Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]1)[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:12]2[C:11]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[N:10][C:9]3[C:13]2=[N:14][CH:15]=[N:16][C:8]=3[O:2][CH3:1])=[CH:19][CH:20]=1
Reactant: C[O-]
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ncnc2c1nc(CC1CCN(Cc3ccccc3)CC1)n2Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a previously prepared sodium methoxide solution, starting from 25 parts of sodium in 400 parts of methanol, were added 49.4 parts of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine. After stirring for 8 hours at reflux temperature, the reaction mixture was cooled and 1000 parts of water were added. The precipitated product was filtered off and dried, yielding 34.5 parts (70.4%) of 9-[(4-fluorophenyl)methyl]-6-methoxy-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine (compound 184).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].C(COC)[O:17]C>O.[N+]([O-])([O-])=O.[Ag+]>[F:11][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH:2]([OH:17])/[C:3]/2=[CH:12]\[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Reactant: COCCOC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1O
Yield: 28 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (5.30 g, 19.25 mmoles) and silver nitrate (10.40 g, 61.18 mmoles, Aldrich) in dimethoxyethane (265 mL) and water (100 mL) was refluxed for 18 hours. The mixture was filtered, and the filtrate was diluted with water (700 mL) and extracted with ethyl acetate (6×100 mL). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane: ethyl acetate (2:1), gradually increasing the polarity to hexane: ethyl acetate (1:1). The fractions containing the compound with Rf=0.18 were combined and evaporated in vacuo to give 1.13 g (28%) of crude (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an orange solid. Recrystallization from ethyl acetate: hexane mixtures gave 0.49 g (12%) of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-white solid, mp 201°-202° C.;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[C:20]([O:22]C(C)(C)C)=[O:21])[C:11]=2[CH:10]=[CH:9]1)C.C([O-])C.[Na+].[NH2:44][C:45]1[NH:46][CH2:47][CH2:48][CH2:49][N:50]=1>C1COCC1>[CH2:31]([O:30][C:28]([NH:27][C@@H:19]([CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:44][C:45]3[NH:50][CH2:49][CH2:48][CH2:47][N:46]=3)[C:12]=2[N:13]=[C:14]([CH3:38])[N:15]=1)[C:20]([OH:22])=[O:21])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Reactant: NC1=NCCCN1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 300 mg (0.5 mmol) of 4-[4-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-butyric acid ethyl ester (example 2b) in 5 ml of absol. THF were added 124 mg (1.82 mmol) of sodium ethanolate and 155 mg (1.56 mmol) of 1,4,5,6-tetrahydro-2-aminopyrimidine and the solution was stirred at room temperature for 6 hours. The mixture was brought to pH 7.0 and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (90:10:1:1). Yield: 28 mg.
Reaction SMILES: O.[C:2]([O:5][C:6]1[CH:7]=[C:8]([O:16][C:17](=[O:19])[CH3:18])[CH:9]=[C:10]([O:12][C:13](=O)[CH3:14])[CH:11]=1)(=[O:4])[CH3:3].[H-].[Na+].C(Cl)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1.Cl>CN(C=O)C>[C:17]([O:16][C:8]1[CH:7]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(OC(C)=O)c1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(OC(C)=O)c1
Reaction time: 16 h

Procedure:
Water (4.3 ml, 236 mmol) in DMF (20 ml) was added drop wise at room temperature with stirring to a mixture of acetic acid 3,5-diacetoxy-phenyl ester (refer Kawamoto. H. et. al. Synth. Commun. M, 531, 1996) (35 g, 139 mmol), NaH (5.66 g, 236 mmol) and benzyl chloride (19.16 ml, 166 mmol) in dry DMF (300 ml). The reaction mixture was stirred overnight (˜16 h), poured into chilled dil. aqueous HCl and extracted with CH2Cl2 to obtain the crude title compound which was purified using flash chromatography (silica ge, 20-50% CH2Cl2 in PE 60-80° C.). Yield, 12.5 g (30%), white solid; mp: 129-30° C.; MS (EI): 300 (M+), 258, 216, 91 (100%); analysis: C17H16O5 requires: C, 67.99; H, 5.37 found: C, 67.50; H, 5.40%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3=[N:19][O:21][C:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[C:17]3[CH:18]=2)=[CH:11][CH:10]=[N:9]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1

Procedure:
The title compound, light yellow solid (27 mg, 20%), MS (ISP) m/z=386.3 [(M+H)+], mp 134° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.Cl.[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>>[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:9]([C:8]4[CH:13]=[CH:14][C:15]([N:17]5[CH2:21][CH2:20][O:19][C:18]5=[O:22])=[CH:16][C:7]=4[N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[O:11])[CH2:38][CH2:39]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 18.5 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (127 mg) described in Preparation Example 49, the title compound (48.7 mg) was obtained.
Reaction SMILES: [OH-].[Na+].CO.[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:22]([O:24]C)=[O:23])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[N:8][N:7]=[N:6]1.Cl>O>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([C:22]([OH:24])=[O:23])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[N:5][N:6]=[N:7]1
Reactant: COC(=O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Aqueous 2 N sodium hydroxide solution (4 mL) was added to an MeOH (40 mL) solution of methyl 5-(tetrazol-5-yl)biphenyl-3-carboxylate (1.18 g), and stirred at room temperature for 45 minutes and then at 50° C. for 5 hours. Further, aqueous 2 N sodium hydroxide solution (2 mL) was added to it, and stirred at 50° C. for 2 hours. With cooling with ice, 2 N hydrochloric acid (12 mL) and water were added to it, the formed precipitate was taken out through filtration, washed with water and dried to obtain the title compound as a white powder.
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21](N)[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11]1>>[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:4])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11]1
Reactant: Nc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Reactant: NC(CO)(CO)CO
Agent: Cl
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Reaction time: 2 h

Procedure:
The washed cells described above were added to 0.05M Tris-HCl buffer (pH 7.2) containing 1 g/dl of 2',3'-dideoxyadenosine in a concentration of 5 g/dl followed by reacting at 30° C. for 2 hours. The amount of 2',3'-dideoxyinosine produced at this stage is shown in Table 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3]C1.C(C[C:10]([O:12][CH2:13][CH3:14])=[O:11])#N.C(=O)C>C(O)(=O)C.O>[C:6](/[C:5](=[CH:4]\[CH3:3])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:1]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Agent: CC=O
Solvent: O
Solvent: CC(=O)O
Product: C/C=C(\C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 cm3 of piperidine are added dropwise to a solution of 64 cm3 of ethyl cyanoacetate and 34 cm3 of acetaldehyde in 80 cm3 of acetic acid. After stirring for 20 hours at ambient temperature, the reaction mixture is diluted with 200 cm3 of water and extracted with ether (3×200 cm3). The combined organic phases are washed with water and then dried over sodium sulphate and evaporated. Distillation under reduced pressure (97° C./10 torr) of the residue obtained allows 40.44 g of the expected product to be obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccncc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(4-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (867 mg, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1.[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH:28]=[O:29]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:20]([CH3:24])([CH:28]([C:27]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:26]=2[F:25])[OH:29])[C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1
Reactant: CC(C(=O)O)c1cncc(Br)c1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C(=O)O)(c1cncc(Br)c1)C(O)c1cc(F)ccc1F
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
In a flame dried flask under nitrogen was added diisopropylamine (0.976 mL, 6.85 mmol), tetrahydrofuran (4 mL) and the vessel was cooled to −78° C. n-BuLi (2.74 mL, 6.85 mmol) was added dropwise and after 10 min, the reaction was warmed to −15° C. and held there for 10 min before recooling to −78° C. 2-(5-bromopyridin-3-yl)propanoic acid (750 mg, 3.26 mmol) held in a flame dried flask was dissolved in tetrahydrofuran (4 mL) and added dropwise to the preformed LDA resulting in a kool-aid orange solution. The ice bath was again removed and the reaction was allowed to stir at ambient temperature for 1.5 h, recooled to −78° C. and 2,5-difluorobenzaldehyde (0.779 mL, 7.17 mmol) in 2 mL tetrahydrofuran was added over 10 min. After 1 h, the reaction was quenched with 10% citric acid and the volatiles were removed under vacuum. The residue was extracted with 3 portions ether, washed with brine, dried over MgSO4, filtered and concentrated to 1.31 g red gum which was used immediately in the next step.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:7]=1[O:8][CH2:9][C:10]#[N:11].C[Si]([N:39]=[N+:40]=[N-:41])(C)C>O>[Br:5][C:6]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:7]=1[O:8][CH2:9][C:10]1[NH:41][N:40]=[N:39][N:11]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: C[Al](C)C
Solvent: O
Product: Brc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1nnn[nH]1
Temperature: 80 °C

Procedure:
Trimethylaluminum (2.55 mL, 3.84mmol, 2.0 M solution in toluene) was added to [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-acetonitrile (0.615 g, 1.02 mmol) under a dry nitrogen atmosphere. Trimethylsilyl azide (0.510 mL, 3.84 mmol) was then added and the solution was heated in a 80° C. oil bath. After 16.5 h the reaction mixture was cooled to room temperature and water was cautiously added. The mixture was partitioned between dilute aqueous HCl and ethyl acetate. The layers were separated and the 2% phosphoric acid in methanol washed silica gel was added to the organic phase. The solvent was removed and the adsorbate was flashed using 2% phosphoric acid in methanol washed silica gel (eluent:gradient: 4:1 to 7:3 petroleum ether:ethyl acetate) to provide the title compound as a white solid, which was recrystallized from cyclohexane (0.365 g, 55%): mp 243-245° C.: NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1H), 8.09 (d, J=8 Hz, 1 H), 7.89 (s, 2 H), 7.80 (ddd, J =8, 7, 1 Hz, 1 H), 7.66-7.57 (m, 2 H), 7.55 (ddd, J=8, 7, 1 Hz, 1 H), 7.40 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1 H), 5.64 (s, 2 H), 1.34 (cyclohexane, 0.3 mole eq); MS (EI): [M+], 3 bromine isotope pattern, 642, 644, 646, 648; Anal. Calc. for C24H13Br3N40S.0.33 C6 H12: C, 46.39, H, 2.55, N, 8.32. Found: C, 46.28, H, 2.43, N, 7.90.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:52]([O:54]P(CC1C=CC(NC2N=C(NC3C=CC(Br)=C4C=3C(=O)N(C)C4)C(C(F)(F)F)=CN=2)=C(OC)C=1)(=O)OCC)C.C(OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O)(C)(C)C>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:49])[F:51])=[CH:19][N:18]=2)=[C:14]([O:54][CH3:52])[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Compound 246A using diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708). MS (ES+): m/z 761.33 (100) [MH+]; HPLC: tR=1.56 min (UPLC, analytical).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([F:15])[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[C:9]([F:15])[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Br)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.1 eq) in tetrahydrofuran (0.13M) at −78° C., was added n-butyllithium (2.5M in hexanes, 1.1 eq) dropwise over 20 min. The reaction mixture was stirred at −78° C. for 15 min, warm to 0° C., stirred for 15 min and cooled back to −78° C. A solution of 4-bromo-2-fluoro-benzaldehyde (1 eq) in 100 mL THF was added dropwise over 30 min. Final mixture was allowed to warm slowly to rt and stirred for 1 h. The resulting mixture was quenched with a saturated NH4Cl solution and diluted with 2 volume of hexane. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with Hexane/EtOAc (9:1) and filtered on a pad of Silica gel. The fractions were combined and concentrated to afford the desired material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:38][CH2:37][O:36][C:35]2=[O:39])[CH:29]=1
Reactant: NCc1ccc(F)cc1N1CCOC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derived from reduction of intermediate 117, 4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H, dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57 (2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1.61 (6H, s). LCMS (M+H)+ m/z 523.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:13]([CH2:23][OH:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:26]1[C:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.ClC1C=C(O)C=NC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:13]([CH2:23][O:24][C:26]2[C:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)C[C@@H]1CO
Reactant: CCOC(=O)c1ncccc1O
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using (2R,4R)-tert-butyl 4-(benzyloxymethoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (EXAMPLE 79 Step 2) and ethyl 3-hydroxypicolinate instead of (R)-pyrrolidin-2-ylmethanol and 5-chloropyridin-3-ol.
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccc(C(F)(F)F)cc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-chloromethyl-4-trifluoromethylbenzene (9.8 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl 2-mercaptoacetate (6.1 g) in ethanol (120 cc). Ethyl (4-trifluoromethylbenzylthio)acetate (12.2 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>>[CH3:38][O:37][P:36]([CH2:2][CH2:3][CH2:4][Si:5]([CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12)([CH3:35])[CH3:34])(=[O:41])[O:39][CH3:40]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCI
Reactant: COP(OC)OC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCP(=O)(OC)OC
Yield: 76 %

Procedure:
A solution of Compound 12 (60 mg) in trimethyl phosphite (1 mL) was heated under argon at 80° C. for 10 hours. Trimethyl phosphite was removed from the reaction mixture under vacuum and the residue was eluted on a silica gel using 4% ethanol in dichloromethane to obtain the required product in 76% yield (44 mg).