Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:20]([Cl:26])=[CH:21][N:22]=[CH:23][C:24]=3[Cl:25])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3]
Reactant: NCc1ccccc1Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccc1Cl
Yield: 58 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 2-chlorobenzylamine to give Compound 31 (0.15 g, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing p-toluenesulfonyl chloride (60 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 57.5 mg of the product: MS m/z 489 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[ClH:13].[CH3:14][CH2:15]O>>[ClH:13].[CH2:14]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])[CH3:15]
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: CCO
Agent: Cl
Product: CCN(CC(=O)O)c1ccc(O)cc1
Yield: 70 %

Procedure:
To a suspension of 4-hydroxyphenylglycine (18.00 g, 0.11 mol) in EtOH (100 mL) was added 20% ethanolic HCl (30 mL). The mixture was heated at reflux for 14 h, then was allowed to cool and was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic extract was concentrated in vacuo to afford the title compound (15.00 g, 70%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C1CCCCC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:28]([O-:33])=[O:29])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)-phenylacetic acid in chloroform with 1.5 equivalents of cyclohexene is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]1[CH:13]=[C:12]([CH3:14])[O:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: Cc1cc(CBr)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(I)cn2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
4-Iodo-1H-pyrazole (0.826 g, 4.26 mmol) (1), 3-(bromomethyl)-5-methylisoxazole (0.75 g, 4.26 mmol) and potassium carbonate (1.18 g, 8.52 mmol) were added to dry DMF (8 ml) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (20 ml) and washed with water, brine and dried. The organic solution was concentrated in vacuo and the residue purified by flash silica chromatography (20% ethyl acetate in hexane). The pure fractions provided the title compound as a white powder (0.7 g, 56.8%). 1H-NMR (500 MHz, CDCl3) 2.4 (s, 3H), 5.33 (s, 2H), 5.92 (s, 1H), 7.51 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:25].[K+].[K+]>Cl>[C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](=[O:25])[NH:18][N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1
Agent: Cl
Agent: [K+]
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(=O)[nH]n1
Reaction time: 2 h

Procedure:
A stirred solution of 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl-6-chloropyridazine (10.0 g, 0.03 mol) in 18% hydrochloric acid (60 ml) was heated under reflux for 8 hours. Potassium carbonate was added to the cold solution to take it to pH 10, and after allowing the mixture to stand for 2 hours the solid was collected by filtration and washed with water to give a crude hydrate (10.35 g). Recrystallisation from ethyl acetate gave 6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone (7.42 g) as a colourless solid, m.p. 161.5°-163.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([C:34]#[N:35])[N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[Cl:33][C:32]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:19][CH2:20]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[N:28][C:29]([C:34]#[N:35])=[N:30][CH:31]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1ncc(Cl)c(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3nc(C#N)ncc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 70 °C
Yield: 15.1 %

Procedure:
2-Bromo-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (168 mg, 0.421 mmol), 4-amino-5-chloropyrimidine-2-carbonitrile (65 mg, 0.421 mmol) Pd2(dba)3 (77 mg, 0.084 mmol), xantphos (48.7 mg, 0.084 mmol) and cesium carbonate (274 mg, 0.841 mmol) were suspended in dioxane (4206 μl) at rt. The reaction was degassed using the vacuum/purge method (4 times) to put the reaction under N2. The reaction was heated to 70° C. for 4 h before cooling to room temperature, diluting with EtOAc, filtered through celite and concentrated. The crude product was purified by column chromatography (40 g SiO2, 0 to 100% EtOAc-hexane gradient elution) to afford 30 mg of 2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>CCOCC>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH:24]2[CH2:25][CH2:26][CH2:27][N:23]2[CH3:22])=[CH:33][N:32]=1
Reactant: CN1CCCC1c1ccc(N)nc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCCC1c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1
Temperature: 125 °C

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (696 mg, 2.12 mmole), dimethylformamide (15 mL), and 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (375 mg, 2.12 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a yellow solid, 580 mg, (58%), mp 174-206° C. dec; MS (ES+): m/z 475.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=[S:12].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[N:34][S:35][CH:36]=2)=[CH:28][CH:27]=1)=O>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:21])([C@H:10]([C:11]1[S:12][CH:23]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:33]=[N:34][S:35][CH:36]=3)=[CH:30][CH:31]=2)[N:13]=1)[CH3:14])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: O=C(CBr)c1ccc(-c2csnn2)cc1
Reactant: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](c1nc(-c2ccc(-c3csnn3)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutyramide (19.7 mg) and 2-bromo-1-[4-(1,2,3-thiadiazol-4-yl)phenyl]ethanone (27.4 mg) in acetonitrile (3.0 ml) was stirred at room temperature for 1.0 hour. The solution was diluted with ethyl acetate (10 ml), washed with saturated sodium hydrogen carbonate solution (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified by silica gel column chromatography developed by hexane-ethyl acetate (1:1) to give (2R,3R)-2-(2,4-difluorophenyl)-3-{4-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-2-yl}-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a pale yellow solid (14.1mg). EI-MS: m/z 497 (M+); 1H-NMR (CDCl3): δ 1.26(3H, d, J=6.9 Hz), 4.10(1H, q, J=6.9 Hz), 4.31(1H, d, J=14.3 Hz), 4.92(1H, d, J=14.3 Hz), 6.04(1H, s), 6.76˜6.87 (2H, m), 7.48˜7.58(1H, m), 7.58(1H, s), 7.68(1H, s), 7.92(1H, s), 8.06(2H, d, J=8.4Hz), 8.16(2H, d, J=8.4 Hz), 8.73(1H, s).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([O:46]C)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:25])[OH:24])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[OH-].[Na+]>CO>[NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:24])[OH:25])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CN)C(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Two grams (g) of BOC-Gly-D-Arg-Gly-Asp-Phe-Val-OMe (SEQ ID NO 1) were first dissolved in 60 milliliters (ml) of methanol to which was added 1.5 ml of 2 N sodium hydroxide solution to form an admixture. The admixture was then stirred for 3 hours at 20 degrees C (20 C). After evaporation, the residue was taken up in water, acidified to pH 3 with diluted HCl and extracted with ethyl acetate. The extract was dried over Na2SO4, evaporated again and the resultant BOC-Gly-D-Arg-Gly-Asp-Phe-Val-OH (SEQ ID NO 2) was stirred at 20 C for 2 hours with 20 ml of 2 N HCl in dioxane. The resultant admixture was evaporated to obtain H-Gly-D-Arg-Gly-Asp-Phe-Val-OH (SEQ ID NO 3) that was subsequently dissolved in a mixture of 1800 ml of dichloromethane and 200 ml of dimethylformamide (DMF) followed by cooling to 0 C. Thereafter, 0.5 g of dicyclohexylcarbodiimide (DCCI), 0.3 g of 1-hydroxybenzotriazole (HOBt) and 0.23 ml of N-methylmorpholine were added successively with stirring.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH3:32][CH:33]([CH3:43])[CH2:34][C:35]([O:37][CH:38](I)[CH:39]([CH3:41])[CH3:40])=[O:36]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:38]([O:37][C:35](=[O:36])[CH2:34][CH:33]([CH3:43])[CH3:32])[CH:39]([CH3:41])[CH3:40])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(C)CC(=O)OC(I)C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(OC(=O)CC(C)C)C(C)C)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 41 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-acetoacetoxymethyl-ceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, 5.0 g of 1-iodo-2-methylpropyl 3-methylbutyrate is added dropwise, followed by stirring for further 5 minutes. Thereafter, following the procedupe of Example 1, 2.5 g of the title compound is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[C:10]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Oc2ccccc2)c(Br)c1
Temperature: 80 °C
Yield: 91 %

Procedure:
Phenol (0.416 g, 4.42 mmol), 3-bromo-2-chloro-5-nitropyridine (Combi-Blocks, CAS [5470-17-7], 1 g, 4.21 mmol) and cesium carbonate (1.372 g, 4.21 mmol) were combined in DMSO (8 mL) and heated at 80° C. for 30 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel, 0-30% ethyl acetate in hexanes) afforded the title compound (1.13 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:48][NH:47][N:46]=2)=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:48][N:47]([C:13](=[O:15])[CH2:12][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH3:16])[N:46]=2)=[CH:43][CH:44]=1
Reactant: CC(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CC(=O)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.1 %

Procedure:
To a stirred mixture of 3-((4-chlorophenyl)sulfonyl)butyric acid (1.85 gram, 7.00 mmol), diisopropylethylamine (3 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.50 gram, 15.7 mmol) was added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.00 gram, 11.7 mmol) and the resulting mixture was stirred for 16 hours at room temperature. After concentration in vacuo the resulting residue was purified by flash chromatography (petroleum ether/diethyl ether=1/2 (v/v), followed by diethyl ether) to give 3-(4-chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro-4-phenyl-1H-pyrazole (3.69 gram, 63% yield) as a diastereomeric mixture. Melting point: amorphous.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:25][C:26]1[C:34]2[C:33](Cl)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[Br:25][C:26]1[C:34]2[C:33]([N:19]3[CH2:18][CH2:17][C:16]([CH3:22])([C:14]([NH:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=5)[CH:8]=4)=[O:15])[CH2:21][CH2:20]3)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 100 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (36 mg, 0.1 mmol) in isopropanol (1 mL), was added to 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine from step A (24 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 100° C. for 10 minutes under microwave condition, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[N:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1nnn(Cc2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3nnn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 2-benzyl-2H-tetrazol-5-ylamine (Journal of the American Chemical Society 76, 923 (1954)). The title compound was obtained as a yellowish solid (Yield=29%). MS ISP (m/e): 357.1 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:20])[CH2:18]Br)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
1.1 Using general procedure A, (R)-(+)-3-(tert-butyloxycarbonylamino)-pyrrolidine was alkylated with bromoacetic acid ethyl ester to give ((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-acetic acid ethyl ester. Off-white solid. MS 273.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[S:8][C:4]=2[CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:9]([C:7]1[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=3[CH:6]=1)=[O:11])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1

Procedure:
900.0 mg (3.50 mmol) of 6-bromo-1-benzothiophene-2-carboxylic acid (Example 10A), 697.0 mg (3.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1597.1 mg (4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamine and 8.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid, and the solution is then concentrated. Recrystallization from methanol/ethanol (1:10) affords 594 mg (42% of theory) of the title compound in the form of yellowish-brown crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-acetamidobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (5.6 mg) with purity >90%. LCMS (pos) m/z 384.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[F:37][C:33]1[CH:32]=[C:31]([C:8]2([CH2:11][CH2:12][N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][CH:16]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH3:30])[CH2:17]4)[CH2:9][CH2:10][N:5]([C:3]([CH:2]([NH:1][C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:38][CH3:39])=[O:4])[CH2:6][CH2:7]2)[CH:36]=[CH:35][CH:34]=1
Reactant: CCC(N)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C(C)(C)C)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 54 %

Procedure:
N-[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-2,2-dimethyl-propionamide was obtained from treating[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.049 g, 0.09 mmol, 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, N-[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-2,2-dimethyl-propionamide (0.030 g, 54%) as an oil. ES-LCMS m/z 616 (M+1).