Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: O=C(CCc1ccccc1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (described in Example 8b) and 3-phenylpropionyl chloride, the title compound was obtained as a white solid (46%) by crystallization from ether-ethyl acetate, mp 149.0°-50.0° C.; MS(CI): 437 (M+H); NMR (300 Hz, DMSO-d6): 1.20-1.40(m, 2H), 1.55-1.69(m, 2H), 2.17-2.40(m, 4H), 2.44(s, 2H), 2.79(t, 2H, J=8.1 Hz), 2.85-2.98(m, 2H), 3.33(m, 2H), 3.53(m, 1H), 4.30(s, 1H), 6.85-6.98(m, 4H), 7.10-7.32(m, 9H), 7.66(d, 1H, J=7.5 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([Mg]Cl)#[CH:10]>C1COCC1>[OH:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]#[CH:10]
Reactant: O=Cc1cccnc1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cccnc1

Procedure:
3-Hydroxy-3-(3-pyridinyl)-1-propyne was prepared according to Method A above using 3-pyridine carboxaldehyde (0.428 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 440 mg, 83%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][S:5]([N:8]([CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6].[OH-].[Na+].Cl>CO.O>[CH3:24][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[S:5]([CH2:4][C:3]([OH:25])=[O:2])(=[O:6])=[O:7]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of methyl-2-({methyl[(4'-cyanobiphen-4-yl)methyl]amino}-sulfonyl)acetate (200 mg, 0.56 nunol) in methanol (2 ml) and tetrahydroflran (5 ml) was added 1 M aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with water (10 ml), acidified to pH 2 with 2 M aqueous hydrochloric acid and extracted with dichloromethane (2×30 ml). The combined organic layers were dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (130 mg).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:23])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[CH3:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([CH3:13])[C:3](=[O:24])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:11]2=[O:23])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(O)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C2(C)C(=O)Nc3ccccc3C2=O)ccc1O
Yield: 50.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-hydroxy-3-methoxy-phenyl)-propionyl amino]-benzoic acid methyl ester (1.00 g, 3.04 mmol) and LiHMDS (9.12 mmol, 1M solution in THF). After normal workup, the objective compound (0.46 g, 51%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.81 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 5.55 (br s, 1H, OH), 6.76-6.87 (m, 4H, ArH), 7.12 (t, J=7.73 Hz, 1H, ArH), 7.49 (t, J=7.32 Hz, 1H, ArH), 7.90 (d, J=8.12 Hz, 1H, ArH), 8.17 (br s, 1H, NH); m.p. 168-169° C.; MS(EI) m/e 297 [M+], 178, 150; HRMS m/e cacld. for C17H15N1O4 297.1002, found 297.0999.
Reaction SMILES: [CH2:1]([C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:36]>O>[NH2:30][C:28](=[O:29])[CH2:27][O:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:33])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:34])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]=3[O-:15])=[N:17][S:18](=[O:31])(=[O:32])[C:19]=2[CH:25]=1.[Na+:36]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A suspension of the product of Example 27I in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.159 mL, 0.158 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.075 g, 64% two steps). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.56 (m, 1 H) 0.69 (m, 3 H) 0.87 (m, 1 H) 1.07 (m, 2 H) 1.28 (m, 1 H) 1.38 (m, 3 H) 1.57 (m, 1 H) 1.71 (m, 1 H) 2.13 (m, 1 H) 4.48 (m, 2 H) 7.29 (m, 6 H) 8.05 (m, 1 H) 15.40 (m, 1 H). MS (ESI−) m/z 482 (M−H)−.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[O:18])=[C:11]([Cl:31])[CH:10]=1)(C(C)(C)C)(C)C>Cl>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([OH:25])=[O:24])=[O:18]
Reactant: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl
Agent: Cl
Product: O=C(CCc1ccc(O)cc1Cl)NCc1ccccc1C(=O)O
Yield: 42.1 %

Procedure:
A solution of methyl 2-({[3-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)propanoyl]amino}methyl)benzoate (460 mg) in concentrated hydrochloric acid (10.0 mL) was stirred at 50° C. for 4 days. The reaction mixture was concentrated under reduced pressure, then to the residue was added chloroform-methanol, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2-({[3-(2-chloro-4-hydroxyphenyl)propanoyl]amino}methyl)benzoic acid (140 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>C1COCC1>[CH:11]1([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCCC2)nc1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 4.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (7.01 g, 44.4 mmol) in THF (30 mL) and cyclopentanol (3.9 g, 45.3 mmol) was added sodium hydride (1.3 g, 54.2 mmol) portionwise with stirring over ˜30 sec with ice-bath cooling at 0° C. After stirring at 0° C. for 5 min, the ice bath was removed and the reaction was stirred at rt for 3 h. It was then concentrated in vacuo and the residue was dissolved in DCM and washed extensively with 1 M NaHCO3 and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 9:1 Hexane:Ethyl Acetate) to obtain pure 2-cyclopentyloxy-5-nitro-pyridine (0.4 g, 4%). 1H-NMR (300 MHz, CDCl3): δ 9.07 (s, 1H), 8.32 (m, 1H), 6.74 (d, 1H), 5.53 (m, 1H), 2.00 (m, 2H), 1.81 (m, 4H), 1.66 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)C(O)=O.O[C:15]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:16]=1C(O)=O.ClC1C=CC([N+]([O-])=O)=CC=1.[OH-].[Na+]>[C].[Pd]>[CH:20]1[C:21]([NH2:24])=[CH:22][CH:23]=[C:15]([O:1][C:2]2[CH:10]=[CH:6][C:5]([NH2:11])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: Nc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
A 5-hydroxy-2-nitrobenzoic acid derivative (e.g. sodium 5-hydroxy-2-nitrobenzoate) or a 2-hydroxy-5-nitrobenzoic acid derivative (e.g. sodium 2-hydroxy-5-nitrobenzoate) is reacted with 4-chloronitrobenzene in the presence of an alkali (e.g. sodium hydroxide), followed by hydrogenation using palladium-carbon, to give the corresponding 4,4′-diaminodiphenyl ether derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:44])[C@H:7]([NH:25][C@H:26]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:4])[CH3:3].C(O)C.O>[Pd].C(OCC)(=O)C>[CH3:1][C:2]([O:5][C:6](=[O:44])[C@H:7]([NH:25][C@H:26]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccc(N)c1
Temperature: 25 °C

Procedure:
200 mg of 4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-(S)-[[(3-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 30 where the protecting group Rp, 1,1-dimethylethyl was not removed following the condensation reaction seen in Scheme 1, was added to ethanol:H2O (20:1). 10 mL of ethyl acetate was added and the mixture was stirred with heating until the solid dissolved. The mixture was cooled to RT and 20 mg of 10% palladium over activated carbon was added. The mixture was purged with nitrogen. The mixture was purged with hydrogen, and stirred under hydrogen for 3 h. The mixture was filtered and washed with ethyl acetate. The solvents were removed by evaporation and the residue was purified by reverse phase H.P.L.C. to give a white solid; 83 mg
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:15])([CH2:13]O)[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>C(Cl)Cl.CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:13][N:38]=[N+:39]=[N-:40])([F:15])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CO)C[C@H]1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-4-fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (1.76 g, 4.98 mmol) in CH2Cl2 (30 mL) and few drops of NEt3 was stirred at RT for 10 min then methanesulfonyl chloride (0.39 mL, 5.03 mmol) was added. The reaction was stirred at RT for 30 min then poured into water and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated. The residue (2.25 g, 4.21 mmol) was dissolved in DMF (50 mL) and sodium azide (1.69 g, 26.1 mmol) was added. The solution was stirred for 16 hours at 80° C. then was cooled to RT, poured into water and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 379 [M+H]+; tR (HPLC conditions f): 2.44 min.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28]Cl)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([O:40][CH3:41])(=[O:39])[CH2:37][SH:38]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:41][O:40][C:36](=[O:39])[CH2:37][S:38][CH2:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCl
Reactant: COC(=O)CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CSCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To 2-(4-chloro-2-chloromethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.23 mmol) in dimethyl formamide (2 ml) was added potassium carbonate (0.070 g, 0.51 mmol), tetrabutylammonium iodide (0.088 mg, 0.24 mmol) and finally methyl thioglycolate (0.02 ml, 0.25 mmol). The reaction was stirred at 50° C. for 19 hours. The reaction was diluted with ethyl acetate and washed with pH 7 phosphate buffer (0.05 M) and aqueous saturated sodium chloride. The organic layer was dried over magnesium sulfate and the title compound was isolated by chromatography on silica gel (0.046 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]1[C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[OH:19][CH2:18][C@@H:12]1[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 46 h
Yield: 92.3 %

Procedure:
To a stirred solution of (−)-(2S,3R)-1-((benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid (6.05 g, 21.8 mmol) in anhydrous THF (80 mL) was added BH3.THF (1 M in THF, 43.6 mL, 43.6 mmol) dropwise over 10 min at rt under nitrogen. The reaction mixture was then stirred at rt for 46 h. After this time, the reaction was quenched by the slow addition of ice cold water (10 mL) followed by 2 N HCl (20 mL). The resulting mixture was stirred at rt for 30 min and then extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 20% to 50% EtOAc/CH2Cl2 to afford the title compound as a colorless oil (5.30 g, 92%). ESI MS (M+H) 264.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1>[C:7]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1NCCN1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCNC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension, cooled to 0°C, of imidazolidin-2-one (17.2 parts by weight) in tetrahydrofurane (200 parts by volume) was treated dropwise over the course of one hour, with pivaloyl chloride (24.2 parts by weight) at the same temperature. The mixture was then stirred for a further 3 hours at 0°C, triethylamine (27.8 parts by volume) was subsequently added dropwise while cooling with ice water, and the mixture was then left to stand overnight at room temperature. The triethylamine hydrochloride which had separated out was then filtered off, the filtrate was completely concentrated in vacuo by means of a rotary evaporator and the residue was further warmed for 1 hour, in vacuo, in a bath at 60°C. The oily product (crude yield: 32.8 parts by weight) was further processed, as it was. When an attempt was made to distill the substance in vacuo, severe decomposition occurred.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2(Cl)[CH2:15][CH2:14]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:17]C1(C2C=C(C(OCC)=O)N(C)N=2)CC1.ClN1C(=O)CCC1=O>>[Cl:1][C:2]1[C:3]([C:13]2([F:17])[CH2:15][CH2:14]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C2(F)CC2)nn1C
Reactant: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Agent: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1c(Cl)c(C2(F)CC2)nn1C

Procedure:
The preparation was carried out analogously to the preparation of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate using ethyl 3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate and 3 eq of N-chlorosuccinimide
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[CH3:23][O:22][CH2:21][CH2:20][N:18]([CH3:19])[CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1
Reactant: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 270. NMR (CDCl3): 1.60-1.68 (m, 2H, CH2), 1.77-1.79 (m, 2H, Ch2), 2.06-2.11 (m, 2H, CH2), 2.34 (s, 3H, CH3), 2.42-2.48 (m, H, CH), 2.67-2.70 (m, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.37 (s. 3H, CH3), 3.47-3.50 (m, 2H, CH2), 3.77 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 3.99-4.01 (m, 4H, 2×CH2), 7.16 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=484.26
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:18][CH:17]([C:19]([OH:21])=O)[CH:16]([C:22](=[O:34])[NH:23][C:24]4([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][CH:25]4[CH:27]=[CH2:28])[CH2:15]3)[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][NH:42][CH:43]=[CH:44][CH2:45][CH2:46][CH2:47][CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([O:31][C:29]([C:24]1([NH:23][C:22]([CH:16]2[CH2:15][CH:14]([O:13][C:11]3[CH:10]=[C:9]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:12]=3)[CH2:18][CH:17]2[C:19](=[O:21])[N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])[CH3:41])=[O:34])[CH2:26][CH:25]1[CH:27]=[CH2:28])=[O:30])[CH3:33]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 94.2 %

Procedure:
The acid 17c (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (340 mg, 3.0 mmol) DIEA (1.29 g, 10.0 mmol) and HATU (1.1 g, 3 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound (1.2 g, 93%), (M+H)+637.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][CH2:18][C@@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=[O:22])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:9]([NH:17][CH2:18][C@@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Benzyl alcohol (0.31 g, 3.0 mmol) was added to a stirred mixture of (S)-3-(benzoylaminomethyl)-5-methylhexanoic acid 4 (0.78 g, 3.0 mmol), 1,3-dicyclo-hexylcarbodiimide (0.61 g, 3.0 mmol), and 4-dimethylaminopyridine (0.36 g, 3.0 mmol) in dichloromethane (40 ml) and the mixture was stirred for 18 hours. The reaction mixture was, filtered and concentrated in vacuo. The residue was chromatographed (SiO2, heptane-ether, 1:0 to 75:25) to give 5(0.83 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.C([Mg]Br)#C.O.O1C[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([C:11](=[O:12])[C:26]#[C:27][CH3:28])=[C:4]2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: C#C[Mg]Br
Solvent: O
Product: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.93 g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added ethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was dissolved in dichloromethane (50 mL) and manganese dioxide (5 g) was added. This slurry was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to a solid. This solid was purified by flash chromatography (dichloromethane) to give 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.63 g, 62% for two steps) as a white solid. 1H-NMR (CDCl3): δ 8.52 (d, 1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s, 1H); 19F-NMR (CDCl3): δ 111.69; MS m/z 299 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-])=O)[CH:24]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:27])=[CH:28][CH:29]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(N2CCOc3ccc(-c4ccc(N)c([N+](=O)[O-])c4)cc3C2)c2ccccc2n1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nc(N2CCOc3ccc(-c4ccc(N)c(N)c4)cc3C2)c2ccccc2n1
Yield: 94.4 %

Procedure:
To a solution of 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-2-nitroaniline (380 mg, 0.89 mmol) in THF (12 mL) was added palladium on carbon (wet, 100 mg). The resulting suspension was subjected to an atmosphere of hydrogen at 40 psi for 5 h. The catalyst was removed by filtration through celite, and the filtrate was concentrated to provide 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine (333 mg, 0.84 mmol, 94% yield) as a yellow-orange solid. MS (EI) for C24H23N5O: 398 (MH+).