Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCC(F)(F)F
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@](O)(CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
To a solution of 0.0041 g (0.0001 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 1.0 ml 2,2,2-trifluoroethanol was added 0.200 g (0.0006 mol) cesium carbonate and the mixture was stirred at room temperature for 7 days. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.042 g (98% yield) of the title compound as white crystals melting at 96-97° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[Cl:49][C:50]1([C:65]([O:67][CH3:68])=[O:66])[CH2:55][CH2:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH2:51]1>>[Cl:49][C:50]1([C:65]([O:67][CH3:68])=[O:66])[CH2:55][CH2:54][C:53]([C:7]2[C:8]([CH3:46])([CH3:45])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:44])([C@@:13]4([CH3:43])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][S:38](=[O:41])(=[O:42])[CH2:39][CH2:40]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:52][CH2:51]1
Reactant: COC(=O)C1(Cl)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(Cl)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diasteroisomers. MS: m/e 743.5 (M+H)+, 3.01 min (method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]([O:32]C)=[O:31])=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Na+].ClCl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]([OH:32])=[O:31])=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: COC(=O)C1CCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 85 %

Procedure:
Prepared analogously to Example 19b from rac.-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-(2-methoxycarbonylpyrrolidin-1-ylcarbonyl)benzamide, and sodium hydroxide solution in isopropanol. Yield: 85%; C22H20Cl2N4O4 (475.33); mass spectrum: (M+H)+=475/477/479 (chlorine isotope).
Reaction SMILES: [N+](C1C=CC(C[C:9]23[CH2:15][C:14](=[O:16])[N:13]2[C:12]([C:17]([O-:19])=[O:18])=[C:11]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:10]3)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:33]>O1CCOCC1.O.[Pd]>[O:16]=[C:14]1[N:13]2[CH:9]([S:10][C:11]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]2[C:17]([O-:19])=[O:18])[CH2:15]1.[Na+:33]
Reactant: O=C([O-])C1=C(Oc2ccccc2)SC2(Cc3ccc([N+](=O)[O-])cc3)CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(Oc2ccccc2)SC2CC(=O)N12
Yield: 74.6 %

Procedure:
A mixture of a solution of 56 mg of 4-nitrobenzyl-7-oxo-3-phenoxy-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 3 ml of dioxan and 12.5 mg of sodium bicarbonate in 2 ml of water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 90 minutes. The mixture was then filtered through Celite, and lyophilized to yield 30 mg of the title compound as a pale yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: OB(O)c1ccco1
Reactant: Clc1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1cncc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,2-Dimethoxyethane (130 mL) was added to a mixture of tetrakis(triphenylphosphine)palladium (0) (0.93 g, 0.80 mmol) and 2,6-dichloropyrazine (2.55 g, 17.1 mmol). After 5 min of stirring at room temperature, furan-2-boronic acid (1.91 g, 17.1 mmol) followed by aqueous Na2CO3 (30 mL; 2 M) were added. The mixture was heated at reflux for 1 h [TLC monitoring by SiO2/n-hexane/ethyl acetate (90:10)]. The layers were separated and the light brownish water layer was extracted with dichloromethane (2×200 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. The brown-yellow oil obtained was purified by silica gel chromatography (18.5×4 cm) eluting with n-hexane/ethyl acetate (90:10). This furnished 1.47 g (48%) of the title compound as a light yellow solid. HRMS m/z calcd for C8H5ClN2O (M)+ 180.0090, found 180.0092. Anal. (C8H5ClN2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].[C:22](Cl)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([NH:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Solvent: c1ccncc1
Product: CC(=O)Nc1c(I)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (447 mg, the compound of Example A1) in pyridine (5ml) was added dropwise acetyl chloride (0.5 ml). The reaction mixture was stirred at room temperature for 2 days and then heated at 50° C. for 4 hours. The reaction mixture was partitioned between ether (50 ml) and water (50ml), the organic layer was separated, dried (MgSO4) and evaporated.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH:19]([N:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]1([CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:32]2[CH2:35][CH:34]([NH:36][C:16]([C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:18])[CH2:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: O=C(NC1CN(C(c2ccccc2)c2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 1-benzhydryl-3-azetanamine [see J. Med. Chem. (1977), 21(1), 78-82]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 60:40, then 50:50, by volume, hexane:ethyl acetate to afford (2S)-N2-(1-diphenylmethyl-3-azetidinyl)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide as a white foam.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:44](P(=O)(OCC)OCC)[P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48].CN(C)C=O.[H-].[Na+]>O>[CH2:47]([O:46][P:45](/[CH:44]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:49][CH2:50][CH3:51])=[O:52])[CH3:48]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)cc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.45 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl {4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as a colorless oil (0.28 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (6:1, v/v).
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11](=O)[CH2:12][S:13][CH3:14])([O-:3])=[O:2].COC(OC)[N:19]([CH3:21])C.O.[NH2:25]N>>[CH3:14][S:13][C:12]1[C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:4]=2[N+:1]([O-:3])=[O:2])=[N:25][NH:19][CH:21]=1
Reactant: COC(OC)N(C)C
Reactant: CSCC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: NN
Solvent: O
Product: CSc1c[nH]nc1-c1cccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
1.5 g (0.0061 mol) of 2'-nitro-3'-chloro-2-(methylthio)acetophenone are dissolved in 1.6 ml (0.012 mol) of N,N-dimethylformamide dimethyl acetal according to the procedure described in Example No. 1 and are heated at 70° C. and then, after isolation of the intermediate enaminone, are treated with 2 ml (0.042 mol) of hydrazine hydrate according to the procedure described in Example No. 1. After purification by passing through a silica column (heptane/ethyl acetate 75/25), 600 mg of the-desired compound are obtained:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCC/C=C\CC1C=CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCC/C=C\CC1C=CCCC1=O
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A solution of 15.8 g of 7-(6-hydroxycyclohex-2-enyl)-hept-5Z-enoic acid (as obtained by ether-pentane extraction as described above) in 300 ml of acetone was stirred with ice-bath cooling as 30 ml of standard Jones reagent was added dropwise. The resultant mixture was stirred for 10 min at 0° and then quenched by the addition of several ml of isopropyl alcohol. After stirring for another 10 min at 0° the solvents were removed by evaporation in vacuo. The residue was dissolved in water and extracted several times with ether. The combined ether extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to yield 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: Ic1ccccc1
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCNCC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: NC(=O)/C=C(/c1ccccc1)c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), iodobenzene (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.1 mL EtOAc (degassed) was heated at 75° C. After 2 hours, an additional 2 mg bis(dibenzylideneacetone)palladium(0) was added and the reaction continued for 18 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous Na2CO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. The crude product was chromatographed eluting with EtOAc/CHCl3 and the resulting solid again chromatographed with MeOH/CHCl3 to give the title compound as an off-white solid (8.8 mg, 23%). 1H NMR (Acetone-d6) δ: 8.79 (dd, J=7.5, 2.2 Hz, 1H), 8.43 (d, J=2.9 Hz, 1H), 8.41 (s, 1H), 7.39-7.44 (m, 2H), 7.27-7.39 (m, 7H), 7.11-7.16 (m, 3H), 6.76 (br. s., 1H), 6.49 (s, 1H)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CCCOCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.0 g (11.5 mmol.) of imidazole (101e), followed by addition of 5 ml of water and 1.84 g (46 mmol) of sodium hydroxide, and then, 250 mg (0.8 mmol) of n-tetrabutylammonium bromide and 2.3 g (14 mmol) of 4-chloromethylpyridine hydrochloride were further added. The mixture was stirred under heating at 50° C. for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) to provide 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (136c) as oil. To thus-obtained oil (136c) was added 27 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 3.8 g (yield 76%) of 3-(5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-propan-1-ol (137c) as crystals. mp 106-107° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:30]=[CH:29][C:9]2[C:10](=[O:28])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:31][CH2:32][CH3:33]>CO.Cl>[CH3:1][O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:30]=[CH:29][C:9]2[C:10](=[O:28])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:31][CH2:32][CH3:33]
Reactant: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCOC1CCCCO1)CC2=O
Agent: Cl
Solvent: CO
Product: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCO)CC2=O
Yield: 87.1 %

Procedure:
A solution of 2.3 g of the chromanone product from Example 2 in 25 ml of methanol and 5 ml of 2N hydrochloric acid was stirred for 1.75 hours at room temperature then concentrated in vacuo to remove most of the methanol. The residue was diluted with water, neutralized with sodium bicarbonate, and extracted 4 times with ether. The combined ether extracts were washed with water and brine, dried (magnesium sulfate), filtered, and concentrated in vacuo in yield 1.85 g of an oil. This material was purified by HPLC (silica gel, 1.5:1 ethyl acetate-hexane) giving 1.65 g (87.1%) of rac.-[[3,4-dihydro-2-(6-hydroxyhexyl)-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH2:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (300 mg, 1.32 mmol), 3,3-dimethyl-butylamine (134 mg, 1.32 mmol) and HBTU (751 mg, 1.98 mmol) in CH2Cl2 (9 mL) under a nitrogen atmosphere was added DIPEA (0.922 mL, 5.28 mmol). The reaction mixture was stirred at RT for 16 h. CH2Cl2 and water were added, the phases were separated and the aqueous layer extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel (c-hexane/AcOEt 1-0 to 0-1) to give the title compound. TLC, Rf (EtOAc)=0.85.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH2:26]3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(N3CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.4 %

Procedure:
1-(2,4-difluoro-phenyl)-5-[2-(piperazin-1-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (30.0 mg, 0.06 mmol) prepared in Example 193, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@H:14]1O[C@@H](P(OCC)(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@@H](CBr)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a stirring suspension of thymine (551 mg, 3.32 mmol) in dry DMF (3 mL) was added sodium hydride (60% oil dispersion, 133 mg, 3.32 mmol). After stirring the mixture for 30 min at room temperature, a solution of cis-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (500 mg, 1.66 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 15 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (102 mg, 40%) and then the title compound as an oil (126 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1>>[F:31][C:32]1[C:33]([CH3:41])=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:36]
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: Cc1c(F)cccc1C(=O)Cl
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: Cc1c(F)cccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
In a manner analogous to Example 66, 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 3-fluoro-2-methylbenzoyl chloride are used to prepare the title compound. HRMS calcd for C31H22F2N6O: 532.1823, found: 533.1921 (M+H+).