Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Temperature: 25 °C
Yield: 87 %

Procedure:
A 2 L 3-neck round bottom flask is charged with 1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (215 g, 0.88 mol) and dimethylformamide dimethylacetal (1.1 L). The mixture is refluxed for 5 hours and then cooled to room temperature. Solvent is removed under vacuum, and the resulting solid is filtered and washed with MTBE (methyl tert-butyl ether) to give the desired product (229.0 g) in 87% yield as light yellow solid. M.p.=187-189° C.; 300 MHz 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.72-7.64 (m, 3H), 7.46 (s, 1H), 7.13-7.10 (m, 2H), 5.19 (d, J=12.5 Hz, 1H), 3.07 (bs, 3H), 2.55 (bs, 3H). LCMS: 300 [M+H]. Calc. for C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04; found. C, 64.22; H, 4.31; N, 14.10.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([O-:8])=O)[CH3:2].[C:11]([O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:11]([O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:6](=[O:8])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)C(C)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Monoethylmethylmalonate [prepared according to the procedure of Organic Syntheses, 37, 34 (1957)](2.92 g.) and L-proline tert.-butyl ester (3.42 g.) are dissolved in dichloromethane (80 ml.). The solution is chilled with stirring in an ice bath. Dicyclohexylcarbodiimide (4.12 g.) is added and the mixture is stirred 15 minutes in the ice bath and 16 hours at room temperature. The precipitate is filtered off and the filtrate concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed with 5% aqueous potassium bisulfate, water, saturated sodium bicarbonate and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 1-(2-ethoxycarbonylpropanoyl)-L-proline tert.-butyl ester, yield 5.9 g.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:6]=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[Cl-].[Na+]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@@H:7]1[CH2:8][C@H:4]([NH2:1])[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](N=[N+]=[N-])C1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](N)C1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
934 mg (3.90 mmol) of ((1R,4S)-4-azido-cyclopent-2-enyloxy)-tert-butyl-dimethyl-silane (35) were dissolved in 16 mL of tetrahydrofuran and 1.13 g (4.29 mmol) of triphenylphosphine were added. After the addition of 2 mL of water, the reaction mixture was stirred at room temperature, until the reaction was complete. Sat. sodium chloride solution was added, the layers separated and the organic layer was evaporated in vacuo. The crude product was purified by silica gel chromatography to yield 890 mg of the title compound (36). Rt=1.02 min (Method C). Detected mass: 214.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.[CH2:60]([SH:64])[CH2:61][CH2:62][SH:63].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[SH:63][CH2:62][CH2:61][CH2:60][S:64][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: CC(C)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N1CCOCC1
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
3.5 g (9.0 mmol) of 1-(4'-Bromo-biphenyl-4-yl)-2-methyl-2-morpholin-4-yl-propan-1-one (prepared by the method described in EP-A-3002) and 5.4 ml (54 mmol) of 1,3-propanedithiol are dissolved in 50 ml of dimethylacetamide, and the solution is stirred at around 140° C. together with 2.5 g of potassium carbonate for 2.5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with methylene chloride, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.35 (s, 6H), 1.38 (t, 1H), 1.98 (tt, 2H), 2.61 (t, 4H), 2.69 (dt, 2H), 3.11 (t, 2H), 3.72 (t, 4H), 7.42 (d, 2H), 7.51 (d, 2H), 7.62 (d, 2H), 8.63 (d, 2H).
Reaction SMILES: [B-][N+](C)(C)C.Cl.[NH:7]1[C:15]2[C:10](=[C:11]([CH:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.O>O1CCOCC1>[NH:7]1[C:15]2[C:10](=[C:11]([CH:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)NCC(O)c1cccc2[nH]ccc12
Agent: Cl
Agent: [B-][N+](C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)NCC(O)c1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
35.5 g of borane-trimethylamine complex and then, slowly and while cooling to 10° C., 40.55 ml of 12N hydrochloric acid aqueous solution were added to a solution of 22.8 g of the product of Step A in 570 ml of dioxane and the mixture was stirred for 16 hours at ambient temperature. It was poured into 1,500 ml of water, washed with ethyl acetate, made alkaline with 48 ml of concentrated ammonia and was extracted with ethyl acetate. The organic phases were dried, filtered and evaporated to dryness to obtain 22.6 g of methyl N-[2-(2,3-dihydro-1H-indol-4-yl)-2-hydroxyethyl]carbamate which was crystallized from methanol to obtain 13.125 g of the product melting at ≃174° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](OCC)=[O:14])[CH:10]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([CH2:18][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C(=O)N1CCC(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 6.4 g (14.6 mmol) of 1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine in 60 mL of THF at 0° C. was added 17.5 mL (17.5 mmol) of a 1M solution of lithium aluminum hydride (LAH) in ether and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with SN NaOH. The reaction mixture was extracted with ether and the combined organic fractions were washed with 5N NaOH solution. The organic fractions were dried over Na2SO4, filtered and the filtrate was purified by chromatography [silica, hexanes:ethyl acetate:(2N NH3 in MeOH), 10:10:1] to give 4.7 g of the title compound. Spectrum (ESI) m/e=383 (M+1). 1H NMR (CDCl3) δc7.31-7.33 (m, 4 H), 7.26-7.28 (m, 1H), 7.16-7.19 (m, 2H), 6.97 (t, 2H, J=8.5 Hz), 3.63-3.66 (m, 2H), 3.57 (d, 1H, J=13Hz), 3.43 (t, 1H, J=10 Hz), 3.22 (d, 1H, J=11 Hz),2.97 (d, 1H, J=11 Hz), 2.80 (d of d, 1H, J=8.5, 7.5 Hz), 2.76 (t, 1H, J=9 Hz), 2.12-2.54 (m, 8 H), 2.02 (t of d, 1H, J=2.5, 12 Hz), 1.75-1.85 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH3:6])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:20])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)C.C(O)(=O)C.CS(C)=O.C1COCC1>[CH:1]1([CH2:4][CH:5]([N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:19](=[O:20])[C:18]3[CH:28]=[CH:29][C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=4)=[N:16][CH:17]=3)[CH2:27][CH2:26]2)[CH3:6])[CH2:3][CH2:2]1
Reactant: CC(=O)CC1CC1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CC1CC1)N1CCC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-cyclopropylpropan-2-one (0.2 mL, 0.08 mmol in 1:1 THF:DMSO) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (in 1:1 THF:DMSO, 0.2 mL, 0.08 mmol), sodium triacetoxyborohydride dispersion (0.33 mL, 2.5 eq, in 1:1 THF:DMSO) and glacial acetic acid (0.01 mL). The reaction mixture was stirred at room temperature for 16-24 h and then aqueous K2CO3 (3 M, 0.2 mL) and ethanol (0.55 mL) was added. The reaction was shaken for 30 min and then the mixture was filtered and the filtrate concentrated and the residue purified by RP-HPLC to give the desired product. LC/MS=382.4 (M+H) observed, 382.23 expected.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH:28]=O)[N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[N:19]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(NCc2cc3c(nn2)OCCO3)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of phenylmethyl 4-amino-1-piperidinecarboxylate (for a synthesis see WO 2004/058144 Example 99(e)) (14.4 g crude, equivalent to 11 g, 47 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (for a preparation see Example 6(e)) (6.46 g, 39 mmol) in DCM (200 ml) and MeOH (10 ml) was stirred for 4 h at rt, then cooled in ice as sodium triacetoxyborohydride (12.4 g) was added over 15 min. After stirring for another 2 h, the mixture was treated with aqueous sodium bicarbonate to neutralise. The aqueous phase was extracted with DCM and the organic fractions were dried and evaporated. Chromatography on silica (750 g), eluting with 0-10% MeOH/DCM, gave the product (11.1 g, 62%).
Reaction SMILES: C([C:6]([CH:22](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:31][C:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34][C:32]1[N:33]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:22][N:31]=1
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Reactant: N=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxyphenyl)propionitrile (7.9 g, 0.02 mol) and an equivalent amount of potassium hydroxide in ethanol (50 ml) was heated at reflux for one hour. A solution of guanidine (0.07 mol) in ethanol (50 ml) was added, and reflux was resumed. Some ethanol was allowed to boil off bringing the reaction temperature up to 85°. After about 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol. The crude product was purified by treating with hot aqueous acetic acid and reprecipitation with ammonium hydroxide. The yield of purified trimethoprim (m.p. 197°-198°) was 3.6g (62%), its identity being confirmed by an NMR spectrum.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([CH3:21])[CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([CH3:21])[CH2:13][C:12]=3[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC2CCC3=C(C2)CC(C)C(=O)N3)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1CC2=C(CCC(Cc3ccc(O)cc3)C2)NC1=O
Yield: 81.9 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-methoxyphenyl)methyl)-3-methylquinolin-2[1H]-one (2.85 g) prepared according to Example 1 (2.85 g) was suspended in dichloromethane (5 ml) and cooled with ice and boron tribromide (3.3 ml) was added. The mixture was left to stir until tlc (SiO2 /chloroform) showed no starting material remained and then the mixture was quenched by slow addition of water (10 ml). The reaction mixture was further diluted with water and the resulting solid was isolated by filtration. The solid was dissolved in methanol (100 ml) and concentrated HCl (1 ml) was added. The methanol was removed under reduced pressure and the procedure repeated three times. The solid was suspended in ethyl acetate, filtered and washed with ether to give the hemihydrate of the title compound (2.22 g), mp.230°-235° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[NH3:13]>CO>[NH2:1][C:2]1[C:3]([C:9]([NH2:13])=[O:11])=[N:4][C:5]([F:8])=[CH:6][N:7]=1
Reactant: N
Reactant: COC(=O)c1nc(F)cnc1N
Solvent: CO
Product: NC(=O)c1nc(F)cnc1N
Reaction time: 4.5 h

Procedure:
In 1 mL of methanol was dissolved 10 mg of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate. After adding 1 mL of 25% aqueous ammonia at room temperature, the mixture thus formed was stirred for 4.5 hours. After removing the solvent under reduced pressure, diethyl ether was added to the residue, and the deposited precipitate was filtered off. Thus, 4 mg of 3-amino-6-fluoro-2-pyrazinecarboxamide was obtained as a light yellow-colored solid product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5][N:4]=1.[OH-].[Li+]>C(O)C>[NH:9]([C:7]1[C:6]([C:16]([OH:18])=[O:17])=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1

Procedure:
A solution of ethyl 2-(methylthio)-4-(phenylamino)pyrimidine-5-carboxylate (4.0 g, prepared according to the reported preparation in Barvian, M.; et al. J. Med. Chem. 2000, 43, 4606) in ethanol (50 mL) was treated with 2 N lithium hydroxide (50 mL) at room temperature for 16 hours. The reaction mixture was washed with ether and then brought to pH 6 via the addition of 1 N hydrochloric acid. The resulting precipitate was collected by filtration, azeotroped with toluene and dried under vacuum to obtain the title compound (2.2 g) having the following physical data.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[CH3:19][O:20][C:21]([CH3:32])([C@H:23]([OH:31])[C@@H:24]([OH:30])[C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH3:22]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:30][C@@H:24]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])[C@H:23]([C:21]([CH3:32])([O:20][CH3:19])[CH3:22])[O:31]1)[CH:2]=[CH2:3]
Reactant: COC(C)(C)[C@H](O)[C@@H](O)C(C)(C)OC
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC[Si]1(Cl)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
Preparation of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-[1,3,2]dioxasilolane: To a cooled (0° C.) solution of allyltrichlorosilane (7.0 mL; 48 mmol) in CH2Cl2 (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15 mL; 102 mmol). A solution of (3R,4R)-2,5-dimethoxy-2,5-dimethyl-hexane-3,4-diol (10.0 g; 48 mmol) in CH2Cl2 (80 mL) was then added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 6.6 g (44%) of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:7]=1.[C:33](O)(=[O:35])[CH3:34].CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([NH:12][S:9]([CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])(=[O:11])=[O:10])(=[O:35])[CH3:34]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CS(N)(=O)=O
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide (0.05 g, 0.10 mmol) in dichloromethane (1 mL) was added acetic acid (0.007 g, 0.12 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide (0.030 g, 0.16 mmol), 4-dimethylaminopyridine (0.019 g, 0.16 mmol) and triethylamine (0.023 g, 0.23 mmol). The reaction was stirred at ambient temperature overnight. The reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and the aqueous layer back extracted with dichloromethane (3×). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.039 g, LRMS: 526.20).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]1[C:21]([NH:22][C:23](=O)[CH3:24])=[CH:20][C:11]2[N:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=1.P(Cl)(Cl)([Cl:28])=O>C1C=CC=CC=1>[F:7][C:8]1[C:21]([N:22]=[C:23]([Cl:28])[CH3:24])=[CH:20][C:11]2[N:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(C)=O)cc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(N=C(C)Cl)cc21
Reaction time: 1 h

Procedure:
First, 10 ml of benzene and 0.4 g of phosphorus pentachloride were added to 0.5 g of N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-acetamide, and the stirring was continued for 1.0 hr at 60° C. After letting the mixture stand to cool the same, the produced phosphorus oxychloride and benzene were distilled out under reduced pressure to quantitatively obtain N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-acetimidoylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[O:4].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:14]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[C:3]([O:2][CH3:1])=[O:4])[O:11][CH2:12][CH2:13]1
Reactant: OCCO
Reactant: COC(=O)C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1CCCCC12OCCO2
Temperature: 25 °C

Procedure:
A mixture of methyl-2-oxocyclohexanecarboxylate (4-1) (7.0 g, 44.8 mmol), ethylene glycol (3.00 mL, 53.8 mmol) and p-toluenesulfonic acid monohydrate (0.853 g, 4.48 mmol) in Benzene (45 mL) was heated to reflux overnight. The reaction was then cooled to rt and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.86-3.99 (m, 4H), 3.69 (s, 3H), 2.69 (dd, 1H, J=4.9 Hz, 9.0 Hz), 1.82-1.97 (m, 3H), 1.58-1.73 (m, 3H), 1.45-1.53 (m, 1H), 1.26-1.37 (m, 1H).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH2:21][CH:22]2[CH2:24][CH:23]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:2]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:41][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.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>[C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:42][C:37]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:3]=[CH:2][C:1]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:6][CH:5]=4)[C:9]([O:20][CH2:21][CH:22]4[CH2:24][CH:23]4[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:10][C:11]=3[C:16]=2[F:17])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: OB(O)c1ccc(-c2ccccc2)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: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 120 °C

Procedure:
A solution of Ethyl 2-({[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}methyl)cyclo-propanecarboxylate (0.0440 g, 0.748 mmol), biphenylboronic acid (0.163 g, 0.823 mmol), and Pd(PPh3)4 (0.035 g, 0.030 mmol) in 7.5 mL of DMF was treated with a 1 M solution of K2CO3 (1.50 mL). The resulting yellow solution was heated at 120° C. for 45 min., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (0% then 0-20% then 20-30% EtOAc/hexanes) afforded the title compound as a white solid. LCMS: calculated for C39H32F2N2O3 614.68, observed m/e 615.1 (M+H)+ (Rt 2.78/4 min).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.CN(C=O)C>CCOC(C)=O.O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h

Procedure:
tert-Butyl bromoacetate was added to a stirring suspension of potassium carbonate (14.6 g, 106 mmol), 4-(trifluoromethoxy)phenol (15.7 g, 88 mmol) and DMF (50 mL). The reaction mixture was stirred for 12 hours. The mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with 3×EtOAc. The combined organic layers were washed with 5% aqueous lithium chloride and brine, dried over sodium sulfate, filtered, and reduced in vacuo to afford the title compound as a colorless oil: 1H NMR (400 MHz, d6-DMSO): 7.27 (d, 2H), 6.98 (d, 2H), 4.68 (s, 2H), 1.42 (s, 9H).