Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36].C(NC(=O)C1C=CC=C(OC2C=CC(NC3C4C=C(N5CCCC5)N=CC=4N=CN=3)=CC=2C)C=1)(C)(C)C>>[C:35]([NH:39][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:17][C:2]=2[CH3:1])=[CH:13][CH:12]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)N
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)O)cc1
Agent: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)NC(C)(C)C)c1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared from 4-[2-Methyl-4-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid and tert-butyl amine by a procedure analogous to the synthesis of N-tert-Butyl-3-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzamide. LRMS: 513.4 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.77 (s, 1H), δ 8.83 (s, 1H), δ 8.42 (s, 1H), δ 7.72-7.78 (m, 4H), δ 7.63 (s, 1H), δ 7.51 (s, 1H), δ 7.03 (d, J=9.14, 1H), δ 6.87 (d, J=8.72, 2H), δ 3.75-3.77 (m, 4H), δ 3.54-3.56 (m, 4H), δ 2.14 (s, 3H), δ 1.33 (s, 9H).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.CCCCCC.COC1C=CC=CC=1[C@H](N[C@H](C1C=CC=CC=1)C)C1C2C(=CC=CC=2)C=CC=1O.[Br:41][C:42]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:43]=1[CH:44]=[O:45].Cl>C1(C)C=CC=CC=1>[Br:41][C:42]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:43]=1[C@H:44]([OH:45])[CH2:4][CH3:5]
Reactant: CC[Zn]CC
Reactant: O=Cc1cc(F)ccc1Br
Agent: COc1ccccc1[C@H](N[C@@H](C)c1ccccc1)c1c(O)ccc2ccccc12
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
With reference to Chirality, 2005, 17, 476-480, 1.06 M solution of diethyl zinc in hexane (18.6 ml, 19.7 mmol) was added dropwise under ice cooling to a solution of 1-[(S)-(2-methoxy phenyl){[(1S)-1-phenylethyl]amino}methyl]-2-naphthol (0.38 g, 0.99 mmol) in toluene (5 ml). The mixture was stirred at room temperature for 1 hour. After stirring, the mixture was added with 2-bromo-5-fluorobenzaldehyde (2.0 g, 9.85 mmol) under ice cooling and stirred at room temperature for 16 hours. The reaction solution was added with 1 N aqueous hydrochloride solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound as a transparent oily substance (1.81 g, yield 79%).
Reaction SMILES: C(C1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:7]C=1)=C.[Br:15][CH:16]1CC(=O)NC1=O.[O:23]1[CH2:27][CH2:26][CH2:25]C1>O>[C:10]([NH:9][C:6]1[N:7]=[CH:25][C:26]([CH:27]([OH:23])[CH2:16][Br:15])=[CH:4][N:5]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: O=C1CC(Br)C(=O)N1
Reactant: C=Cc1cnc(NC(=O)C(C)C)nc1
Solvent: O
Product: CC(C)C(=O)Nc1ncc(C(O)CBr)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 764 mg of 5-ethenyl-2-(isobutyramido)pyrimidine in a mixture of 3 ml of water and 7 ml of tetrahydrofuran, 710 mg of N bromosuccinimide was added. The reaction mixture was stirred at room temperature for 18 hours and then partially concentrated under reduced pressure. To the aqueous residue 25 ml of methylene chloride was added and the layers separated. The aqueous layer was further extracted with methylene chloride (20 ml). The combined organic extracts were washed with 20 ml of water and then dried over anhydrous magnesium sulfate. Concentration afforded 977 mg of a glassy product. This material was chromatographed on silica gel (95:5 methylene chloride:methanol) to give 491 mg of pure bromohydrin.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]>C(O)(=O)C>[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)CBr)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid is added dropwise while stirring and within 30 minutes at 20°-25° to a solution of 112.5 g or 2-bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml of glacial acetic acid. Yellow-brown crystals thereby separate. After 90 minutes the reaction mixture is poured on to 300 g of ice. The crystals are filtered under suction, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is evaporated at 50° in a water-jet vacuum until crystallization begins. The crystallizate, cooled to room temperature, is removed by filtration under suction and washed with a small amount of methylene chloride. There is obtained 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone of m.p. 147°-149°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:27]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Reaction time: 12 h
Yield: 71 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-Boc-3-(S)-aminopiperidine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50 then 75%) as eluant to afford intermediate N-Boc protected product as a colorless solid (87 mg, 76%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately ½ volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (70 mg, 71% overall). 1H NMR (D2O) 1.36 (m, 1H), 1.58 (m, 2H), 1.90 (s, 3H), 1.96 (m, 1H), 3.08 (m, 3H), 3.21 (m, 1H), 3.65 (m, 1H), 4.18 (br d, J=11.4, 1H), 7.06 (br d, 1H), 7.09 (br d, 1H). 19F NMR −64.6. LC/MS 4.40 min, [M+1]+ 360.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(O)cc2)c(CC(=O)OC)c1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (1.0 g, 3.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (9.0 mL), and 4-hydroxybenzoic acid (1.4 g, 10 mmol) and trifluoroacetic anhydride (1.2 mL) were added thereto, followed by stirring at room temperature for 20 hours. To the mixture were further added 4-hydroxybenzoic acid (0.92 g, 6.6 mmol) and trifluoroacetic anhydride (1.4 mL), followed by stirring for 6 hours. The reaction mixture was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (0.10 L), and the resulting mixture was extracted with ethyl acetate (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in a 7 mol/L solution of ammonia in methanol (100 mL), followed by stirring at room temperature for 1 day. After the reaction mixture was concentrated under reduced pressure, 3 mol/L hydrochloric acid (40 mL) was added thereto, followed by extraction with ethyl acetate (50 mL×3). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10-1/2) to obtain methyl 3,5-diallyloxy-2-ethyl-6-(4-hydroxybenzoyl)phenylacetate (0.84 g, 57%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=1)[C:9]([O:11]CC(C)C)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>CO.O>[CH2:20]([O:19][C:17]1[CH:16]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:18]=1)[C:9]([OH:11])=[O:10])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)c1cc(OCC(C)C)cc(OCC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1cc(OCC(C)C)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
In 13 ml of methanol is dissolved 2.5 g of isobutyl 3,5-diisobutoxybenzoate, to which is then added 2.3 ml of 5 mol/L sodium hydroxide solution. The mixture thus obtained is stirred at 50° C. for 3 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 1.8 g of 3,5-diisobutoxybenzoic acid is obtained as a white solid product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[C:10](=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][C:26](=[O:28])[CH3:27])=[CH:19][CH:20]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccc(OC(C)=O)cc1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester (2.19 g) and 4-hydroxybenzaldehyde (1.32 g, 11 mmol) in acetic anhydride (6.5 ml) is heated at reflux temperature for 18 hours. The solution is evaporated, the residue dissolved in tetrahydrofuran and crude 8-[[4-(acetyloxy)phenyl)methylene]-5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester is precipitated with water to yield 3.4 g. Purification on silica gel (250 g) with 9:1 Skelly B:ethyl acetate gives pure 8-[[4-(acetyloxy)phenyl)-methylene]-5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester (2.76 g), m.p. 112° C., after ethanol crystallization.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[O:11]1[CH2:15][CH2:14][CH2:13]C1.[CH2:16]([Li])CCC.O>CCCCCC>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:11])[CH:14]([CH3:16])[CH3:13]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(I)c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)C(=O)c1cccc(C(=O)O)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising 2.48 g of m-iodobenzoic acid and 40 ml of tetrahydrofuran was cooled to −70° C., then 13.8 ml of n-butyllithium (1.6 M-n-hexane solution) was dropwise added over a period of 10 minutes, followed by stirring at the same temperature for 30 minutes. Then, a mixture comprising 1.5 g of N-isobutyrylpropyleneimine and 5 ml of tetrahydrofuran was added thereto at −70° C., and then the temperature was raised to room temperature, and a reaction was carried out overnight. After completion of the reaction, the reaction mixture was added to 100 ml of water and stirred, and then hexane was added thereto, followed by liquid separation. The aqueous layer was acidified by concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure to obtain a crude product of m-isobutyrylbenzoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([OH:30])[CH3:29].Cl>C(Cl)(Cl)Cl>[CH2:28]([O:30][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1)=[NH:2])[CH3:29]
Reactant: CCO
Reactant: N#Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 96 h

Procedure:
1-[1-(4-Cyanobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) is dissolved in chloroform (10 ml) and thereto is added ethanol (0.18 ml). Under ice cooling, hydrochloric acid gas is passed through the mixture to saturate and further the mixture is stirred at 5°-7° C. for 4 days. After the reaction, the solvent is concentrated to give 1-{1-[4-(1-ethoxy-1-iminomethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g). The product is used for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[N:9]=[CH:8]1.[Br:20]Br.N.C(O)(C)C.C(Cl)(Cl)Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[C:15]([Br:20])[C:10]=2[N:9]=[CH:8]1
Reactant: COc1cccc(Cn2cnc3cc(N)ccc32)c1
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1cccc(Cn2cnc3c(Br)c(N)ccc32)c1
Yield: 66 %

Procedure:
To a solution of 1-(3-methoxybenzyl)-5-aminobenzimidazole (0.37 g, 1.3 mmol) in 10 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd Isopropanol/CHCl3) to provide 0.31 g (1.0 mmol, 66%) of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH2:18][CH3:19])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:26])=[O:14])=[C:11]([CH2:18][CH3:19])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(C(=O)O)ccc(OCc2ccccc2)c1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1c(C(=O)OC)ccc(OCc2ccccc2)c1C
Temperature: 67 °C

Procedure:
19.7 g of 4-benzyloxy-2-ethyl-3-methylbenzoic acid (D1) are dissolved in 200 ml of methanol. 5.0 ml of H2SO4 (95-98%, extra pure) are subsequently added. The reaction solution is heated under reflux at 67° C. for 18 h overnight and subsequently evaporated to ⅓ of the volume in vacuo, and 200 ml of water are added. The mixture is then extracted twice with 200 ml of ethyl acetate each time. The combined organic phases are subsequently washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo, giving 17.5 g of the title compound as a colourless oil; MS: 285.2 (MH+); TLC: Rf=0.72 (cyclohexane/methyl tert-butyl ether 1:1 parts by volume).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](O)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][OH:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
cis-4-[(tert-Butoxy)carbonylamino]cyclohexane carboxylic acid (2.6 g, 10.68 mmol) was dissolved in THF (20 mL) and cooled to −10° C. (MeOH-ice). N-Methyl morpholine was added followed by isobutyl chloroformate (1.175 mL, 10.68 mmol). After 10 min, NaBH4 was added as a solid in one portion (1.213 g, 32.06 mmol). The reaction mixture was warmed to 0° C. and methanol was added dropwise (13.35 mL). After about 30 min, the reaction was quenched with 5% aqueous KHSO4. The reaction monitored by LC-MS was complete. The crude product was extracted with ethyl acetate and the combined extracts were dried over Na2SO4. A colorless oil was obtained and solidified slowly at room temperature. The product and purity were assessed by LC-MS and 1H NMR. No further purification was necessary. (quantitative yield) ES-MS (m/z) 230.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:52]=[CH:51][CH:50]=C[C:46]=1[C:47]#[N:48]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:51][CH:52]=[CH:45][C:46]=3[C:47]#[N:48])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: N#Cc1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C#N)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)benzonitrile and isolated as white solid (6.8 mg, 41%). MS(m/e): 398.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>CCO>[C:13]([O:17][C:18]([N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
4,7-Dichloroquinoline (0.49 g, 2.0 mmol), 3-[tert-butoxycarbonyl(methyl)amino]pyrrolidine (1.96 mL, 10.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.12 g, 10.0 mmol) are heated in EtOH for 15 h at reflux. The reaction mixture is concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as a colorless solid.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21]([O:23][C:24]1[CH:29]=CC=CC=1)=O.C([O:37][C:38](=O)[NH:39][C:40]1SC2C(C3C=CC=CC=3)=CC=C(OC)C=2N=1)C1C=CC=CC=1.N1CCOCC1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:38]([N:39]4[CH2:40][CH2:21][O:23][CH2:24][CH2:29]4)=[O:37])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)nc12
Solvent: C1COCCN1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine was first reacted with phenyl chloroformate as described for (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid benzyl ester in WO01/97786 and then with morpholine. Usual workup, peparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown powder. MS: m/e=394(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:6]=1.Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.[OH-].[K+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])[CH:6]=1)[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCC1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CC1CCC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reaction time: 16 h
Yield: 43.9 %

Procedure:
[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over 15 min. The reaction mixture was stirred for 16 h and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of the product as a yellow oil. (The synthesis was repeated with temperature kept at 40° C. over 16 h to give the product in quantitative yield). 1H NMR (300 MHz, CDCl3/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d, 1JCF=277.6 Hz), 116.0, 67.5 (q, 1JCF=36.7 Hz), 52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=O)[CH:19]([CH3:21])[CH3:20]>>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH:19]([CH3:21])[CH3:20])[NH:12][C:13]2=[N:14][NH:15][CH:16]=[C:17]12)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C(C)C)Nc2n[nH]cc2C1c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitrobenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.