Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:17][CH2:18][C:19]([F:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:18][C:19]([F:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(F)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (2.14 g, 11.0 mmol) in anhydrous acetone (30 ml) at 0° C., was added dropwise a solution of compound ethyl 3-(cyclopentylamino)-2-fluoro-2-methylpropanoate (2 g, 9.22 mmol) in acetone (10 mL) over 10 min. After which, potassium carbonate (3.8 g, 27.7 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue which was used directly for next step. [M+H] calc'd for C15H20ClFN4O4, 375. found 375.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH:29]=[O:30])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:29]([OH:30])[CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A stirred solution of diisopropylamine (14 mL) in dry tetrahydrofuran (150 mL), is treated dropwise with a solution of butyl lithium in hexanes (40 mL; 2.5 M), under nitrogen, while keeping the temperature at below −70° C. The resulting mixture is then stirred for a further period of 30 minutes at below −70° C. The stirred mixture, while it is still maintained at below −70° C., is then treated dropwise with a solution of 4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred mixture is maintained at below −70° C. for a further 45 minutes. The stirred mixture, while it is still maintained at below −70° C., is then treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) in dry tetrahydrofuran (100 mL), and it is stirred at below −70° C. for a further 30 minutes. The resulting mixture is then allowed to warm to room temperature overnight, and then treated with saturated aqueous ammonium chloride solution (200 mL). The layers are separated and the aqueous layer is further extracted with ethyl acetate (3×300 mL). The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from ethyl acetate, to give (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (28.5 g), in the form of a cream solid, m.p. 102-103° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:23])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21]C)[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:25])([CH3:24])[CH2:5][C:4]1=[O:26])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:23])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[OH:21])[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:25])([CH3:24])[CH2:5][C:4]1=[O:26])[CH3:2]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of 7.05 g of Compound 1B (20.1 mmol) in 60 mL of dry dichloromethane was treated with 40 mL of 1M BBr3 in dichloromethane. The reaction flask was then equipped with a reflux condenser, nitrogen inlet and heated to reflux. After 2 hours another 20 mL of BBr3 was added and refluxing continued for an additional 2 hours. The reaction mixture was allowed to cool to room temperature. The crude reaction mixture was diluted with dichloromethane and washed with water (2×50 mL) and brine (50 ml), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product Compound 1C was purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%) to give 3.6 g (53%) of product as a white solid. MS (electrospray): mass calculated for C21H23NO3, 337.17; m/z found 338.3, [M+H]+. 1HNMR (400 MHz, CDCl3): 9.91 (s, 1H), 7.85 (dd, J=2.0, 8.5 Hz, 1H), 7.70 (d, J=1.98 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.20 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 2.52 (s, 2H), 2.15 (s, 3H), 1.33 (s, 6H), 1.22 (t, J=7.09 Hz, 3H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1
Reactant: NCCc1ccccc1F
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccccc3F)cc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde (32.8 mg, 0.1 mmol) in anhydrous THF (0.6 mL) was added the 2-(2-fluorophenyl)ethylamine (11.8 mg, 0.1 mmol) and Ti(iPrO)4 (0.035 mL, 0.12 mmol). The mixture was stirred for 3 h at 60° C. then sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added and the reaction mixture was stirred overnight at rt. THF (0.75 mL) was added followed by the PS-DEAM resin (Argonaut, 148 mg, 1.68 mmol/g), and the reaction mixture was stirred at rt overnight. The reaction mixture was filtered and the filtrates were eluted through a SCX column (Isolute, 1 g) with DCM (6 mL), then NH3 (2M in MeOH, 4 mL). The desired fractions (TLC monitoring) were concentrated under vacuum to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]2)=[C:4]([F:26])[CH:3]=1.Br[CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([N:16]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]2)=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1n(CCCF)nnn1-c1cc(Oc2ccc(O)cc2)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(-n3nnn(CCCF)c3=O)c(F)cc2Cl)cc1
Yield: 39.8 %

Procedure:
A stirred mixture of 1.0 g (0.0026 mole) of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, 1.5 g (0.0083 mole) of ethyl 2-bromopropionate, and 0.64 g (0.0046 mole) of potassium carbonate in 50 ml of acetone was heated at reflux for approximately 18 hours. The mixture was cooled and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 0.5 g of ethyl 2-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxotetrazol-1-yl]phenoxy]phenoxy]propionate as an oil, compound 8 of Table 1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([Cl:36])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:46](Cl)(=[O:48])[CH3:47].Cl>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:46](=[O:48])[CH3:47])=[CH:32][CH:31]=3)[C:26]([Cl:36])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C(C)=O)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To a solution of the acetate 176 (500 mg, 0.85 mmol) in CH2Cl2 (20 mL) were added AlCl3 (691 mg, 5.18 mmol) and acetyl chloride (0.37 mL, 5.18 mmol) at 0° C. The mixture was warmed up to rt slowly and left at rt for 3 hours. The mixture was cooled to 0° C. and added aq. 1N HCl solution to quench the reaction. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 177 (540 mg, quantitative yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][N:22](CC2C=CC=CC=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C([OH:50])C>C(O)(=O)C.[Pd]>[C:30]([OH:50])(=[O:29])[CH3:31].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1ccc2c([C@@H](O)CNCCCCCCOCCCCc3ccccc3)ccc(O)c2[nH]1

Procedure:
A solution of 8-(benzyloxy)-5-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one (33 mg) in ethanol (15 ml) and acetic acid (0.4 ml) was stirred under hydrogen in the presence of palladium on charcoal (10 mg) for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) to give the title compound (19.5 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@:8]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[OH:9])(=[O:3])[CH3:2]>CC#N.Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@:8]([OH:9])([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-tert-butyl 3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate (0.1773 g, 0.4172 mmol) in CH3CN (50 mL) and 2 N aq HCl (45 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide, which was used in the next step without further purification. LC-MS (3 min) tR=0.91 min, m/z 325, 327 (MH+).
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]>C(COC)OC.[Pd]>[C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCCCC#CCOC1CCCCO1)C(C)=O
Agent: [Pd]
Solvent: COCCOC
Product: CCOC(=O)C(CCCCCCCOC1CCCCO1)C(C)=O
Yield: 76.3 %

Procedure:
Ethyl 2-acetyl-9-tetrahydropyranyloxy-non-7-ynoate (25.9 g) was hydrogenated over 10% Pd/C (3 g) in dry dimethoxyethane (300 ml) at atmospheric pressure and room temperature. When hydrogen absorption was completed the mixture was filtered through kieselguhr and the filtrate was evaporated in vacuo. The residual oil was chromatographed on silica gel (600 g) using chloroform as eluant. Ethyl 2-acetyl-9-tetrahydropyranyloxy-nonanoate (20 g) was obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22]>ClCCl>[CH3:19][C:20]([CH3:27])([CH2:25][C:24]([NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)=[O:26])[C:21]([OH:23])=[O:22]
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C(=O)O)cn1)c1ccccc1

Procedure:
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.49 g, 2.00 mmol) and 2,2-dimethylsuccinic anhydride (0.26 g, 2.00 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. Evaporation of the solvent in vacuo yielded the title compound.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:30](B(O)O)=[CH:31][S:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCO>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:30]5[C:29]([CH3:28])=[CH:33][S:32][CH:31]=5)[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Reactant: Cc1cscc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1cccc2c1nnn2-c1ccnc(NC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A mixture of [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (364 mg), 4-methyl-3-thiopheneboronic acid (109 mg) and Na2CO3 (2 M aq, 1.1 mL, degassed), toluene (13 mL, degassed) and EtOH (1 mL), was bubbled with argon and stirred at RT for 10 min in a screw cap pressure flask. To this was added Pd(PPh3)4 (25 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a solid. The solid was chromatographed on silica, eluting with 0-30% Magic Base/DCM, then chromatographed again on silica using 0-100% EtOAc/hexanes. The product was titurated with Et2O, filtered, and evaporated in vacuo overnight to provide (1-methanesulfonyl-piperidin-4-yl)-{4-[4-(4-methyl-thiophen-3-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 5, 219 mg). Mp=244.0-245.0° C.; M+H=470.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]([CH3:25])[C:22](=O)[CH3:23]>ClCCl>[CH3:9][O:10][N:11]=[C:22]([CH:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])[CH3:25])[CH3:23]
Reactant: CC(=O)C(C)Nc1c(C)cccc1C
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C)C(C)Nc1c(C)cccc1C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A sample of 50.5 g triethylamine was added dropwise to a solution of 50.1 g (0.6 mol) methoxyamine hydrochloride in 75 ml dichloromethane at 9°-20° C. To the resulting solution was added about one-half of a 95.6-g (0.5-mol) sample of 3-(2,6-dimethylphenylamino)-2-butanone. The reaction temperature rose from 16° C. to 30° C. The reaction mixture was cooled in an ice bath, and the remaining 3-(2,6-dimethylphenylamino)-2-butanone was added dropwise. The reaction mixture was then stirred about 18 hours at about 20° C., washed with 50 ml of water and evaporated under reduced pressure to give 100.3 g of 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The nuclear magnetic resonance spectrum showed a sharp 3-proton singlet (--OCH3) at 3.9 ppm (relative to tetramethylsilane) and a sharp 6-proton singlet (2,6-dimethyl groups) at 2.2 ppm.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15](O)=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:21](CC)CC)C.ClC(OCC(C)C)=O.N>C1COCC1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15]([NH2:21])=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(N)=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxylic acid (6.8 g, 25 mmol) was dissolved in THF (100 ml), and triethylamine (2.53 g, 25 mmol) was added. After the mixture had been cooled to −20° C., a solution of isobutyl chloroformate (3.41 g, 25 mmol) in THF (10 ml) was added dropwise. After the mixture had been stirred for 30 minutes at −20° C., ammonia gas was passed into the pale brown suspension for 45 minutes. The mixture was then warmed to room temperature. The residue was filtered off with suction and extracted with THF, and the filtrates were concentrated.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1CCN2C(=NCCC2)CC1>CCOC(C)=O.O>[CH3:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 1-naphthol (1.0 g, 6.94 mmol) in DMC (10 mL), DBU (1.06 g, 6.94 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 16 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give 1-methoxynaphthalene as an oil. The yield of 1-methoxynaphthalene as determined by HPLC was 99% conversion.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].O>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)=[O:22]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylene chloride. The reaction was then allowed to warm to room temperature and followed by heating to refluxed. After 5 hours at reflux the reaction mixture was allowed to cool to room temperature and stirred for 72 hours. The reaction mixture was then poured into 100 mL of iced water and stirred for 20 minutes. This mixture was extracted with CH2Cl2 (3×60 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the crude product as a green solid. The crude product was purified by flash column chromatography (silica gel, CH2Cl2) to afford 2.21 g (39%) of the product as a yellow solid: mp 133-135° C.; 1H NMR (CDCl3) δ 8.64-8.56 (m, 1 H), 8.49-8.39 (m, 1 H), 8.10-8.05 (m, 1 H), 7.76-7.65 (m, 1H), 7.55-7.47 (m, 1 H), 7.36-7.29 (m, 1 H), 7.00-6.87 (m, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H); 13C NMR (CDCl3) δ 192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@@H:7]([CH2:16][CH3:17])[N:6]([C@@H:18]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]3)[C:5]=2[N:4]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=1[O:37][CH3:38]>C(O)C.O>[F:23][C:20]1([F:24])[CH2:21][CH2:22][C@@H:18]([N:6]2[C:5]3[N:4]=[C:3]([NH:25][C:26]4[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=4[O:37][CH3:38])[N:12]=[CH:11][C:10]=3[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@H:7]2[CH2:16][CH3:17])[CH2:19]1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)c2nncn2-3)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Concentrated hydrochloric acid (36 □l) was added to a mixture of (R)-7-chloro-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.21 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (59.84 mg, 0.31 mmol) in ethanol (0.9 mL) and water (3.6 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (82 mg, 80% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: N#CCc1ccccc1I
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccc1CC#N
Yield: 87 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-phenylacetonitrile instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 80:20, 156 mg, 87%) which was obtained as a light brown oil. MS: m/e=375.1 [M+H]+.
Reaction SMILES: Br[C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[N:22]([C@@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](Br)CN12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 70 °C

Procedure:
The mixture of (6R,7aS)-6-Bromo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step b) (1.45 g, 4 mmol) and NaN3 (0.34 g, 5.2 mmol) in DMF (50 mL) was heated to 70° C. for 1.5 h. Then to the mixture was added water (100 mL) and extracted with EtOAc (100 mL×2), the organic layer was washed water (100 mL) and brine (100 mL). The combined organic layer was evaporated to dryness and the crude product (1.0 g, 77%) was used without further purification in the next step.