Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
Bromo-4-(trimethylsilyl)benzene (1.15 g, 5 mmol) was dissolved in THF (30 ml) and cooled to −78° C. Under argon a 1.6 M solution of n-butyl lithium in hexane (3.13 ml, 5 mmol) was added dropwise keeping the temperature below −70° C. The clear colorless solution was stirred at −78° C. for 15 min and DMF (1.156 ml, 15 mmol) was added quickly. The reaction temperature increased to −68° C. The reaction was stirred for additional 15 min at −78° C., quenched with 1N aqueous hydrogen chloride solution and extracted twice with diethyl ether. The combined organic layers were washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the product as a colorless oil (920 mg, 100%). The product was pure enough to be used directly in the next step. MS (ISP) 179.2 (M+H+). 1H NMR (CDCl3, 300 MHz): δ 10.02 (s, 1H) 7.84 (d, 2H), 7.69 (d, 2H), 0.31 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:8]1[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)([OH:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(C(F)(F)F)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-aminopropanol with 3-hydroxy-(3-(m-trifluoromethylphenyl)-)-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 2-(3-hydroxypropylamino)-3-(m-trifluoromethylphenyl)-3H-indol-3-ol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]5[S:27][C:26]([CH2:28][N:29]6[CH2:33][CH2:32][CH2:31][C@H:30]6CC(N)=O)=[CH:25][CH:24]=5)=[CH:21][N:22]=4)[CH:19]=3)=[CH:12][N:11]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[N:57]1C=CC=C[CH:58]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]5[S:27][C:26]([CH2:28][N:29]6[CH2:33][CH2:32][CH2:31][C@H:30]6[C:58]#[N:57])=[CH:25][CH:24]=5)=[CH:21][N:22]=4)[CH:19]=3)=[CH:12][N:11]([C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: c1ccncc1
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(CN5CCC[C@H]5CC(N)=O)s4)n3c2)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(CN5CCC[C@H]5C#N)s4)n3c2)cc1
Reaction time: 0.5 h

Procedure:
While 144 mg of (2S)-1-[(5-{6-[3-(4-cyanophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}-2-thienyl)methyl]tetrahydro-1H-2-pyrrole carboxyamide obtained in Example 35 was cooled in 1 mL tetrahydrofuran under ice-cooling, 0.05 mL pyridine and 0.57 mL trifluoroacetic anhydride were added thereto, and the mixture was stirred for 30 minutes. The solvent was removed, and the residue was purified with an NH silica gel column (hexane/ethyl acetate) to give 116 mg of the title compound (film)
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:25])[CH3:2].IC.[CH2:28]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[N:5]([CH3:28])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one was treated with iodomethane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 379 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C)C=O.N1C=CC=CC=1.[CH2:20]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1)[CH2:21][CH2:22][CH3:23]>O>[CH2:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:31])[CH2:28][CH2:29]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Oc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCC[C@H]1CC[C@H](C(=O)Oc2ccc(Br)cc2)CC1

Procedure:
26 g of 4-bromophenol, 100 ml of dimethylformamide, and 13 g of pyridine were dissolved. 31 g of commercially available trans-4-n-butylcyclohexane carboxylic acid chloride was added dropwise to the solution and the mixture was heated while stirring. The reaction mixture was poured into water to produce crystals. The crystals were collected by filtration, washed with dilute HCl and then water, dried in vacuum, and recrystallized from a mixed solvent of ethyl acetate and methanol to obtain 44 g of 4-bromophenyl trans-4-n-butylcyclohexane carboxylate. To this were added 20 g of 4-ethoxyphenyl acetylene, 0.09 g of bis(triphenylphosphine)-palladium(II) chloride, 0.1 g of copper iodide, 0.79 g of triphenylphosphine, and 260 ml of triethylamine, and the mixture was heated while stirring. After the reaction, the reaction product was poured into water and neutralized with HCl to produce crystals. The crystals were collected by filtration, washed with water, dried in vacuum, and recrystallized from a mixed solvent of ethyl acetate and methanol to obtain 40 g of a compound having the following formula. ##STR43##
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH3:28])=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: Cc1ccc(CBr)cc1
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methyl acetate and 4-methylbenzyl bromide in substantially the same manner, as described in step 3 of Example 4. The product was obtained as a white solid. Mass-spectrum (ESI, [M+H)+) m/z 400. 1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, 2H, J=8.34 Hz), 7.37 (t, 2H, J=7.19 Hz), 7.31 (d, 1H, J=7.30 Hz), 7.26 (d, 1H, J=7.56 Hz), 7.15 (d, 1H, J=2.44 Hz), 7.07 (d, 2H, J=8.76 Hz), 6.85 (d, 2H, J=8.81 Hz), 6.84 (s, 1H), 6.25 (s, 1H), 5.35 (s, 2H), 5.17 (s, 2H), 5.09 (s, 2H), 2.22 (s, 3H), 1.84 ppm (s, 3H).
Reaction SMILES: CC(NCC(O)C1C=CC(O)=C(CO)C=1)(C)C.C(C1C=CC=CC=1)(=O)C.Br[CH2:28][C:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])=[O:30].[CH3:41][C:42]([NH:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:44])[CH3:43]>>[CH3:44][C:42]([N:45]([CH2:28][C:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])=[O:30])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:41])[CH3:43]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(CBr)OC(=O)c1ccccc1O
Agent: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Solvent: CC(=O)c1ccccc1
Product: CC(C)(C)N(CC(=O)OC(=O)c1ccccc1O)Cc1ccccc1

Procedure:
Albuterol has been prepared, see Irish Patent Specification No. 31391, Aug. 9, 1972, starting from the appropriate acetophenone derivative methyl-5-(bromoacetyl-2-hydroxybenzoate, by condensation with N-(1,1-dimethylethyl)benzenemethanamine in the presence of base to form the ketonic ester, methyl-5[[(1,1-dimethylethyl)(phenylmethyl)-amino]acetyl-2-hydroxybenzoate. The ketonic ester is reduced with lithium aluminum hydride in tetrahydrofuran under nitrogen to yield α1-[[(1,1-dimethylethyl)-(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol which is subsequently debenzylated with hydrogen in the presence of palladium on carbon catalyst to produce albuterol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (0.100 g, 0.35 mmol) and triethylamine (0.10 mL, 0.71 mmol) in THF at 0° C. was added methanesulfonyl chloride (0.05 mL, 0.62 mmol) and the reaction stirred at 0° C. for 1 hour. The mixture was diluted with H2O and extracted with EtOAc, and the combined organic layers were washed with H2O, saturated aqueous NaHCO3, and brine. Dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:5][C:3](=[O:4])[C@@H:2]1[CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8][NH:1]1
Reactant: CO
Reactant: CC1(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC(C)(C)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Boc-Pro(4,4-diMe)-OH (0.5 g, 2.06 mmol) in anhydrous methanol (8 ml) was added dropwise thionylchloride (448 g, 6.18 mmol) and the reaction was stirred for six hours at room temperature. The reaction mixture was concentrated to an amorphous solid (377 mg, 95%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=3[CH:3]=[CH:2]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a solution of methyl indole-4-carboxylate (10.0 g, 57.1 mmol) was added sodium hydride (60% dispersion in mineral oil (5.7 g, 142.8 mmol) in DMF (200 mL) at 0° C. The mixture was stirred under an atmosphere of nitrogen for 15 min. To this were added 4-methoxybenzyl bromide (10.7 g, 68.5 mmol) and tetrabuylammonium iodide (3.2 g, 8.6 mmol). The resulting mixture continued to stir for 10 min and then warmed to room temperature and stirred for 2.5 h. The mixture was quenched with sat. aqueous ammonium chloride (200 mL) and extracted with diethyl ether (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 5 to 20% ethyl acetate in hexanes), providing methyl 1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.6 g, 98%) as a pale yellow oil: 1H NMR δ (500 MHz, CDCl3) 7.90 (d, J=10.0 Hz, 1H), 7.49 (d, J=1.0 Hz, 1H), 7.26-7.25 (m, 1H), 7.20 (t, J=10.0 Hz, 1H), 7.16-7.15 (m, 1H), 7.04 (d, J=10.0 Hz, 2H), 6.82 (d, J=10.0 Hz, 2H), 5.29 (s, 2H), 3.98 (s, 3H), 3.77 (s, 3H); MS (ESI+) m/z 296 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[O:5][C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][C:11]1[CH:10]=[C:9]([C:4]2[O:5][C:6]([CH2:7][O:8][S:24]([CH3:23])(=[O:26])=[O:25])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nc(C)c(CO)o2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C)c(COS(C)(=O)=O)o2)c1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
Cool (0° C.) a solution of [2-(3-methyl-phenyl)-4-methyl oxazol-5-yl]-methanol (Example 3, 756 mg, 4 mmol) in dichloromethane (16 mL) and add, sequentially, DMAP (51 mg, 0.4 mmol), triethylamine (552 μL, 4 mmol) and methanesulfonyl chloride (323 μL, 4.2 mmol). Stir the resulting solution for 5 min., remove the cooling bath and stir for 25 min. Dilute this solution with ether, wash with hydrochloric acid (5 mL, 2M), brine, dry over MgSO4 and concentrate to give the title compound (743 mg).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:33]1([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: NS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 85 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem.Soc.; 16; 1939; 100, 106) and morpholine and obtained in 85% yield. MS (m/e): 285.1 (MH− 100%).
Reaction SMILES: [NH2:1][C@@:2]([C:12]1[C:13]([F:19])=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1)([CH2:10][F:11])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[C:20]([N:28]=[C:29]=S)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O.O>[Br:18][C:16]1[CH:17]=[C:12]([C@:2]2([CH2:10][F:11])[CH2:3][C@@H:4]([C:5]([F:6])([F:8])[F:7])[O:9][C:29]([NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:1]2)[C:13]([F:19])=[N:14][CH:15]=1
Reactant: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Reactant: O=C(N=C=S)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1=N[C@](CF)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
(2S,4S)-4-amino-4-(5-bromo-2-fluoropyridin-3-yl)-1,1,1,5-tetrafluoropentan-2-ol (2.83 g, 8.11 mmol) in MeCN (70 mL) was added benzoyl isothiocyanate (1.20 ml, 8.92 mmol) and the mixture was stirred at room temperature for 1 h. N,N′-dicyclohexylcarbodiimide (1.840 g, 8.92 mmol) and diisopropylethylamine (2.82 ml, 16.21 mmol) were added. The mixture was stirred at 50° C. for 7 h. The reaction was worked up with water and EtOAc. The separated organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 0-25% EtOAc/hexane to give N-((4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.27 g, 4.75 mmol, 58.6% yield). MS m/z=479.8 [M+H]+. Calculated for C18H13BrF5N3O2: 478.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2.[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[N:16]([CH2:37][CH2:38][O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2
Reactant: COCOc1ccc(-c2[nH]c3cc(C(=O)OC)ccc3c2C2CCCCC2)c(OCOC)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2CCOC2CCCCO2)c(OCOC)c1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (16.9 g, 37.3 mmol) in N,N-dimethylformamide (120 ml) was added sodium hydride (2.1 g, 52.2 mmol) under ice-cooling, and the mixture was stirred for 20 min. To the reaction mixture was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (8.5 ml, 55.9 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The obtained compound was used in Step 5 without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CO>[N:11]1([CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Product: O=C(Cn1ccnc1)c1ccccc1
Yield: 60 %

Procedure:
Phenacyl bromide (0.05 mol) and imidazole (0.02 mol) were stirred in methanol (50 ml) at 0° for 3 hours. The methanol was removed in vacuo and the residue taken up in methylene chloride (300 ml), washed with water (3 × 100 ml), and dried (anhydrous sodium sulphate). Removal of the solvent left a solid residue which on recrystallisation from ethyl acetate gave 2-(imidazol-1-yl)-acetophenone (60%) as light brown needles, m.p. 112°-113°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:23]([CH3:25])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a8) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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.ClC1C=CC(B(O)O)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 140 °C
Yield: 107.4 %

Procedure:
A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol), 4-chlorophenylboronic acid (1.72 g, 11 mmol) and Pd(Ph3P)4 (462 mg, 0.4 mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene (10 mL) was heated at 140 ° C. in a microwave oven for 30 min. Analysis by HPLC/MS indicated that the reaction was not complete. Additonal 4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed by Pd(Ph3P)4 (116 mg, 0.1 mmol). The reaction mixture was again heated at 140° C. in a microwave oven for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanes to afford 2.6 g of the product (˜60% pure) as an off-white solid. This was crystallized in EtOAc-hexanes to obtain the pure title compound (0.9 g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]+=242.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Product: O=Cc1cccc(-c2cccs2)c1
Yield: 93 %

Procedure:
Ex-42A: 3-(Thiophen-2-yl)-benzaldehyde was prepared from 3-bromobenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 93% yield. 1H-NMR (CDCl3) δ 10.06 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.55 (dd, J=7.2, 8.4 Hz, 1H), 7.40 (dd, J=1.5, 3.6 Hz, 1H), 7.34 (dd, J=1.5, 5.3 Hz, 1H), 7.11 (dd, J=3.6, 5.3 Hz, 1H). HRMS m/z: calc. 188.0296. found 188.0293.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1CCNCC1)C(CCCc1ccccc1)CCCc1ccccc1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (1-benzyl-piperidin-4-yl)-amide (23) (0.5 g; 1.07 mmol) is combined with ethanol (25 mL) and 20% Pd(OH)2 on carbon (0.2 g) in a hydrogenation bottle. The mixture is hydrogenated at 50 psi for 18 hours then filtered through a celite pad and washed with ethanol. The combined filtrate plus wash is concentrated in vacuo affording the desired product (0.38 g) as an oil. ESMS:MH+ 379.4 (base).