Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:22]([O:24]CC)=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:22]([OH:24])=[O:23])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1

Procedure:
A mixture of 257 g. of diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, 35 g. of 86 percent potassium hydroxide, 530 ml. of ethyl alcohol, and 530 ml. of water was stirred and refluxed for seven and one-half hours. The reaction mixture was concentrated under reduced pressure until only water distilled. More water was added to the reaction mixture, which was then extracted twice with diethyl ether. The ether extracts were combined, washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure to recover 108 g. of unhydrolyzed diester starting material. The aqueous layers from the extractions were combined and acidified with concentrated hydrochloric acid, causing separation of an oil. This oil crystallized when shaken with a few ml. of diethyl ether. The mixture was filtered and the solid thus collected was washed with diethyl ether and air-dried. This product was a first crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. By repeating the hydrolysis procedure on the 108 g. of recovered diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, using 14.6 g. of 86 percent potassium hydroxide, 225 ml. of ethyl alcohol, and 225 ml. of water, there was obtained a second crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. The two crops were combined and recrystallized from ethyl alcohol to yield 157 g. of this product as a white solid. When recrystallized from ethyl alcohol, this compound melted at 186°-188° C. (dec.); ir (K·Br) 1740 (ester C=O), 1720 (acid C=O), and 1650 cm-1 (urethane C=O).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Br:18][C:19]1[C:24](F)=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:20]=1[F:29]>C1COCC1>[Br:18][C:19]1[C:20]([F:29])=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[C:24]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
LiHMDS (1.0M in THF, 16.8 mL, 16.8 mmol) was added dropwise to a stirred solution of aniline (821 mg, 8.80 mmol) in anhydrous THF (20 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 2-bromo-1,3-difluoro-4-nitrobenzene (2.0 g, 8.40 mmol) in THF (10 mL) was added and stirring at −78° C. was continued for 30 min. The reaction mixture was quenched by addition of water and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound (2.4 g, 91%). 1H NMR (CDCl3, 400 MHz): δ 8.48 (1H, s), 8.19-7.12 (1H, m), 7.33-7.25 (2H, m), 7.09 (1H, t, J=7.41 Hz), 6.93-6.83 (3H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[C:31]([F:42])[C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:33]([OH:35])[CH:34]=1>>[F:42][C:31]1[CH:30]=[C:29]([NH:28][C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[C:4]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[N:3]=2)[CH:34]=[C:33]([OH:35])[C:32]=1[N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reactant: Nc1cc(O)c(N2CCOCC2)c(F)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3cc(O)c(N4CCOCC4)c(F)c3)nc3c2cnn3C2CCCCO2)c1

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can then be reacted with 5-amino-3-fluoro-2-morpholinophenol under palladium catalyzed aminolysis conditions to yield N-(3-(6-((3-fluoro-5-hydroxy-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide, which can be deprotected under mild acidic conditions to provide N-(3-(6-((3-fluoro-5-hydroxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:29](Cl)(=[O:34])[O:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:29](=[O:34])[O:30][C:31]([CH3:33])=[CH2:32])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: C=C(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Yield: 94.5 %

Procedure:
To a solution of 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-amine (89 mg, 0.315 mmol) and NMM (45 μl, 0.410 mmol) in THF (2.0 mL) at 0° C. was added, dropwise, a solution of prop-1-en-2-yl carbonochloridate (45 μl, 0.410 mmol) in THF (1.0 mL) and the reaction mixture warmed to RT for 15 hr and then partitioned between EtOAc (20 mL) and water (5.0 mL). The aq layer was separated and extracted with EtOAc and the combined organic layers were dried (MgSO4) and then evaporated in vacuo to afford the title compound as a yellow oil (109 mg, 87%); Rt 2.54 min (Method 2); m/z 367 (M+H)+ (ES+). This material was used directly in the next step (below) without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25]CSC[CH2:21]1.CN(C)C=O>O>[CH3:21][N:20]([CH3:25])[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1
Reaction time: 5.5 h

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (10 g), thiomorpholine (10 g) and dimethylformamide (20 ml) was heated at 100° for 22 hours and then at 140° for 5.5 hours. The mixture was cooled and poured into water (220 ml). The resulting precipitate was collected and purified by high performance liquid chromatography on silica using dichloromethane:industrial methylated spirit:isopropanol 98.25:0.5:1.25 as the eluent. This gave the novel compound 7-dimethylamino-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 280°-283°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccnc(OC)c3)cc2)C(=O)O1

Procedure:
(S)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following conditions analogous to those described in Example 6 using PdCl2(dppf) as catalyst. tR=2.25 min, m/z 457 (M+1). 1H NMR (CD3OD) δ 8.08 (t, 1H), 7.50-7.27 (m, 7H), 7.11 (t, 1H), 6.92 (d, 1H), 6.86 (t, 2H), 5.13 (m, 1H), 4.71 (s, 1H), 4.53 (s, 1H), 3.88 (d, 3H), 2.95 (m, 2H), 2.58 (m, 2H), 2.47 (m, 1H), 2.04 (m, 1H), 1.51-1.40 (m, 6H), 1.26 (m, 2H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[C:34]1([CH:41]=[CH:40][CH:39]=[C:37](O)[CH:36]=1)[OH:35].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:37]2[CH:39]=[CH:40][CH:41]=[C:34]([OH:35])[CH:36]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:28])=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(O)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 40.8 %

Procedure:
A mixture of 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate (0.045 g, 0.091 mmol), resorcinol (0.020 g, 0.183 mmol) and K2CO3 (0.063 g, 0.457 mmol) in MeCN (2 ml) was heated in a microwave reactor at 120° C. for 10 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 0-50% EtOAc in DCM as eluent to give the title compound (0.016 g, 41%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.48 (m, 2H), 7.46-7.41 (m, 3H), 7.13 (t, 1H), 6.46-6.41 (m, 2H), 6.39-6.36 (m, 1H), 5.75 (t, 1H), 5.14 (s, 1H), 3.86 (t, 2H), 3.11-3.04 (m, 2H), 1.86-1.78 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): 159.9, 157.1, 135.4, 131.8, 130.4, 129.8, 128.8, 125.3, 108.5, 107.1, 106.9, 102.3, 66.1, 61.8, 42.5, 28.9, 27.8; Mass Spectrum: M+H+ 431.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH:14]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[CH:20][C:19]=1[O:29][CH3:30])[CH3:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:26]([NH:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:17]([NH:16][CH:14]([CH3:15])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:32])=[O:31])=[C:19]([O:29][CH3:30])[CH:20]=1)(=[O:28])[CH3:27]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)O

Procedure:
Prepared from 96c by treatment with TFA/CH2Cl2. After complete reaction, the solvent is removed in vacuo and the residue repeatedly concentrated from toluene. The resulting residue was dried under vacuum to a constant weight.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[C:15]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:16]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Product: N#Cc1ccccc1-c1cc(-c2cnc3c(F)c(Cl)ccn23)ccc1F
Yield: 70.3 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (70 mg, 0.28 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (109 mg, 0.34 mmol), as described in Example 1, to afford the title compound as a white amorphous solid (72 mg, 71%): δH (400 MHz, DMSO) 7.11 (1H, t, J 7.0), 7.60-7.70 (2H, m), 7.78 (1H, s), 7.85-7.89 (3H, m), 7.93 (1H, s), 8.04 (1H, dd, J 0.8, 7.8), 8.52 (1H, dd, J 1.0, 7.2); m/z (ES+) 366 (100%, [MH]+).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].Br.CS(C)=[O:18]>>[F:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)=O)cc1F
Reactant: CS(C)=O
Agent: Br
Product: COC(=O)c1ccc(C(=O)C=O)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-acetyl-2-fluorobenzoate (1.6 g, 0.0082 mol), 48% of hydrogen bromide aqueous solution (2.8 mL) in dimethyl sulfoxide (20 mL) was stirred at 60° C. overnight. After cooling, the mixture was poured into ice-water. The product was extracted with ethyl ether. The combined extracts were washed with brine; dried over Na2SO4, filtered concentrated to yield 1.60 g of the product which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:22]1(C)C=CC=C[CH:23]=1>C(Cl)(=O)C(Cl)=O>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:22][CH3:23])=[O:17])=[CH:19][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccccc1
Reactant: CN(C)CCC(c1ccc(C(=O)O)cc1)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)c1ccc(C(CCN(C)C)c2ccccn2)cc1
Reaction time: 1 h

Procedure:
Acid 18a (927 mg, 3.26 mmol) was stirred in oxalyl chloride (5 mL) at room temperature for 2 minutes and dry toluene (4 mL) was added to facilitate stirring. After 1 h, the mixture was concentrated. Ethanol (10 mL) and triethylamine (1.35 mL) were added and the dark yellow mixture was stirred overnight. The mixture was then concentrated and partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (20 mL) and the combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to yield 18c as an oil. Purification by flash chromatography (4/1 CH2Cl2/MeOH) yielded 18c (136 mg) as a yellow oil. The structure was confirmed by 1H NMR and LC/MS. (Esters 18d, 18e, and 18f were similarly prepared.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH:22]C(OCC1C=CC=CC=1)=O)[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH2:22])[C:9]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)N(OCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(=N)N(OCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)-ethoxyguanidine (730 mg, 1.5 mmol), as prepared in the preceding step, and 10% Pd/C (70 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (290 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 4.08 (t, J=5.2 Hz, 2H), 2.99 (q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15]Br)=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][N:31]1[CH:32]=[CH:33][C:28]([C:27]([O:26][CH3:25])=[O:35])=[CH:29][C:30]1=[O:34])=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: COC(=O)c1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)c(=O)c1
Yield: 46.4 %

Procedure:
A solution of 3-bromomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (550 mg, 1.35 mmol), methyl-2-hydroxyisonicotinate (290 mg, 1.89 mmol) and potassium carbonate (280 mg, 2.03 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. Flash chromatography (ISCO column, 40% ethyl acetate/hexanes) afforded 7-chloro-3-(4-methoxycarbonyl-2-oxo-2H-pyridin-1-ylmethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (300 mg, 46%) as a white solid. MS m/e calcd for C25H19ClN2O6 [(M+H)+] 479.0. Found 479.0.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH:17]=1
Reactant: CC(Oc1cc(Cl)ccc1CO)c1ccccc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1)c1ccccc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(1-phenylethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C24H19ClN4O2, 431; Found, 431.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH:13]1([NH:16][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[CH2:15][CH2:14]1
Reactant: CSc1nc(Cl)n2nccc2n1
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1nc(NC2CC2)n2nccc2n1
Yield: 78.8 %

Procedure:
4-Chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.0 eq, 6.26 g, 31.19 mmol) was suspended in anhydrous NMP (50 ml). Cyclopropylamine (1.5 eq, 3.2 ml, 46.26 mmol) was added through syringe dropwise. Internal temperature rose to 47° C. The mixture was stirred without any external cooling for one hour. An additional amount of cypropylamine (1 ml) was added and the mixture stirred for another 1.5 hours. The mixture was slowly poured into water (500 ml) under stirring. The resulting solid was filtered, washed with water and dried in a vacuum oven to give N-cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine as a tan solid (5.44 g, 79% yield). LCMS (ES): >95% pure, m/z 222 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl([O-])(=O)(=O)=O.[Li+]>>[N:15]([C@@H:12]1[CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C@H:10]1[OH:11])=[N+:16]=[N-:17]
Reactant: c1ccc(CN2CCC3OC3C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: [N-]=[N+]=N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Yield: 67 %

Procedure:
A solution of 1.2 g of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane (6.3 mmol) was refluxed in the presence of 0.62 g of sodium azide (9.5 mmol) and 3 g of lithium perchlorate (19 mmol) for 4 hs. After completion reaction mixture was evaporated and the residue was extracted with dichloromethane, washed with water and combined organic fractions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 4:1 as eluent affording 980 mg of trans-4-azido-1-benzylpiperidin-3-ol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14])(=[O:3])[CH3:2].[Br:16]Br>>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Product: CC1(C)CCSc2ccc(C(=O)CBr)cc21

Procedure:
In a manner analogous to Example 1(b), the synthesis is carried out starting from 1 g (4.42 mmol) of 6-acetyl-4,4-dimethylthiochroman and 700 mg (4.42 mmol) of bromine. After treatment and purification by chromatography on a silica column, eluting with a mixture of dichloromethane/hexane (40:60), 700 mg (53%) of expected bromo derivative are obtained in the form of a chestnut-brown oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[Cu](I)I>[C:17]1([C:2]#[C:1][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Ic1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Tert-butyl 4-ethynylpiperidine-1-carboxylate (12.5 g) and iodobenzene (12.8 g) was dissolved in THF:TEA=1:1 (v/v) mixed solvent (125 ml), then at room temperature, copper iodide (455 mg) and palladium tetrakistriphenylphosphine complex (1.38 g) were added thereto in that order, followed by stirring overnight at room temperature. The solvent was evaporated, EtOAc was added to it, and washed with aqueous 1 M hydrochloric acid solution, water and saturated brine in that order. This was dried over magnesium sulfate, and the solvent was evaporated to obtain a light brown oil. This was purified by silica gel column chromatography (eluent: hexane:EtOAc=19:1 (v/v)) to obtain tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (15.5 g) as a light brown oil.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9](=[CH:19]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9]3[CH:19]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Reactant: CNN
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=O)N1Cc2cnn(C)c2-c2cc(Cl)ccc21
Yield: 39.6 %

Procedure:
Methylhydrazine(30.56 g) was added dropwise to a mixture of 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(160.3 g) and acetic acid (75.8 ml) in methanol(1.6 liters) with stirring and cooling over a period of 10 minutes. After being stirred for 1 hour at room temperature, the mixture was filtered by sunction and the filtrate was evaporated in vacuo after addition of acetic acid (160 ml) to it. The residue was neutralized with aqueous sodium hydroxide under ice cooling. The resulting precipitate was collected by filtration, washed with water and recrystallized from aqueous methanol and then ethanol to give 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H -pyrazolo[4,3-c]-quinoline (65.84 g). The physical data of the compound was identical to that of the object compound of Example 3.