Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Yield: 102.4 %

Procedure:
A mixture of ethyl 2-bromoacetate (0.23 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.40 g), anhydrous potassium carbonate (0.19 g) and methyl ethyl ketone was heated under reflux for 12 hrs. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil, which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}acetate (0.52 g) as a yellow crystalline solid, mp 99° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1Br.C1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=CC=CC=3)[C:28](=O)[C:27]=2C=CC=1>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1[O:37][C:35]1[CH:36]=[CH:27][CH:28]=[CH:29][CH:34]=1
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1c(N)c(Br)cc(O)c1C2=O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: Nc1c(Br)cc(O)c2c1C(=O)c1c(N)c(Oc3ccccc3)cc(O)c1C2=O

Procedure:
When 11.7 g of 1,8-diamino-4,5-dihydroxy-2,7-dibromoanthraquinone (compare Example 350a) are used as the anthraquinone component in Example 415a, then 4.5 g, corresponding to 37% of theory, of 1,8-diamino-4,5-dihydroxy-2-phenoxy-7-bromoanthraquinone are correspondingly obtained. Colour shade on silica gel: blue of Indicator Number 14 (Colour Index Hue Indication Chart).
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)C(O)=O.C[C@H]1[C@]2(O)[C@H]3[C@](O)(CC(COC(C)=O)=C[C@H]2[C@@H:24]2[C:25](C)(C)[C@:23]2([O:47][C:48](CC2C=CC=CC=2)=[O:49])[CH2:22]1)C(=O)C(C)=C3.CC(O)(C)C>C1(C)C=CC=CC=1>[C:23]([O:47][C:48]([NH:3][C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH3:8])[C:11]=1[CH3:19])=[O:49])([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(=O)OCC1=C[C@H]2[C@@H]3C(C)(C)[C@]3(OC(=O)Cc3ccccc3)C[C@@H](C)[C@]2(O)[C@@H]2C=C(C)C(=O)[C@@]2(O)C1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(=O)O)c1C
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)OC(C)(C)C)c1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2-methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 50° C. for 0.5 h, at 70° C. for 0.5 h then at 100° C. for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 100° C. and the resulting mixture was refluxed for 7 h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of the target product: m/z=237 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:11][C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)=[O:32])[CH2:29][CH2:30]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Oc1n[nH]c2cc(F)ccc12)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were dissolved in 5 ml of pyridine. Addition of 365 μl (2.63 mmol) of triethylamine and 355 mg (1.56 mmol) of 4-phenylpiperazine-1-carbonyl chloride was followed by stirring at room temperature for 3 h. Addition of 730 μl of triethylamine and 177 mg of 4-phenylpiperazine-1-carbonyl chloride was followed by stirring for a further 20 h. The reaction mixture was concentrated and mixed with water and ethyl acetate, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 12 mg (2%), M+H+: 529.34, 6-fluoro-1-(4-phenylpiperazine-1-carbonyl)-1H-indazol-3-yl 4-phenylpiperazine-1-carboxylate; 30 mg, (4%), M+H+: 529.40, 6-fluoro-1,2-bis(4-phenylpiperazine-1-carbonyl)-1,2-dihydroindazol-3-one. It was additionally possible to isolate 6-fluoro-1H-indazol-3-yl 4-phenylpiperazine-1-carboxylate as compound not of the invention.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].Br[CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)=O>>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11]([C:9]3[N:6]=[C:4]([CH2:3][C:1]#[N:2])[S:5][CH:8]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: N#CCC(N)=S
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(CC#N)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 576 mg (5.75 mmol) of 2-cyanothioacetamide and 2 g (4.72 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone.
Reaction SMILES: N#N.Cl.Cl.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=[O:32]>ClCCl>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:31]([NH:30][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (934.9 mg, 2.6 mmol) and Hunig's base [7087-68-5] (1.8 mL, 10.6 mmol) in dichloromethane (26 mL) was added 2-isocyanato-2-methylpropane [1609-86-5] (340 μL, 2.9 mmol). The suspension was permitted to stir and warm to ambient temperature over 17 h and was then partitioned between brine and ethyl acetate. The organic phase was reduced in volume to precipitate product as 442.1 mg of yellow solid. A 129.3 mg aliquot was purified by preparative RP-HPLC to yield 61.8 mg of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N-(tert-butyl)piperazine-1-carboxamide as a white powder, mp. 199-200° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 8H) 2.51 (s, 1H) 3.30 (s, 1H) 3.39-3.46 (m, 4H) 3.48-3.54 (m, 4H) 7.26 (d, J=10.11 Hz, 1H) 7.61 (s, 1H) 7.88 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.15, 43.05, 45.27, 49.94, 99.27, 110.77, 126.00, 131.50, 136.54, 155.16, 156.93. LRMS (ESI) m/z 381.1/383.1 [(M+H)]+, calc'd for C15H21BrN6O: 381.28.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([F:43])=[N:41][CH:42]=1>>[F:43][C:40]1[N:41]=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 71 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-2-fluoro-pyridine following a procedure analogous to that described in Example 1. Yield: 71% of theory; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.[C:24]1([CH2:30][CH2:31][C:32]([N:34]2[CH2:41][CH2:40][CH2:39][C@H:35]2[C:36](O)=[O:37])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: -25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To L-proline benzyl ester hydrochloride (0.98 g) in dichloromethane (20 ml) were added N-methylmorpholine (0.49 ml), N-(3-phenylpropionyl)-L-proline (1.00 g) and HOBt (0.60 g) under ice-cooling. After cooling to -25° C. , DCC (0.92 g) was added, and the mixture was stirred at a temperature between -25° C. and 0° C. for 2 hours, and then at room temperature for 14 hours. The reaction mixture was treated and purified as in Example 7-A) to give 1.39 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.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.CN(C)C=O>[CH3:15][O:14][N:12]([CH3:13])[C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:17][CH3:16])[CH:23]=2)=[CH:3][CH:4]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cc1
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: CN(C)C=O
Product: CON(C)C(=O)C=Cc1ccc(-c2cccc(SC)c2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 125.6 %

Procedure:
3-(4-Bromo-phenyl)-N-methoxy-N-methyl-acrylamide (11.7 g, 43.2 mmol) prepared in Step 1 of Preparation 1, 3-(methylthio)phenylboronic acid (14.5 g, 86.4 mmol), Pd(PPh3)4 (2.5 g, 2.2 mmol) and sodium carbonate (13.7 g, 129.6 mmol) were added to a mixed solvent of N,N-dimethylformamide (200.0 mL) and distilled water (50.0 mL). The reaction mixture was stirred at 80° C. for 7 hours and then extracted with ethyl acetate. The extract was washed with a saturated solution of ammonium chloride, 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=1/5) to give 17.0 g of the titled compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C1C=CC=CC=1>[C:14]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a well stirred solution of 3.62 g of trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (1:1) in 30 ml of water at 0-5° C is added 2.1 ml of benzoyl chloride in 10 ml of benzene. To this stirred two-phase mixture is added, over 30 minutes at 0°-5° C, a solution of 1.45 g of sodium hydroxide in 30 ml of water--precipitation of a pink solid begins immediately. After stirring the mixture for an additional 2 hours at 0°-5° C, the solid is filtered, washed with ether, and dried in vacuo to give 4.2 g of crude trans-3-benzamido-1,2,3,4-tetrahydro-2-naphthalenol.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].C(N(CC)CC)C.[CH3:16][OH:17]>>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:17][CH3:16])=[O:5]
Reactant: CO
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCl
Temperature: 25 °C

Procedure:
219 g of chloropivaloyl chloride was added drop-by-drop to a chilled (0°-5° C.), stirred solution of 141.4 g of triethylamine in 320 g of anhydrous methanol. The resulting mixture was warmed to room temperature in one hour, and most of the methanol was evaporated under reduced pressure. The residue was mixed with water and extracted with ether. The extract was dried (MgSO4), and the solvent was evaporated. The residue was distilled to give methyl 3-chloro-2,2-dimethylpropionate (3A), b.p.: 40°-50° C. (14 Torr.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:3]=1.Cl.C(OCC)C>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate (1.04 g, 2.8 mmol) was dissolved in ethanol (60 mL) and treated with 1M hydrochloric acid in diethyl ether (16 mL, 16 mmol) and stirred at 40° C. for 17 h. The reaction mixture was filtered and the white solid was collected and dried in vacuo. The hydrochloride salt precipitate was dissolved in water (25 mL) and potassium carbonate was added until the pH reached 10. The aqueous layer was washed with 5% methanol in dichloromethane (4×100 mL) then 10% methanol in dichloromethane (4×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo, affording the title compound as a brown oil (0.69 g, 91%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38]>C1COCC1>[CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH:4][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34]
Reactant: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)C#N)ccc21
Reactant: O=C(O)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)CNC(=O)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
(b)(c) To a stirred solution of (S)-2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropanenitrile (54 mg, 0.193 mmol) in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (0.5 mL, 0.5 mmol) portionwise at RT under nitrogen. After stirring at RT for 3 hr, the mixture was carefully quenched with MeOH, poured into brine, extracted with ethyl acetate (2×100 mL), dried (MgSO4) and concentrated. The crude product was coupled with 3,3,3-trifluoropropanoic acid (29 mg, 0.226 mmol) using General Coupling Method A to give 40 mg (51% yield) of (S)—N-(2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropyl)-3,3,3-trifluoropropanamide. MS found: (M+H)+=404.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:34][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCCC1
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (63, 505 mg, 1.16 mmol) and cyclopentylamine (1.74 mmol, 172 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 323 mg (0.81 mmol, 70%), mp 114–116° C.; Rf 0.55 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.34 (s, 1H, H-8), 8.32 (bs, 1H, NH), 5.82 (d, 1H, J=5.15 Hz, H-1′), 5.53 (d, 1H, J=5.18 Hz, OH-2′), 5.29 (d, 1H, J=5.15 Hz, OH-3′), 4.47–4.37 (m, 2H, CH, H-2′), 4.11–4.10 (m, 1H, H-3′), 4.00 (q, 1H, J=4.47 Hz, H-4′), 3.62–3.58 (m, 2H, H-5′), 3.47 (q, 2H, J=7.21 Hz, CH2CH3), 2.00–1.83 (m, 2H, cyclopentyl), 1.71–1.51 ((m, 4H, cyclopentyl), 1.12 (t, 3H, J=7.21 Hz, CH3); MS m/z 399 (M+H)+; Anal. (C17H24ClN5O4) C, H, N.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14](C(Cl)(Cl)Cl)[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:33][CH:30]([CH3:32])[CH3:31])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Reactant: CC(C)N
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
To a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg, 1.03 mmol) in DMSO (6 mL) was added isopropyl amine (1.2 mL). The reaction was heated to 90° C. in a sealed tube for 12 h then cooled to RT. The mixture was treated with water and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 35% EtOAc in petroleum ether) to give 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (450 mg, 83.3%) as an off brown solid. MS (ESI, pos. ion) m/z: 523.0 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 9.44 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 8.09-8.07 (m, 1H), 7.96-7.93 (m, 3H), 7.83 (d, J=1.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 3.88-3.83 (m, 1H), 2.32 (s, 3H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: CS[C:3](SC)=[C:4]1[CH2:10][CH2:9][CH:8]([CH2:11][CH3:12])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[C:5]1=O.[BH4-].[Na+].C[OH:23].[CH2:24]([OH:26])C>>[CH2:11]([CH:8]1[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[CH:5]=[C:4]([C:3]([O:26][CH3:24])=[O:23])[CH2:10][CH2:9]1)[CH3:12]
Reactant: CCO
Reactant: CCC1CCC(=C(SC)SC)C(=O)c2ccccc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCC1CCC(C(=O)OC)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-[Bis(methylthio)methylene]-9-ethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.35 g, 1.31 mmol) was dissolved in ethanol (7 ml), followed by adding thereto sodium tetrahydroborate (0.16 g, 4.35 mmol), and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and boron trifluoride diethyl ether complex (0.56 g, 3.95 mmol) was added to the residue, followed by stirring at room temperature for 20 minutes. Then, methanol (5 ml) was added thereto and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 0.20 g of methyl 5-ethyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([O:1][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(C=O)cc(O)c1OC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.2 g of 3-hydroxy-4,5-dimethoxybenzaldehyde in 50 ml of DMF there were added 1.49 g of imidazole and 4.5 ml of chlorotriisopropylsilane. The mixture was stirred at room temperature for 21 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3,4-dimethoxy-5-triisopropylsilanyloxybenzaldehyde (6.08 g) as a light yellow oil.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.[H-].[Na+].[CH3:18][N:19](C)[CH:20]=O>>[CH3:18][N:19]([CH3:20])[CH:14]1[O:15][CH:13]1[CH2:11][O:9][C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: BrCC1CO1
Reactant: CN(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)C1OC1COc1ccccc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 4.00 g of 3-dimethylaminophenol, 4.5 ml of epibromohydrin, 1.53 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 50 ml of dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 4.18 g of the title compound having an Rf value of 0.36 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH:13]1(C#N)C[CH2:14]1>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([CH:11]1[CH2:14][CH2:13]1)=[O:12]
Reactant: N#CC1CC1
Reactant: CC(=O)c1cc(C)cc(C)c1N
Product: Cc1cc(C)c(N)c(C(=O)C2CC2)c1

Procedure:
Cyclopropyl 2-amino-3,5-dimethylphenyl ketone was synthesized in the same fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except that cyclopropyl cyanide was used instead of acetonitrile.