Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23](SC)[N:22]=1.C(OCC)(=O)C.Cl.[NH2:38][NH2:39]>ClCCl.C(O)CC.O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[N:22]=[C:23]2[NH:38][N:39]=[C:25]([NH2:26])[C:24]2=[CH:27][CH:28]=1
Reactant: NN
Reactant: CSc1nc(Nc2ccc(F)cc2F)ccc1C#N
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1n[nH]c2nc(Nc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a stirring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room temperature before adding a fraction of ethyl acetate and washed this organic phase with a NaHCO3 saturated solution. The combined organic phases are dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 10 mL of propanol and 2 equivalents of hydrazine hydrochloride in water are added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (67%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH2:22][O:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])=[N:19]2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH2:22][O:23][C:24]3[CH:25]=[C:26]([NH:27][C:7](=[O:9])[CH2:8][C:3]([CH2:1][CH3:2])([CH3:10])[C:4]([OH:6])=[O:5])[CH:28]=[CH:29][CH:30]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: CCC1(C)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Product: CCC(C)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2-ethyl-2-methylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 179°-180°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:4]1[N:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(Cl)cc3ccccc23)CC1
Yield: 98.8 %

Procedure:
1,3-Dichloroisoquinoline (9.30 g), N-ethylpiperazine (5.90 g) and potassium carbonate (10.0 g) were reacted in dimethylformamide (70 ml) at 70° C. for 5 hr. The reaction solution was evaporated and partitioned between ethyl acetate and water. The resulting organic phase was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 12.80 g of the title compound as a pale brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:20]=[C:21]([NH:22][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2cccc(-c3nccs3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 2,4-dinitrofluorobenzene (1.14 ml, 9.1 mmol), 2t from Example 2 (1.6 g, 9.1 mmol) and potassium carbonate (1.51 g, 10.9 mmol) in dry N-methyl-2-pyrrolidone (10 ml) is heated to 80° C. for 2 hours. The cooled mixture is poured into ice-water. The precipitate is filtered off, washed with water and dried to yield: 3.05 g (98%). Mp 1 97-203° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.2 g, 0.34 mmol) prepared in Example 72 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.39 g, 3.4 mmol), then aqueous solution (1N) of NaOH (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.18 g, 87%)
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].N.[CH2:9](Br)[CH:10]=[CH2:11].[Cl-].[NH4+]>>[CH3:6][C:5](=[O:7])[CH2:4][C:1](=[O:3])[CH2:2][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: CC(=O)CC(C)=O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCCC(=O)CC(C)=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
After 30 minutes, a powdery complex compound produced by mixing acetylacetone (15 g; 10.15 mol) with ammonia was gradually added to the solution. The mixture was stirred for about 1 hour, and then allyl bromide (18.2 g; 0.15 mol) was added to it. After stirring 1 hour, the solution was neutralized with solid ammonium chloride (15 g) and ammonia was removed by vaporiation. The reaction mixture was treated by the conventional method. The resulting oily product was distilled under a reduced pressure to obtain 10.1 g of 7-octene-2,4-dione.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:57])C=1>C(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:22]34[O:57][C:17]3([CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:36])[CH3:37])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(O[Si](C)(C)C(C)(C)C)CCC1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(O[Si](C)(C)C(C)(C)C)C21O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of Compound 209 (mixture of diastereomers, 13.0 g, 19.06 mmol) in CH2Cl2 (100 mL) cooled at zero degrees C was added mCPBA (50 percent, 7.9 g, 22.98 mmol) followed by stirring at 25° C. for one hour. The reaction mixture was diluted with CH2Cl2 ()500 mL), washed with saturated aqueous NaHCO3, dried over anahydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent ethyl ether in petroleum ether) to afford Compound 210 (9.5 g, 71 percent) as a mixture of diastereomers. Major isomer: Rf =0.38 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1730 (shoulder), 1721, 1382, 1307, 1118, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=8.6 Hz, 1 H, H1), 7.40-7.10 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.6, 1.9 Hz, 1 H, H2), 5.84-5.62 (m, 3 H, H6 and olefinic), 4.76 (dd, J=9.6, 5.7 Hz, 1 H, H10), 2.45 (dd, J=14.5, 4.6 Hz, 1 H, H7), 1.97- 1.57 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.19 (s, 12 H, Si(CH3)3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 681 (6), 624 (9), 534 (11); HRMS for C40H51NO6Si2Cs (M+Cs), calcd 830.2309, found 830.2361. Minor isomer: Rf =0.22 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1747 (shoulder), 1721, 1494, 1381, 1306, 1256, 1181, 1118, 909, 844 cm-1 ; 1H NMR (300MHz, CDCl3) δ 7.58 (d, J=8.7 Hz, 1 H, H1), 7.40-7.10 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.7, 2.5 Hz, 1 H, H2), 5.80-5.60 (m, 3 H, H6 and olefinic), 4.89 (d, J=2.4 Hz, 1 H, H10), 2.66-2.50 (m, 1 H, H7), 2.18-1.63 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3), 0.94 and 0.79 (s, 9 H, SiC(CH3)3), 0.23, 0.21 and 0.19 (s, 9 H, Si(CH3)3), 0.14 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 708 (8), 640 (13), 534 (7); HRMS for C40H51NO6Si2Cs (N+Cs), calcd 830.2309, found 830.2296.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:11][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[C:2]([Br:1])=[C:3]([O:12][CH2:6][C:5]2[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:4]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a stirred solution of 4-bromo-3,5-dihydroxy-benzoic acid (350 g, 1.5 mol) in dry DMF (2 L) were added K2CO3 (725 g, 5.25 mL) and BnBr (769 g, 4.5 mol) in one portion. The mixture was stirred at room temperature for 2 days and then filtered. The filter cake was washed with CH2Cl2. The combined filtrates were concentrated to give the title compound (225 g, 40% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.22-7.52 (m, 17 H), 5.38 (s, 2 H), 5.21 (s, 4 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.COC1C=CC=CC=1C1N=[C:37]([NH:39][CH2:40][C:41]2[O:42][C:43]([CH3:46])=[N:44][N:45]=2)C2C(=CC(C)=CC=2)N=1.C(O)(=O)C(O)=O.CC1OC(CN)=NN=1.C(N(CC)CC)C>CN(C=O)C>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:39]([CH3:37])[CH2:40][C:41]3[O:42][C:43]([CH3:46])=[N:44][N:45]=3)=[N:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Agent: Cc1nnc(CN)o1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Reaction time: 6 h
Yield: 56 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine 4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline (400 mg, 1.48 mmol) was dissolved in 10 ml dry DMF followed by the addition of C-(5-Methyl-[1,3,4]oxadiazol-2yl)-methylamine oxalate (234 mg, 1.48 mmol) then triethylamine (413 μl, 2.96 mmol). After 6 hours the reaction was complete, partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered and concentrated to an oil. Purified by flash chromatography 60% EtOAc/40% hexanes to afford the desired product a white solid. Recovered 290 mg 56% yield. LC/MS (10-99%) M/Z 348.4, retention time 2.17 minutes.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[CH2:8][CH2:9][CH2:10][C:11](O)=[O:12]>>[Br:5][C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[CH2:8][CH2:9][CH2:10][C:11]([Cl:3])=[O:12]
Reactant: O=C(O)CCCC(F)(F)C(F)(F)Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCC(F)(F)C(F)(F)Br
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
In nitrogen atmosphere, 780 g (6.33 mol) of thionyl chloride was added to 1300 g (4.87 mol) of the 6-bromo-5,5,6,6-tetrafluorohexanoic acid obtained as discussed above, followed by stirring at 50° C. for 4 hours. Then distillation was conducted under reduced pressure thereby obtaining 1223 g of the objective 6-bromo-5,5,6,6-tetrafluorohexanoyl chloride in the form of a light yellow liquid (88% yield, 91% GC purity).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][C:12]=1[O:25][CH2:26][CH3:27]>CC(N(C)C)=O>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)=[CH:13][C:12]=1[O:25][CH2:26][CH3:27]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: N#Cc1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Yield: 10 %

Procedure:
A solution of 4-fluoro-benzonitrile (36.3 mg, 0.30 mmol, 1.0 equiv; commercially available) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (96.8 mg, 0.36 mmol, 1.2 equiv; intermediate A2) in DMAc (2 mL) was heated by microwave irradiation to 210° C. for 3 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (10%) of the title compound. MS (ISP): 370.1 [M+H]+.
Reaction SMILES: C(OC(N1CCCC(CO)C1)=O)(C)(C)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][NH2:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[C:44]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:43]=[C:42]([CH2:52][CH3:53])[CH:41]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][NH:30][C:38]([NH:39][C:40]2[CH:45]=[C:44]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:43]=[C:42]([CH2:52][CH3:53])[CH:41]=2)=[O:37])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Agent: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
Racemic 3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester was resolved using the procedure of B. Wirz and W. Walther, Tetrahedron Asymm. 1992, 3, 1049. The (R) isomer was converted into (S)-3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester by the method of K. Hilpert et al., J. Med. Chem. 1994, 37, 3889. A solution of this material (119 mg, 556 μmol) in N,N-dimethylformamide (4 mL) was treated with [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (180 mg, 556 μmol) and triethylamine (155 μL, 1.11 mmol) and the mixture was stirred at room temperature for 21 hours. The mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane. The solution was washed with 1.0 N aqueous sodium hydroxide, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, elution with 70% ethyl acetate in hexane, to provide a white glassy solid (193 mg, 78%). 1H NMR (300 MHz, CDCl3) δ7.64 (s, 1H), 7.55 (s, 1H), 7.18 (s, 1H), 4.20 (s, 3H), 3.9-3.6 (m, 3H), 3.28 (m, 1H), 3.05 (m, 2H), 1.83 (m, 1H), 2.66 (q, J=8 Hz, 2H), 1.9-1.5 (m, 5H), 1.46 (s, 9H), 1.24 (t, J=8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[C:26]([CH3:30])=[N:27][NH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1n[nH]cc1-c1cccc2c1C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1n[nH]cc1-c1cccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of 2,5-dibromopyridine (50 g, 211 mmol) in tetrahydrofuran (175 mL) at 0° C. was added 2.0 M isopropylmagnesium chloride (274 mmol) at a rate to maintain the temperature below B° C. The reaction mixture was stirred at 0° C. for 45 minutes, then cooled to −15° C. A solution of methanesulfonyl chloride (32.2 g, 281 mmol) in tetrahydrofuran (40 mL) was added to the reaction mixture at such a rate to maintain the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and then quenched with waler (500 mL) and tert-butylmethylether (300 mL). The layers were separated the aqueous layer was extracted twice with tert-butylmethylether (2×200 mL). The combined organic extracts were washed with water (200 mL) and concentrated. The crude product was crystallized from toluene (110 mL), the solids were filtered to afford 29.4 g (59% yield) of 2-bromo-5-(methanesulfonyl)-pyridine. 1H NMR (300 MHz, CDCI3) δ3.13 (s, 3H), 7.73 (d, J=8.3 Hz, 1H), 8.07 (dd, J1=8.3 Hz, J2=2.7 Hz, 1H), 8.91 (d, J=2.5 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>>[Br:29][C:26]1[CH:27]=[CH:28][C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:45][CH:44]=4)=[C:15]([NH:30][C:31]4[C:32]5[CH:40]=[CH:39][C:38]([CH:41]([CH3:42])[CH3:43])=[N:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH:16]=3)[NH:24][C:23]=2[CH:25]=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]
Reactant: CC(C)c1ccc2c(Nc3cc(-c4nc5ccc(Br)cc5[nH]4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(-c4nc5ccc(Br)cc5[nH]4)ccc3Oc3ccc(O)cc3)ncnc2n1

Procedure:
A solution of the product from Example 147D (38.8 mg, 0.059 mmol) and pentamethylbenzene (87 mg, 0.5901 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation under vacuum and co-evaporated with methylene chloride/hexanes (2×). The resulting solid was triturated with hexanes (3×) and purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (22 mg, 47%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J=6.99 Hz, 6H), 3.20-3.39 (m, 1H), 6.78 (d, J=8.82 Hz, 2H), 6.95 (d, J=9.19 Hz, 2H), 7.02 (d, J=8.82 Hz, 1H), 7.36 (dd, J=8.64, 2.02 Hz, 1H), 7.55 (d, J=8.46 Hz, 1H), 7.78 (d, J=1.47 Hz, 1H), 7.91 (d, J=8.82 Hz, 1H), 8.11 (dd, J=8.64, 2.02 Hz, 1H), 8.35 (d, J=1.84 Hz, 1H), 8.94 (s, 1H), 9.03 (d, J=8.82 Hz, 1H), 9.46 (br s, 1H), 11.63 (br s, 1H); MS (APCI+) m/z 567/569 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:35][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[CH:33][CH:32]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1ccc(COC2CCCCO2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccnc1OCc1ccc(COC2CCCCO2)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (0.1 g), [4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (0.27 g) and potassium tert-butoxide (2 mL of a 1M solution in tetrahydrofuran) in N-methylpyrrolidinone (1 mL) was stirred at 50° C. After 2 h, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was washed with water and brine and evaporated to dryness. Used directly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[NH:9][CH:8]=1)[NH2:5].O.O.[Sn](Cl)Cl>CN(C=O)C.O.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(N)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 148.9 %

Procedure:
The 5-nitrotryptophan methyl ester intermediate of example 47 (0.400 g, 0.72 mmol) was dissolved in DMF (3 mL). Water (0.1 mL) and tin dichloride dihydrate (0.812 g, 3.6 mmol) were added and the mixture heated at 60° C. for 3 h and stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL), saturated aqueous NaHCO3 (20 mL) and EtOAc (50 mL). The mixture was vigorously stirred for 5 min and filtered to remove solids (wash cake with 50 mL of EtOAc). The organic layer from the filtrate was washed with water (3×50 mL) and brine (50 mL), and subsequently dried over MgSO4. Volatiles were removed under reduced pressure and the residue was triturated with TBME (10 mL) to give the 5-aminotryptophan methyl ester derivative as a white solid (0.250 g). Following saponification and purification by preparative C18 reversed-phase HPLC, the title compound of example 48 (W=H) was obtained.