Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:1][C:2]4=[N:3][CH:4]=[C:5]([Cl:26])[C:6]([N:11]5[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]6[S:22][CH:23]=[CH:24][N:25]=6)=[O:19])[CH2:13][CH2:12]5)=[C:7]4[N:8]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.028 g, 0.07 mmol) and EtOH (3.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.017 g, 0.09 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 ml, 0.30 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.006 g, 16%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 5.41 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.23 (d, J=3.5 Hz, 1H, thiazole H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.49 (d, 2H, thiazole-H, and pyrazole-H), 7.86 (d, J=1.84 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.89 min—534, 536 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 534.1595, calculated for C25H25ClN9OS (M+H)+: 534.1591.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1
Reactant: Oc1ccccc1F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a mixture of 2-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed twice with water and then washed with saturated aqueous sodium chloride, was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (940 mg, 28%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([C:14]2([OH:25])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([C:14]2([OH:25])[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(C2CCCCC2)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 120 mg (0.47 mmol) of 3-cyclohexyl-3-hydroxy-1-(tert-butoxycarbonyl)azetidine dissolved in 3 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour and then concentrated to dryness and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4cccc5ccccc45)nc3n2)CC1
Yield: 70.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.378 g of 1-naphthyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.97 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]-pyrimidin-7-yl}-3-naphthalen-1-yl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=615 (Base), 446; mp 186.5-189° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[C:17]([Cl:23])=[CH:16][C:15]=2[C:24]([O:26]C)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[C:17]([Cl:23])=[CH:16][C:15]=2[C:24]([OH:26])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(C(=O)O)cc(Cl)c3cncn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Methyl 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-8-chloroimidazo[1,5-a]pyridine-6-carboxylate (120 mg, 0.3123 mmol) was stirred in methanol (2 mL) and 3.0 M sodium hydroxide in water (0.4 mL, 1.0 mmol) was added. The mixture was stirred at room temperature overnight. Acidification with a few drops of 1 M HCl (checked with litmus paper pH 6), evaporation and trituration with water gave the desired compound (94 mg, 79%). LCMS calculated for C17H22ClN4O4 (M+H)+: m/z=381.1. found: 380.9.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C1COCC1.CCO>[Cl:24][C:21]1[N:22]=[C:23]([NH:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:18]([F:17])=[CH:19][N:20]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1n[nH]c2cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(Nc3nc(Cl)ncc3F)ccc12
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol) and NaHCO3 (1.26 g, 0.045 mol) in THF (15 mL) and EtOH (60 mL) was added 5-fluoro-2,4-dichloropyrimidine (3.2 g, 0.019 mol) at room temperature. After the reaction was stirred overnight, the brown suspension was filtered and washed thoroughly with EtOH. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ether to remove excess pyrimidine to yield 3.7 g of the desired product (89%). HNMR: δ 12.57 (s, 1H), 10.01 (s, 1H), 8.28 (d, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.27 (dd, 1H) 3.11 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]([C:18]([OH:20])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:14]([C:18]([O:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OCC(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl bromoacetate (263 μL, 2.37 mmol) was added to a solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 1000 mg, 1.48 mmol), and potassium carbonate (347 mg, 2.51 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 2 hours at room temperature. Water was added and the solution was extracted with diethyl ether (2×). The organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was used crude in the following step. LC-MS: m/z 787.1 (M+Na).
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.[NH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].C(NCC(O)=O)(=O)C.CN(CC(O)=O)CC(O)=O>COCCOC>[C:1]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(O)CNCC(=O)O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: CN(CC(=O)O)CC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 95 %

Procedure:
The regenerated catalyst precursor was transferred under CO:H2 pressure, into the autoclave at 95° C. containing CO:H2 (95:5) at 900 psi (6,210 kPa), acetamide (VII) (59.0 g, 1.0 mole), 95% paraformaldehyde (68.0 g, 2,16 mole), water (64.5 g, 3.60 mole) and DME (600 mL). A CO:H2 atmosphere (95:5) at 2200 psi (15,170 kPa) was immediately established. This mixture was heated to 125° C. and was maintained at this temperature for one hour. HPLC analysis of this stream gave a 95% yield of (XVI), 4% (XIV), 7.0% (XVIII), and 0.1% N-methyliminodiacetic acid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](F)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Tl].[C:25]1(=[O:30])[CH2:28][C:27](=[O:29])[CH2:26]1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([CH:26]3[C:27](=[O:29])[CH2:28][C:25]3=[O:30])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C1CC(=O)C1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)F
Agent: [Tl]
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)C1C(=O)CC1=O

Procedure:
In the same manner, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid fluoride is reacted with the thallium salt of cyclobutane-1,3-dione to yield 2-[[2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]]cyclobutane-1,3-dione (V; Y is H, Z is CF3, R1 is CH3 and n is zero).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5]O)[CH:3]=[O:4].[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>ClCCl>[CH3:7][C:2]([CH3:1])([CH2:3][OH:4])/[CH:5]=[CH:13]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C=O)CO
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(C)(C)CO
Yield: 58.9 %

Procedure:
A solution of 2,2-dimethyl-3-hydroxypropanal (22 g, 0.22 mol) and (carboethoxymethylene)triphenylphosphorane (75 g, 0.22 mol) in dry dichloromethane (150 ml) was refluxed for 46 h. The solvent was then evaporated and the crude product was distilled at 15 Torr through a very short column. The distillate was separated into two fractions by redistillation through a 40-cm Widmer column. The first fraction gave 22.3 g (60%) of ethyl trans-4,4-dimethyl-5-hydroxypent-2-enoate, b.p. 133 136° C./15 Torr, nD23 1.4641. 1H NMR (CDCl3): (=1.10 [s, 6H, C(CH3)2], 1.25 (t, 3H, CH3CH2), 3.40 (s, 2H, CH2), 3.80 (br. s, 1H, OH), 4.15 (q, 2H, CH2CH3), 5.80 (d, 1H, J=16 Hz, 3-H). Anal. Calad. for C9H16O3: C, 62.76; H, 9.36. Found: C, 62.92; H 9.50.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9]I>>[CH3:9][N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CI
Reactant: CC1NC(=O)NC1=O
Product: CC1NC(=O)N(C)C1=O

Procedure:
Using 5-methylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.57 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (1.66 g, containing DMF) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=2)=[C:7]([OH:9])[CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:25](O)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)(=[O:27])[CH3:26]
Reactant: CCc1ccc(Oc2cccc(F)n2)c(O)c1
Reactant: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2cccc(F)n2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol (20 mg; 0.09 mmol), under argon, in dimethylformamide (2 mL), cooled to 0° C., was added triethylamine (36 μL; 0.26 mmol) and acetic acid (10 μL; 0.18 mmol). The reaction mixture was allowed to stir overnight, with gradual warming to room temperature. The reaction was concentrated, diluted with saturated NaHCO3 (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (8 mg; 34%) was obtained as clear oil, after purification on neutral alumina gel (cyclohexane/ethyl acetate: 9/1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:5])[S-:4].C([NH+](CC)CC)C.Br[CH:14]([CH3:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CC#N>[CH3:1][N:2]1[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:23])[S:5][C:3]1=[S:4]
Reactant: CNC(=S)[S-]
Reactant: CC(Br)C(=O)c1ccccc1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: Cc1sc(=S)n(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a 100 mL flask was added freshly prepared triethylammonium methyldithiocarbamate (2.0 g, 9.5 mmol), anhydrous MeCN (50 mL), and 2-bromopropiophenone (2.04 g, 9.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was treated with conc H2SO4 (5 mL) with stirring at room temperature. After 20 min, the reaction mixture was diluted with water (75 mL) and then mixed with DCM (75 mL). The layers were separated and the aqueous layer extracted once more with DCM (75 mL). The combined organic layers were washed with water (3×50 mL) and then brine (50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the title product (1.95 g, 92%) as an off-white solid, which was used without further purification. 1H-NMR (CDCl3): δ 7.50 (2H, m), 7.27 (2H, m), 3.45 (3H, s), 2.06 (3H, s).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
Triethyl phosphite (0.98 ml, 5.7 mmol) was added dropwise to a solution of dimethyl acetal 27 (1.08 g, 4.7 mmol), boron trifluoride etherate (1.2 ml, 9.8 mmol) and CH2Cl2 (10 ml) at 0° C. After warming the reaction to room temperature overnight, the solution was partitioned with 3N HCl and the aqueous layer was washed with CH2Cl2 twice. The organic layers were washed with dilute NaHCO3, dried over Na2SO4, decanted and evaporated. The crude residue was purified on a silica gel column, eluting with 0-80% EtOAc/hexanes, to give 1.36 g (86%) phosphonate 28 as a slightly yellow oil.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:10]=[CH:11][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si](C)(C)C)[OH:13])(C(C)(C)C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C(#N)C>[OH:13][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([OH:22])[CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:11]=[CH:10][CH:9]([OH:8])[CH2:38][CH2:39][CH2:40][OH:41]
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(C(O)C=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(C(O)C=CC(O)CCCO)C1=O
Yield: 71.3 %

Procedure:
To a solution of 270 mg of 5-[4,7-bis(t-butyldimethylsilyloxy)-1-hydroxy-2-heptenyl]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 62 dissolved in 15 ml of acetonitrile, 2 ml of pyridine was added. While stirring the mixture under ice-cooling, 1 ml of a hydrogen fluoride-pyridine solution was added and the mixture was stirred at 0° C.-room temperature for 16 hours. The mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel chromatography to give 114 mg (yield 71%) of 5-(1,4,7-trihydroxy-2-heptenyl)-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [CH3:1][N:2]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8][N:9]2COCC[Si](C)(C)C)=[CH:5][CH:4]=1.CN(C1C=C2C(C(C=CC3C=CC=CC=3)=NN2COCC[Si](C)(C)C)=CC=1)C1C=CC=C(N)C=1>C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
Methyl-(3-nitro-phenyl} {3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine was converted to N-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl) ethoxymethyl]-1H-indazol-6-yl)-benzene-1,3-diamine as described in Example 11, step (iv). Rf sm 0.55, Rf p 0.31 (ethyl acetate:hexane 3:7); FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, 1H, J=8.8 Hz) 7.58 (d, 2H, J=7.21 Hz), 7.26-7.50 (m 5H), 7.12 (t, 1H, J=7.93 Hz), 7.01 (d, 1H, J=1.73 Hz), 6.95 (dd, 1H, J=1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, J=8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, J=8.13 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5, 77.8, 66.6, 41.0, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 471, Found 471.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 11H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][N:19]([CH2:30][C:31]([O:33][CH3:34])=[O:32])S(C1C=CC(C)=CC=1)(=O)=O)C.C[O-].[Na+].CC(O)=O>CN(C=O)C>[CH3:34][O:33][C:31]([C:30]1[N:19]=[CH:18][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:7]=2)=[O:32]
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Temperature: 0 °C
Yield: 55.8 %

Procedure:
A mixture of 2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (745 mg), and NaOMe (0.702 mL, 0.5 M solution in HOMe) in DMF (5 mL) was stirred with ice/water bath cooling for 4 h. HOAc (2.5 eq relative to NaOMe) was added, diluted with ice/water; then the solids were collected via filtration and washed with water to give product (247 mg). Filtrate was back extracted with EtOAc; EtOAc phase was washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered, concentrated and column purified to give more product (135 mg). LC MS ESI+: 297 (M+1)+.