Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][C:27]=3[O:38][CH3:39])=[N:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:35]1[CH2:34][CH2:33][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22]3[N:21]=[CH:20][C:19]4=[CH:18][CH:17]=[C:16]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][CH3:8])[N:24]4[N:23]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:37][CH2:36]1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C2CCN(Cc3ncc[nH]3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 8.8 %

Procedure:
Imidazole-2-carboxaldehyde (0.011 g, 0.112 mmol) and [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (53 mg, 0.12 mmol) were treated with sodium triacetoxyborohydride (0.033 g, 0.157 mmol) and acetic acid (0.064 mL, 0.112 mmol) in tetrahydrofuran (0.900 mL) at room temperature overnight. The reaction mixture was then concentrated and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. It was dried on NaSO4, filtered and concentrated. The product was isolated by reverse phase hplc (Gilson) to afford {4-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-2-methoxy-phenyl}-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow foam (5 mg, 9%). 1H-NMR (CDCl3) δ 9.63 (s, 1H), 8.69 (s, 1H), 8.29 (d, J=8.7 Hz, 1H), 8.00 (d, J=6.2 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.02 (s, 2H), 6.83 (d, J=4.7 Hz, 1H), 6.73 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.71 (s, 2H), 2.97 (d, J=11.4 Hz, 2H), 2.49 (m, 1H), 2.25 (m, 2H), 1.85 (m, 5H); LC/MS (ESI+): 510.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:19])[N:9]=1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cc2ccccc2c(-c2ccccc2Cl)n1)N1CCCCC1
Yield: 68.3 %

Procedure:
Operations are carried out as for Example 7, starting with 1.42 g of 1-(2-chlorophenyl) isoquinoline 3-carboxylic acid, 0.58 g of triethylamine, 0.62 g of ethyl chloroformate and 0.55 g of piperidine in 50 ml of chloroform. 1.2 g of 1-[[1-(2-chlorophenyl) 3-isoquinolyl]carbonyl]piperidine, melting at 161° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:22]([O:25][C@@H:26]([CH3:48])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30]1)=[O:28])(=[O:24])[CH3:23]>>[C:22]([O:25][C@@H:26]([CH3:48])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][N:13]2[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=[C:12]2[S:11][C:3]2[C:2]([Br:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[CH2:31][CH2:30]1)=[O:28])(=[O:24])[CH3:23]
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine (350 mg, 0.95 mmol) and (2S)-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (662 mg, 1.66 mmol). LC-MS [M+H]+ 590.1. This product is used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>>[Br:22][CH2:23][CH2:24][C:25]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:26]
Reactant: O=C(Cl)CCBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Product: O=C(CCBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Yield: 65 %

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (5 g, 0.018 mol) was reacted according to the procedure of Example 142 with 3-bromopropionyl chloride (6.8 g, 0.04 mol, 4 ml), using a bath temperature of 100° C. A white crystalline product was obtained in 65% yield (4.9 g), m.p. 133°-134° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.79; H, 4.12; N, 6.69; Br, 19.25. The product has the formula: ##STR1537##
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([CH3:21])=[O:20]>C1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:18][C:19](=[O:20])[CH3:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Solvent: c1ccccc1
Product: CC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]-pyridine-3-carbaldehyde (0.50 g) and acetonylidenetriphenylphosphorane ##STR11## (0.82 g) in benzene (6 ml) was refluxed for 4 hours and then the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3-buten-2-one (trans isomer) (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([SH:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)[C@@H](Sc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 26 mg of zinc acetate dihydrate, 948 mg of 5-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 9 ml of toluene at 25° C. The temperature rises to 29° C., whilst stirring is maintained for 45 mn. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[CH3:6][NH:7]N.[Cl:9][CH2:10][C:11](Cl)=O>CO>[Cl:9][CH2:10][C:11]1[N:7]([CH3:6])[N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: O=C(Cl)CCl
Reactant: CNN
Reactant: CC(=N)N
Agent: Cl
Solvent: CO
Product: Cc1nc(CCl)n(C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared by a modification of a reported method (Kuebel, B. DE 3118258, Dec. 2, 1982): A 2 L-round bottomed flask equipped with a magnetic stirrer was charged with acetamidine hydrochloride (94.5 g, 1.0 mol) and methanol (500 mL). Methylhydrazine (50.0 g, 1.1 mol) was added slowly via a dropping funnel over 30 min at room temperature under nitrogen blanket. After 2 d, the solvent was removed in vacuo, and the resulting residue triturated with ethyl acetate, filtered, and washed with ethyl acetate (3×400 mL). After drying the residue in a vacuum oven at 50° C., the crude intermediate amidrazone, N′-methylethanehydrazonamide hydrochloride (109.8 g) was used directly in the next step. This intermediate (109.8 g) was suspended in dichloromethane (400 mL), cooled to 0–5° C., and treated slowly with triethylamine (100.2 g) at this temperature. Chloroacetyl chloride (103.7 g, 1.02 mol) was added slowly over 30 min at 0–5° C. via a dropping funnel. The reaction mixture was allowed to warm to room temperature and stirred for 18 h under nitrogen blanket. The solvent was then removed under reduced pressure, affording a residue (432.6 g) containing the N-chloroacetyl amidrazone intermediate. Polyphosphoric acid, PPA (400 g) was added to this material in a 2 L-3 necked flask, which was equipped with an overhead stirrer, a water condenser and a thermometer. The reaction mixture was stirred and heated at 120–130° C. for 4 h. Upon cooling to 80° C., water (400 mL) was added slowly and stirring continued for an additional 2 h. Aqueous NaOH (100 g/150 mL) was used to adjust the pH from 3 to 9. The organic material was extracted with chloroform (4×1 L), and the resulting solution treated with activated charcoal, dried with Na2SO4, filtered, and evaporated carefully. The dark oily residue thus obtained was extracted with a mixture of ether (700 mL) and pentane (300 mL) to separate the product from insoluble impurities. The yellow supernatant was decanted and the solvent removed carefully in vacuo (30° C. and ˜10 Torr), affording 60.0 g (46% overall) of the title product as an oil (95% pure by NMR).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:18])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[N:10]1([C:9]2[CH:2]=[CH:3][C:4]([OH:18])=[C:5]([CH3:6])[CH:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(N2CCCCC2)ccc1O
Reaction time: 16 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9 mL), and acetic acid (4.7 mL) in DCE (200 mL) was treated with sodium triacetoxyborohydride (24 g). After 16 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (5×100 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a white crystalline solid (5.5 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[F-:11].[K+].COCCOCCOC.Cl[C:23]([F:30])([F:29])[C:24]([Cl:28])=[C:25]([F:27])[F:26]>O>[F:11][C:3]([O:4][C:23]([F:30])([F:29])[C:24]([Cl:28])=[C:25]([F:27])[F:26])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: [F-]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: FC(F)=C(Cl)C(F)(F)Cl
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)=C(Cl)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 39 %

Procedure:
Hexafluoroacetone (16.6 g, 0.10 mol) was distilled into a stirred mixture of potassium fluoride (5.80 g, 0.10 mol) and 1-(2-methoxyethoxy)-2-methoxyethane (hereinafter referred to as diglyme) (100 ml) to give a homogeneous solution. This mixture was maintained at 25°-30° C. and treated with 1,2-dichloro-1,1,3,3,-tetrafluoropropene (18.3 g, 0.10 mol, prepared according to J. E. Bissey, H. Goldwhite and D. G. Rowsell, J. Org. Chem., 32, 1542 (1967)). The mixture was stirred overnight and then it was poured into water (500 ml). The lower layer was washed with water (250 ml), dried, and distilled to give 1-(heptafluoro-2-propoxy)-1,1,3,3-tetrafluoro-2-chloropropene (13.0 g, 0.039 mol, 39%), bp 82°-83° C. whose structure was confirmed by the following: λmax 5.72 (CCl=CF2) and 7.5-10 μm (CF, C-O); 19F NMR, -64.9 (m) 2F, -- OCF2C=C; -76.0 (2nd order m) 2F, C=CF2 ; -81.2 (t J=5.7 Hz, each member d J=2.2 Hz) 6F, CF3 ; and -146.7 ppm (t J=22.9 Hz each member septet J=2.2 Hz) 1F, CFO.
Reaction SMILES: CN(C)C(=[O:14])N(C1C=CC(F)=C(Cl)C=1)N.[F:16][C:17]([F:28])([F:27])[C:18]1C=C(C(=O)C)C=C[CH:23]=1.[CH:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:16][C:17]([F:28])([F:27])[CH2:18][C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:14]
Reactant: c1ccccc1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(=O)N(N)c1ccc(F)c(Cl)c1
Product: O=C(CC(F)(F)F)c1ccccc1

Procedure:
To a solution of 10 grams of 4,4-dimethyl-2-(3-chloro-4-fluorophenyl)semicarbazide in 200 milliliters of benzene was added 8.1 grams of m-trifluoromethylacetophenone. This mixture was stirred and heated at reflux for 18 hours. The solvent was removed and the residue purified by silica chromatography to give 13 grams (75.1 yield) of 2-trifluoromethylacetophenone, 4,4-dimethyl-2-(3-chloro-4-fluorophenyl) semicarbazone as an amber syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1F.[C:32]([NH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CN1CCOCC1.CN1CCCC1=O>CCOC(C)=O>[Cl:1][C:2]1[C:7]([N:43]2[CH2:42][CH2:41][CH:40]([NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:45][CH2:44]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Cl)c(F)n2)c2cc(-c3cccnc3)ncc21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)ccc2Cl)CC1
Temperature: 120 °C

Procedure:
In a pressure tube was charged with 3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (103.4 mg, 0.2268 mmol), 4-(N-Boc-amino)-piperidine (136.24 mg, 0.6803 mmol), 4-Methylmorpholine (249.30 uL, 10 mmol), and N-Methylpyrrolidinone (3 mL). The mixture was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed 3 times with water. The organic layer was dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl 1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. It was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight. The mixture was concentrated, and the residue was purified by reverse phase HPLC to afford 241 as an off-white solid (8.7 mg, 19%). 1H NMR (400 MHz, DMSO) δ 9.24 (d, J=10.3 Hz, 2H), 8.99 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 3.99 (d, J=12.0 Hz, 2H), 3.09 (d, J=12.4 Hz, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.56 (d, J=11.1 Hz, 2H). ESI MS m/z=406.1 (M+1)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([OH:16])=O)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:19]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([N:19]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)=[O:16])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CC(c3cccc(C(F)(F)F)c3)=NO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid (259 mg, 1 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (186 mg, 1 mmol) in DMF (0.5 mL) and methylene chloride (5 mL) at 0° C. was added triethylamine (120 mg, 1.2 mmol) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (442 mg, 1 mmol). The mixture was allowed to warm to room temperature over 1 h and stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate to give the desired coupling intermediate (410 mg) as a white solid. LCMS: (M+H)+ 428.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O.P([O-])(OCC)(OCC)=[S:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23](=[S:28])[NH2:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOP([O-])(=S)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(C(N)=S)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A mixture of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)ethyl]benzoic acid methyl ester (8.76 g, 25.08 mmol), water (4.7 mL) and diethyl thiophosphate (4.67 mL, 27.8 mmol) was stirred and heated to 80° C. for two hours. The mixture was cooled and aqueous sodium hydrogen carbonate (100 mL, 10%) and ethyl acetate (200 mL) were added. The organic phase was washed with brine. Drying (MgSO4) and concentration in vacuo afforded 7 g of the crude material, which was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate:heptane 1:2, containing 2% ethanol. This afforded 2.6 g (27%.) of 4-[2-thiocarbamoyl-2-(4-trifluoromethoxy-phenyl)ethyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][NH2:13])[CH:10]=2)[C:5]([NH2:14])=[N:4][CH:3]=1.[C:15]([CH:18]1[C:23](=[O:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:19]1=O)(=O)[CH3:16]>CCO.C(O)(=O)C>[NH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N:12]3[C:19]4[CH2:20][C:21]([CH3:25])([CH3:26])[CH2:22][C:23](=[O:24])[C:18]=4[C:15]([CH3:16])=[N:13]3)=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][N:4]=1
Reactant: NNc1ccc2c(N)ncc(Br)c2c1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(-c2ccc3c(N)ncc(Br)c3c2)c2c1C(=O)CC(C)(C)C2
Yield: 80.6 %

Procedure:
A suspension of 4-Bromo-6-hydrazino-isoquinolin-1-ylamine (0.097 g, 0.38 mmol) and 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (0.074 g, 0.41 mmol) in EtOH/Acetic acid (3:1, 7 mL) is microwaved at 150° C. for 20 min. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) afforded 0.1223 g (80%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indazol-4-one. LC/MS m/z=400 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 17.1 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2,4-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.6 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give 2-[2-nitro-3-(2,4-dichlorophenoxy)phenyl]acetic acid (2.4 g.).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH2:14])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)#[N:33]>>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH:14][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][N:38]=2)=[O:41])=[CH:8][CH:7]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(OC(C)(C)C)cc2)CC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C#N)cn2)CC1
Yield: 47.8 %

Procedure:
Reaction of 2.5 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]acetate with 0.85 g of 5-cyano-2-picolinic acid (as in Example 1d) yields 1.55 g of t-butyl [[1-[3-(p-t-butoxyphenyl) -N-[[5-cyano-2-pyridyl]carbonyl]-L-alanyl ]-4-piperidinyl]oxy]acetate. M.p. 122°-123° C. (diethyl ether/petroleum ether 4:1). MS (FAB): 565 (M+H)+.
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[C:27]([C:31]1[CH:40]=[C:39]2[C:34]([C:35](=[O:41])[CH2:36][CH2:37][O:38]2)=[CH:33][CH:32]=1)([O:29][CH3:30])=[O:28].C(#N)C>C(O)(C)C>[OH:41][C@@H:35]1[C:34]2[C:39](=[CH:40][C:31]([C:27]([O:29][CH3:30])=[O:28])=[CH:32][CH:33]=2)[O:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CC#N
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of (1S,2S)-TsDPEN (1.709 g, 4.85 mmol) in isopropanol (5 mL) was added to a 35 mL schlenk-flask and cooled to 0° C. The solution was degassed by three cycles of evacuation/nitrogen refill. Then, [RuCl2(η6-p-cymene)]2 (1.313 g, 2.425 mmol) was added, followed by TEA (1.352 mL, 9.699 mmol). The reaction mixture was heated to 80° C. under N2 for 1 h and cooled. The iso-propanol was removed under a stream of nitrogen, and dissolved in 10 mL acetonitrile. The catalyst solution was added to nitrogen filled 1 L 3-N flask equipped with overhead stirring. 7-Carbomethoxy-4-chromanone (100 g, 485 mmol) and 400 mL acetonitrile was added to the flask, followed by 5:2 formic acid-TEA (50 mL). The reaction mixture was incubated for 24 h at 30° C. An additional portion of formic acid-TEA (5 mL) was added and the reaction mixture stirred for an additional 24 h. The solution was concentrated completely by rotary evaporation. The product was purified by crystallization from 200 mL 2-propanol and 100 mL hexanes. The solids were collected by filtration and washed with cold 2:1 iPrOH-Hex. Final drying of the solids afforded the title compound. MS (m/z): 208.9 (m+H). Chiral HPLC showed the enantiomeric purity to be greater than 98%, when compared to racemic material.