280 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 1).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:10])[CH2:7][CH2:8][OH:9].Br[CH2:12][CH:13]=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH2:12][O:9][CH2:8][CH2:7][CH2:6][OH:10]
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Reactant: OCCCO
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of n-butyllithium in hexanes (15.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to 1,3-propanediol (31 ml) on an ice-bath. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1, 1-bis(2-methylphenyl)-1-propene (11.5 g, 38 mmol), prepared in a similar way to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 48 h and at 75° C. for 36 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was washed with water (2×50 ml), dried (MgSO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (300 g) using a gradient of n-heptane in ethyl acetate as eluent provided 3.5 g (31%) of 3-(3,3-bis(2-methyl phenyl)-2-propen-1-yloxy)-1-propanol.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:16][C:17]1[C:22](F)=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].O>CN(C)C=O>[F:16][C:17]1[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=1[O:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Temperature: 50 °C
Yield: 44 %

Procedure:
To a suspension of sodium hydride (60% in oil, 6.4 g) in 50 ml of dry dimethylformamide was added, over a period of ten minutes, a solution of 25 g of 4-hydroxy-4-phenylpiperidine in 100 ml of dry dimethylformamide. After stirring at 50° C., for thirty minutes, the reaction mixture was cooled to ice bath temperature (5° C.). A solution of 18.6 ml of hexafluorobenzene in 100 ml of dry dimethylformamide was then added over a period of thirty minutes, and the resulting mixture stirred at ambient temperature for twenty hours. The mixture was poured into 500 ml water, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 20% methanol/dichloromethane) to afford 21 g (44%) of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine as an oil.