Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=O)[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.[NH3:25]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([NH2:25])=[O:24])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCCO)c12
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3OCCO)c12

Procedure:
Prepared analogously to example 28.3 using 4-(2-(2-hydroxyethoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (30.5 mg) and ammonia in dioxane (0.5M; 1.6 ml)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[S:12][C:13]2[C:14]([NH:20][C:21]3[CH:22]=C(C=[CH:27][N:28]=3)C#N)=[N:15][CH:16]=[CH:17][C:18]=2[N:19]=1.Br[C:30]1C2SC(C3C(Cl)=CC(C#N)=CC=3Cl)=NC=2C=C[N:31]=1.NC1N=CN=C([N:56]2[CH2:59][CH:58]([OH:60])[CH2:57]2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[S:12][C:13]2[C:14]([NH:20][C:21]3[C:22]([N:56]4[CH2:59][CH:58]([OH:60])[CH2:57]4)=[CH:30][N:31]=[CH:27][N:28]=3)=[N:15][CH:16]=[CH:17][C:18]=2[N:19]=1)[C:8]#[N:9]
Reactant: N#Cc1ccnc(Nc2nccc3nc(-c4c(Cl)cc(C#N)cc4Cl)sc23)c1
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Reactant: Nc1cc(N2CC(O)C2)ncn1
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Nc4ncncc4N4CC(O)C4)c3s2)c(Cl)c1
Yield: 52 %

Procedure:
Following the procedure described for 2-[2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridine-4-ylamino]-isonicotinonitrile (Example 19), 4-(4-bromo-thiazolo[5,4-c]pyridine-2-yl)-3,5-dichloro-benzonitrile and 1-(6-amino-pyrimidin-4-yl)-azetidin-3-ol were reacted to give the desired compound as a yellow solid (56 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 8.37 (s, 2H), 8.20 (d, J=1.0 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 6.58 (s, 1H), 5.72-5.69 (m, 1H), 4.63-4.56 (m, 1H), 4.20 (t, J=7.8 Hz, 2H), 3.73 (dd, J=9.1, 4.5 Hz, 2H). LCMS (Method C): RT=3.21, m/z: 470 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]([F:17])([F:16])[CH2:7][C:8]1[N:9]=[C:10]([N+:13]([O-:15])=[O:14])[NH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)(Cl)Cl>[N+:13]([C:10]1[NH:11][CH:12]=[C:8]([CH2:7][C:6]([F:17])([F:16])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:26]([O:28][CH3:29])=[O:27])=[O:18])[N:9]=1)([O-:15])=[O:14]
Reactant: COC(=O)Cl
Reactant: O=C(NCCO)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)OCCNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1

Procedure:
3-(2'-Nitroimidazolyl)-2,2-difluoropropionic acid hydroxyethylamide (6.0 g, 22.7 mmol) was dissolved in a solvent mixture of methyl chloroformate (30 ml) and chloroform (30 ml) and cooled by ice. To the solution, a solution of pyridine (6.0 ml) in chloroform (30 ml) was dropwise added over 2 hours. The completion of the reaction was confirmed by thin-layer chromatography. Then, the reaction solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography to obtain methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionamidoethoxyformate (6.89 g). m.p. 50.5°-52.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]([C:20](OCC)=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]3[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:15]=23)[CH:11]=[N:12][CH:13]=1>C(OCC)C>[Br:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH2:20][OH:21])=[C:18]([CH3:25])[N:17]=[C:16]3[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:15]=23)[CH:11]=[N:12][CH:13]=1
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1-c1cncc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCn1ncc2c(-c3cncc(Br)c3)c(CO)c(C)nc21
Temperature: -10 °C
Yield: 67.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (8.8 mg) in diethyl ether (0.5 ml) was added a solution of ethyl 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (30 mg) in diethyl ether (1.5 ml) at −78° C. The mixture was gradually warmed to −10° C. over 8 hours and quenched with water at −10° C. The mixture was filtered through celite pad, and the filtrate was evaporated. The residue was purified by preparative thin layer chromatography eluting with a mixture of EtOAc and n-hexane (2:1) to give [4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (18 mg) as a colorless crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([CH3:25])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:21]([CH3:25])[N:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nn1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 3-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-ol (0.65 g), methyl bromoacetate (0.38 g, 2.48 mmol), potassium carbonate (0.60 g, 4.3 mmol) in N,N-dimethylformamide (5 mL) was stirred at 40° C. for 4 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by silica gel column chromatography (hexane/ethyl acetate 80:20 to 20:80). Solvent was removed to obtain a solid (0.573 g, 73%). LC/MS; ESI(+) m/z: 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][CH2:21][CH:22](P(OCC)(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:22]([CH2:21][CH3:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-methoxy-3-(2-phenylethoxy)benzaldehyde (5.09 g), triethyl 2-phosphonobutyrate (10.76 g) and an aqueous solution of 6 M potassium carbonate (8.3 ml) was heated to 150° C. (oil bath temperature) and stirred vigorously for 8 hours. After the reaction mixture was cooled to room temperature, it was extracted with toluene. The toluene extract was washed with an aqueous solution of 0.5 N sodium hydroxide and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=25:1) to obtain 4.08 g of ethyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-ethylacrylate as a mixture of E- and Z-isomers (E-isomer:Z-isomer=5. 7:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C@@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(/C=C/[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(CC[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of the compound obtained from step e above (0.62 g) in a solvent mixture of ethyl acetate (20 mL), 10% palladium on charcoal (0.3 g) was added at room temperature, and the reaction mixture was hydrogenated at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C>[CH3:11][S:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of 2.0 g (9.85 mmol) 2-bromo-5-nitropyridine dissolved in 8 mL DMF was added 690 mg (9.85 mmol) of sodium thiomethoxide. The mixture was stirred at room temperature for 1 h, and partitioned between ethyl acetate and water, dried over MgSO4 and concentrated to obtain 1.13 g of 2-methylthio-5-nitro-pyridine, pure by 1H NMR.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[N:4]=[C:5]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=3)[N:7]=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=3)[N:1]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccccc1C
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(-c2nc(-c3ccc(C)c(C)c3)nc(-c3ccc(C)c(C)c3)n2)cc1C
Temperature: 25 °C

Procedure:
A mixture of 36.8 g. (0.20 mole) of cyanuric chloride, 88.0 g. (0.66 mole) of anhydrous aluminum chloride and 250 ml. of o-xylene was heated at 45°C for 1.5 hours. After cooling to room temperature, the mixture was poured into ice water, and then steam distilled to remove the excess o-xylene. The water was decanted from the pot residue and the remaining solid filtered, washed with acetone and dried to yield 58.1 g. of product, m.p. 220°-230°. Recrystallization from benzene gave an analytically pure sample, m.p. 235°-236°.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CN(C=O)C.[CH2:16]1COC[CH2:17]1>>[CH2:16]([N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[CH3:17]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cnc2c(N)ncnc21
Yield: 43 %

Procedure:
Coupling of 2b with adenine in THF in the presence of Ph3P and DEAD formed the desired N9 -substituted derivative 1a in only 5% yield. The low yield may be due to the insolubility of adenine in THF. After replacement of THF with DMF, compound 1a was produced in 43% yield without any detection of the N7 - derivative or the N9 -ethyladenine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Brc1ccc2ncccc2c1
Product: Cc1ccccc1C(CC(=O)c1ccc2ncccc2c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 6-bromoquinoline (CAS RN: [5332-25-2]) was prepared the title compound as a yellow oil, MS (ESI+): m/z=430.0791 ([M+H]+, 1Br).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 31.5 %

Procedure:
To a solution of trans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene (1.14 g, 4.79 mmol) in THF (50 mL) and water (5 mL) was added triphenylphosphine (2.60 g, 10 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated and the thus obtained material was purified by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.32 g (31%) of trans-1-amino-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorless oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.92 (m, 2H), 1.99-2.10 (m, 2H), 3.32 (br s, 1H), 4.10-4.19 (m, 1H), 4.47-4.60 (m, 1H), 5.57-5.77 (m, 2H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N:28]#[C:29]Br.[Cl:31]CCl>>[ClH:31].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[C:29]#[N:28])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN2CCC(Nn3cccc3)CC2)cc1
Reactant: ClCCl
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CCN2CCC(N(C#N)n3cccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine of Example 12a (4 g, 13.4 mmole) in 150 ml dichloromethane containing sodium bicarbonate (3.4 g, 40 mmole) was added a solution of cyanogen bromide (1.6 g, 14.7 mmole) in 25 ml dichloromethane. After stirring twenty hours at ambient temperature, the reaction mixture was evaporated, stirred with water and extracted with ether. The organic extract was washed with water and saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 5 g of an oil. The oil was converted to the hydrochloride salt as in Example 2 and was recrystallized from isopropanol-ether to give 2.8 g (58%) N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-N-(1H-pyrrol-1-yl)cyanamide hydrochloride, d 227°-229° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH:5]=[CH:4]1.Br[CH2:15][C:16]([NH2:18])=[O:17].O>CN(C=O)C>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]2[CH2:15][C:16]([NH2:18])=[O:17])#[N:13]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1ccn2CC(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 60% NaH (12.38 g) in DMF (480 ml) was added a solution of 1H-indole-4-carbonitrile (40.0 g) in DMF (80 ml) at 0° C. After stirring at 0° C. for 30 min, it was stirred at room temperature for 0.5 hour. Thereafter, a solution of 2-bromoacetamide (40.76 g) in DMF (80 ml) was added dropwise thereto at 0° C. The solution was warmed from 0° C. to room temperature, and stirred for 12 hours. To the reaction solution was added water (1200 ml), and the precipitated white solid was collected by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml) to obtain 2-(4-cyano-1H-indol-1-yl)acetamide (52.1 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1CC[CH2:25][CH2:24]1>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:24](=[O:23])[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 0.15 ml of acetic anhydride and 0.24 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction solution was filtered with silica gel and NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (459 mg, 100% yield).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O)[CH:2]([CH3:4])[CH3:3]>Br>[CH2:1]([C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC(C)C
Agent: Br
Product: CC(C)C[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1
Yield: 69.3 %

Procedure:
Racemic cis-methyl 2-isobutyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.29 g, 1.03 mmol) was stirred in HBr (12 mL, 33% in HOAc) for 24 h. The volatiles were concentrated and the residue purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 10 minutes with a flow of 100 mL/min. The title compound (160 mg) was isolated. 1H NMR (600 MHz, d2o) δ 0.79 (2 d, 6H), 1.34-1.51 (m, 3H), 1.54-1.72 (m, 2H), 2.13 (m, 1H), 2.25 (m, 1H), 2.99 (m, 2H), 3.21 (m, 1H), 3.38 (m, 1H), 5.61 (s, 1H).
Reaction SMILES: [CH:1]([C@@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][C@H:7](N)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].C1(=O)C=CC=CC1=[O:34].Cl.[OH-].[Na+]>CO.O.O1CCCC1>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:6][C:7](=[O:34])[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)C=C[C@@H](N)C1
Reactant: O=C1C=CC=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of (1S,4S)-4-isopropyl-4-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopent-2-en-1-amine (3.5 g, 9.2 mmol) and 3,5-Cyclohexadiene-1,2-dione, 3,5-bis(1,1-dimethylethyl)-(2.20 g, 9.99 mmol) in Methanol (85 mL) was stirred at room temperature for 30 minutes. Tetrahydrofuran (85 mL) and 1N HCl (10 mL) were added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and the organics evaporated. The remaining aqueous was made basic with 1N NaOH and extracted with EtOAc three times. The combined extracts were dried (Magnesium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (1:1 EtOAc/Hexanes) to yield (3.16 g, 90%) of the title compound. MS calculated for C19H22F3N3O2: (M+H) 382; found 382.1. Step B:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:14]=3)[CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:11]3[CH2:12][N:8]([C:4]4[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:36])[CH:7]=[CH:6][CH:5]=4)[C:9](=[O:27])[CH2:10]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(c3cccc(NC(=O)Nc4ccccc4)c3)C2)cc1OC1CCCC1
Reaction time: 20 h

Procedure:
A solution of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (8 mg, 0.022 mmol) in CH2Cl2 (0.5 mL) was created. Phenylisocyanate (0.023 mmol) was added, and the reaction mixture was stirred for 20 h. Concentration under reduced pressure and purification by column chromatography on silica gel (EtOAc:Hexane=1:2) gave the desired product.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20][F:21])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]>OO>[C:8]([C:10]1[C:14]([S:15]([C:16]([F:18])([F:17])[F:19])=[O:4])=[C:13]([CH2:20][F:21])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1SC(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: OO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1S(=O)C(F)(F)F
Reaction time: 6 h
Yield: 32 %

Procedure:
A 30 wt % aqueous solution of hydrogen peroxide (50 μL) was added to a trifluoroacetic acid solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole (205 mg) prepared as described in Example 30. The reaction mixture was stirred for 6 h whereupon solvent was evaporated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/DCM) to afford the title compound as a white solid (66.5 mg, 32%). MS (ES): M/Z [M−H] 452. 1H NMR: (400 MHz, DMSO-d6): 5.48-5.75 (m, 2H) and 8.41 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −62.05 (s, 3F), −73.68 (d, 3F) and −82.41 (m, 1F).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:34]2[CH:39]=[CH:38]C=CC=2)(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:32]([O:31][C:29]([N:28]=[S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)=[CH:25][CH:24]=1)([CH:34]1[CH2:39][CH2:38]1)=[O:27])=[O:30])[CH3:33]
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(=O)(c1ccccc1)c1ccc(N)cc1
Product: CCOC(=O)N=S(=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Yield: 49 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)butan-1-ol (151 mg, 0.53 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-phenylsulfoximide (147 mg, 0.48 mmol) according to procedure 5c, the desired product is obtained in 49% yield (130 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).