Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)=[O:28]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(-n2ccc(N)n2)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3,4-dimethylphenyl)-1H-pyrazol-3-amine (408 mg, 2.18 mmol, 1.00 equiv) in dichloromethane (10 mL), pyridine (518 mg, 6.56 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (575 mg, 2.61 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 7 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 600 mg (59%) of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH2:38]([C@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@@H:40]2[CH2:38][CH3:39])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC[C@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine (150 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and powdered potassium carbonate (117 mg) in dry N,N-dimethylformamide (1 ml) was stirred at 50° C. for 1.5 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (177 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:36](B1OB(C=C)OB(C=C)O1)=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:36]=[CH2:37])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 90.3 mg (0.375 mmol) 2,4,6-trivinyl-cyclotriboroxane, 43 mg (0.038 mmol) tetrakis triphenylphosphine palladium(0) and 51.8 mg (0.375 mmol) potassium carbonate in 2.9 mL dimethoxyethane and 1 mL water were heated in a microwave vial at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase extracted once more with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (244 mg) was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:25]([CH3:35])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31]CC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:25]([CH3:35])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH3:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1C
Yield: 88.8 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-ethoxypiperidin-4-yl)carbamate obtained in Example (112f) (0.88 g, 2.74 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (4 g, 15.8 mmol), sodium bicarbonate (0.7 g, 8.33 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 1.05 g of the title compound as a light brown oily substance (83%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:33][CH2:32]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CC2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclopropylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring at 50° C. for 4 days, to give the desired product as a light brown foam (12%).
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10]([O-])=[O:11].[BH4-].[Li+].CO>C1COCC1>[NH:1]1[N:9]2[CH:4]([O:5][CH2:6][CH:7]=[CH:8]2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: O=C([O-])c1cc2n(n1)CCCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CC2OCC=CN2N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
To the stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate: (4.0 g, 20 mmol) of in 100 ml of THF was added 0.71 g of lithium borohydride and 1.03 g of methanol. The solution was heated at 40 C. for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographyed to give 2.08 g of the desired product (67%); (M+H) 155.
Reaction SMILES: C(=[N+]([O-])[CH:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[C:9]1([F:23])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])C1OC=CC=1.[CH:25](=[N:31]/[OH:32])\[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.CC(C)=O>[F:23][C:9]1([C:16]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[O:17])[CH:8]([O:32]/[N:31]=[CH:25]/[C:26]2[O:30][CH:29]=[CH:28][CH:27]=2)[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: O/N=C/c1ccco1
Reactant: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1[N+]([O-])=Cc1ccco1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 51 h
Yield: 55.1 %

Procedure:
In 3 ml of pyridine-acetone (pyridine-acetone=2:1) were dissolved 341 mg (1 mmol) of N-(furfurylidene)-(5-fluoro-5-isobutoxycarbonyl-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-6-yl)amine N-oxide and 133 mg (1.2 mmol) of (E)-furfuraldoxime, and the solution was stirred at room temperature for 51 hours. The reaction solution was treated in the same manner as described in Example 9 to give 188 mg of isobutyl 5-fluoro-6-[(E)-furfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[C-:24]#N.[K+]>CC(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH:19]([CH3:24])[CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
934 mg (3 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are stirred at 60° C. for 48 hours with 198 mg (3 mmol) of potassium cyanide in 30 ml of dry 2-propanol. The mixture is evaporated in vacuo. The residue is treated with 30 ml of 2-propanol and 198 mg (3 mmol) of potassium cyanide and heated to boiling under reflux for 22 hours. After evaporation in vacuo, the residue is treated with water and extracted three times with 30 ml of chloroform each time. The combined chloroform phases was washed three times with 20 ml of water each time, dried over magnesium sulphate and evaporated. After recrystalisation from ethyl acetate/n-hexane, there is obtained isopropyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 207°-208° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].CCN(CC)CC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCC1CCCCO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC1CCCCO1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A CH2Cl2 solution of (tetrahydro-2H-pyran-2-yl)methanol (7.91 g, 68.1 mmol), Et3N (14 mL, 102 mmol), and catalytic DMAP was treated with 4-bromobenzenesulfonyl chloride (14.3 g, 74.9 mmol). After 2 h, the reaction was quenched with water. The organic layer was washed with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography on silica gel (EtOAc/Hex) to afford ((tetrahydro-2H-pyran-2-yl)methyl 4-bromobenzenesulfonate as an oil (16 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(Cl)(Cl)Cl.Cl[C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC1(OC(=O)Cl)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: O.C([O:9][C:10]1[C:11]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:12][C:13]([CH2:40][CH3:41])=[C:14]([CH:39]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:40]([C:13]1[CH:12]=[C:11]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[C:10]([OH:9])=[CH:39][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:36][CH2:37][CH3:38])=[C:22]([NH:26][C:27](=[O:35])[CH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1)[CH3:41]
Reactant: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Yield: 112.3 %

Procedure:
Hydrogenate a slurry of 10% palladium on charcoal, 50% wet (with water by weight) (13 g) and 4-[[3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-phenyl]amino]-2,2-dimethyl-4-oxo-butanoic acid (260 g, 405 mmol)) in THF (1560 mL) starting at a hydrogen pressure of 900 psi. Continue the hydrogenation 20 h while not adding additional hydrogen. Hydrogenate two additional days maintaining hydrogen pressure of 200 psi. Filter the mixture through diatomaceous earth and concentrate the filtrate in vacuo to yield the title compound (251 g, quantitative) as a solid. Excess weight is due to the presence of THF. ES/MS m/z 552 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:20])=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 2-nitrocinnamic acid (7) (10.38 g, 53.76 mmol) dissolved in methanol (200 ml) was dropped a small amount of concentrated sulfuric acid at room temperature, and the reaction mixture was stirred at 70° C. for 12 hours. After the reaction was completed, the resulting solution was basified with a saturated aqueous solution of sodium bicarbonate to weak basicity and extracted with dichloromethane three times. Then, the organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:5) to give the target compound (11.03 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29]B(O)O>CN(C=O)C.O>[CH3:29][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: Nc1cnc(Oc2ccc(Br)c(OC(F)(F)F)c2)nc1
Reactant: CB(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ncc(N)cn2)cc1OC(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a solution of 2-({4-bromo-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinamine (Intermediate 162, 270 mg) in DMF (4 mL) were added K3PO4 (490 mg, 2.31 mmol), Pd(tBu3)2 (197 mg, 0.385 mmol) and methyl boronic acid (276 mg, 4.62 mmol) and the reaction mixture was stirred for 30 minutes at 110° C. under microwave irradiation. After cooling the reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with ice cold brine (2×5 mL), dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 80:20 to 50:50 cyclohexane/ethyl acetate to afford the title compound as white solid (135 mg).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][Zn+]>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>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3ccc(F)cc3F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (20 mg, 59%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 2,4-difluoro-benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 340 (base, M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH:13]([O-])([O-])[O:14][CH3:15].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>COCCOC>[CH3:13][O:14][CH:15]1[O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=2[CH2:9][O:10]1
Reactant: COC([O-])[O-]
Reactant: OCc1ccc(CO)c(CO)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: COCCOC
Product: COC1OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4 g of (3,4-bis-hydroxymethylphenyl)methanol (23.8 mmol), 40 ml of 1,2-dimethoxyethane, 2.78 g of methyl orthoformate (26.2 mmol) and 0.24 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask. The reaction medium is stirred at room temperature for 4 hours 30 minutes and then the montmorillonite is filtered off and the 1,2-dimethoxyethane is evaporated under vacuum at 30° C. The residue is chromatographed on silica gel (dichloromethane/methanol=98/2) to give 3.2 g of (7-methoxy)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C=O)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanal (5.7 g, 25 mmol) and trimethyl(trifluoromethyl)silane (7.1 g, 50 mmol) in THF (60 mL) under nitrogen was added a solution of TBAF (0.66 g, 2.5 mmol) in THF (10 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for an additional 1 hour before the addition of 1 N aqueous HCl (20 mL). The mixture was vigorously stirred at ambient temperature for 10 minutes, and then extracted with EtOAc (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-4% EtOAc/hexane) to afford (S and R)-3-(4-bromophenyl)-1,1,1-trifluoro-3-methylbutan-2-ol as a light yellow oil. The racemic mixture was resolved by preparative chiral HPLC (Chiralpak IA, 2*25 cm; Mobile phase: 5% ethanol in hexane) to afford the two enantiopure title compounds.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[H-].[Na+].[CH3:16][Si:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([CH2:19][CH2:18][Si:17]([CH3:25])([CH3:24])[CH3:16])(=[O:22])=[O:21])[CH:9]=[CH:8]2)=[O:4]
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carboxylic acid methyl ester (3.6 g, 20.6 mmol) in tetrahydrofuran (180 mL) at 0° C., was added sodium hydride (0.65 g, 21.9 mmol). After 10 min., 2-trimethylsilanylethanesulfonyl chloride (4.4 g, 21.9 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 3 h, acetic acid (1.6 mL, 26.8 mmol) was added and the reaction mixture was concentrated. The crude product was chromatographed (Biotage 40M column, 2.5% ethyl acetate-hexanes) to afford 1-(2-trimethylsilanylethanesulfonyl)-indole-5-carboxylic acid methyl ester (5.43 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[NH3:18]>CO>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: CSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CO
Product: CSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.), methanol (100 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (4.3 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethanol to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (1.5 g.), m.p. 201°-202°.