Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].BrN1C(=[O:21])CCC1=O.[OH2:23]>CS(C)=O>[CH2:1]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](=[O:23])[C:7]1=[O:21])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1ccc2cccnc21
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Product: CCCCCN1C(=O)C(=O)c2cccnc21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 2-neck round bottom flask (1 L) was charged with 1-pentyl-1H-pyrrolo[2,3-b]pyridine (17.4 g, 92.6 mmol) in anhydrous dimethylsulfoxide (300 mL) and bubbled with nitrogen. To the reaction solution was added N-bromosuccinimide (34.3 g, 193 mmol) in portion over 15 min at 0° C. The reaction mixture was heated at 60° C. for 6 h followed by at ambient temperature for 16 h. The reaction mixture was diluted with water (200 mL) and stirred for 0.5 h followed by extraction with ethyl acetate (3×200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound as a yellow solid, which was crystallized from ether as an orange solid (14.6 g, 72%): 1H NMR (300 MHz, CDCl3) δ 8.41 (dd, 1H), 7.78 (dd, 1H), 7.03 (dd, 1H), 3.79 (t, 2H), 1.77-1.66 (m, 2H), 1.34-1.29 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 219.1, 182.2, 164.0, 158.2, 155.8, 132.8, 119.4, 112.0, 39.3, 28.9, 27.2, 22.3, 13.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCc1ccc(CCl)cc1

Procedure:
[4-(2-Methoxyethyl)phenyl]methanol (415 mg) synthesized in Reference Example 42 was dissolved in carbon tetrachloride (8 mL), triphenylphosphine (720 mg) was added thereto, and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in hexane, the insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1) to give the title compound (225 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:3]1[C:2]([C:18]2[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=2)=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2cc(C=O)c([N+](=O)[O-])cc2F)c1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-2-nitrobenzaldehyde (10.0 g, 40.0 mmol), 3,5-dimethoxyphenylboronic acid (7.3 g, 40.0 mmol), bis(triphenylphosphino) palladium(II) chloride (1.4 g, 2.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in dioxane/water (550 mL, v/v=10/1) was degassed with nitrogen for three times and heated at 90° C. for 3 hours. The mixture was cooled to room temperature, concentrated, diluted with ethyl acetate (1000 mL), and washed by water (500 mL) and brine (500 mL). The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1 to 5/1) to afford the title compound (9 g, 61%) as a yellow solid. MS (ES+) C15H12FNO5 requires: 305, found: 306 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[Br:18][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]([C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[N:12][CH:13]=1
Reactant: COC(=O)C1(c2ncc(Br)cc2C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Br)cnc1C1(C(=O)O)CCOCC1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid methyl ester (745 mg) in tetrahydrofuran (5 ml) and methanol (5 ml) was added 4 N aqueous solution of sodium hydroxide (5 ml) at room temperature, and stirred overnight. After completion of the reaction, the organic solvent was evaporated, diluted with 1 N aqueous solution of sodium hydroxide and water, diethyl ether was added thereto, and the aqueous layer was separated. The aqueous layer was ice-cooled, concentrated hydrochloric acid was added thereto to adjust the layer to pH 4, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (421 mg) as a white solid. MS (ESI) m/z: 300, 302 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH3:20])([CH2:17][CH:18]=[CH2:19])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:21]([Br:24])[CH:22]=[CH2:23]>C(OCC)(=O)C>[Br-:24].[CH2:23]([N+:12]1([CH2:11][C:10]([CH3:20])([CH2:17][CH:18]=[CH2:19])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: C=CCC(C)(Cc1ccc(Cl)cc1Cl)CN1CCCC1
Solvent: CCOC(C)=O
Product: C=CCC(C)(Cc1ccc(Cl)cc1Cl)C[N+]1(CC=C)CCCC1
Product: [Br-]

Procedure:
A solution of 40 g of (X) and 31.5 g of allyl bromide in 300 ml of ethyl acetate was refluxed for 5 hours. The precipitated product was filtered off under suction, washed with ethyl acetate and dried under reduced pressure. Yield: 15 g; melting point: 174° C. (compound No. 56).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(OCC4C=CC=CC=4)=O)[CH2:19]3)[C:15]2=[O:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]3)[C:15]2=[O:35])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(NC(=O)OCc4ccccc4)C3)C2=O)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(N)C3)C2=O)CC1
Yield: 77.6 %

Procedure:
4-(7-Benzyloxycarbonylamino-1-oxo-2-aza-spiro[4.5]dec-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.54 mmol) in methanol (50.0 mL) was shaken under hydrogenated at 50 psi and rt for 2.5 hrs. The catalyst was filtered off, and the filtrate was concentrated to afford 0.42 g (77%) of the title compound. LC-MS (method C): RT: 0.94 min; ESI-MS m/z: 352 (M+H)+. It was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=[C:14]2[C:34]2[CH:35]=[N:36][C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][C:39]=2[O:40][CH2:41][CH3:42])=[O:12])[CH2:7][CH2:6]1.[OH-].[Li+]>CO.O1CCCC1.O>[C:43]([C:37]1[N:36]=[CH:35][C:34]([C:14]2[N:13]([C:11]([N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:47])=[O:2])[CH2:10][CH2:9]3)=[O:12])[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=2)=[C:39]([O:40][CH2:41][CH3:42])[CH:38]=1)([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1

Procedure:
{1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid methyl ester (example 162) was hydrolyzed using lithium hydroxide in methanol/tetrahydrofuran and water to give the title compound. HR-MS (ES, m/z) calculated for C36H43Cl2N4O4 [(M+H)+] 665.2656, observed 665.2656.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:20]O>>[CH3:20][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:14]
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
4-(4-Bromophenyl)-4-oxobutyric acid (86.4 g, 0.336 mol) (Preparation 1) in MeOH (1.7 l) containing H2SO4 (86 ml) was refluxed for 21 h. After cooling, the light precipitate was filtered off and the reaction mixture concentrated to dryness. The obtained solid was placed in water and extracted twice with EtOAc. The organic layer was washed with diluted NaOH and twice with brine, dried over Na2SO4 and concentrated to yield the desired 4-(4-bromophenyl)-4-oxobutyric acid methyl ester as a low melting point solid (87.5 g, mp=50° C.). 1H NMR (CDCl3): 7.85 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz), 3.71 (3H, s), 3.28 (2H, t, J=6.5 Hz), 2.76 (2H, t, J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:12][O:11][S:10](=[O:14])(=[O:13])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16](I)[CH:17]=[CH2:18].[OH-].[Na+]>C(Cl)Cl>[CH2:18]([N:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:15])[CH2:12][O:11][S:10]1(=[O:14])=[O:13])[CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: CC1(c2cccc(Br)c2)COS(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCN1C(C)(c2cccc(Br)c2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 4-(3-bromophenyl)-4-methyl[1,2,3]-oxathiazolidine-2,2-dioxide (7.3 g, 25 mmol) in DCM (77 mL) was added allyl iodide (9.1 mL, 100 mmol, 4 eq), followed by BnBu3NCl (0.39 g, 1.3 mmol) and 40% NaOH (28 mL). The mixture was stirred at RT for 16 h. The organic layer was separated and the solvent was evaporated. Silica gel chromatography using 5-20% EtOAc/hexanes gave 8.3 g (100%) of 3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC5; R6=Me) as a colorless oil. 1H NMR (CDCl3) 7.64 (t, J=1.8 Hz, 1H), 7.46-7.54 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 5.77-5.89 (m, 1H), 5.19-5.33 (m, 2H), 4.38 (dd, J1=8.7 Hz, J2=23.7 Hz, 2H), 3.46-3.68 (m, 2H), 1.83 (s, 3H).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C@H:7]([NH:9][CH2:11][CH2:12][CH2:13][OH:14])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCl
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@@H](NCCCO)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
To a solution of (R)-1-phenylethanamine (364 g, 3.00 mol) in water (43.7 ml) was added 3-chloropropan-1-ol (142 g, 1.50 mol) at room temperature. The mixture was stirred at 100° C. for 5 hours. The resulting mixture was cooled to 0° C. and basified with saturated aqueous potassium carbonate. The organic layer was extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The crude product was distilled under reduced pressure to remove excess (R)-1-phenylethanamine. The residue was diluted with chloroform and activated carbon was added to the solution. The mixture was refluxed for one hour and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford (R)-3-(1-phenylethylamino)propan-1-ol as pale yellow oil (224 g, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([C:15]([CH3:17])=O)[C:9]([O:11][CH2:12][CH2:13][Br:14])=[O:10])([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:29])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH3:29][C:22]1[NH:21][C:15]([CH3:17])=[C:8]([C:9]([O:11][CH2:12][CH2:13][Br:14])=[O:10])[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCBr
Reactant: CCOC(=O)/C=C(/C)N
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
58.8 g of 2-bromoethyl 2-(3-nitrobenzylidene)-acetoacetate and 22.5 g of ethyl 3-aminocrotonate in 250 ml of tetrahydrofuran are heated at the boil for 3 h. The mixture is stirred for 8 h at room temperature, after which the solvent is distilled off in vacuo and the solid residue is dissolved in hot 2-propanol. The title compound crystallises out on cooling. It is filtered off under suction, washed with cold 2-propanol and dried. 65 g of product of m.p. 158°-159° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[NH2:18][C:17]1[CH:12]=[CH:13][C:14]([O:19][C:5]2[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1ccc(Oc2ncc(Cl)cn2)cc1

Procedure:
A mixture of 5-chloro-2-methylsulfonylpyrimidine* (94 g), p-aminophenol (53 g), potassium carbonate (50 g) and methyl ethyl ketone (350 ml) was heated under reflux for a period of 3 hours. The mixture was filtered and the residue was washed with 2×200 ml of boiling acetone. Evaporation of the combined organic liquors left an orange oil. This readily dissolved in benzene and on standing the product crystallised and was collected by filtration and dried. Yield 80 g (74%), m.p. 125° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:33][CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1Nc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)O)c(Nc3ccc4c(c3)OCO4)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoic acid 2.8 mg of a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:22][OH:23])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 64 h
Yield: 44.8 %

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (780 mg, 2.9 mmol) in a mixture of ethanol (8 ml) and water (2 ml) was added hydroxylamine hydrochloride (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8.7 mmol) and the solution stirred for 64 h at room temperature. The mixture was concentrated in vacuo and the residue diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The product was recrystallised from diethyl ether/hexane to yield 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (380 mg, 1.3 mmol) as a yellow powder.
Reaction SMILES: [C:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[ClH:19].[N:20]([O-])=O.[Na+]>C1(C)C=CC=CC=1.O>[Cl-:19].[C:1]([C:9]1[CH:15]=[CH:14][C:12]([N+:13]#[N:20])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cl
Reactant: O=N[O-]
Reactant: CC(C)(C)CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc([N+]#N)c([N+](=O)[O-])c1
Product: [Cl-]
Temperature: 38 °C
Reaction time: 1 h

Procedure:
In a 100-ml flask fitted with a stirrer and thermometer, 15.0 grams (0.06 mole) of 4-tert-octyl-2-nitroaniline is suspended in 20 ml of toluene. To this is added at 25° C. 17.3 grams (0.18 mole) of concentrated hydrochloric acid. The suspension is stirred at 38° C. for 1 hour followed by the addition of 6 ml of water. The mixture becomes thick as the corresponding hydrochloride salt crystallized as a granular precipitate. The mixture is cooled to 0° C. and diazotized by the addition over a period of 30 minutes of 4.3 grams (0.062 mole) of sodium nitrite in 6 ml of water keeping the temperature at -5° C. to -2° C. The mixture is stirred at -2° C. for 1 hour. Two phases occur. The combined phases contain the desired diazonium chloride and are used as is.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:36]2([CH2:39][NH:38][CH2:37]2)[CH2:35][N:34]1C(OC(C)(C)C)=O>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:34]3[CH2:35][C:36]4([CH2:39][NH:38][CH2:37]4)[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC3(CNC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate to afford a white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=461 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.30 (br. s, 2H) 3.63 (s, 4H) 3.75-3.92 (m, 4H) 6.41 (d, J=2.35 Hz, 1H) 7.26-7.35 (m, 2H) 7.77 (br. s, 1H) 7.81-7.89 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:25][CH3:26])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1
Reactant: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
676 mg (2.413 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-purine are dissolved in 10 ml of abs. DMF by means of gentle heating. 375 mg (2.713 mmol) of potassium carbonate, followed by 0.97 ml (12.01 mmol) of ethyl iodide are added at room temperature. The reaction mixture is stirred at room temperature for 2 hours. When the reaction is complete, the reaction mixture is poured onto ice/water (60 ml) and stirred for 10 minutes. The inhomogeneous mixture is extracted three times with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and dried under an HV. The resulting crude product (crystalline oil) is purified by crystallization from diethyl ether/hexane. 2-Chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; Rf=0.55 (ethyl acetate:hexane=3:1); APCI-MS: (M+H)+=308; HPLC: tret(grad 20/1)=12.40 minutes; m.p. 127–128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.17
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:27][C:23]2[N:22]([CH3:21])[CH:26]=[CH:25][N:24]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: Cn1ccnc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ccnc1COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperazine (556 mg, 2.0 mmol, 1.0 eq.), (1-methyl-1H-imidazol-2-yl)-methanol (448 mg, 4.0 mmol, 2.0 eq.), triphenylphosphine (1.04 g mg, 4.0 mmol, 2.0 eq.) and THF at 0° C. under nitrogen was added DEAD (0.629 mL, 4.0 mmol, 2.0 eq.) slowly so that temperature of the reaction does not rise above 10° C. After addition was complete, the ice bath was removed and the mixture was stirred at r.t. overnight. Methanol was added, and the mixture was stirred for about 15 minutes and then concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient 0-8% 2.0 M NH3 in MeOH/CH2Cl2 for 25 minutes and 8% 2.0 M NH3 in MeOH for 7 minutes) afforded the title compound (279 mg, 0.75 mmol, 37%). LRMS (ESI+): 373.3 (M+1).