Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5](=[O:7])[CH3:6])=[O:2].O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16].N1CCCC1>C1(C)C=CC=CC=1>[CH3:6][C:5]1([CH2:4][NH:3][CH:1]=[O:2])[CH2:16][C:15](=[O:17])[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)CNC=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1(CNC=O)CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
20.2 g (0.2 mol) of formylaminoacetone [A. Treibs u.a., Chem. Ber. 84 96 (1951)] and 27.2 g (0.2 mol) of o-hydroxyacetophenone are dissolved in 100 ml of toluene, and 10 ml of pyrrolidine are added. The mixture is stirred at 25° C. for 20 hours and then at 115° C. for 2 hours. After cooling, the mixture is extracted by shaking successively with 2N HCl, 2N NaOH and water, the organic phase is concentrated and the 2-methyl-2-formylaminomethylchroman-4-one formed is isolated by chromatography. Melting point: 96°-8° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:25][C:26]([NH2:28])=[O:27])[CH2:22][S:21](=[O:24])(=[O:23])[CH2:20]1>>[NH2:28][C:26](=[O:27])[CH2:25][C:19]1([NH:18][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:20][S:21](=[O:23])(=[O:24])[CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid (example 145d) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (51 mg, 59%); MS (ESI, m/z): 404.3 (M+H+).
Reaction SMILES: CN(OC)[C:3](=[O:10])[C@@H:4]([CH:6]1[CH2:9][CH2:8][CH2:7]1)[CH3:5].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:6]1([C@@H:4]([CH3:5])[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:9][CH2:8][CH2:7]1
Reactant: CON(C)C(=O)[C@H](C)C1CCC1
Reactant: [Li]c1ccccc1
Product: C[C@@H](C(=O)c1ccccc1)C1CCC1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A dry flask was charged with N-Methyl-N-methoxy-(R)-2-cyclobutylpropionamide (2.62 grams, 15.4 mmol, from Step D). The vessel was purged with nitrogen and 40 mL THF was added. The mixture was cooled to −10 C and a solution of phenyllithium (30 mL, 1.8 M, 53.9 mmol) was added. The solution was stirred for 1 h at −10 C then the reaction was quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (99/1 hexane/ethyl acetate) afforded 2.06 grams (70%) of the title compound. 1H NMR 400 MHz, CDCl3). δ 1.13 (d, 3H), 1.59-1.7 (m, 1H), 1.73-2.0 (m, 5H), 2.05-2.15 (m, 1H), 2.6-2.7 (m, 1H), 3.43-3.53 (m, 1H), 7.44-7.5 (t, 2H), 7.55-7.6 (m, 1H), 7.97-8.0 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:24]([CH2:26][CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])#[N:25]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][N:28]([CH2:27][CH2:26][C:24]#[N:25])[CH2:29][C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: N#CCCNCC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCC#N)CC(=O)O

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with N-(2-cyanoethyl)glycine using an analogous method to that described for the equivalent step in Example 1 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-cyanoethyl)glycine; 1H NMR Spectrum: (DMSO-d6) 2.70 (t, 2H); 3.04 (t, 2H); 3.40 (s, 2H); 3.95 (m, 5H); 7.20 (s, 1H); 7.27 (t, 1H); 7.48 (t, 1H); 7.55 (t, 1H); 8.36 (s, 1H); 8.44 (s, 1H); 9.69 (brs, 1H); Mass Spectrum: (M+H)+ 444.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[N:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:23]2[N:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cccnn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cccnn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) and 3-pyridazinamine (CAN 5469-70-5) as starting materials; MS (ESI) 367.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cc(Cl)cnc1Br
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]1[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23].CCN(CC)CC.CCOC(C)=O.C1CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:10][C@@H:11]1[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[CH2:13][C@@H:12]1[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCC(=O)C1CC(C)(C)CCC1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)[C@H]1CC(C)(C)CC[C@H]1OC(=O)c1ccccc1
Temperature: 45 °C
Yield: 28.4 %

Procedure:
Benzoyl chloride (12.8 g, 91 mmoles) was added dropwise to a stirred solution of 1-(2-hydroxy-5,5-dimethyl-1-cyclohexyl)-4-penten-1-one (16 g, 75 mmoles), Et3N (10 g, 99 mmoles) and DMAP (1.8 g, 15 mmoles) in CH2Cl2 (380 ml) at 20° C. and under nitrogen. The solution was heated at 45° C. during 22 hours, cooled to room temperature and washed successively with 5% aqueous HCl, 10% aqueous Na2CO3, and again with water. The organic phase was dried over Na2SO4 and concentrated to afford a brown oil. Chromatography (SiO2, AcOEt/Cyclohexane 1:9) and afforded 6.7 g of the title compound (yield=28%).
Reaction SMILES: [Na].[N+:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:4])=[O:3].Br[C:12]([N+:15]([O-:17])=[O:16])([CH3:14])[CH3:13]>>[CH3:13][C:12]([C:5]1([N+:2]([O-:4])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([N+:15]([O-:17])=[O:16])[CH3:14]
Reactant: CC(C)(Br)[N+](=O)[O-]
Reactant: O=[N+]([O-])C1CCCCC1
Agent: [Na]
Product: CC(C)([N+](=O)[O-])C1([N+](=O)[O-])CCCCC1

Procedure:
Seigle and Hass, J. Org. Chem., 5, 100(1940), reported the reaction of the sodium salt of nitrocyclohexane with 2-bromo-2-nitropropane to give 1-(1-methyl-1-nitroethyl)-1-nitrocyclohexane. From the sodium salt of 2-nitropropane and 2-bromo-2-nitropropane they obtained 2,3-dimethyl-2,3-dinitrobutane. Other compounds prepared in like manner were 2,3-dimethyl-2,3-dinitropentane and 3,4-dimethyl-3,4-dinitrohexane. The method is limited to the preparation of α,β-dinitro compounds, and only low yields were reported.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.58 g, 3.81 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopropylcarbamate (0.41 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopropylamino)carboxamide (0.53 g, 77%) as a white solid: mp 245-247° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.87-7.69 (m, 3H), 6.58 (t, J=5.7 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H) 5.19-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.65 (d, J=6.1 Hz. 2H), 2.96-2.83 (m, 1H), 2.64-2.40 (m, 3H), 2.08-2.04 (m, 1H), 0.62-0.55 (m, 2H), 0.40-0.34 (m, 2H); 13C NMR (DMSO-d6) δ 172.75, 169.82, 167.63, 167.04, 158.69, 141.11, 134.61, 133.26, 131.49, 126.94, 121.60, 48.83, 30.93, 22.37, 21.97, 6.59; Anal. Calcd. For C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.26; H, 4.82; N, 14.85.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
1.0 g (3.9 mmol) of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride was suspended in 20 ml of dimethylformamide (DMF), and potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 6 hours, cooled to room temperature, and water was added thereto, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), and concentrated to dryness under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:20][C:21]1[S:25][C:24]([C:26]#[N:27])=[CH:23][CH:22]=1>C1COCC1>[Br:20][C:21]1[S:25][C:24]([C:26]([NH:4][C:3]2[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=2[Cl:1])=[NH:27])=[CH:23][CH:22]=1
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: N#Cc1ccc(Br)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(Nc1cc(Cl)ccc1Cl)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.3 %

Procedure:
Under N2 atmosphere, to a solution of 2,5-dichloroaniline (341 mg, 2.1 mmol) in 2 mL dry THF was added sodium bis(trimethylsilyl)amide (2.1 mL, 1M solution in THF, 2.1 mmol). After the mixture was stirred at ambient temperature for 40 min, a solution of 5-bromo-thiophene-2-carbonitrile (376 mg, 2 mmol) in 2 mL dry THF was added dropwise. The reaction mixture was stirred overnight, and then poured into 100 mL ice water. The orange precipitate was collected by filtration, washed with a solution of ether and hexane (3/7, v/v), and air dried to give a light orange solid (653 mg, 94% yield). 1H-NMR (400 MHz, MeOH-d4): δ 6.94 (d, 1H), 6.99 (dd, 1H), 7.06 (d, 1H), 7.32 (d, 1H), 7.37 (d, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:26][C:27]([C:29]1[NH:30]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O>>[OH:26][CH2:27][CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCCO)n(C)n1
Yield: 46 %

Procedure:
As described for example 6, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (30 mg, 0.09 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (15 mg, 46%) which was obtained as a colorless oil. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[C:3]=1[O:11][C:12]1[CH:17]=[C:16]([CH:18]2[CH2:20][CH2:19]2)[CH:15]=[C:14]([Cl:21])[CH:13]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][C:12]2[CH:17]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:15]=[C:14]([Cl:21])[CH:13]=2)[C:4]=1[F:10])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amine (86 mg, 0.264 mmol), 4-chloro-1-({[2(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (73.0 mg, 0.264 mmol) and HATU (100 mg, 0.264 mmol) in DMF (5 ml) was added diisopropylethyl amine (0.092 ml, 0.527 mmol) and the reaction mixture was stirred at rt for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give the desired compound which was only ˜85% pure. This was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (98 mg, 0.168 mmol, 64% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].O[CH2:12][C@@H:13](N)[CH2:14]C(C)C.OCCN.C(=O)C(C)C>>[CH:13]([CH:1]1[NH:5][C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:3][O:2]1)([CH3:14])[CH3:12]
Reactant: CC(C)C[C@H](N)CO
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)C=O
Solvent: NCCO
Product: CC(C)C[C@H]1COC(C(C)C)N1

Procedure:
(L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3-methylbutylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-oxazolidine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][C:8]1([CH3:11])[CH2:10][O:9]1>>[CH3:7][C:8]([OH:9])([CH3:11])[CH2:10][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: CC1(C)CO1
Product: Cc1nccn1CC(C)(C)O

Procedure:
The title compound was prepared according to the method described for Preparation 146 using 2-methyl-1H-imidazole and 2,2-dimethyloxirane.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(OC)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Si:26]([O:33][CH2:34][C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][C:37]([CH2:45][O:46][C:47]4[C:56]([Cl:57])=[CH:55][C:50]([C:51]([O:53]C)=[O:52])=[C:49]([F:58])[CH:48]=4)([CH2:38]3)[CH2:36]1)[CH2:42]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[Si:26]([O:33][CH2:34][C:35]12[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][C:37]([CH2:45][O:46][C:47]4[C:56]([Cl:57])=[CH:55][C:50]([C:51]([OH:53])=[O:52])=[C:49]([F:58])[CH:48]=4)([CH2:43]3)[CH2:36]1)[CH2:44]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4CC(C2)CC(CO[Si](C)(C)C(C)(C)C)(C4)C3)cc1F
Agent: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CC(C)(C)[Si](C)(C)OCC12CC3CC(CC(COc4cc(F)c(C(=O)O)cc4Cl)(C3)C1)C2

Procedure:
Following the procedure as described in Example 150 step 4 and making variations as required to replace methyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate with methyl 4-((3-(((tert-butyldimethylsilyl)oxy)methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a colorless solid (1.02 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 13.03 (br s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.12 (d, J=12.7 Hz, 1H), 3.70 (s, 2H), 3.12 (s, 2H), 2.05-1.96 (m, 2H), 1.63-1.42 (m, 6H), 1.41-1.27 (m, 6H), 0.81 (s, 9H), −0.05 (s, 6H); MS (ES+) m/z 483.1, 485.1 (M+1).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][CH2:35][C:36]1[N:40]([C:41]2[S:42][C:43]([CH2:55][CH3:56])=[CH:44][C:45]=2[C:46](=[O:54])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:39]([CH3:57])=[N:38][N:37]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:46]([C:45]1[CH:44]=[C:43]([CH2:55][CH3:56])[S:42][C:41]=1[N:40]1[C:39]([CH3:57])=[N:38][N:37]=[C:36]1[CH2:35][NH:34][C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:54]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2)s1
Reaction time: 24 h
Yield: 66.3 %

Procedure:
trans-Cinnamic acid (1.48 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g) and triethylamine (5.6 ml) were dissolved in dimethylformamide (50 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g) was added, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give 5.05 g of crude crystals. The crystals were recrystallized from ethyl acetate to give 3.25 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-phenylacrylamide.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10](=[O:22])[CH2:9]1)[CH3:7]>>[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=2[S:2]([Cl:1])(=[O:5])=[O:3])[C:10](=[O:22])[CH2:9]1)[CH3:7]
Reactant: CCN1CCN(Cc2cccc(F)c2)C(=O)C1
Reactant: O=S(=O)(O)Cl
Product: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Cl)C(=O)C1

Procedure:
Chlorosulphonic acid (2 mL) was added to 4-ethyl-1-(3-fluorobenzyl)-piperazin-2-one (Intermediate 175, 0.59 g) with stirring and cooling in ice. The cooling was removed and the solution was stirred at room temperature for 4 hours before being carefully added to a mixture of ethyl acetate, ice and sodium bicarbonate. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluoro-benzenesulfonyl chloride (0.37 g) as a colourless gum.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=O)[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[CH3:14][CH:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]([C:18]1C=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH3:17]>>[CH2:1]([CH:3]1[C:7]2[C:21]3[C:22]([OH:23])=[CH:24][C:18]([CH:16]([CH:15]([CH3:14])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:17])=[CH:13][C:12]=3[O:11][C:9](=[O:10])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CCC(CC)C1=O
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CCC3CC

Procedure:
5-Ethyl-2-carboethoxycyclopentanone is reacted with 5-(3-methyl-2-octyl)-resorcinol to produce 1-ethyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [1]benzopyran.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=2[O:25]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:29]4[CH:28]=[CH:27][C:26]5[O:25][CH2:24][O:32][C:31]=5[CH:30]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and 3,4-methylenedioxyphenylboronic acid (264 mg, 1.59 mmol) the subtitle compound was obtained (337 mg, 51%). The product was used directly in the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:28])[C@:5]([F:27])([CH3:26])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])C.O.[OH-].[Li+]>O1CCCC1.O>[F:27][C@@:5]([CH3:26])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
A solution of 75 mg (0.2 mmol) of (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid ethyl ester in 1 ml of tetrahydrofurane was treated for 2 h at room temperature with a solution of 8 mg (0.2 mmol) of lithium hydroxide monohydrate in 0.5 ml of water. For the working-up, the tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous layer was extracted twice with 10 ml of diethylether. The combined organic layers were washed with 5 ml of water and, thereafter, the combined aqueous layers were acidified with 0.025 ml of hydrochloric acid (25%). Thereupon, the aqueous layer was extracted three times with 15 ml of ethyl acetate. The organic layers were washed with 15 ml of a saturated solution of sodium chloride, then combined, dried over sodium sulphate, and evaporated under reduced pressure. There were obtained 69 mg (99% of theory) of the title compound as a white foam;