Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH2:16]([C@@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: CC[C@@H](N)CCCc1cccnc1

Procedure:
As in Example 16, a solution of 195 g of [R-(R*,R*)]-alpha-hydroxy-N-[1-ethyl-4-(3-pyridinyl)butyl]benzeneacetamide in 1.1 L of 6N HCl was treated with 104 mL of conc. HCl and then was heated at reflux for 2 days. The crude amine, obtained by the normal work up, was distilled to give 109 g of (R)-alpha-ethyl-3-pyridinebutanamine, (bp 105° C./0.2 mm); [α]D25 -11.9° (c, 1.0, MeOH)
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: Nc1nc(Oc2ccc(OCc3ccccc3)cc2)nc2nc(-c3ccco3)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(Oc2ccc(O)cc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-5-(4-benzyloxyphenoxy)-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.0 g) in methanol (400 ml) containing palladium-on-carbon catalyst (10% w/w, 200 mg) and acetic acid (20 ml) was treated with hydrogen gas at atmospheric pressure. The reaction was monitored by tlc analysis (system as Example 1) and once no further starting material was detected, the catalyst was removed by filtration. Solvent was evaporated from the filtrate. The solid residue obtained was crystallised from ethanol to give 7-amino-2-(2-furyl)-5-(4-hydroxyphenoxy)-[1,2,4]triazolo[1,5-a][1,3,5]triazine as colourless hygroscopic crystals, m.p. 292°-294° C.; microanalysis, found: C, 53.5; H, 3.6; N, 26.4; H2O, 2.1%; C14H10N6O3 0.33H2O requires: C, 53.2; H, 3.4; N, 26.6; H, 3.6; N, 26.4; H2O, 2.1 %; NMR: 6.7(dd, 1H, furyl-4H), 6.8(d, 2H, phenyl), 7.0(d, 2H, phenyl), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.7-9.1(d, 2H, NH2), 9.4(br s, 1H, OH;m/e 310 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C@H:33]([CH3:37])[C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:35])[C@H:33]([OH:32])[CH3:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Product: C[C@H](NC(=O)[C@@H](C)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and (R)-2-hydroxypropanoic acid (12 mg, 150 μmol). Yield 14 mg (60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O>[C:27]([O:26][C:25]([N:24]([CH2:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:14])=[O:15])[CH:11]=1)[CH3:32])=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (146 mg, 0.45 mmol) and ethyl bromoacetate (102 mg, 0.67 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, 50 mL of water were added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 9a (84 mg, a brown oil) in 70% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: O=C1CCCN1CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
Into a solution of 50 mL of 1-(2-hydroxyethyl)-2-pyrrolidone and 85 mL of triethylamine in 150 mL of chloroform, a solution of 50 mL of acryloyl chloride in 100 mL of chloroform was dropped over 2 hours with stirring. The reaction mixture was stirred at 4° C. for 20 hours, then at 50° C. for 2 hours. After being cooled, the solution was filtered and the filtrate was washed with a 15% aqueous sodium carbonate solution and then concentrated under vacuum. The obtained oily material was distilled under vacuum to give the title compound in a yield of 70%.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](/[CH:10]=[CH:11]/[CH2:12][CH:13]([OH:15])[CH3:14])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:13]([CH2:12]/[CH:11]=[CH:10]/[C:4]2[CH2:3][N:2]([CH3:1])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=2)[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC1=CN(C)CC(/C=C/CC(C)O)=C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC1=CN(C)CC(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)=C1

Procedure:
The manner in which certain aryl substituted olefinic amine compounds possessing a branched side chain are provided can vary. Using one synthetic approach, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The required halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Recl. Tray. Chim. Pays-Bas 74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluensulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.
Reaction SMILES: [Br-].[H-].[Na+].[CH2:4]([O:6][C:7](=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)[CH3:5].[CH3:17]N(C=O)C>>[CH2:4]([O:6][C:7](=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[CH2:17])[CH3:5]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=C1CCCCC1CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Triphenylphosphoniummethyl bromide (6.9 g, 19.5 mmol) was added to a suspension of sodium hydride (0.78 g, 60% oil dispersion, 19.5 mmol) (hexane washed) in DMF (50 mL) cooled to 0° C. under a nitrogen atmosphere. The reaction was stirred for 1 h, and then (2-oxo-cyclohexyl)-acetic acid ethyl ester (3.0 g, 16.2 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a residue. The product was purified by FCC on silica gel eluting with hexane:ethyl acetate (95:5) to give (2-methylene-cyclohexyl)-acetic acid ethyl ester (1.5 g, 50%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)C(O[C:40]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:41]=1[F:50])=O>CN(C=O)C>[F:46][C:45]1[C:40]([O:24][C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=3)=[O:25])=[C:41]([F:50])[C:42]([F:49])=[C:43]([F:48])[C:44]=1[F:47]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 32 (0.154 g, 0.44 μmol) in DMF (5 mL) in the presence of DIEA (93 ml, 0.53 mmol) was added dropwise pentafluorophenyl trifluoroacetate (92 μl, 0.53 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. HPLC showed that the reaction was completed. The solvent was then evaporated to dryness, and the residue was carefully washed with ether to give compound 33 in quantitative yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(Cl)ncn2)CC1

Procedure:
A solution of 4,6-dichloropyrimidine (5.22 g), ethyl isonipecotate (5.50 g) and triethylamine (7 ml) in ethanol (60 ml) was stirred at room temperature for 2 hours, and solvent removed in vacuo. The crude mixture partitioned between ethyl acetate (100 ml) and water (50 ml), washed with brine, dried (MgSO4) and solvent removed to give 1-(6-chloropyrimidin-4-yl)-4-(ethoxycarbonyl)piperidine.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3OC=CC=3)=O)C)=CN=2)=CC=1.[F:26][C:27]1[CH:52]=[CH:51][C:30]([C:31]([NH:33][CH:34]([C:36]2[N:41]=[N:40][C:39]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)=[N:38][CH:37]=2)[CH3:35])=O)=[CH:29][CH:28]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:26][C:27]1[CH:52]=[CH:51][C:30]([C:31]2[N:41]3[C:36]([CH:37]=[N:38][C:39]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[N:40]3)=[C:34]([CH3:35])[N:33]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccc(F)cc4)n3n2)cc1

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-furancarboxamide (Intermediate 60) (85 mg, 0.23 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 7-(4-fluorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (30 mg) as a yellow solid. MS m/z 350 (M+1).
Reaction SMILES: [NH2:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][OH:11].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([NH:27][C:28]([NH:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][OH:11])=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC1CC[C@@](N)(c2ccccc2F)[C@H](CO)C1
Solvent: ClCCl
Product: COC1CC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-[(1R*,2S*)-2-Amino-2-(2-fluorophenyl)-5-methoxycyclohexyl]methanol obtained in Preparation Example 59-(6) (5.49 g) was dissolved in dichloromethane (22 mL). Then, benzoyl isothiocyanate (3.04 mL, specific gravity: 1.21 g/cm3) was added and the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (7.16 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][C:12]([O:15]CC1C=CC=CC=1)=[CH:11][CH:10]=3>[Pd].C(O)C>[CH3:1][C:2]1([CH3:23])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3
Reactant: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCCc2c1[nH]c1ccc(O)cc21
Reaction time: 18 h
Yield: 115.1 %

Procedure:
A mixture consisting of 10% Pd/c on charcoal (0.7 g), ethanol (150 mL) and 1,3,4,9-tetrahydro-1,1-dimethyl-6-(phenylmethoxy)pyrano[3,4-b]indole (4.2 g, 0.014 mol) of Step A, is hydrogenated at 30 psi for 18 hours. The reaction mixture is filtered and concentrated to give 3.5 g product which is used in the next reaction without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=1[O:26][CH3:27].[OH-].[Na+].Cl>CC(=O)CC>[CH:9]1([CH2:8][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:26][CH3:27])[CH2:12][CH2:11][CH2:10]1
Reactant: BrCC1CCC1
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(CC(=O)O)ccc1OCC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of ethyl ethyl (4-hydroxy-3-methoxyphenyl)acetate (1.05 g, 5.0 mmol) and potassium carbonate (1.38 g, 10 mmol) in 40 mL of 2-butanone at ambient temperature was added in one portion of (bromomethyl)cyclobutane (97% pure) (1.53 g, 10.0 mmol). The stirred reaction mixture was heated at reflux for 24 hr. HPLC revealed the disappearance of the starting material of ethyl (4-hydroxy-3-methoxyphenyl)acetate. The mixture was allowed to cool to ambient temperature. The solid was filtered off. The filter cake was washed with acetone. The combined filtrate was concentrated in vacuo to nearly dryness. Methanol was added (5 mL) was added to the residue, followed by the addition of a 2-N aqueous solution of NaOH (20 mL, 40 mmol). The reaction was stirred overnight at about 40° C. HPLC indicated that the saponification was completed, and revealed one single peak signal of the expected carboxylic acid. The reaction mixture was subjected to roto-vaporation to remove methanol. Ice was added to the basic aqueous solution. The acidification with a 25 mL of HCl aqueous 2N solution (50 mmol) led to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with three 50-mL portions of water, and two 25-mL portions of hexane. The collected solid was dried in vacuo for two days at ambient temperature to afford 1.20 g (95%) of [4-(cyclobutylmethoxy)-3-methoxyphenyl]acetic acid as a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.[N+:32]([C:35]1[CH:36]=[C:37]([C:41](OS(C(F)(F)F)(=O)=O)=[CH2:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:32]([C:35]1[CH:36]=[C:37]([C:41]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)=[CH2:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: C=C(OS(=O)(=O)C(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Product: C=C(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (330 mg, 0.693 mmol) in TBF (3.0 mL) at −78° C. was added n-butyllithium (0.56 mL, 1.5 M, 1.2 equiv). After 20 min, this solution was then added to anhydrous zinc chloride (170 mg) and the mixture was warmed to 23° C. and stirred for 15 min. To this mixture was added 1-(3-nitro-phenyl)vinyltriflate (146 μL, 1.05 equiv) and Pd(PPh3)4 (40 mg, 0.05 equiv). This mixture was stirred for 30 min, was partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (1:9 ethyl acetate-hexane) then a second column (1% ethyl acetate-benzene) gave 6-(1-(3-nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448, 1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.26 (t, 1H, J=1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, J=8.5 Hz), 7.69 (dt, 1H, J=1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, 1H, J=1.4, 8.4 Hz), 5.72 (s, 3H), 5.69 (s, 1H), 3.60 (t, 2H, J=8.2 Hz), 0.89 (t, 2H, J=8.2 Hz), −0.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 149.9, 149.6, 144.7, 144.5, 142.8, 140.7, 138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0, 124.4, 124.2, 124.1, 123.8, 122.6, 121.2, 118.9, 111.0, 79.2, 68.0, 19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 520.2031, found 520.2046.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](SC)=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][CH:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:29][CH:24]([CH3:23])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CSC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 49 %

Procedure:
3-(3-Fluoro-5-trifluoromethylphenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.176 g, 0.5 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 98 mg (49%) of the title compound. Mp 183-1850° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 1.03 (d, 3H), 3.05 (m, 1H), 3.13 (s, 3H) 7.02 (br d, 1H), 7.15 (m, 2H); EI SP/MS: 407 (M+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][N:10]=[C:11]4[C:3]([CH3:19])([CH3:2])[C:4]3=[O:18])[CH2:13][CH2:14]1)[N:30]=[CH:29]2
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: Fc1ccc2nc(Cl)ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3ncc4cc(F)ccc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 35.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-fluoroquinazoline (0.063 g, 0.342 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The mixture was cooled, H2O was added, and the solid was collected, dried, and purified by ISCO (40% EtOAc/Hexanes) to give the title compound (43 mg, 35%). MS (M+1): 393. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (1 H, s), 8.08 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=3.1 Hz), 7.62-7.74 (2 H, m), 7.46-7.62 (1 H, m), 5.00 (2 H, d, J=13.5 Hz), 4.47-4.67 (1 H, m), 2.97-3.14 (2 H, m), 2.36-2.48 (2 H, m), 1.80 (2 H, d, J=9.6 Hz), 1.32 (6 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][NH2:62])([CH3:60])([CH3:59])[CH3:58].Cl>C(#N)C.C(OCC)(=O)C>[C:57]([O:61][NH:62][C:13]([C:11]1[S:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:10]=1)=[O:15])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)ON
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Part B; 5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid (1.00 gram, 2.6 mmol) is suspended in anhydrous acetonitrile (20 mL) under a nitrogen atmosphere at room temperature. Diisopropylethylamine (DIPEA) (1.36 mL, 7.8 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (1.08 gram, 2.85 mmol) and O-tert-butylhydroxylamine.HCl (0.35 gram, 25.1 mmol) are successively added and the resulting mixture is stirred overnight at room temperature. The resulting mixture is concentrated in vacuo and dichloromethane is added. The resulting solution is successively washed with water and brine, dried over MgSO4, filtered and evaporated in vacuo. Subsequent flash chromatography (ethyl acetate:petroleum ether (40-60)=1:3 (v/v)) gives N-(t-butoxy)-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (0.60 gram, 51% yield) as a white foam. 1H-NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.47 (t, J=2 Hz, 1H), 7.25-7. (m, 4H), 7.14 (dt, J=8 Hz, J=2 Hz, 2H), 1.36 (s, 9H).