Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC(C)=CC=1S(O)(=O)=O.OOS([O-])=O.[K+].[CH3:19][CH2:20][CH2:21][CH2:22][CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][CH3:27]>[N+](C)([O-])=O>[CH3:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)CCCC
Agent: Cc1ccc(I)c(S(=O)(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 7 h

Procedure:
1.8 mg (0.006 mmol) of 2-iodo-5-methylbenzenesulfonic acid, prepared by Preparation Example 2, 1.11 g (1.8 mmol) of powdered Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added in 3.75 ml of nitromethane, and the mixture was heated at 70° C. while being stirred for seven hours. The later treatment was carried out in the same way as in Example 1, and then 5-nonanone was obtained. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]([NH2:34])[CH2:29][CH2:28][CH2:27]2>>[CH2:1]([C:3]1[C:4]([NH:34][CH:30]2[C:31]3[C:26](=[CH:25][C:24]([O:23][CH3:22])=[CH:33][CH:32]=3)[CH2:27][CH2:28][CH2:29]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: COc1ccc2c(c1)CCCC2N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3cc(OC)ccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2075; Anal. Calcd for C19H25N3O: C, 73.28; H, 8.09; N, 13.49. Found C, 73.38; H, 8.11; N, 13.32.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(Cc2cc(Br)ccc2F)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2-fluorobenzaldehyde and 4-bromophenetole.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:29][CH3:30]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][CH3:30])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCI
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (61.5 mL, 61.5 mmol) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (6.71 g, 27.8 mmol) in THF (10.0 mL) at −78° C. over 10 min. The resulted light brown solution was stirred at −78° C. for 30 min before iodoethane (2.67 mL, 33.4 mmol) was added in one portion. The mixture was then kept at −25° C. overnight. The reaction was quenched with aqueous NH4Cl. The organic layer was separated and the aqueous layer was further extracted with ether three times. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to yield the desired product as a 7:1 cis/trans mixture (4.83 g, 65%). MS calculated for C14H23NO4: (M+H) 170.2; found 170.1 (M+H-Boc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[OH:25][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Product: COc1cc2ncc(C#N)c(Nc3cccc(O)c3)c2cc1OC
Yield: 91.8 %

Procedure:
Using the method described in Example 105, 0.7 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.38 g of 3-aminophenol was converted to 0.83 g of the title compound: mass spectrum (electrospray, m/e,): 321.9, 322.8 (M+H)+
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH2:8][C:9]([NH:11][CH2:12][C@H:13]([OH:16])[CH2:14][OH:15])=[O:10].CO.Cl>O>[OH:15][CH2:14][C@@H:13]1[CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:16]1
Reactant: O=C(CCl)NC[C@H](O)CO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CO[C@H](CO)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
To a solution of t-BuOK (13.7 g, 122 mmol) in t-AmOH (175 mL) was added a solution of 2-chloro-N—[(S)-2,3-dihydroxypropyl]acetamide (8.1 g, 48.3 mmol) in t-AmOH (325 mL) at room temperature over 2 h. The resulting suspension was stirred for 1 h at room temperature. Methanol (50 mL) and water (5 mL) were added and the resulting solution was stirred for 0.5 h at room temperature before adjusting the pH to 5 by the addition of conc. HCl. The suspension was filtered and the solid washed with methanol. The filtrate was evaporated in vacuo, the resulting solid was slurried in methanol (50 mL) and filtered off to afford (S)-6-(hydroxymethyl)morpholin-3-one (1.3 g) as a white solid. A second crop was obtained by adding EtOAc (200 mL) to the filtrate and filtering the resulting solution through a silica plug (1×10 cm). The solvent was evaporated in vacuo to afford (S)-6-(hydroxymethyl)morpholin-3-one (3.9 g, overall yield 5.2 g, 82%) as a white solid.
Reaction SMILES: [C:1](=[O:3])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:15]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:25]=[C:1]=[O:3].[CH2:15]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCC(=O)OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing glycine benzyl ester p-toluenesulfonic acid salt (0.01 mol, 3.37 g) and triethylamine (0.04 mol, 4.0 g) at -10° C. (ice and salt bath) for 30 min at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.01 mol, 1.6 g) in 20 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (40 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×20 mL diethylether. The ether layers were concentrated and the residue distilled under vacuum (ca. 0.1-0.3 torr) collecting product, glycine benzyl ester isocyanate, at 105°-106° C. (0.91 g, 47.5%) of 98% purity as judged by GC. IR (neat) 2253, 1747 cm-1. 1H NMR (CDCl3) δ 7.37 (s, 5H), 5.24 (s, 2H), 3.96 (s, 2H) ppm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>CCN(CC)CC.C1C=CC=CC=1.[Cu]I.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>[CH3:14][O:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(C(=O)O)cc(C#C[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzoic acid (6.16 g, 20.0 mmol) in a mixture of Et3N (40 mL) and benzene (40 mL) at room temperature, was added CuI (380 mg, 2 mmol), Pd(PPh3)4 (462 mg, 0.4 mmol) and (trimethylsilyl)acetylene (3.4 mL, 24 mmol). After stirring for 3 days at room temperature, the solvent was removed in vacuo, the residue was diluted with 1 N HCl aqueous solution (300 mL) and then extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-(trimethylsilanylethynyl)benzoic acid (5.6 g). The product was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[S:26]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[O:36][CH3:37])(=[O:28])=[O:27])=[CH:19][CH:18]=2)=[O:16])=[CH:10][CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:35][C:33]1[CH:32]=[CH:31][C:30]([O:36][CH3:37])=[C:29]([S:26]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:38])=[O:5])=[CH:9][CH:10]=4)=[O:16])[CH:25]=3)[CH:21]=[CH:22]2)(=[O:28])=[O:27])[CH:34]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(CC(=O)OC(C)(C)C)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid tert-butyl ester (0.25 g, 0.46 mmol) was dissolved in 4M HCl in dioxane (4.00 mL) and stirred at room temperature for 18 hours. The volatiles were evaporated and the residue taken up in ethyl acetate/heptane 1:1 and sonicated. The solid was filtered washing with ethyl acetate/heptane 1:1 and dried under vacuum. (4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid was obtained as an off-white solid, 0.14 g (63%), MS (ISP): m/e=497.1 (M−H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@H:13]2[C@H:4]1[C:5](=[O:16])[O:6][C:7]1[C:8]([F:15])=[CH:9][CH:10]=[C:11]([F:14])[C:12]=12.[OH-:17].[Na+]>O>[F:15][C:8]1[C:7]2[O:17][CH2:2][C@H:3]3[C@@H:4]([C:5]([OH:16])=[O:6])[C@H:13]3[C:12]=2[C:11]([F:14])=[CH:10][CH:9]=1
Reactant: O=C1Oc2c(F)ccc(F)c2[C@@H]2[C@H](CBr)[C@H]12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
(1S,1 aR,7bS)-1-(bromomethyl)-4,7-difluoro-1 a,7b-dihydrocyclopropa[c]chromen-2(1 h)-one (360 mg, 1.2 mmol) was mixed with the solution of NaOH (0.1 g, 2.5 mmol) in 5 ml of water and heated at stirring for 1 h at 90° C. After completion the reaction mixture was cooled down and extracted into diethyl ether (2×20 ml). Water phase was acidified with conc. HCl. The precipitate formed was collected by filtration to give 180 mg of pure product. Mother liquor was extracted into ether and washed with brine, dried over magnesium sulfate. Concentration gave additional 70 mg of product (containing up to 15% of impurities). Overall yield about 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#N.C(O)=[O:13].O.[Al]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:13]
Reactant: N#Cc1c(Cl)cc(Cl)cc1Cl
Reactant: O=CO
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 100 °C
Yield: 93 %

Procedure:
Add 2,4,6-trichlorobenzonitrile (206 mg, 1.0 mmol) to 96% formic acid (5 mL, 96%) and water (1 mL). Add nichol/aluminum alloy (206 mg) to the mixture. Heat at 100° C. for 4 hours. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 2,4,6-trichlorobenzaldehyde (195 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[CH:15])=[CH:4][CH:3]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:20]=[N:21][NH:22][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1-c1ccc(C)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: Cc1ccc(-c2ccccc2-c2c[nH]nn2)cc1
Yield: 44 %

Procedure:
A solution of 2.52 g (13.1 mmol) of 4-methyl-2'-ethynyl-1,1'-biphenyl in 18 mL of trimethylsilyl azide under a nitrogen atmosphere was heated at 120° C. for 72 hours. The volume was reduced by distillation at atmosphere pressure. The residue was dissolved in methylene chloride. The organic layer was washed with water (3×) dried over magnesium sulfate, filtered and evaporated under vacuum to yield 3.1 g of crude product which was purified over silica gel, eluting with hexane/ethyl acetate (3:1) to yield 1.35 g (5.77 mmol, 44%) of the product. FAB-MS: calculated for C15H13N3 235; found 237. 1H NMR (400 MHz, CDCl3): 2.38 (s, 3H), 7.0 (s, 1H), 7.20 (dd, 4H), 7.40 (m, 3H), 7.80 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C1COCC1>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc3ccccc3c2)oc1C

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylfuran, 2-(bromomethyl)naphthalene and 1.6M n-BuLi/hexanes in THF. 1H NMR (DMSO-d6) δ 1.89 (s, 3 H), 2.15 (s, 3 H), 4.08 (s, 2 H), 5.95 (s, 1 H), 7.40 (d, 1 H), 7.45-7.57 (m, 2 H), 7.77 (s, 1 H), 7.83-7.91 (m, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[C:10]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)#[N:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:14]1[CH2:15][CH2:16][CH:12]([C:10]#[N:11])[CH2:13]1
Reactant: N#CC1CCNC1
Reactant: Clc1c(Br)cncc1Br
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2c(Br)cncc2Br)C1

Procedure:
General procedure C was followed using 3,5-dibromo-4-chloropyridine (71 mg, 0.26 mmol), 3-cyanopyrrolidine (25 mg, 0.26 mmol), NMP (3 mL) and triethylamine (72 μL, 0.52 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound E22 as a white solid (9 mg, 10%), m.p. 159-161° C.; umax (CHCl3)/cm−1 3022, 3008, 1678, 1591, 1446, 1235; m/z (ESI) C10H12Br2N3O requires 347.9342, found [M+H]+ 347.9339.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[N+:21]([O-])=O)[CH:10]([CH2:24][C:25](OC)=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[NH:21][C:25](=[O:26])[CH2:24][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2cc(Cl)ccc2N1
Temperature: 85 °C

Procedure:
A round bottom flask was charged with methyl 2-(4-benzyl-1-(5-chloro-2-nitrophenyl)piperazin-2-yl)acetate (Example 24A, 19.4 g, 48.0 mmol) and iron (8.05 g, 144 mmol) followed by acetic acid (70 mL). The solution was heated at 85° C. for 2 hours. The solution was concentrated onto silica gel, and eluted through a silica column (0-10% methanol/dichloromethane). The product was then concentrated and redissolved in dichloromethane. Addition of sodium hydroxide (1 M) caused the title compound to precipitate. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.56 (s, 1 H), 7.22-7.40 (m, 5 H), 7.00-7.09 (m, 2 H), 6.88-6.96 (m, 1 H), 3.54 (s, 2 H), 3.07-3.21 (m, 1 H), 2.94-3.05 (m, 1 H), 2.71-2.87 (m, 2 H), 2.52-2.61 (m, 1 H), 2.04-2.27 (m, J=10.71 Hz, 2 H), 1.84-1.95 (m, 2 H); MS (ESI) m/z 341.9 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[N:15][CH:16]=1.C1COCC1>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[N:13][CH:12]=1
Reactant: CCCCC[C@H](COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC[C@H](COc1cnc(-c2ccc(O)cc2)nc1)OC1CCCCO1
Yield: 102 %

Procedure:
In a 2 l four-necked flask were charged 25.3 g (51.2 mmol) of the compound obtained in step 1, 506 ml of THF, and 506 ml of methanol. After purging the flask with nitrogen, 5 g of 10% palladium-on-carbon was added thereto to conduct hydrogenation at 30° to 35° C. under atmospheric pressure for 2 hours. After completion of the reaction, the catalyst was removed by filtration in a nitrogen stream, and the solvent was recovered to afford 20.18 g of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:67]([O:71][CH3:72])(=[O:70])[CH:68]=[CH2:69]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](/[CH:69]=[CH:68]/[C:67]([O:71][CH3:72])=[O:70])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(/C=C/C(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 74.7 %

Procedure:
(2R,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.5 mmol), palladium(II) acetate (15 mg, 0.05 mmol), tri(o-tolyl)phosphine (36 mg, 0.1 mmol), triethylamine (0.2 mL, 1.5 mmol), and methyl acrylate (0.15 mL, 1.5 mmol) are dissolved in DMF (5 mL) and heated in a microwave at 150° C. for 30 minutes. The reaction mixture is filtered through Celite with EtOAc and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-((E)-2methoxycarbonyl-vinyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (225 mg, 75%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[CH:18][C:17]=1[CH3:27].[NH4+].[Cl-]>C1COCC1>[F:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([N:5]2[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:23])=[CH:18][C:17]=1[CH3:27]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: Cc1cc(OCC(=O)Cl)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To the solution of (S)-( )-4-Isopropyl-2-oxazolidinone (992 mg, 5.6 mmol) in anhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.5 mL, 5.6 mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture was stirred for 30 min at −70° C. and to it was slowly added a solution of 2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF. The resulting mixture was stirred at −70° C. for 2 h and the temperature was slowly raised over a period of 1 h. The mixture was poured into 30 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 2.2 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:9]=1[NH2:10])(=[O:3])[CH3:2].[Li+].[OH-]>>[C:1]([C:4]1[C:5]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:9]=1[NH2:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(C(=O)O)cc2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound methyl 4-(6-acetyl-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate was treated with 2 equivalents of LiOH and stirred at room temperature for 4 hrs. Neutralization with dil.HCl and extraction in to organic layer, gave the product, 4-(6-acetyl-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid in quantitative yield. The compound dissolved in to water-acetonitrile and lyophilized to give a white powder. HPLC-MS tR=1.49 min (UV254 nm); mass calculated for formula C26H19N5O3 449.1, observed LCMS m/z 450.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([Cl:27])=[N:24]2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([Cl:27])=[N:24]3)=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2ccc(CBr)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 7-bromomethyl-2-chloro-quinoline in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated in 20% EtOAc/hexanes and filtered to afford the title compound as a beige solid.