Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([NH:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:3]([O:5]CC1C=CC=CC=1)=O.C(OC(N1CCC(C(NNC([C:50]2[CH:64]=[CH:63][C:53]([O:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[C:52]([O:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH:51]=2)=O)=O)CC1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>[Pd].CN(C=O)C.CO>[CH3:1][N:2]([NH:13][C:14](=[O:30])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:19][CH:20]=1)[C:3]([C:64]1[CH:50]=[CH:51][C:52]([O:65][CH2:66][C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[C:53]([O:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:63]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Reactant: CN(NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
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: CO
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1

Procedure:
In a similar manner to Example 9, starting material step (b), the product of step (a) (440 mg), 10% Pd on C (100 mg) and methanol (40 ml) were hydrogenolysed. A mixture of the oily residue so obtained, the product of Example 2, starting material step (c) (470 mg), HBTU (460 mg), HOBT (190 mg), diisopropylethylamine (0.63 ml) and DMF (3 ml) was reacted to give a residue which was purified by column chromatography on silica, eluting with ethyl acetate/hexane, 3:2, to give t-butyl 4-[2-methyl-3-(4-t-butoxycarbonylaminomethylbenzoyl)-carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (380 mg) as a glass; NMR (DMSO-d6) 1.33 (9H, s), 1.38 (9H, s), 1.43 (9H, s), 3.20 (3H, s), 4.13 (2H, d), 4.59 (2H, s), 4.67 (2H, s), 6.83 (1H, d), 7.13 (2H, m), 7.28 (2H, d), 7.62 (2H, d), 7.40 (1H, t), 10.98 (1H, s); Mass Spectrum m/Z 666 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)=[O:8].C[Li].[CH2:16](O)C.[Cl-].[Na+]>C(OCC)C>[O:11]1[CH:12]=[CH:13][C:9]([C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])([OH:8])[CH3:16])=[CH:10]1
Reactant: CCO
Reactant: Cc1ncoc1C(=O)c1ccoc1
Agent: [Cl-]
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Furyl 4-methyl-5-oxazolyl ketone (1 g) in dry diethylether (15 ml) at -70° C. under a nitrogen atmosphere was treated dropwise with methyllithium (1.5M solution in diethylether, 4.1 ml). After 45 minutes the reaction mixture was allowed to warm to room temperature and ethanol (2 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. Chromatography and crystallisation then gave 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol identical to the material obtained in (a) above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[CH:13]/[C:14](/[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[N:15]/[H].C[O:26][C:27]1C=CC=C2[C:28]=1CCN=C2C.[Li+].CC([N-]C(C)C)C.COC1C=C(C=CC=1)C#N>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:27](=[O:26])[CH2:28][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:13]=[C:8]12
Reactant: COc1cccc2c1CCN=C2C
Reactant: [H]/N=C(/C=C1NCCc2c(OC)cccc21)c1cccc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: COc1cccc(C#N)c1
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(C2=NCC(=O)N3CCc4c(OC)cccc4C3=C2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethanimine. 1-1. A flask was charged with 5-methoxy-1-methyl-3,4-dihydroisoquinoline (3.0 g, 17.1 mmol) and Et2O (100 mL) under N2 and cooled to −30° C. A 2M solution of LDA (8.56 mL, 17.1 mmol) was added dropwise. The resulting brown suspension was stirred for 30 min at this temperature, and then cooled to −78° C. A solution of 3-methoxybenzonitrile (2.28 g, 17.1 mmol) in Et2O (25 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, and then allowed to warm to RT and stirred for another 18 h. the mixture was then poured onto H2O and extracted with AcOEt. The org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (5.9 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 309.3 (M+H+); UPLC rt 0.73 min.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2ccsc2)SCC(NC(CCc2ccccc2)C(=O)O)C1=O
Reaction time: 16 h

Procedure:
150 mg of α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid (prepared as described in Example 43) were mixed with 2 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred for 16 hours. The reaction mixture was then adjusted to a pH value of 2.0 with 1N hydrochloric acid and the resulting solid, which was the title compound, was collected by filtration and washed with small amount of water and diisopropyl ether, to yield 120 mg.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@H:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[O:23][C:22](=[O:33])[NH: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.[Cl:34][C:35]1[CH:40]=[C:39](Cl)[N:38]=[C:37]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[N:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>O1CCOCC1.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[Ar]>[Si:1]([O:18][CH2:19][C@H:20]1[C@H:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[O:23][C:22](=[O:33])[N:21]1[C:39]1[CH:40]=[C:35]([Cl:34])[N:36]=[C:37]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[N:38]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc([C@@H]2OC(=O)N(c3cc(Cl)nc(N4CCOCC4)n3)[C@H]2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 100 °C
Yield: 99 %

Procedure:
To a solution of (4S,5S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(4-methoxyphenyl)-oxazolidin-2-one (1.65 g, 3.57 mmol), 4-(4,6-dichloropyrimidin-2-yl)morpholine (920 mg, 3.93 mmol) and Cs2CO3 (1.75 g, 5.36 mmol) in dioxane (20 mL) was added after purging with argon 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (145 mg, 250 μmol) and Pd2(dba)3 (65 mg, 0.071 mmol), and the reaction mixture was heated for 5 h at 100° C. The reaction mixture was added to 10% aqueous NaHCO3 solution and extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 50% in order to give the title compound as a white solid (2.33 g, 94%). TLC (heptane/EtOAc 1:1) Rf=0.52; LC-MS: [M+H] 659,661; Rt 1.58 min; (LCMS method 2). 1H NMR (400 MHz, CDCl3): 7.64 (m, 4H), 7.54 (s, 1H), 7.55-7.35 (m, 6H), 7.26 (m, 2H), 6.95 (d, 2H), 5.21 (d, 1H), 4.56 (m, 1H), 4.22 (dd, 1H), 3.96 (dd, 1H), 3.84 (s, 3H), 3.60-3.40 (m, 8H), 1.09 (s, 9H).
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]([Cl:34])[C:23]([F:35])=[CH:22][N: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.CC1SC([CH:42]=[O:43])=NC=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH2:42][OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(C=O)s1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(CO)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 5-methylthiazole-2-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:16][NH2:17])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CNc1ccc(Cl)cc1
Yield: 58.4 %

Procedure:
Ethyl 2-(4-chlorophenylamino)acetate (A) (25.6 g, 120 mmol) and hydrazine monohydrate (7.0 mL, 144 mmol) were heated to reflux in ethanol (120 mL) for 22 hours. After concentration in vacuo, the solid obtained was recrystallised from ethanol to yield the title compound (14.0 g, 59%) as a pale brown powder. 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, d), 4.18 (2H, br), 6.53 (2H, d), 7.16 (2H, d), 7.60 (1H, br).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[ClH:13].Cl.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:33].[ClH:13].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[O:12])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 135.7 %

Procedure:
The procedure described in Example 29 was followed, using 4-ethoxyphenyl isocyanate (1.63 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (16 ml), and triethylamine (4.3 ml; 31 mmole). Recrystallization from ethanol provided the title compound (3.42 g; 68% yield) as colorless crystals, m.p. 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:6][C:5]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([N:29]=C(C)C)[C:19]2=[O:33])=[C:4]([F:34])[CH:3]=1.Cl>CO>[NH2:29][N:20]1[C:21]([C:25]([F:28])([F:26])[F:27])=[CH:22][C:23](=[O:24])[N:18]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[F:34])[C:19]1=[O:33]
Reactant: CC(C)=Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: Cl
Solvent: CO
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A suspension of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-1-[(1-methylethylidene)-amino]-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.300 g, 0.60 mmol), 1 N HCl (3.0 mL,), and methanol (3.0 mL) was heated to reflux for 2 hours. The reaction was cooled to room temperature, partitioned between water and ethyl acetate, and the phases separated. The aqueous phase was extracted ethyl acetate (3×50 mL) and concentrated. Chromatography (20% ethyl acetate/hexane) of the residue afforded 1-amino-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)-phenyl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione 0.12 g (43.5%) of a white solid. 1H-NMR (CDCl3): δ 4.58 (bs, 2H), 6.25 (s, 1H), 6.94 (dd, J=8.38, 1.13 Hz, 1H), 7.03 (d, J=6.52 Hz, 1H), 7.24 (dt, J=7.29, 1.22 Hz, 1H), 7.43 (d, J=8.83 Hz, 1H), 7.53 (dt, J=7.12, 1.69 Hz, 1H), 7.97 (dd, J=8.15, 1.65 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[CH2:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: BrCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
Benzyltrimethylammonium chloride (4.61 g, 24.8 mmol) was added to a mixture of tert-butyl 2-hydroxyethylcarbamate (40.0 g, 248 mmol), dichloromethane (600 mL), and 50% aqueous sodium hydroxide (400 mL). Benzyl bromide (29.5 mL, 248 mmol) was then added, and the reaction was stirred for three hours. Ice water was added (1 L), and the aqueous solution was extracted with chloroform (5×). The combined organic solutions were washed with water (2×) and brine (3×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Upon concentration, a white precipitate formed, and the organic solution was washed again with water (3×100 mL). The combined washings were extracted with chloroform (3×50 mL). The combined organic solutions were washed with brine (3×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 59.1 g of tert-butyl 2-(benzyloxy)ethylcarbamate as a colorless oil.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8]>ClC(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccccc1C
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)OC)c1ccccc1CBr
Yield: 45.7 %

Procedure:
21.4 g (0.133 mole) of bromine are added to 27.5 g (0.133 mole) of 2-methylphenylglyoxylic acid methyl ester O-methyloxime dissolved in 400 ml of tetrachloromethane, while stirring. Thereafter, the mixture is refluxed for four hours with exposure to a 300 W Hg vapor lamp. It is thenevaporated down, the residue is taken up in ethyl acetate/water and the solution is washed with H2O, dried with sodium sulfate and evaporated down. The crude product is purified by chromatography over silica gel using 9:1 cyclohexane/ethyl acetate. 17.4 g (46%) of the abovementioned compound is obtained as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:26][NH:27][CH2:28][CH3:29]>>[CH2:24]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:8]=1)=[O:16])([C:19](=[O:21])[N:27]([CH2:28][CH3:29])[CH3:26])[CH2:22][CH3:23])[CH3:25]
Reactant: CCNC
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Product: CCN(C)C(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and N-methylethanamine (CAN 624-78-2) as starting materials. MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:50]2([CH2:55][CH2:54][CH:53]([CH2:56][OH:57])[CH2:52][CH2:51]2)[CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:57][CH2:56][CH:53]2[CH2:52][CH2:51][C:50]3([CH2:49][CH2:48][CH2:47]3)[CH2:55][CH2:54]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC1CCC2(CCC2)CC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[3.5]nonan-7-ylmethanol, the title compound was obtained as a colorless solid (0.26 g, 47%): 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 8.05 (d, J=8.4 Hz, 1H), 6.65 (d, J=13.5 Hz, 1H), 3.82 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.89-1.65 (m, 11H), 1.35-1.04 (m, 4H); MS (ES−) m/z: 431.2, 433.2 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[F:16][C:15]([F:18])([F:17])[C:14]1[C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ncccc2C(F)(F)F)CCN1
Temperature: 120 °C

Procedure:
A mixture of piperazin-2-one (4.85 g, 48.47 mmol, Avocado Research), 2-chloro-3-trifluoromethyl-pyridine (8.8 g, 48.47 mmol, TCI America) and diisopropylethylamine (11 mL, 58.16 mmol, Aldrich) in DMSO (160 mL) was heated at 120° C. for 16 h. The mixture was cooled to room temperature, diluted with H2O (500 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane/MeOH (15:1) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 206 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:16])[C:5]2[CH2:6][CH:7]=[C:8](C)[CH:9]([CH3:14])[C:10]=2[C:11](=[O:13])[CH:12]=1.[K+].[Br-].[CH:19](Cl)(Cl)Cl>O=[Mn]=O>[CH3:1][O:2][C:3]1[C:4](=[O:16])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[C:9]([CH3:14])[CH:8]=[C:7]([CH3:19])[CH:6]=2
Reactant: ClC(Cl)Cl
Reactant: COC1=CC(=O)C2=C(CC=C(C)C2C)C1=O
Agent: O=[Mn]=O
Agent: [Br-]
Agent: [K+]
Product: COC1=CC(=O)c2c(C)cc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5,8-dihydro-2-methoxy-5,6-dimethylnaphthalene-1,4-dione (4.00 g, 18.3 mmol) in CHCl3 (150 mL), there was added MnO2 (9.49 g, 110 mmol, Fluka). The stirred suspension was heated at reflux and monitored by 1H NMR (filtered aliquot through celite and removed solvent in vacuo). After 4.5 h, an additional portion of MnO2 (4.8 g, 55 mmol) was added and the reaction was allowed to reflux for an additional 3 h (7.5 h total). The reaction was allowed to stir overnight at rt and was filtered through Celite. The pad was washed with CHCl3 (3×30 mL). Solvent removal yielded a yellow powder (3.80 g, 95%, pure by TLC and 1H NMR); mp 146°-148° C.; 1H NMR (CDCl3) δ2.43 (s, 3H), 2.71 (s, 3H), 3.87 (s, 3H), 6.07 (s, 1H), 7.33 (s, 1H), 7.87 (s, 1H); IR (KBr) 3070 (w), 2982 (w), 2968 (w), 2946 (w), 2926 (w), 2850 (w), 1676 (s), 1646 (s), 1636 (s), 1619 (s), 1601 (s), 1247 (s), 1243 (s), 1236 (s), 1105 (s), 865 (m), 705 (m). Crystallization from EtOH yielded yellow needles (mp 147.5°-149° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH2:30])[CH2:28][C:27]([CH3:32])([CH3:31])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[OH-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH:30][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:28][C:27]([CH3:32])([CH3:31])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)C[C@@H](NC(=O)c2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step B (35.6 mg, 0.08 mmol) and NEt3 (43 μL, 0.31 mmol) in 10 mL of CH2Cl2 was added benzoyl chloride (20 μL, 0.17 mmol). After stirring at rt for 1 h, 2.0 mL of CH3OH and 100 μL of 5.0 N NaOH was added to the reaction mixture. After stirring for 30 min, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aq NaHCO3 (20 mL). The organic layer was separated and washed with brine (20 mL). After the phases separated, the organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 7:3 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.50 (s, 3H), 1.56 (s, 3H), 1.96 (t, J=12.4, 1H), 2.36 (dd, J=6.4, 13.2, 1H), 5.73 (m, 2H), 6.61 (d, J=8.7, 1H), 7.02 (d, J=8.5, 2H), 7.13 (d, J=8.5, 2H), 7.14-7.55 (m, 6H), 7.72-7.83 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[F:24][C:4]1[CH:3]=[C:2]([N:27]2[C@H:26]([CH3:25])[CH2:30][O:29][C:28]2=[O:31])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4C(=O)OC[C@H]4C)cc3F)CC2)nc1
Yield: 67.1 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (393 mg) described in Preparation Example 185 and (R)-4-methyloxazolidin-2-one (132 mg) described in Preparation Example 25, the title compound (277 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:23])[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH3:22])[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=1)#[N:2]>[OH-].[Na+]>[C:1]([C:3]1[C:4](=[O:23])[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH3:22])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCOc1ccc(C(=O)OC)cc1-c1ccc(C#N)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccc(C(=O)O)cc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A mixture of methyl 3-(3-cyano-1,2-dihydro-2-oxo-6-pyridinyl)-4-propoxybenzoate (2.0 g) and 1 Normal sodium hydroxide (30 ml) was heated under reflux for 45 minutes and the resultant solution was acidified to give a quantitative yield of 3-(3-cyano-1,2-dihydro-2-oxo-6-pyridinyl)-4-propoxybenzoic acid, m.p. 277-279° C. This acid was heated with thionyl chloride (10 ml) for 90 minutes, the solution was evaporated, and the acid chloride was dissolved in dichloromethane (60 ml). Methylamine was passed slowly through the stirred solution for 45 minutes and both the resultant solid and solution were washed with dilute hydrochloric acid and water. The solid was combined with the residue left after evaporation of the solution to give 1.66 g of solid m.p. 234-236° C. Recrystallization from ethanol gave the title compound, m.p. 235-237° C.