Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH3:17])[CH2:3][C:4]1[S:8][C:7](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]2[O:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>CS(C)=O>[OH:28][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=1)[CH2:27][N:1]([CH2:27][CH:26]([OH:28])[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:21]=1)[CH:2]([CH3:17])[CH2:3][C:4]1[S:8][C:7](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(CC(C)N)s1
Reactant: FC(F)(F)c1cccc(C2CO2)c1
Solvent: CS(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(CC(C)N(CC(O)c2cccc(C(F)(F)F)c2)CC(O)c2cccc(C(F)(F)F)c2)s1

Procedure:
5 g of ethyl (E)-5-[(RS)-2-aminopropyl]-β-methyl-2-thiopheneacrylate and 3.7 g of m-(trifluoromethyl)phenylethylene oxide were stirred at 90° for 22 hours in 50 ml of dimethyl sulphoxide. A further 1.23 g of m-(trifluoromethyl)phenylethylene oxide were added and the mixture was heated to 90° for a further 19 hours. The working-up was carried out in analogy to Example 4. Chromatography on silica gel gave ethyl (E)-5-[(RS)-2-[bis-[(RS)-β-hydroxy-m-(trifluoromethyl)phenethyl]amino]propyl]-β-methyl-2-thiopheneacrylate; ε323 =17310.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: O=C1CN(c2cncc(Cl)n2)CCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C1CN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CCN1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 4-(6-chloropyrazin-2-yl)piperazin-2-one (132) (33 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.409 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-2-one 133 in 9 mg quantity. The compound 133 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.84 (s, 1H), 8.95 (d, J=2.07, 1H), 8.64 (d, J=1.95, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H, 7.53 (m, J=2.92, 1H), 6.56 (m, J=1.70, 1H), 4.18 (s, 2H), 3.89 (m, J=5.36 2H); MS m/z 294.9 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH3:14]O>>[OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 0 °C

Procedure:
7.1 30 g of (2R,4R)-4-hydroxy pyrrolidine-2-carboxylic acid are suspended in 200 ml of methanol and cooled to 0° C. Thionyl chloride (18.1 ml) is subsequently added dropwise at the same temperature distributed over an hour. The reaction mixture (RM) is warmed to room temperature (RT) over 12 h, during which a clear solution forms. The solvent is removed in vacuo, and the residue obtained is recrystallised from ether, giving 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2-carboxylate; Rt.: 0.386 min; [M+H]+146.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[N:10]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH3:18])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:15][CH2:16][C:11]=3[N:10]([C@@H:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(c1ccc(F)cc1)n1nc(-c2ccc(F)cc2)c2c1CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccc(F)cc1)n1nc(-c2ccc(F)cc2)c2c1CCN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a mixture of 3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (enantiomer 1) (7e) (0.120 g, 0.353 mmol) and triethylamine (0.135 ml, 1.06 mmol) in CH2Cl2 at 0° C. was added methanesulfonyl chloride (49 mg, 0.424 mmol) and the mixture was stirred at 25° C. for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 96 mg of 3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (9a).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.O>CN(C=O)C>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:4]([CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)(=[O:7])=[O:6])=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)nn2)cc1
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.42 g (10.5 mmol)) in 10.0 ml of DMF, N-methyl-p-toluenesulfonamide (1.85 g (9.99 mmol)) was added under ice-cooling and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3,6-dichloropyridazine (1.49 g (10.0 mmol)) was added. The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.41 g (47%) of the title compound as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CC3)CC1)O2

Procedure:
Compound 122 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (bromomethyl)cyclopropane and conditions outlined in procedure V. M.p.=161-164° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.95 (m, 4H), 2.5 (t, 2H), 2.35 (d, 2H), 2.15 (d, 2H), 1.9 (t, 2H), 0.9 (s, 1H), 0.55 (d, 2H), 0.15 (s, 2H); LCMS: 356 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:6]=3[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCCCc3ccccc3)c2n1
Reactant: C1CNCCN1
Product: c1ccc(CCCSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-morpholino-8-(3-phenylpropyl-thio)-pyrimido-[5,4-d]-pyrimidine (m.p.: 127°-129° C.) and piperazine.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1ccccc1Br
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3OC)c2)cn1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromoanisole
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[S:41][C:40]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:36][C:37]1[S:41][C:40]([S:42]([NH:45][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([N:8]3[C:7](=[O:20])[C:6]4[CH:21]=[C:2]([F:1])[C:3]([NH:22][CH3:23])=[CH:4][C:5]=4[O:10][CH2:9]3)=[CH:12][CH:13]=2)(=[O:44])=[O:43])=[CH:39][CH:38]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)O)cc1)CO2
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 160 %

Procedure:
To 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (0.02 g, 0.063 mmol) in methylene chloride (2 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.013 g, 0.068 mmol), N,N-dimethylpyridin-4-amine (0.008 g, 0.068 mmol) followed by 5-chlorothiophene-2-sulfonamide (0.014 g, 0.07 mmol) and the mixture stirred at room temperature for 8 hr. The solvent was removed and the product purified on HPLC (C18) to give N-(5-chlorothiophen-2-ylsulfonyl)-4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e] [1,3] oxazin-3(4H)-yl) benzamide (0.05 g, 15%). RP-HPLC: 2.58 min; ES-MS (M+H)+=496.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 7.1 (d, 1), 7.3 (d, 1), 7.4 (d, 2), 7.7 (d, 1), 7.9 (d, 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:14][N:15]=[CH:16]OCC.[OH-].[Na+]>C(O)C>[CH3:14][NH:15][CH:16]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC=NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC=Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
A suspension of 0.8 gm of 4-(4-aminophenyl)-1-H-imidazole and 1.86 gm of ethyl N-methyl-formimidate hydrochloride [F. H. Suydam et al., J. Org. Chem. 34, 292 (1969)] in 20 ml of anhydrous ethanol was stirred at room temperature for two days. The clear solution was evaporated to dryness, and the oily residue was dissolved in water. The solution so obtained was adjusted to pH 10 with 10% NaOH. The product which separated was extracted with ethyl acetate, the organic solution was evaporated to dryness, and the product obtained was purified through its hydorchloride salt to give 0.35 gm of the desired compound as crystalline solid.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.O>P(Cl)(Cl)(Cl)=O>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([C:16]2[O:1][C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)=[N:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnn(CC(=O)NCC(=O)c2cccc(C(F)(F)F)c2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(Cc2ncc(-c3cccc(C(F)(F)F)c3)o2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
The compound (0.73 g) obtained in Example 124a was dissolved in phosphorus oxychloride (10 mL), and the mixture was stirred at 110-130° C. overnight with heating. The reaction mixture was cooled to room temperature, slowly poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.50 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[NH3:31]>O1CCOCC1>[NH2:31][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(Cl)c4C3=O)cc2)CC1
Reactant: N
Solvent: C1COCCO1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl {trans-4-[4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate, from Preparation 1, (5.29 g, 12.3 mmol) in 0.5M ammonia in p-dioxane (120 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, diluted into EtOAc (1 L), washed with water, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as an off-white solid, 5.04 g. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.16 (br s, 1H), 7.23 (d, 2H), 7.16 (d, 2H), 5.75 (br s, 1H), 4.63 (m, 2H), 3.98 (m, 2H), 3.64 (s, 3H), 2.44 (m, 1H), 2.21 (m, 2H), 1.81 (m, 5H), 1.42 (m, 2H), 1.10 (m, 2H). m/z=411.3 (M+1). IC50 34.5 nM (range 30-40 nM).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12](Cl)=[O:13]>O.[OH-].[Na+].C1COCC1>[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:13]
Reactant: NCCCCC(=O)O
Reactant: CC(C)CC(CCl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(CCl)C(=O)NCCCCC(=O)O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
5-Aminovaleric acid (3.2 g) is dissolved in 15 ml of water containing 1.09 g of sodium hydroxide. This is cooled to 5° C. and 2-[chloromethyl]-4-methylvaleryl chloride in 30 ml of THF is added dropwise. The pH is maintained at 8-9 by the dropwise addition of 1.09 g sodium hydroxide in 20 ml of water as needed. After stirring for about 16 hours the reaction mixture is diluted with 30 ml of water and concentrated in vacuo to remove THF. The aqueous layer is washed with ether, and acidified with 10% hydrochloric acid. Product is extracted with ethyl acetate. The ethyl acetate is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 4.3 g of product. Product is purified by chromatographing on 200 g of silica using as the solvent system 500 parts ether: 10 parts methanol: 5 parts acetic acid, yielding 2.0 g of material.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:4][N:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:11]1[C:10]2[CH:9]=[N:8][C:7]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: ClCCCBr
Reactant: Cc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc3c4ccccc4n(CCCCl)c3cn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 3-(3-methyl-1,2,4-oxadiazol-5-yl)-β-carboline (2.00 g, 0.008 mol) in anhydrous DMF (50 mL) was added 50% sodium hydride in mineral oil (0.42 g, 0.01 mol). The mixture was stirred for 1 h at room temperature, and then carefully added to a solution of 1-bromo-3-chloropropane (1.39 g, 0.0088 mol) in anhydrous DMF (150 mL). The resulting mixture was stirred at ambient temperature over night. The reaction mixture was concentrated in vacuo, and the crude product was purified on a silica gel column (Eluent: CH2Cl2 /methanol (9:1)) to give the title compound 2.11 g (81%). M.p. 180°-185° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20][CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH3:17][C:14]([O:13][C:11](=[O:12])[NH:10][C:9](=[N:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[N:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 163.1 %

Procedure:
To a solution of the compound prepared in Example 27 (0.045 g, 0.056 mmol) in ethanol (10 mL) was added Pd/C (20% by wt, 0.010 g). The reaction was stirred under an atmosphere of hydrogen (40 psi) at room temperature for 2 h. The reaction mixture was filtered through diatomaceous earth and the filtrate concentrated to afford the title compound (0.03 g, 69%) as a pale green solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N(c2cccc(C#N)c2)C2CCCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Yield: 93.8 %

Procedure:
N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea (3.2 g, 7.76 mmol) was stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at ambient temperature for 1.5 h. The reaction mixture was evaporated and the residue taken up in water. The aqueous suspension was made basic (pH 11) by the dropwise addition of aqueous sodium hydroxide solution (50%). The basic aqueous suspension was extracted with ethyl acetate (2×); the ethyl acetate extracts were washed with brine, dried (Na2SO4), and evaporated to give N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.17 g, 7.28 mmol, 94%). This sample was in all respects identical to the sample of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea prepared in Example 5.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH3:13])=[CH:7][C:5]=2[CH:6]=1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:12][CH3:13])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][Cl:15])=[CH:20][CH:21]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=O)c1ccc2oc(Cl)cc2c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Yield: 72.3 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(2-chlorobenzofuran-5-yl)propan-1-one (140 mg, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (371 mg, 2.0 eq) to give 220 mg desired product (72%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.16 & 7.10 (d, J=8.6 Hz, 2H), 7.00 & 6.99 (d, J=8.4 Hz, 1H), 6.90 & 6.81 (d, J=8.6 Hz, 2H), 6.76 & 6.70 (d, J=8.8 Hz, 2H), 6.52 & 6.44 (d, J=9.0 Hz, 2H), 6.45 (s, 1H), 4.73 & 4.48 (s, 1H), 4.26 & 4.08 (t, J=6.0 Hz, 2H), 3.83 & 3.72 (t, J=6.0 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:21][CH2:19][CH3:20])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: CCN
Reactant: O=C(Nc1ccc(Cl)nc1Cl)c1cccnc1Cl
Product: CCNc1ncccc1C(=O)Nc1ccc(Cl)nc1Cl
Temperature: 165 °C
Yield: 59.8 %

Procedure:
A mixture of N-(2,6-dichloro-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (12.0 g, 39.8 mmol), ethylamine (3.6 g, 80.7 mmol), and 30 mL of xylenes in a sealed vessel was heated at 165° C. for 6 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate to give 7.4 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:16])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc(Br)c(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To 6-bromo-5-fluoro-1H-indole (9.4 g, 43.9 mmol) in DMF (50 mL) at −78° C. was added chlorosulfonyl isocyanate (4.6 mL, 53 mmol). After complete addition the mixture was allowed to warm to room temperature and stir for 2 hrs. The reaction mixture was poured into ice water and stirred for 30 minutes. The precipitate was collected on a filter, washed with ice water and dried in a vacuum oven to give 6-bromo-5-fluoro-1H-indole-3-carbonitrile as a light-beige solid (10.5 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[NH:18]1[C:22]([CH2:23][C:24](O)=[O:25])=[N:21][N:20]=[N:19]1>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[NH:1][C:24](=[O:25])[C:23]([C:22]1[NH:21][N:20]=[N:19][N:18]=1)=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Product: O=c1[nH]c2cc(F)c(Cl)cc2c(-c2ccccc2)c1-c1nnn[nH]1

Procedure:
The title compound was prepared in analogy to example 102 step A from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone (prepared as described in example 105 step D) and 2-(1H-tetrazol-5-yl)acetic acid. Off-white solid. MS (ESI): 342.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]=[C:19]([NH:22][C:29]([NH:28][CH2:27][C:26]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:24]([Cl:23])[CH:25]=2)=[O:30])[S:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC1C[C@H](c2csc(N)n2)N(C(=O)OC(C)(C)C)C1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CC(=O)OC1C[C@H](c2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
(R)-4-Acetoxy-2-(2-amino-thiazol-4-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (327 mg, 1 mmol) was combined with 3,4-dichlorobenzyl isocyanate (303 mg, 1.5 mmol) in DCM (10 mL) and stirred overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM/MeOH/NH4OH) to afford (R)-4-acetoxy-2-{2-[3-(3,4-dichloro-benzyl)-ureido]-thiazol-4-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester.