Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].C(O)=O.C(N(CC)CC)C.Cl>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4]
Reactant: COc1ccccc1C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccccc1C(O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2-Chloro-2′-methoxyacetophenone (186.6 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (1.35 mg, 0.002mmol, s/c=500) in ethyl acetate (2.0ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, 1 M hydrochloric acid (1.2 ml) was added, and the reaction product was extracted with ethyl acetate (2 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a desired compound, (+)-2-chloro-1-(2′-methoxyphenyl)ethanol (170.6 mg; yield: 90.4%; optical purity: 95.2% ee).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([NH2:39])=[NH:38].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:38]=[C:37]([N:33]3[CH2:34][CH2:35][CH2:36][CH:32]3[CH3:31])[N:39]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCCN1C(=N)N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)c2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1CCCN1c1nc2c(c(-c3ccc(F)cc3)n1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a mixture of 3-(4-fluoro-benzoyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.62 mmol) and 2-methyl-pyrrolidine-1-carboxamidine trifluoroacetate (0.14 g, 0.58 mmol) in MeCN (3 mL) was added K2CO3 (0.190 g, 1.4 mmol). The mixture was heated at reflux for 15 h, then cooled to rt, diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The residue was purified by FCC to give the title compound (0.193 g, 81%) as a clear oil. MS (ESI): mass calcd. for C23H23FN4O2, 412.5; m/z found, 413.4 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[ClH:27].[C:23]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1C(C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccc(CN2CCNCC2)cc1C(C)(C)C
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 3.5 g of N-(tert-butyloxycarbonyl)-N′-(3-tert-butyl-4-methoxy-benzyl)piperazine 30 ml of 10% HCl and 5 ml of ethanol are added, the mixture is stirred for 5 h at 20° C., and evaporated to dryness in vacuum at 50÷80° C. Then 20 ml of dry acetone is added to the residue, the mixture is boiled with stifling for 20 min, then cooled down to 10° C. After 1 h the product is filtered off, washed with 10 ml of acetone and dried at the air. Yield of (3-tert-butyl-4-methoxybenzyl)piperazine dihydrochloride—2.2 g (68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[CH2:33]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:34]#[CH:35]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:35]#[C:34][CH2:33][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280.4 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 300 mg; 92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of the above alcohol (450 mg, 1.38 mmol), SiO2 (1.50 g) and PCC (895 mg, 4.15 mmol) in CH2Cl2 (25 mL) was stirred at room temperature for 1 hour to afford 4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (440 mg, 99%) after purification.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:25]=[C:22]([CH:23]=O)[C:21]([OH:26])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([CH:25]=1)[CH:23]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1cc(Br)ccc1O
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc(Br)ccc1O
Yield: 81.6 %

Procedure:
6-Phenyl-2-oxindole (50 mg, 0.3 mmol) was condensed with 5-bromosalicylaldehyde (50 mg, 0.25 mmol) using method B to give 80 mg (82%) of 3-(5-bromo-2-hydroxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[Na].[OH2:24]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)[OH:24])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Reactant: O
Agent: [Na]
Solvent: CCO
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1.1 g of 5-(4-chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 15 ml of ethyl alcohol at 0° C. was added potionwise 0.06 g of sodium borohrdride. After 30 minutes, the rection mixture was poured into iced water and extracted with chloroform, the chloroform solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with n-hexane to afford 1.0 g of 5-(4-chloro-α-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][C:5]=1[O:23][CH3:24])([O-:3])=[O:2].CO[CH2:27][Cl:28]>ClCCl>[CH:17]([C:16]1[CH:15]=[C:14]([CH:13]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:11]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:23][CH3:24])[CH:6]=1)[CH2:27][Cl:28])([CH3:19])[CH3:18]
Reactant: COCCl
Reactant: COc1cc(Oc2c(C(C)C)cccc2C(C)C)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(Oc2c(C(C)C)cc(CCl)cc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Stannous chloride (0.46 mL) was carefully added under nitrogen gas to a ice-cooled mixture of 2-nitro-5-(2,6-diisopropylphenoxy)anisole (3.8 g), chloromethyl methyl ether (1.8 mL) and dichloromethane (5 mL). After 16 hours, the reaction mixture was concentrated and purified on column (silica gel, ethyl acetate/petroliumether, 97:3), to give 1.4 g of 3,5-diisopropyl-4-(3-methoxy-4-nitrophenoxy)benzylchloride.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:30])=[O:22])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(C)C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-leucine methyl ester hydrochloride using the procedure described in Method 3. the title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[C:29]([CH3:35])[C:28]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:28]4[C:29]([CH3:35])=[C:30]([CH3:34])[CH:31]=[C:32]([CH3:33])[C:27]=4[CH3:26])(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)Cl)c1C
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(C)c(C)cc(C)c4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,3,5,6-tetramethylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([O:49][CH3:50])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:50][O:49][C:12]1[C:11]([NH2:10])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([C:39]1[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=1)=[N:15][N:16]2[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(NC(=O)OCc2ccccc2)ccc2c1c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(N)ccc2c1c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
466 mg of (4-methoxy-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl)-carbamic acid benzyl ester obtained in Production Example II-38-a was dissolved in 20 ml of a 1:1 solvent mixture of ethyl acetate and methanol. 300 mg of 10% palladium-carbon was added and the mixture was subjected to catalytic hydrogenation at room temperature and normal atmospheric pressure. The reaction mixture was filtered through Celite, and the solvent was removed, to give 252 mg of the title compound.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Br-].[C:15]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC>>[CH2:15]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Br-]
Agent: [Li]CCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.05 h

Procedure:
The title compound was prepared according to the procedure of Intermediate 71 starting from tert-butyl 3-oxopyrrolidine-1-carboxylate (0.8 g, 4.3 mmol), triphenylphosphonium bromide (2.31 g, 6.5 mmol) and n-BuLi (1.8 M; 2.4 mL, 6.5 mmol). Yield: 0.23 g (29%) after purification by flash chromatography with DCM as eluent. HPLC purity 99%, RT=2.28 min (System A; 10-97% MeCN over 3 min); 99%, RT=2.21 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.40 (m, 9H) 2.42 (t, J=6.78 Hz, 2H) 3.31 (t, J=7.40 Hz, 2H) 3.71-3.85 (m, 2H) 4.74-4.91 (m, 2H). MS (ESI+) for C10H17NO2 m/z 128 (M-C4H8)+. *Previously reported in Tetrahedron 1997, 53, 539-556.
Reaction SMILES: BrC1C2C(=NN(C3C=CN=CC=3)N=2)C(Br)=CC=1.Br[C:19]1[C:27]2[C:23](=[N:24][N:25]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:26]=2)[C:22](Br)=[CH:21][CH:20]=1>>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[N:25]1[N:26]=[C:27]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]2=[N:24]1
Reactant: Brc1ccc(Br)c2nn(-c3cnccn3)nc12
Agent: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Product: c1ccc2nn(-c3cnccn3)nc2c1
Yield: 23 %

Procedure:
A similar two-step procedure as that of Intermediate A was applied to give 2-(pyrazin-2-yl)-2H-benzo[d][1,2,3]triazole (23% yield) in the first step and 4,7-dibromo-2-(pyrazin-2-yl)-2H-benzo[d][1,2,3]triazole (Intermediate B, 26%) in the second step. 1H NMR (400 MHz, CDCl3): δ 9.75 (d, J=1.5 Hz, 1H, pyrazine), 8.81 (d, J=2.2 Hz, 1H, pyrazine), 8.71 (dd, J=2.5 and 1.5 Hz, 1H, pyrazine), 7.56 (s, 2H, benzotriazole).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22])[CH:5]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
To a 250 mL round bottom flask was added 3-formyl-benzoic acid methyl ester (2.20 g, 13.4 mmol), ammonium acetate (1.03 g, 13.4 mmol), and nitroethane (60 mL). Mixture heated to reflux under an atmosphere of nitrogen while stirring for 1.5 h. Solvent removed under vacuum then residue partitioned between ethyl acetate (100 mL) and 5% sodium bicarbonate. Organic washed with saturated sodium chloride, dried with magnesium sulfate, then concentrated to a oil under vacuum. Product purified on silica and isolated as a yellow solid. 1H NMR (CDCl3) s (3H, 2.47 ppm), s (3H, 3.96 ppmm), t (1H, 7.55 ppm), d (2H, 7.61 ppm) m (3H, 8.09 ppm).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[OH:10][CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(#N)C>[OH:10][C:11]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCC1(O)CCCCCCCCCCC(=O)O1
Yield: 66 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 150 mg (0.5 mmol) of 12-hydroxyoctadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 12-hydroxyoctadecane-1,12-lactone was obtained in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ncn1

Procedure:
22.4 g (0.15 mol) of 4,6-dichloropyrimidine were introduced into 250 ml of methanol. 27 g of a 30% strength sodium methylate solution were added dropwise at 0° C. After concentration, the mixture was worked up using a water/methylene chloride mixture. 15.0 g (69.2% of theory) of yellow crystals were obtained; m.p. 32°-34° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:28][CH3:29])[CH2:34][O:33][C:32]4=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 42.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (874 mg) described in Preparation Example 61 and (R)-4-ethyloxazolidin-2-one (300 mg) described in Preparation Example 26, the title compound (399 mg) was obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:48]=[CH:47][CH:46]=[CH:45][C:38]=1[C:39](N(OC)C)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:38]2[CH:45]=[CH:46][CH:47]=[CH:48][C:37]=2[F:36])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccccc1F
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccc3F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2-fluoro-N-methoxy-N-methylbenzamide.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: NCCCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCO)cc2)cc1

Procedure:
The product from Example 104A and 3-amino-1-propanol were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.95 (s, 1 H), 7.75 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 3.35 (m, 2 H), 3.07 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.34 (t, 2 H), 1.50 (m, 2 H); MS (ESI+) m/z 602 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:39]1([C:46]([NH:48][C@@H:49]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:50](O)=[O:51])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:50](=[O:51])[C@@H:49]([NH:48][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH2:21][CH2:20]2)[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
(4-Benzyloxycarbonylamino-phenyl)-(3-methyl-butyl)-piperidin-4yl-amine (0.22 g, 5.64 mmol) was dissolved in DMF (30 mL), treated with Hunig's base (3.93 mL, 22.6 mmol), (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (1.36 g, 5.64 mmol), and HBTU (2.04 g, 5.64 mmol), and stirred for 1 hour. The reaction was diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 5% MeOH/CH2Cl2 to give 2.76 g (77%) of the desired product.