Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O)=CC=1.O>CN(C=O)C.C(OCC)(=O)C>[F:25][C:24]([F:27])([F:26])[CH2:23][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
Sodium hydride (787 mg, 55%, 18.0 mmol) was suspended in DMF (10 mL) under a nitrogen atmosphere, and a solution of DMF (5 mL) containing 4-hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dropwise added thereto over 5 minutes at room temperature. A light yellow insoluble substance was precipitated immediately after the addition. After 5 minutes, a solution of DMF (5 mL) containing 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (4.00 g, 17.2 mmol) was added dropwise thereto to give a brown solution. This brown solution was stirred at room temperature for 1 hour, and then water (100 mL) and ethyl acetate (150 mL) were added thereto. The organic layer was separated, further washed with water (50 mL) five times, with a 10% sodium hydroxide aqueous solution (50 mL) three times, and with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a crude product. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1, v/v) to give 1.40 g of the title compound (light yellow oil, yield: 42%).
Reaction SMILES: [NH2-].[Na+].CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]#[N:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=2)[C:17]#[N:18])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 67.6 %

Procedure:
1.95 g of sodium amide are added in small quantities to an ether solution of 9.3 g of 3,4-dichlorophenylacetonitrile. The mixture is heated for 2 hours to reflux, 11.8 g of 2-(4-benzylpiperidino)-1-chloro ethane are added and heating is repeated for another 5 hours to reflux. The resulting mixture is cooled and 200 ml of water are added, after what the organic phase is decanted, washed with water and extracted with a 10% solution of hydrochloric acid. The aqueous phase is then neutralized with soda, extracted with ether, washed with water, dried over magnesium sulfate and evaporated. 13 g of oily product are thus obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[O:19][CH:20]=2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.ClC1C=C(C2N=C(CCC(O)=O)OC=2)C=C(C(F)(F)F)C=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:19][CH:20]=2)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1
Reactant: COC(=O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Agent: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: O=C(O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Yield: 71 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 47) by a procedure similar to the one described for 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (Reference example 52) to provide 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.094 g, 71%) as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:38])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])=[C:15]([C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:20]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:38])=[N:14][C:15]=2[C:26]#[C:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: Cc1noc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2cnccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)noc2C)c(C#Cc2ccc3cnccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-(2-isoquinolin-6-yl-ethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate E2a (191 mg, 0.36 mmol) and DCM:TFA (9:1, 10 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 101 mg (65%). HPLC-MS: M+H=426; tR=1.30 min (*Method—1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(C(=O)O)cnc2[nH]1
Yield: 91.7 %

Procedure:
A solution of ethyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-6-carboxylate (0.14 g) and 1N aqueous sodium hydroxide solution (6.5 ml) in ethanol (10 ml) was stirred at room temperature for 18 hr. The reaction mixture was adjusted with 1N hydrochloric acid to pH 4, and the precipitated crystals were collected by filtration, and washed with water and ethanol to give the title compound (0.12 g, yield 93%) as colorless crystals. purity 96%. M+H: 404. 1H NMR (DMSO-d6) (: 1.35 (6H, d, J=6.0 Hz), 4.70-4.78 (1H, m), 5.19 (2H, s), 7.35-7.53 (8H, m), 8.44 (1H, s), 8.92 (1H, s).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5](N)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([NH:1][C:2]([NH2:4])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCN
Reactant: NC(N)=O
Product: CCCCCCNC(N)=O

Procedure:
A mixture of 6.0 g (0.1 mole) of urea and 11.1 g (0.11 mole) of n-hexylamine was heated at 130°-135° C. for 4 hours to form monohexylurea. Without isolation, the reaction mixture was cooled to 70° C., and 31.0 g (0.21 mole) of chloral was slowly added while the temperature was maintained below 80° C. using external cooling. The reaction mixture was vigorously stirred and heated at 80°-85° C. for 1 hour. On cooling 43.9 g of a viscous syrupy product was isolated.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[C-:24]#N.[K+]>CC(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH:19]([CH3:24])[CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
934 mg (3 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are stirred at 60° C. for 48 hours with 198 mg (3 mmol) of potassium cyanide in 30 ml of dry 2-propanol. The mixture is evaporated in vacuo. The residue is treated with 30 ml of 2-propanol and 198 mg (3 mmol) of potassium cyanide and heated to boiling under reflux for 22 hours. After evaporation in vacuo, the residue is treated with water and extracted three times with 30 ml of chloroform each time. The combined chloroform phases are washed three times with 20 ml of water each time, dried over magnesium sulphate and evaporated. After recrystallisation from ethyl acetate/n-hexane, there is obtained isopropyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 207°-208° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](I)=[C:22]([F:27])[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:18])[N:8]([C@H:5]4[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[C:22]([F:27])[CH:21]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCNC2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (1.04 g, 0.00412 mol), 4-bromo-2-fluoro-1-iodobenzene (Aldrich, cat #: 283304) (1.85 g, 0.00615 mol), copper(I) iodide (Aldrich, cat #: 215554) (0.122 g, 0.000640 mol), potassium phosphate (2.63 g, 0.0124 mol) and 1,2-ethanediol (0.48 mL, 0.0086 mol) in 1-butanol (3.90 mL) was heated at 100° C. under nitrogen for 2 d. The reaction was quenched with water, and extracted with ether. The organic layers were combined, washed with water, brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column eluting with 0 to 5% methanol in DCM to yield the desired product (950 mg, 54.2%). LC/MS m/e 425.1/427.0 (M+H)+.
Reaction SMILES: CS(C)=[O:3].[OH-].[Na+].OO.[NH2:9][C:10]1([C:31]#[N:32])[CH2:15][CH2:14][N:13]([S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([NH:28][CH3:29])=[CH:23][C:22]=2[CH3:30])(=[O:18])=[O:17])[CH2:12][CH2:11]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO>[NH2:9][C:10]1([C:31]([NH2:32])=[O:3])[CH2:15][CH2:14][N:13]([S:16](/[CH:19]=[CH:20]/[C:21]2[C:22]([CH3:30])=[CH:23][C:24]([NH:28][CH3:29])=[CH:25][C:26]=2[CH3:27])(=[O:17])=[O:18])[CH2:12][CH2:11]1
Reactant: CS(C)=O
Reactant: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC(N)(C#N)CC2)c(C)c1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
DMSO (0.9 ml, 12.8 mmol), a 1 N aqueous NaOH solution (1.06 ml, 1.06 mmol) and 30% aqueous hydrogen peroxide (0.72 ml, 6.40 mmol) were sequentially added to a solution of 4-amino-1-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-piperidine-4-carbonitrile (1.85 g, 5.33 mmol) in MeOH (30 ml) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. A saturated Na2S2O3 solution was added to the reaction mixture, and the precipitated solid was obtained by suction filtration. The resulting solid was washed with water, dissolved in a CH2Cl2-MeOH (3:2) solution, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was triturated with hexane:CH2Cl2=4:1 to give 4-amino-1-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-piperidine-4-carboxylic amide (1.36 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:21]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CI.Cl>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[C@@H:17]([CH3:21])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: C[C@H]1c2onc(-c3ccc(Cl)cc3)c2CCC[C@H]1C(=O)O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.46 g (0.005 mol) of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid in 20 ml of tetrahydrofuran was added slowly at -70° C. to a solution of lithium diisopropylamide prepared by adding 4.4 ml of a 2.5M solution of n-butyllithium in hexane to 1.11 g (0.011 mol) of diisopropylamine in 20 ml of dry tetrahydrofuran at -70° C. After 15 minutes, 0.78 g of methyl iodide was added and the mixture was allowed to warm to 20° C. The mixture was added to water, acidified with 2N hydrochloric acid and extracted with diethyl ether. The resulting mixture of the cis- and trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-8-methyl-4H-cyclohept[d]isoxazole-7-carboxylic acid were separated by a combination of crystallization from acetic acid and chromatography on silica gel using toluene/methanol for the elution. There was obtained 0.4 g of cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-8-methyl-4H-cyclohept[ d]isoxazole-7-carboxylic acid of melting point 230°-233° C. (from acetic acid).
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CC(OC)(C)C>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Ic1ccc[se]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CCOc1ccc(-c2ccc[se]2)c(F)c1F

Procedure:
A mixture of 34.8 g (0.14 mol) of 2-iodoselenophene, 32.8 g (0.16 mol) of 4-ethoxy-2,3-difluorophenylboronic acid, 8.10 g (77.01 mmol) of tetrakis -(triphenylphosphine)palladium(0) and 300 ml of 2 N sodium carbonate soln. in 800 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. The mixture is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=15:1-10:1→5:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[ClH:14].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: COC(=O)c1ccc(F)c(CN)c1

Procedure:
Methyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride was prepared from methyl 3-cyano-4-fluorobenzoate in an analogous manner to Intermediate 2.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:8]=[CH:7][N:6]1[C:14]([CH3:17])([CH3:16])[CH3:15]>CCCCCC>[C:14]([N:6]1[CH:7]=[CH:8][N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[SiH:5]1[NH:3][CH2:1][CH3:2])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
In an argon atmosphere, 3.40 g (75.5 mmol) of ethylamine was dissolved in 30 mL of hexane, and a solution obtained by dissolving 5.78 g (24.8 mmol) of Si(tBuNCHCHNtBu)(H)Cl in 5 mL of hexane was added thereto at −20° C. After stirring at room temperature for 2 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 86° C./4.1×102 Pa) to obtain 1,3-di-tert-butyl-2-ethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHEt) as a pale yellow liquid (yielded amount: 5.77 g, yield: 96%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:26])=[O:10])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCCCCO
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC#CC(OCC)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of the product from example 22 in 15 ml of dry DMF was added in portions to a solution of pyridinium dichromate (4.4 g) in 30 ml of dry DMF. The solution was stirred at room temperature for 24 hours, then poured into water (300 ml). The aqueous mixture was extracted several times with Et2O, the combined extracts were washed with water and dried over Na2SO4. The reaction mixture was purified by column chromatography (SiO2) (1% MeOH/CHCl3). The partially purified product (0.54 g) was further purified by preparative thin layer chromatography (SiO2) (2%MeOH/CHCl3). Yield: 0.35 g.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>O>[Br:1][C:2]1[C:3]2[O:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(COc1ccccc1Br)c1ccccc1
Solvent: O
Product: Brc1cccc2c(-c3ccccc3)coc12
Reaction time: 4 h

Procedure:
Polyphosphoric acid (4200 g.) and alpha-(2-bromophenoxy)acetophenone from Example 1 (596 g., 2.05 mole) are heated and stirred well at about 120° to 125° C. internal temperature for four hours. The reaction mixture is then poured into stirred ice and water (about 8 l. total volume) to give a suspension of white solid. The solid is collected and washed with water, cold dilute sodium hydroxide solution and water until the wash is neutral. The solid is recrystallized from hexane to give white crystals of 7-bromo-3-phenylbenzofuran, m.p. 72°-74° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3].C([O:34][C@@H:35]([CH3:39])[C:36](Cl)=[O:37])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:36](=[O:37])[C@@H:35]([OH:34])[CH3:39])[CH2:29][CH2:30]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)[C@H](C)O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f17) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:25][C:26]([F:35])([F:34])[C:27](N1C=CN=C1)=[O:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:27](=[O:28])[C:26]([F:35])([F:34])[F:25])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CC(=O)c1ccc(Br)c(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
To a solution of 1-[4-bromo-3-(trifluoromethyl)phenyl]-1-ethanone (1.34 g, 5.65 mmol) in THF (30 ml) was added lithium bis(trimethylsilyl)amide (1.0 M THF solution, 6.8 ml, 6.8 mmol) at −78° C. The mixture was stirred at 0° C. for 15 minutes and the solution was again cooled to −78° C. N-trifluoroacetylimidazole (1.15 g, 6.78 mmol) was added to the solution at the same temperature. The resulting mixture was stirred at −78° C. for 15 minutes and at room temperature for 2.5 hours. The reaction was quenched with 2N HCl (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (200 ml), dried over MgSO4, and concentrated in vacuo to give 1.80 g (88%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:25]=[CH:24][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([O:34][C:35](=[O:40])[C:36](Br)([CH3:38])[CH3:37])[CH3:33].FC(F)(F)OC1C=CC(CBr)=CC=1>C(#N)C>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:25]=[CH:24][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][C:36]([CH3:38])([CH3:37])[C:35]([O:34][CH2:32][CH3:33])=[O:40])=[CH:21][CH:22]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc(CCNCc2ccc(-c3coc(C4CC4)n3)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3coc(C4CC4)n3)cc2)cc1
Yield: 74.9 %

Procedure:
To a warm solution of 4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenol (0.42 g, 1.25 mmol) in acetonitrile (6 ml) was added Cs2CO3 (1.34 g, 4.11 mmol) followed by ethyl-2-bromoisobutyrate (0.60 mL, 4.09 mmol). The mixture was heated at 80C for 20 h. Upon cooling, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (2×25 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (MeOH/EtOAc, 2:98) to yield ethyl 2-[4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.42 g, 74%).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(Cl)cccc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 21.2 g (99.2 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 150 ml tetrahydrofuran at 0° C. was added dropwise 38.0 ml (114 mmol) of a 3 M solution of ethylmagnesium bromide in ether at such a rate that the temperature of the reaction mixture was maintained below 20° C. After the addition was complete, the reaction mixture was stirred for a further 1 h at room temperature. The reaction mixture was then quenched by dropwise addition of water and diluted with ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 19.7 g (89%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 226.3 ([M+H]+, 30%), 224.3 ([M+H]+, 100%).