Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of 4-[2-(5,6,7,8,-tetrahydro-2-naphthoxy)ethoxy]benzaldehyde (1.26 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.68 g, 96%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:20][C:21]([OH:23])=[O:22])O>ClCCl>[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:20]\[C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (39.9 g, 0.35 mol) was added dropwise to a stirred, chilled (ice-methanol bath) mixture of 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid (11.3 g, 0.05 mol) in dichloromethane (250 mL). After 35 min. the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo. This procedure was repeated once more to give 6.4 g of crude (E)-2-(4,6- difluoro-1-indanylidene) acetic acid. Recrystallization of 0.9 g from acetone: water mixtures gave 0.15 g of (E)-2-(4,6-difluoro-1-indanylidene) acetic acid as a white solid: mp 238°-239° C.; NMR (DMSO-d6): d12.25 (br, 1H), 7.23-7.65 (m, 2H), 6.46 (t, 1H), 3.20-3.28, 2.97-3.20(2 m's, 4H); steady-state nOe: irradiation at 6.46 d, observed 21.6% nOe at 7.63 d.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(F)cc3)c2)ccc1N1CCC(N2CCOCC2)CC1
Yield: 34.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)pyrrole-3-carboxylic acid (0.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (0.7 g), the title compound (0.4 g) was obtained, melting point: 182–183° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][CH:39]([C:37]([O:36][CH3:35])=[O:38])[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)C1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COC(=O)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
Methyl 1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid methyl ester following General Procedure C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:17]([O-])=O.[H][H]>[Ni].C(O)C>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 5 h

Procedure:
A mixture of 59 g. (0.185 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)nitrobenzene, about 15 g. of Raney nickel and 1200 ml. of ethanol is hydrogenated by shaking on a Parr hydrogenation apparatus with a hydrogen pressure of 40 to 50 p.s.i. for about five hours. The mixture is filtered, and the filtrate is evaporated to a liquid residue. The residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)aniline as a clear, colorless liquid, b.p. 95°-98° C/0.35 mm Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:41])[CH:25]=1.C(O)(C(F)(F)F)=O>>[F:41][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[C:38]([O:39][CH3:40])=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1cc(OC)c(N)cc1F)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1F)OCC
Yield: 54 %

Procedure:
A solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 75.0 mg, 0.227 mmol) and diethyl (4-amino-2-fluoro-5-methoxybenzyl)phosphonate (Compound 130A, 79.0 mg, 0.271 mmol) in TFE (1.1 mL) was charged with TFA (77.3 mg, 0.678 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 30 min. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The reaction was purified by silica gel chromatography on the combi-flash Rf system using EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 71.3 mg (54% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (t, J=7.07 Hz, 6H), 2.77 (d, J=4.55 Hz, 3H), 3.16-3.25 (m, 2H), 3.79 (s, 3H), 3.95-4.04 (m, 4H), 7.01 (d, J=5.05 Hz, 1H), 7.10-7.17 (m, 1H), 7.42 (t, J=7.58 Hz, 1H), 7.70 (d, J=7.58 Hz, 2H), 8.40 (br. s., 1H), 8.44 (s, 1H), 8.67 (s, 1H), 8.73 (d, J=3.79 Hz, 1H), 11.41 (s, 1H). MS (ES+): m/z 586.19 [MH+] (TOF, polar).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CN
Product: CNCc1csc(N)n1

Procedure:
4-(Chloromethyl)-1,3-thiazol-2-amine (490 mg, 2.65 mmol) was stirred in 40% aqueous methylamine (25 ml) overnight. The reaction mixture was evaporated. The residue was diluted with 95:5 dichloromethane/methanol (25 ml), was dried over sodium sulfate, was filtered and was evaporated to provide 4-[(methylamino)methyl]-1,3-thiazol-2-amine that was used without purification. LCMS: (M+H)+: 144.0.
Reaction SMILES: ClCC([Si](C)(C)C)[CH2:4][O:5][CH2:6][CH:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])CCl.[Cl:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:25][O:26][CH2:4][O:5][CH2:6][CH2:7][Si:10]([CH3:11])([CH3:12])[CH3:13])[N:24]=1
Reactant: C[Si](C)(C)C(CCl)COCC(CCl)[Si](C)(C)C
Reactant: OCc1cccc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOCc1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
3.20 ml of chloromethyl-2-(trimethylsilyl)ethyl ether (18.2 mmol) are added dropwise to a solution containing 2.50 g of (6-chloropyridin-2-yl)methanol (17.4 mmol), 3.30 ml of diisopropylethylamine (19.1 mmol) and 20 ml of dichloromethane cooled to 0° C. maintained under a nitrogen atmosphere. The mixture is stirred for 3 hours at room temperature and then the dichloromethane is evaporated off, the residue is taken up in water, the mixture is extracted with diethyl ether, the organic phase is washed with water and then dried over sodium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: dichloromethane).
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I>C1COCC1>[CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:5][O:6][CH3:18])[CH2:3][CH2:2]1
Reactant: CI
Reactant: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](N[C@@H](C)c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (29.2 g, 0.143 mol) in THF (700 mL) at 0° C. was added NaH (6.29 g, 0.157 mol, 60% dispersion in mineral oil). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. Methyl iodide (20.30 g, 0.143 mol) was then added dropwise via syringe. Some warming occurred soon after the addition was complete. The temperature of the reaction mixture was controlled at ˜25° C. with a water bath containing a small amount of ice. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then slowly quenched with saturated aqueous NaHCO3 solution and was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (400 mL). The aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (5% MeOH in 1:1 ethyl acetate/hexanes) to afford (S)-1-cyclopropyl-2-methoxy-N-[(S)-1-phenylethyl]-ethanamine (26.52 g, 85% yield) as a light brown oil: [α]25D−61.5 (c 0.72, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 4H), 7.20-7.16 (m, 1H), 3.98-3.93 (q, J=6.8 Hz, 1H), 3.50 (dd, JAB=9.5, JAX=3.5 Hz, 1H), 3.35 (s, 3H), 3.34 (dd, JBA=9.5, JBX=5.8 Hz, 1H), 1.79-1.74 (m, 2H), 1.33 (d, J=6.5 Hz, 3H), 0.73-0.67 (m, 1H), 0.36-0.34 (m, 2W), 0.03-0.06 (m, 2H); GC/MS (ESI) m/e 220.2 [(M+H)+, calcd for C14H22NO 220.2].
Reaction SMILES: [OH:1][C@H:2]1[C:12]2[C@@H:6]([C@H:7]3[N:10]([C:11]=2[C:13]([O-:15])=[O:14])[C:9](=[O:16])[C@@H:8]3[C@H:17]([OH:19])[CH3:18])[O:5][CH2:4][CH2:3]1.[Na+].O[C@@H:22]([C@@H:24]1[C@@H]2N(C(C([O-])=O)=C3[C@@H]2CCC[C@@H]3CCOC(=O)C2C=CC=NC=2)C1=O)[CH3:23].[Na+]>C1(C)C=CC=CC=1>[OH:1][C@H:2]1[C:12]2[C@@H:6]([C@H:7]3[N:10]([C:11]=2[C:13]([O:15][CH2:24][CH:22]=[CH2:23])=[O:14])[C:9](=[O:16])[C@@H:8]3[C@H:17]([OH:19])[CH3:18])[O:5][CH2:4][CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C3[C@H](O)CCO[C@@H]3[C@H]12
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C3[C@@H](CCOC(=O)c4cccnc4)CCC[C@@H]3[C@H]12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C2[C@H](O)CCO[C@@H]2[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Sodium (5S,6S, 7S, 11R)-11-hydroxy-5-[(R)-1-hydroxyethyl]-4-oxo-8-oxa-3-azatricyclo[5.4.0.03,6 ]undec-1-ene -2-carboxylate ##STR54## (1) A solution of the compound obtained in Reference Example 29 (220 mg) in toluene (5 ml) was stirred at 50° C. for 4 hours and, then, at 80° C. for 8 hours. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (70-230 mesh, 20 g; ethyl acetate-hexane =1:2) to give allyl (5S,6S,7S,11R)-11-hydroxy-5-[(R) -1-hydroxyethyl]-4-oxo-8-oxa-3azatricyclo[5.4.0.03,6 ]undec-1-ene-2-carboxylate (R2 =CH2CH=CH2) (93 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: NN
Reactant: CCc1nc(C)cn1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: O
Product: CCc1nc(C)cn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, reaction of 4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([OH:22])=[C:16]2[CH:15]=[N:14]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=4[N:2]([CH3:23])[CH3:1])[N:14]=[CH:15][C:16]=23)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (66 mg, 0.200 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (61 mg, 0.300 mmol) and triphenylphosphine (52 mg, 0.200 mmol) were dissolved in toluene (5 mL) and the mixture stirred at 0° C. for 15 min. Diisopropyl azodicarboxylate (28 μL, 0.200 mmol) was then added and the reaction kept going at rt for 16 h. The solvent was removed under reduced pressure and the crude was purified by HPLC. Compound A100 was obtained as a yellowish solid. Exact mass calculated for C24H32N6O5S 516.22, found 517.3 (MH+, 100%). 1H NMR (400 MHz CDCl3) δ (ppm): 8.50 (s, 1H); 8.22 (s, 1H); 7.42(m, 3H); 5.52 (m, 1H); 3.81 (m, 2H); 3.26 (m, 2H); 3.03 (s, 3H); 2.47 (s, 6H); 2.03 (m, 2H); 1.80 (m, 2H); 1.42 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][CH:33]=[C:10]3[N:9]=2)=[CH:5][CH:4]=1.C1C(=O)N([I:43])C(=O)C1>C(#N)C>[I:43][C:33]1[CH:32]=[N:31][N:11]2[C:12]([N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])=[CH:13][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:35][CH:34]=3)=[N:9][C:10]=12
Reactant: CSc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CSc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
5-(4-(methylthio)phenoxy)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (490 mg, 0.81 m) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, 3-iodo-5-(4-(methylthio)phenoxy)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (541 mg) as yellowish oil. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C25H39IN4O3SSi2 658.1, observed LCMS m/z 659.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1[N+:19]([O-])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[NH2:19])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(COc1ccc(C=O)cc1[N+](=O)[O-])OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COc1ccc(CO)cc1N)OCC

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 36 followed by Step D of Example 34 to give 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole (39.1). mp 181–184° C. Anal. Calcd. for C10H10N3O5PS2+0.35H2O: C, 33.97; H, 3.05; N, 11.88. Found: C, 33.76; H, 2.66; N, 11.61.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:41])([F:39])[F:40])=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Reactant: OC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (381 mg, 1.06 mmol, Example 264, step 1), 2-(6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (148 mg, 0.53 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (22 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (517 mg, 1.59 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (99 mg) as a white solid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:52][OH:53]>CC(N(C)C)=O>[CH2:54]([C@H:51]([NH:50][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1)[CH2:52][OH:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
In a microwave vial containing 3 eq. of PS-DCC, 4-(pyridin-4-yl)benzoic acid (20 mg, 0.1 mmol) was added dissolved in DMA (1.0 ml). Then a solution of HOBT (14 mg, 0.1 mmol) dissolved in DMA (0.3 ml) was added followed by the addition of DIEA (36 μl, 0.2 mmol) dissolved in DMA (0.3 ml) and the addition of (S)-2-amino-3-phenylpropan-1-ol (17 mg, 0.11 mmol) dissolved in DMA (0.6 ml). The mixture was heated in the microwave to 100° C. for 600 seconds. The reaction was filtered through Si-Carbonate, 6 ml-1 g supplied by Silicycle chemical Division and transferred to 20 ml vials. The reaction was checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (TFA method). Product was characterized by 1H NMR, MS and LC/MS.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCOCOc1cc(Br)cc(Br)c1
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)c(F)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1cc(Br)cc(-c2ccc(OCCCOCc3ccccc3)c(F)c2)c1

Procedure:
17.0 g (50.0 mmol) 1,3-dibromo-5-(2-methoxy-ethoxymethoxy)-benzene, 19.3 g (50.0 mmol) 2-[4-(3-benzyloxy-propoxy)-3-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 41.3 g (150 mmol) sodium metaborate-tetrahydrate are suspended in 200 ml THF and 200 ml water and 1.6 g (2 mmol) palladium(dppf) are added. The mixture is heated overnight at reflux. After partial removal of the solvent and addition of 100 ml MTB ether, the mixture is acidified with 2M hydrochloric acid. The organic layer is separated and the aqueous layer is extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. The crude product is filtered through silica gel with toluene/ethylacetate (7:3 to 1:1) to yield 4-(3-benzyloxy-propoxy)-3′-bromo-3-fluoro-5′-(2-methoxy-ethoxymethoxy)-biphenyl as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]1[C:11](=[O:12])[C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:8]1=[O:9])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-nitrophthalimide (82.54 g, 0.43 mol), ethyl bromoacetate (78.92 g, 0.47 mol) and potassium carbonate (130.6 g, 0.94 mol), and acetone (1.5 l) was refluxed for eighteen hours before it was cooled to room temperature, filtered and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (107.39 g): MS: (+) m/z 279.25 (M+1).