Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][C:31]([CH3:35])([CH3:34])[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NCC(C)(C)C)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropionamide (0.5 g, 1.3 mmol) and trimethylacetaldehyde (0.26 mL, 2.3 mmol) in 1,2-dichloroethane (10 mL), was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) at room temperature. After 1 day, the mixture was extracted with methylene chloride (50 mL) and water (20 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 25 mL) and brine (25 mL), and dried over MgSO4. Removal of solvent gave a yellow oil, which was purified by prep HPLC to give (3R)-3-[7-(2,2-dimethyl-propylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-propionamide as a white solid (0.59 g, 99% yield): mp 111-113° C.; 1H NMR (CDCl3) δ 1.01 (s, 9H, 3 CH3), 1.43 (t, J=7 Hz, 3H, CH3), 2.89 (s, 3H, CH3), 2.98 (d, J=6 Hz, 2H, CH2), 3.07 (dd, J=6, 15 Hz, 1H, CHH), 3.11 (s, 3H, CH3), 3.45 (dd, J=9, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.12 (d, J=16 Hz, 1H, CHH), 4.33 (d, J=16 Hz, 1H, CHH), 5.59 (dd, J=7, 9 Hz, 1H, NCH), 6.47-6.51 (m, 2H, Ar), 6.79-7.01 (m, 4H, NH, Ar), 7.22 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 27.63, 32,27, 35.52, 36.67, 37.54, 48.56, 53.10, 54.49, 55.95, 64.42, 107.82, 108.77, 111.25, 112.66, 114.58, 119.22, 132.35, 132.96, 143.09, 148.16, 148.41, 148.81, 169.97, 170.79. Analy. calculated for C27H37N3O4: C 69.35; H 7.98; N 8.99. Found: C 69.70; H 7.95; N 8.74.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1([CH3:47])[CH2:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([CH3:46])([CH3:45])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[CH2:33][C:32]([CH3:46])([CH3:45])[NH:31][C:30]([CH3:47])([CH3:29])[CH:35]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.5 g, 1.12 mmol), was added 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.36 g, 1.35 mmol) and Pd(PPh3)4 (0.066 g, 0.057 mmol) in 1,4-dioxane (10 mL) and the flask purged with argon for 10 min. 2M Na2CO3 solution (0.43 g, 4.06 mmol) was then added and the flask again purged with argon for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion, water was added and extraction carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-4-carboxamide (0.53 g, 77.6%). LCMS: 502.55 (M+1)+; HPLC: 99.25% (@ 254 nm) (Rt; 5.528); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (bs, 1H), 8.54 (t, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 6.26 (s, 1H), 5.88 (s, 1H), 5.29-5.24 (m, 1H), 4.37 (d, 2H, J=5.2 Hz), 2.32 (m, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.99-1.93 (m, 4H), 1.92-1.88 (m, 2H), 1.72-1.69 (m, 2H), 1.23 (s, 6H), 1.17 (s, 6H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:16][C@H:15]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.N1(CC2C=CC(C3CC(CN4CCNCC4)C3)=CC=2)CCCC1.C(N(C(C)C)CC)(C)C.[C:67](Cl)(=[O:71])[CH:68]([CH3:70])[CH3:69]>ClCCCl>[CH3:69][CH:68]([CH3:70])[C:67]([N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C@H:15]2[CH2:16][C@H:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)[CH2:14]2)[CH2:23][CH2:22]1)=[O:71]
Reactant: CC(C)C(=O)Cl
Reactant: c1cc([C@H]2C[C@H](CN3CCNCC3)C2)ccc1CN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc(C2CC(CN3CCNCC3)C2)ccc1CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)C(=O)N1CCN(C[C@H]2C[C@H](c3ccc(CN4CCCC4)cc3)C2)CC1

Procedure:
To a stirring solution of Example 111, (3-(4-Pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl]-piperazine) (100 mg, 0.32 mmol) in 1,2-dichloroethane (4 mL) was added diisopropyl ethylamine (111 uL, 0.64 mmol) followed by the addition of isobutyryl chloride (50 uL, 0.48 mmol). After 15 min the reaction was quenched with 1N NaOH, extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 12 g ISCO column, eluting with 4% MeOH/CH2Cl2 with 0.2% NH4OH. The product containing fractions were collected and concentrated to give the title compound (118 mg, 97% yield) as colorless oil. Rf=0.27 (10% MeOH/CH2Cl2 w/0.2% NH4OH); 500 MHz 1H NMR (CDCl3) δ 7.23 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 3.61–3.44 (m, 7H), 2.74 (septet, J=7.1 Hz, 1H), 2.56–2.45 (m, 7H), 2.42–2.34 (m, 4H), 2.28–2.20 (m, 2H), 2.17–2.09 (m, 2H), 1.79–1.70 (m, 4H), 1.08 (d, J=7.1 Hz, 6H); 125 MHz 13C NMR (CDCl3) δ 175.5, 145.1, 136.7, 129.1, 126.5, 64.3, 60.5, 54.3, 45.6, 41.8, 36.5, 33.4, 30.1, 29.0, 23.6, 19.6; LRMS m/z Calcd for C24H37N3O 383.6; obsd LRMS APCI (M+1) m/z 384.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[CH2:17][Cl:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(F)c(F)c1
Reaction time: 8 h
Yield: 418.3 %

Procedure:
The method of Cervena et al.3 was followed. To a stirred solution of 3,4-difluoroaniline (10 mmol) in toluene (5 mL) and pyridine (10 mmol) maintained at 5-10 deg C was added chloroacetyl chloride (10 mmol) in toluene (5 mL) dropwise. The mixture was allowed to stand overnight at room temperature. The organic layer was then separated and the residue was mixed with water (60 mL). The separated solid product was recrystallized from toluene to give N-(3,4-difluorophenyl) chloroacetamide (8.6 g, 84.3% yield). 1HNMR (300 MHz, CDCl3) δ 8.24 (s, 1H, NH), 7.63 (td, J=8.1 Hz, 1H, Ar—H), 7.16-7.12 (m, 2H, Ar—H), 4.19 (s, 2H, COCH2Cl).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Br-].[Li+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN1CCCC1=O>[NH2:1][C@H:2]([C:4]([O:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)C(=O)OCc1ccccc1

Procedure:
In a similar operation, 0.45 gram (0.005 mole) of alanine, 0.87 gram (0.01 mole) of lithium bromide, 0.95 gram (0.0055 mole) of benzyl bromide and 4.8 grams of N-methylpyrrolidinone were stirred together for 5.5 hours at 55° C. to obtain the desired benzyl alaninate product. High pressure liquid chromatographic assay showed yield of the product to be 89 percent.
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=[N:11][C:10]=2C=C(C(F)(F)F)C=1.CN1CC[N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[C:10]([CH2:28][CH2:29][NH:30][C:33](=[O:55])[CH:34]=[CH:35][C:36]1[C:44]2[N:43]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[N:41][C:40]=2[CH:39]=[C:38]([C:51]([F:53])([F:54])[F:52])[CH:37]=1)#[N:11]
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: N#CCCNC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford, after removal of the solvent, the title compound as a white solid (13 mg, 5%), m/z 385.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:25](=[O:27])[CH3:26])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (300 mg) was dissolved in 1.5 ml of dry pyridine. Acetic anhydride (1.5 ml) was added thereto. The resulting mixture was stirred at room temperature for 5 hours, diluted with water, extracted with ether, washed successively with brine, dilute hydrochloric acid, brine, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-acetoxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([S:15][CH3:16])[CH:9]=[C:8]([CH3:17])[N:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([S:15]([CH3:16])=[O:26])[CH:9]=[C:8]([CH3:17])[N:7]=1
Reactant: COCCOc1nc(C)cc(SC)c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1nc(C)cc(S(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(2-methoxyethyl)oxy]-6-methyl-4-methylthio-3-nitropyridine (2.00 g, 7.74 mmol) was dissolved in dichloromethane (25 mL). m-Chloroperbenzoic acid (60%, 5.0 g, 17.38 mmol) was added to the solution, followed by stirring at room temperature for 12 hours. Saturated aqueous sodium sulfite was added to the reaction mixture, followed by stirring for 1.5 hours so that excessive m-chloroperbenzoic acid was deactivated. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was recrystallized from ether, to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-4-methylsulfinyl-3-nitropyridine as colorless crystals (1.93 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22]>Cl.C(Cl)Cl>[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Cc1cccc(O)c1C
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)c1C

Procedure:
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-epoxypyrrolidine, 18.3 g. (0.15 mole) of 2,3-dimethylphenol and 2 drops of concentrated hydrochloric acid was heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture was dissolved in methylene chloride and washed with four 100-ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate-potassium hydroxide and concentrated to give 28.6 g. of dark oil as residue. This oil was chromatographed or 600 g. of silica gel and the product was eluted with an acetone-benzene solution. The appropriate fractions were concentrated to give an oil which crystallized upon standing. This solid was recrystallized from ligroin to give 9.1 g. (31%) of white solid, m.p. 100°-4° C.
Reaction SMILES: C1C2C=CC3C4C=CC=CC=4C=CC=3C=2OC=1C=O.[CH:20]1[C:21]2[CH:38]=[CH:37][C:36]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH:29]=[CH:28][C:27]=3[C:22]=2[S:23][C:24]=1[CH2:25][OH:26]>C(Cl)Cl.CCCCCC>[CH:20]1[C:21]2[CH:38]=[CH:37][C:36]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH:29]=[CH:28][C:27]=3[C:22]=2[S:23][C:24]=1[CH:25]=[O:26]
Reactant: OCc1cc2ccc3c4ccccc4ccc3c2s1
Agent: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2s1
Yield: 82.9 %

Procedure:
Using the procedure outlined in 14B, phenanthro[1,2-b]thiophene-2-methanol (16A) gave a 82.9% yield of phenanthro[1,2-b ]thiophene-2-carbaldehyde, mp 209°-210°, (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].[OH2:20].[Br-].[Li+].O>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]([OH:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(O)C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 3,4,6-tri-O-acetyl-D-glucal (25.0 g) and lithium bromide hydrate (25.0 g) in acetonitrile (750 ml), activated resin prepared as in Example 1 (25.0 g) and water (30 ml) were added and stirred at room temperature for 4 h. The product was isolated as described for Example 1. Crystallization from ethyl acetate-hexane gave the title compound as colorless crystals (17.8 g). [α]D20 =+71.2°±2° (c 1.06, CHCl3). 1H NMR δ: 5.40 (broad s, H-1α), 5.35 (m, H-3α), 4.9-5.05 (H-4α,β, H-3β, H-1β), 4.18-4.28 (H-6a, H-5α), 4.10 (H-6bβ), 4.06 (H-6bα). 3.65 (m, H-5β), 2.38 (m, H-2eqb), 2.25 (H-2eqα), 1 79 (H-2axα), 1.67 (H-2axβ). MS m/e 273.11 (M-H2O), 213.10, 153.07.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:20])C.C([NH2:24])=O.C[O-].[Na+]>CN(C=O)C.CO>[Cl:20][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=2)[C:6]=1[CH2:5][C:4]([NH2:24])=[O:3]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)cc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-dimethylaminomethyl-naphthalen-1-yl)-acetic acid ethyl ester (2.70 g, 8.82 mmol) and formamide (1.17 ml, 29.57 mmol) are dissolved under an atmosphere of argon in dry DMF (25 ml). The solution is heated to 105° C., and NaOMe (1.64 ml of a 5.4 M solution in MeOH, 8.82 mmol) is added dropwise during 10 minutes. After 1 hour at 105° C., TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water, and adjusted to a pH of 6-7 by the addition of 1 M NaHSO4 solution. The mixture is concentrated and purified by FCC (CH2Cl2/EtOH/NH3 conc. 90:9:1) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.01 (s, 6H), 3.48 (s, 3H), 4.02 (s, 3H), 6.9-7.0 (br, 1H), 7.41-7.47 (m, 2H); 7.47-7.85 (br, 1H), 7.75-7.88 (m, 2H), 7.80 (d, J=12.1 Hz, 1H). ES+−MS: 277.3, 279.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:17]=1[NH2:18]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:18][C:17]2[C:16]([F:15])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1c(F)cccc1F
Solvent: CC#N
Product: CCOC(=O)c1cnc(SC)nc1Nc1c(F)cccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 102 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10.0 g, 43.1 mmol) in acetonitrile (107 mL) is added 2,6-difluoroaniline (9.3 mL, 86.2 mmol). The mixture is heated to 90° C. for 4 hours. The reaction is cooled to room temperature and stored at 0° C. for 15 hours. The white precipitate which forms is filtered and washed with 20% EtOAc/hexanes to afford 14.3 g of the desired product which is used without further purification: 1H NMR (300 MHz, CDCl3/MeOH) δ 9.70 (s, 1H), 8.20 (s, 1H), 7.82 (s, 2H), 5.23 (s, 2H), 3.18 (s, 3H), 2.25 (s, 3H); ESI+ MS: m/z (rel intensity) 326.0 (100, M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[CH2:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[CH2:13][CH3:14].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:16]3[C@@H:15]([CH2:12][CH2:13][CH3:14])[CH2:19][O:18][C:17]3=[O:20])=[N:7][C:6]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: CCC[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Reaction time: 18 h
Yield: 41.8 %

Procedure:
To a solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (5.30 g, 22.8 mmol) and (S)-4-propyloxazolidin-2-one (0.354 g, 2.74 mmol) in dry DMF (10 mL) at ambient temperature was added sodium hydride (0.110 g, 2.74 mmol) and the solution was stirred for 18 hours. Saturated aqueous NH4Cl solution was added and the solids were collected by filtration. Purification of the crude material by normal phase column chromatography, eluting with 1-10% EtOAc/dichloromethane afforded 0.372 g (63%) of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-propyloxazolidin-2-one as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH2:50][NH2:51].CCOC(C)=O>O1CCOCC1>[CH3:40][O:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH2:50][NH:51][C:6]1[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(Cl)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (300 mg, 0.640 mmol) in 1,4-dioxane (8 mL) was added Hunig's base (0.22 mL, 1.28 mmol) followed by {[2,4-bis(methyloxy)phenyl]methyl}amine (0.19 mL, 1.28 mmol), and the reaction mixture was stirred overnight at 60° C. into a sealed tube. This reaction mixture was combined with another similar reaction mixture (˜⅓ the scale) before work up. The combined reaction mixtures were poured onto water and EtOAc. The layers were separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (322 mg) as a white foam. LC-MS (ES) m/z=556 [M+H]+.
Reaction SMILES: N#N.[CH2:3]([P:5]([CH2:12][CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:4].[N-:14]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16].[C:29](=O)(OC)OC>CO>[F:28][C:25]([F:26])([F:27])[S:22]([N-:14][S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])(=[O:23])=[O:24].[CH2:12]([P+:5]([CH2:3][CH3:4])([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: COC(=O)OC
Reactant: CCP(CC)c1ccccc1
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CC[P+](C)(CC)c1ccccc1
Temperature: 15 °C

Procedure:
In a reactor wherein air was replaced by N2, 200.0 g of (1.2 mol) diethylphenyl phosphine and 400 mL of methanol were added and cooled to 15° C. by a ice-bath. 338.6 g (1.2 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added after the reaction was complete. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 2 hours of reaction at temperature of 180° C. and at pressure of from 1.2 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 507.1 g of diethyl methyl phenyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])([CH3:25])[CH3:24].OC([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](N(C)C(=O)CC2)CC3)CC1)C.C(CCCCCCCCCCC(O)=S)C>>[CH:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:1][CH:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)=[O:39])([CH3:25])[CH3:24]
Reactant: CC(C)SCCCCCCCCCCCC(=O)O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(O)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCCCCCCCCCC(O)=S
Product: CC(C)SCCCCCCCCCCCC(=O)OC1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 191, but substituting 17-hydroxy-4-methyl-5a-4-azaandrostan-3-one and 12-(isopropylthio)dodecanoic acid for the 20-hydroxy-4-methyl-5α-4-azapregnan-3-one and 11-ethylthioundecanoic acid, respectively, used therein, the title compound was obtained. MS M+ calculated for C34H59NO3S, mw=561.92: observed m/e 561.