Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:40])[NH:32][C:33]2([C:36](OC)=[O:37])[CH2:35][CH2:34]2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[Li+].[BH4-].Cl>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:32][C:33]2([CH2:36][OH:37])[CH2:35][CH2:34]2)=[O:40])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: COC(=O)C1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1(CO)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 84.5 %

Procedure:
To a solution of (R)-methyl 1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylate (112 mg, 0.2 mmol), prepared by the method described in Procedure 30, in THF (0.2 mL) was added LiBH4 (0.2 mL, 2 M in THF, 0.4 mmol) at room temperature. The reaction mixture was stirred for 14 h, then cooled to 0° C. and 1 N HCl was added. The reaction mixture was diluted with ether. The organic layer was washed with H2O and sat. NaCl, dried over MgSO4, filtered and concentrated to give a colorless oil. The resulting oil was purified by ISCO chromatography (4 g column, eluting with 0-100% hexane/EtOAc over 16 min) to yield (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(1-(hydroxymethyl)cyclopropyl)urea (Example 241) as a white foam (91 mg, 84% yield). LCMS: RT=2.97 min [M+H] 539.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% CH3CN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.61-0.81 (m, 4H), 2.50 (brs, 1H), 3.31-3.50 (m, 2H), 3.84 (qt, J=12 Hz, 2H), 4.93 (s, 1H), 5.84 (t, J=53 Hz, 1H), 6.53-7.05 (m, 8H), 7.05-7.24 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5](O)=[O:6].CO.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
BH3 (1M in THF, 250 mL, 250 mmol) was added dropwise to a cooled sol. of 3,5-dichloro-4-hydroxybenzoic acid (20 g, 96.6 mmol) in THF (200 mL) at 0° C. The resulting mixture was stirred at 0° C. for 15 min., and then at rt for 13 h. The milky mixture was cooled to 0° C., and MeOH (150 mL), then water (100 mL), were added dropwise. The mixture was further stirred at 0° C. for 15 min, and then at rt for 5 h. The mixture was then partially concentrated under reduced pressure. EtOAc (200 mL) and water (50 mL) were added to the residue, and the phases were shaken and separated. The aq. phase was further extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC(CH2Cl2/CH3OH, 100:1) led to the title compound as a slightly beige solid (17.86 g, 96%). LC-MS: tR=0.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29](O)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.CCN(S(F)(F)[F:40])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@H:29]([F:40])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 40.3 %

Procedure:
A solution of tert-butyl 5-chloro-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.010 g, 0.021 mmol) in DCM (0.3 mL) was cooled to about −20° C. The solution was treated with DAST (0.0084 ml, 0.064 mmol) and stirred at about −20° C. for 1.5 hours. The reaction was quenched with ice then warmed to ambient temperature. The mixture was diluted with saturated aqueous NH4Cl solution. The organic layer was separated. The aqueous phase was extracted with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-50% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.004 g, 40%). LCMS (APCI+) m/z 473, 475 [M+H]+; Rt=3.98 min.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:14])[CH2:5][C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[S:8][C:7]=1[Cl:13].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][NH:3][CH:4]([CH3:14])[CH2:5][C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[S:8][C:7]=1[Cl:13]
Reactant: CON=C(C)Cc1c(Cl)sc(Cl)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CONC(C)Cc1c(Cl)sc(Cl)c1Cl
Temperature: 15 °C
Reaction time: 7 h

Procedure:
In a sulfonation flask 299 mg (1.1 mmol) 1-(2,4,5-trichlorothiophene-3-yl)propan-2-one O-methyl oxime were dissolved in 3.5 ml acetic acid and the resulting mixture was cooled to a temperature of 15° C. Then 138 mg (2.2 mmol) sodiumcyanoborohydride was added and the reaction mixture was stirred for 7 hours at ambient temperature. The mixture was then carefully diluted with 20 ml of water and the pH was adjusted to ca.10 by slowly adding 16 ml of 4N sodiumhydroxide solution. The mixture was extracted 3 times with ethylacetate and the combined organic phase was washed 2 times with water. After drying and evaporation of the solvent, the residue was purified by column chromatography (eluent: ethylacetate/heptane 1:9). Yield: 304 mg (100% of theory) of a colourless liquid (NMR-data see table 9).
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH2:40])=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (15 mg, 0.05 mmol) in anhydrous CH2Cl2 (4 mL) was added HOBt (15 mg, 4 mL), EDCI (22 mg, 0.11 mmol) and DIEA (32 mg, 0.25 mmol) at 0° C. and the mixture was stirred overnight under NH3 at rt. The reaction mixture was washed with 1 N aq HCl and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic phases were dried, filtered and concentrated to give (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (2.4 mg, 10%). 1H NMR (CD3OD): 1.94 (m, 4H), 3.27 (s, 3H), 4.01 (m, 1H), 4.28 (m, 3H), 7.10 (d, 1H), 7.26 (d, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.76 (m, 1H), 8.00 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:36]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][C:24]=3[CH3:36])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8].[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:7](=[O:8])[CH2:6][CH2:5][C:4]([N:3]([CH3:11])[CH3:2])=[O:10])[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
Proceeding as in Example 1, but substituting 4-(dimethylamino)-4-oxobutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 89, (2S,4R)-4-benzyl-1-(4-(dimethylamino)-4-oxobutanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (6.2 mg, 20%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.68 (s, 1H), 7.57 (m, 2H), 7.27 (m, 2H), 7.23-7.15 (m, 7H), 6.93 (m, 2H), 4.43 (m, 1H), 3.68 (m, 1H), 3.27 (m, 1H), 2.94 (s, 3H), 2.78 (s, 3H), 2.67-2.58 (m, 4H), 2.44 (m, 3H), 1.91 (m, 2H). MS (EI) for C30H32FN3O4. found 518.6 (MH+).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1C=CC(O)=CC=1)CC.[O-]CC.[Na+]>[Ni].C(O)C>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(=O)CC1
Agent: [Ni]
Agent: CCCc1ccc(O)cc1
Agent: CC[O-]
Solvent: CCO
Product: CCCC1CCC(O)CC1

Procedure:
In addition, the 4-propylcyclohexanone employed as a raw material in this preparation example was prepared as follows: A commercial p-n-propylphenol was hydrogenated in the presence of ethanol, sodium ethoxide and Raney nickel catalyst, under a hydrogen pressure of 100 atm, at 150° C. to form 4-n-propylcyclohexanol, which was then oxidized with Jones reagent (CrO3 /H2SO4 /H2O) in acetone to obtain 4-n-propylcyclohexanone having a b.p. of 110°~113° C./26 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:30])([F:29])[C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:26]2[NH:25][N:24]=[C:23]([C:22]([F:30])([F:29])[F:21])[CH:27]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Product: O=C(Nc1cc(C(F)(F)F)n[nH]1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-(trifluoromethyl)-1H-pyrazol-5-amine (18.0 mg, 0.12 mmol). The title compound was obtained as a solid (13.0 mg, 27% yield). MS m/z: 483.93, 485.93 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:19])[CH2:17][CH3:18]
Reactant: COC(=O)[C@H](C)N
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@@H](C)C(=O)OC

Procedure:
L-Alanine methyl ester hydrochloride salt (14 g, 0.1 mol) was dissolved in dichloromethane (150 mL) and treated with triethylamine (30.45 g, 0.3 mmol). The solution was stirred and propionyl chloride added dropwise. After stirring overnight the mixture was quenched by addition of 1 M hydrochloric acid (200 mL) and the organic layer separated. The aqueous layer was re-extracted with dichloromethane (3×200 mL) and the combined organic layers were dried with magnesium sulfate, filtered and evaporated to a to a clear oil (16.0 g, quant.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[C:11](O)(=O)[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:5]2=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(N)c(N)cc1Br
Reactant: CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc2nc(C)c(Br)cc2[nH]1
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
9.0 g (44.6 mmole) of the compound obtained in step 3 and 5.5 g (58 mmole) of valeric acid were mixed with 30 ml of polyphosphoric acid and stirred for 3 hours at 110° C. The reaction solution was dissolved in a mixture of 50 ml of cold water and 50 ml of THF and the resulting solution was neutralized to Ph 8 with cold 40% aqueous NaOH solution with stirring vigorously and extracted with ethyl acetate (50 ml×3). Thereafter, the organic layer was dried over Na2SO4, concentrated under reduced pressure and recrystallized from hexane-methylene chloride to obtain 9.8 g of the title compound (yield 82%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:16][CH2:15][CH2:14]C1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C=O)CC1.[Si](OCCN)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][CH:16]1[CH2:15][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Agent: CC(C)(C)[Si](C)(C)OCCN
Agent: O=CC1CC1
Product: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Yield: 28.51 %

Procedure:
This compound was prepared following the same method as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) from cyclopropanecarbaldehyde (300 mg, 4.23 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (975 mg, 5.56 mmol). The product was obtained as a colourless liquid (280 mg, 28.51%).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1.N1C=CC=CC=1>[C:16]([NH:14][C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCC(=O)Nc1ccc(C(=O)O)cc1C(=O)O
Yield: 94.9 %

Procedure:
Dimethyl-4-amino-isophthalate (9 g) in 60 ml of dioxane and 18 ml of pyridine is treated with hexanoyl chloride (8.8 g) at room temperature for 16 hours. After dilution with water and extraction with ethyl acetate, the solution is washed with 40% citric acid and 5% NaHCO3 and evaporated to dryness, so obtaining dimethyl-4-hexanoylamino-isophthalate (14.8 g) that is dissolved in 75 ml of dioxane and treated with 75 ml of 2 N NaOH at room temperature for 6 hours. After acidification with HCl the precipitate is collected under vacuum and washed until neutral. 4-hexanoylamino-isophthalic acid (11.4 g) is obtained, which is treated with 26 ml of acetic anhydride at reflux for 10'. After cooling, dilute with 30 ml of isopropyl ether and filter. 6-carboxy-2-pentyl-4H-3,1-benzoxazin-4-one (7.3 g; m.p. 185°-190° C.) is obtained, which is treated at room temperature first with 70 ml of 32% ammonium hydroxide for 16 hours and then with 50 ml of 2 N NaOH for 2 hours. After acidification with 2 N HCl, the precipitate is filtered off and crystallized from ethanol, so obtaining 6-carboxy-2-pentyl-3,4-dihydro-4-oxo-quinazoline (6.1 g; m.p. 311°-313° C.).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:23](Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), phenethyl bromide (0.2 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 7 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless solid which was recrystallised from aqueous ethanol to give the title compound, yield, 0.17 g, m.p. 175°-1780° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:12])([F:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(F)(F)CCC1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:12])[CH2:9][O:10][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[CH:3]=1
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Reactant: OCC(F)(F)c1cccc(Br)c1
Product: FC(F)(COCCCCCCBr)c1cccc(Br)c1

Procedure:
Obtained from Intermediate 49 (17.6 g, 74 mmol) by the procedure described in Intermediate 3. The crude oil was purified by distillation to yield the title compound as oil of 60% of purity (9.5 g). The distillation residue was purified by column chromatography with silica gel and methylene chloride as eluent to yield a second batch of 1-bromo-3-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}benzene of 65% of purity (15.2 g) (overall yield: 53%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[C:12]([S:14][C:15]#[N:16])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][N:9]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([N+:35]([O-])=O)[CH:22]=1>C(#N)C.[Cl-].[Na+].O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[C:23]([NH:35][C:8]2[N:13]=[C:12]([S:14][C:15]#[N:16])[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][N:9]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Reaction time: 15 h
Yield: 80.3 %

Procedure:
Potassium carbonate (207 mg) was added to a stirred solution of 2-chloro-5-nitro-4-thiocyanatopyrimidine (108 mg) and tert-butyl 4-fluoro-2-nitrophenylcarbamate (113 mg) in ACN (5 mL) and stirred for 15 hr. The solution was diluted with brine and extracted with EtOAc (2×). The combined organics were evaporated and purified via column chromatography, elution with 30% EtOAc/Hex gave the titled compound (144 mg, 71% yield). 1H-NMR (300 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.3 (br s, 1H), 8.9 (br s, 1H), 7.7-7.4 (m, 2H), 7.1 (br s, 1H), 1.5 (s, 9H), 1.5 (s, 9H); MH+=407, 307 (-BOC), 351 (-tBu).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH2:30][CH3:31])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH2:30][CH3:31])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.5 g, 3.40 mmole) in THF/water (16 mL, 1:1) was added LiOH (286 mg, 6.80 mmole) followed by 3 mL of methanol at room temperature. The reaction mass was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified with aqueous 1.5 N HCl solutions. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get desired product (1.3 g, 90%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.81-0.93 (m, 6H), 1.12-1.29 (m, 5H), 1.30-1.50 (m, 11H), 1.71-1.80 (m, 2H), 1.91-2.51 (m, 4H), 3.57-3.59 (m, 1H), 4.27-4.35 (m, 3H), 4.92-4.97 (m, 2H), 5.01-5.15 (m, 1H), 5.74-5.79 (m, 1H), 6.30-6.80 (m, 1H), 12.50 (sb, 1H). MS: MS m/z 427.6 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:19]1[CH:20]=[CH:21][C:22]([Si:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:18]=1[F:17])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1[nH]c2c(F)cncc2c1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2c(F)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A degassed solution of 3-amino-7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.0 g, 4.48 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (1.6 g, 4.93 mmol), Pd2dba3 (205 mg, 0.22 mmol), Xantphos (258 mg, 0.45 mmol) and cesium carbonate (2.0 g, 6.28 mmol) in toluene (20 ml) was subjected to microwave irradiation at 150° C. for 20 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 0:100) to afford the title compound as a yellow solid (505 mg, 29%). LCMS (method B): RT=3.39 min, M+H+=390.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(NS(N)(=O)=O)cc1OC

Procedure:
Prepared as in Example 77a from 2-amino-4,5-dimethoxybenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 3.77-3.80 (d, J=14.8, 6H), 7.05 (s, 1H), 7.06 (s, 1H), 7.29 (s, 1H), 9.15 (s, 1H).