Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:24][CH2:25][CH3:26])[C:13](I)=[C:14]([O:16][S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH:15]=2)=[CH:4][N:3]=1.I[C:28]1[CH:29]=[C:30]([F:41])[CH:31]=[C:32]([NH:34]C(=O)C(F)(F)F)[CH:33]=1.C(O)C>O1CCOCC1.C(COC)OC>[NH2:34][C:32]1[CH:33]=[C:28]([C:13]2[C:12]([O:24][CH2:25][CH3:26])=[CH:11][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:15][C:14]=2[O:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:29]=[C:30]([F:41])[CH:31]=1
Reactant: O=C(Nc1cc(F)cc(I)c1)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1I
Solvent: CCO
Solvent: C1COCCO1
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1-c1cc(N)cc(F)c1
Yield: 30 %

Procedure:
Starting from cyclopropanesulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester (294 mg; 0.60 mmol) and N-(5-iodo-3-fluoro-phenyl)-2,2,2-trifluoroacetamide (preparation described in example 4t) (333 mg; 1.0 mmol) (first step in 12 ml dioxane instead of dimethylformarmide with bis-triphenylphosphine-palladium dichloride (56 mg; 0.08 mmol) and second step in dimethoxyethane (8 ml) and ethanol (2 ml) with tetrakis-triphenylphosphine-palladium (69 mg; 0.06 mmol)), 147 mg (30%) cyclopropanesulphonic acid 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-5′-fluoro-biphenyl-2-yl ester are obtained as a colourless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.ClC1C=CC(NN)=CC=1>>[ClH:1].[CH2:13]([C:4]1[NH:5][CH:6]=[C:7]2[C:8](=[O:10])[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:28]=[C:2]2[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc(CC)c(-c2ccccc2)c1Cl
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: CCc1[nH]cc2c(=O)n(-c3ccccc3)nc-2c1-c1ccccc1
Yield: 35 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 4-chloro-2-ethyl-3-phenyl-5-pyridinecarboxylate and phenylhydrazine instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared in 35% yield as a yellow solid; mp 239-247° C.; 1H NMR (500 MHz, DMSO-d6) δ1.14 (3H, t, J 7.5 Hz), 2.54 (2H, q, J 7.5 Hz), 7.12 (1H, t, J 7.4 Hz), 7.39 (2H, t, J 7.6 Hz), 7.42-7.54 (5H, m), 8.02 (2H, d, J 7.7 Hz), 8.58 (1H, s), 12.59 (1H, br s); MS (ES+) m/z 316 [MH]+; Anal. found: C, 68.03; H, 5.22; N, 11.79. C20H17N3O.HCl requires: C, 68.28; H, 5.16; N, 11.94%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: OCCCCCCBr
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=P(Cl)(Cl)OCCCCCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Bromohexan-1-ol was added dropwise to phosphorusoxy chloride (equimolar) in dichloromethane over 30 minutes under nitrogen. The mixture was stirred at room temperature under nitrogen for 16 hours. The mixture was evaporated, dried under vacuum, then distilled under vacuum, to give the pure 6-bromohexyldichlorophosphate compound. Triethylamine and dichlorophosphate (equimolar) were added dropwise over 2 minutes under nitrogen to 1,3-dihexadecyloxy-2-(hydroxymethyl)-2-methyl propane (0.3×molar amount of dichlorophosphate) in dry diethyl ether. The mixture was heated at 60° C. under nitrogen for 16 hours before triethylamine (same molar amount as dichlorophosphate) and water were added and heating maintained for a further two hours. After cooling, the aqueous layer was removed and the residue evaporated to dryness and azeotroped with benzene (×3). The residue was dissolved in diethylether, filtered and evaporated to give a crude product, which was at least partially purified by silica gel chromatography using chloroform:methanol:25% ammonia (690:270:64). Triphenylphosphine was added to the intermediate thus prepared in dry chloroform. The mixture was heated at 60° C. for 16 hours before it was cooled and the solvents evaporated under reduced pressure. The residue was purified by silica gel chromatography, elusing with chloroform:methanol (3:1) to chloroform:methanol:water (65:25:4). Fractions containing the desired compound were combined and evaporated under reduced pressure to give the desired final compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH:5]=1)(=[O:3])[CH3:2].[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31]>>[C:1]([C:4]1[CH:5]=[CH:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([NH:31][NH:30][C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:27])=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[CH2:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=CCN(c2ccc(CCc3ccc(CCC(=O)O)cc3)nc2)C=C1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(=O)C1=CCN(c2ccc(CCc3ccc(CCC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)C=C1
Yield: 85 %

Procedure:
By a method similar to Production Example 118, step 3, 3-(4-{2-[5-(4-acetylpyridin-1-yl)pyridin-2-yl]ethyl}phenyl)propionic acid (267.2 mg, 0.700 mmol) and tert-butyl carbazate (559.9 mg, 4.237 mmol) were condensed to give tert-butyl 2-[3-(4-{2-[5-(4-acetylpyridin-1-yl)pyridin-2-yl]ethyl}phenyl)propanoyl]hydrazinecarboxylate (292.0 mg, yield 84.1%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(P(N(C)C)(N(C)C)=O)C>[C:24]1([CH2:23][CH2:22][CH2:21][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: BrCCCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(CCN2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 55 °C
Yield: 76 %

Procedure:
A mixture of 40 ml. HMPT, 23.6 g. (90 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate and 8.96 g. (45 mmole) 3-bromopropylbenzene is maintained at 110° C. for 22 hours, whereby, immediately after mixing together, the temperature increases to about 55° C. and the formation of a pale precipitate is observed. At 110° C., a clear, red-brown solution is present, from which, upon cooling, a product crystallises out. It is poured into a little water, extracted with diethyl ether, the ether phase is washed with water, dried with anhydrous sodium sulphate and evaporated. The crude product is dissolved in diethyl ether and converted into the dihydrochloride by means of hydrogen chloride-containing diethyl ether and recrystallised from ethanol containing 2 drops of concentrated hydrochloric acid; m.p. 273° C. (decomp.). Yield 76% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>C1COCC1>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a cooled (-78° C.), stirred solution of 2-bromo-5-(tert-butyldimethylsilyloxy)methylpyridine (6.8 g, 0.022 mol) in THF (60 mL) was added 1.6M nBuLi in hexanes (14.1 mL, 0.22 mol). After 1 h, tri-n-butyltin chloride (6.1 mL, 0.022 mol) was added and stirring was continued for 3 h. Water was added, and the mixture was warmed to room temperature and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 11.5 g (100%) of product as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=O)C(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A mixture of 5-methyl-1H-indole-2,3-dione (5-methylisatin, 2.0 g, 12.41 mmol), phenylboronic acid (3.027 g, 24.82 mmol), anhyd cupric acetate (4.50 g, 24.77 mmol), activated 4A molecular sieve (6.6 g), triethylamine (3.47 mL, 24.9 mmol), pyridine (2.01 mL, 24.9 mmol) and dichloromethane (165 mL) is stirred for 24 hr at room temperature. The mixture is filtered through a pad of hyflo and evaporated. The residue is stirred with ethyl acetate, the insoluble copper salts removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography eluting with dichloromethane to give the title compound (1.91 g, 65% yield) as an orange solid. MS 238 (M+H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[NH:11][C:12](=O)[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:6]([NH:9][C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(Cl)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Phosphorus oxychloride (6.42 mL, 70.2 mmol) was added dropwise to a solution of 16 (3.40 g, 7.02 mmol), triethylamine (1.96 mL, 14.04 mmol), and chloroform (14 mL) over 30 minutes at room temperature under nitrogen. The reaction mixture was then heated to 70° C. for 30 h. The mixture was cooled to ambient temperature, added dropwise over 2 h to a 0° C. solution of saturated aq. NaHCO3 (500 mL), and stirred for an additional 1 h. The layers were separated, aqueous layer back extracted with methylene chloride (2×100 mL), combined organic layers were dried (MgSO4), filtered and concentrated to a yellow solid. Purification was achieved via flash chromatography (SiO2, 5% Acetone-CHCl3) to afford 81 (3.17 g, 90%) as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 11.08 (s, 1H), 6.09 (d, J=4.0 Hz, 1H), 5.99 (dd, J=6.0, 4.0 Hz, 1H), 5.76 (t, J=6.8 Hz, 1H), 4.41 (dd, J=11.2, 3.2 Hz, 1H), 4.32 (td, J=7.2, 3.2 Hz, 1H), 4.24 (dd, J=11.6, 6.8 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H); [M+H]+ 503.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:20]=1[NH2:21]>C(O)(C)C>[ClH:2].[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:20]=1[NH:21][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: COc1cc2c(Cl)ncnc2cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])c(OC)cc23)c(F)cc1C
Yield: 91.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-nitroquinazoline hydrochloride (784 mg, 2.8 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (621 mg, 3.1 mmol), (prepared as described for the starting material in Example 26), in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the precipitated product collected by filtration, washed with isopropanol, ether and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-nitroquinazoline hydrochloride (1.12 g, 90%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.042 mL, 0.31 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.102 g, 0.0.31 mmol) in DCM (3 mL) under argon and stirred at RT for 40 minutes. 2-Amino-5-methylpyrazine (57 mg, 0.52 mmol) and pyridine (0.043 mL, 0.52 mmol) were added and the reaction stirred for a further 3 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 mL), washed with water (2×10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo. The crude material was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound as a white foam (86 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (14 mg, 14%), MS (ISP) m/z=415.4 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 1-hydroxy-cyclopropane-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[N:6]=1)([CH3:4])[CH3:3].[CH:24](N(C(C)C)CC)(C)C.CI.Cl>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:15][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20]([S:22][CH3:24])=[N:19][C:18]2=[O:23])[N:8]=1)([CH3:13])[CH3:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1nc(C=C2SC(=S)NC2=O)nc(C(C)(C)C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC1=NC(=O)C(=Cc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)S1
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of 5-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-2-thioxo-4-thiazolidinone (1.00 g, 2.85 mmol) and diisopropylethylamine (0.75 g, 5.8 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere is added methyl iodide (0.80 g, 5.6 mmol). The resulting mixture is stirred 16 hours, diluted with ethyl acetate, and with aqueous 1N hydrochloric acid solution and brine. The organic phase is dried over magnesium sulfate, concentrated, and purified by flash chromatography (SiO2, 10% ethyl acetate/hexane) followed by recrystallization from ethyl acetate and hexane to give 0.62 g (60%) of the title compound, mp 205°-208° C.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20](Cl)(=[O:22])=[O:21])[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])[CH3:2].[NH3:24]>O1CCCC1>[CH2:1]([N:3]([C:10]1[C:11]2[C:16](=[C:15]([S:20](=[O:22])(=[O:21])[NH2:24])[CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])[CH3:2]
Reactant: CCN(C(=O)C(F)(F)F)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: N
Solvent: C1CCOC1
Product: CCN(C(=O)C(F)(F)F)c1cccc2c(S(N)(=O)=O)cccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-(N-ethyl-2,2,2-trifluoroacetamido)naphthalene-1-sulfonyl chloride (100 mg) was dissolved in tetrahydrofuran (1.0 mL), cooled to 0° C., then concentrated ammonia (0.11 mL) was added. The reaction was stirred at 0° C. for 3 hours, then concentrated and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCC1CCCCC1)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Yield: 99.2 %

Procedure:
A solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoic acid (0.74 g, 2.5 mmol) and 1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (18 mg, 25 μmmol) in methanol (2.5 ml) was stirred at 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (0.74 g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([O:9][CH3:10])=[O:8])=O)=O.[NH2:11][NH2:12]>C(O)C>[CH3:10][O:9][C:7]([C:5]1[NH:11][N:12]=[C:2]([CH3:1])[CH:4]=1)=[O:8]
Reactant: COC(=O)C(=O)CC(C)=O
Reactant: NN
Solvent: CCO
Product: COC(=O)c1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2.0 g (13.87 mmol) of methyl acetopyruvate in 40 mL of absolute ethanol at 0° C. is added 0.48 mL (15.27 mmol, 1.1 equiv) of hydrazine. The resultion solution is stirred for 1 h at RT then heated to reflux for 3 h. The solution is then cooled to RT and the solvent removed in vacuo to give 5-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a clear yellow oil which is used without further purification: 1H NMR (CDCl3, 300 MHz) δ6.61 (s, 1H), 3.97 (s, 3H),2.40 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCCCC(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 55.7 gms 9(4-methoxyphenyl)nonanoic acid, 640 ml 48% HBr and 640 ml acetic acid was refluxed for 7 hours and cooled to room temperature overnight. The solution was diluted with a large excess of water, whereupon a solid precipitated. The solid was filtered off, re-suspended in water, and filtered again. It was dissolved in ether, washed four times with water, and the organic phase was dried over MgSO4 overnight. The drying agent was filtered off and the solvent removed in vacuo to give a solid which was recrystallized from toluene to give 31.8 gms (58%) 9(4-hydroxyphenyl)nonanoic acid, m.p. 103°-5°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=4)[CH2:14][O:13][C:12]3=[O:23])=[N:7][C:6]=12.[F:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[C:40]1[N:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=5)[CH2:14][O:13][C:12]4=[O:23])=[N:7][C:6]=23)[CH:28]=[CH:27][C:26]=1[C:40]1[N:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:41]=1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Reactant: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cn5)nc34)cc2F)n1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To a solution of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (6.7 g, 18 mmol) and 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (11 g, 27 mmol) in dioxane (150 mL) was added sodium carbonate (44 ml, 89 mmol) (2 M in water) and the reaction mixture bubbled with nitrogen gas for 30 minutes, followed by addition of 750 mg each of Pd2 dba3 and X-phos, and the reaction heated to 80° C. while the nitrogen purge continued. The reaction was poured into water (150 mL) and extracted with ethyl acetate (400 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The material was chromatographed using a gradient of 70% EtOAc/DCM to EtOAc as eluent to yield (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (5.8 g, 9.8 mmol, 55% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.[K].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:43]1(=[O:53])[N:47]([CH2:1][C:2]2[CH:3]=[C:4]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)C(Cc1cc(C)ccc1[N+](=O)[O-])C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-])C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A mixture of diethyl 3-methyl-6-nitrobenzylmalonate (25.0 g, 80.8 mmol), N-bromosuccinimide (18.5 g, 103.9 mmol), and azobisisobutyronitrile (AlBN, 1.1 g) in carbon tetrachloride (400 mL) was refluxed for 11 h, while 3×100 mg of AlBN were added every 3 h during the reaction. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (100 mL) and potassium phthalimide (13.5 g, 72.9 mmol) was added. The mixture was stirred for 3 h at 5°~60° C., poured into saturated sodium bicarbonate, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 hexane/ethyl acetate to give 18.66 g of the title compound (51%).