Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:6]=1)=[O:4].O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]([NH:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:16])[CH:18]=1
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1

Procedure:
1,6-dihydro-1-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.39 g, 1.3 mmol) was hydrolysed in a mixture of methanol (3.9 ml), water (3.9 ml), and 15% aqueous sodium carbonate (3.9 ml) at 65°-70° C. for 1.5 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: >295 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CC(C)=O>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: N#CCCl
Reactant: Cc1cccc(O)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OCC#N)c1N
Temperature: 50 °C
Yield: 50.9 %

Procedure:
Into a 1-Neck round-bottom flask was added 2-Amino-3-methyl-phenol (1.00 g, 0.00812 mol), Chloroacetonitrile (0.617 mL, 0.00974 mol), K2CO3 (1.35 g, 9.7 mmol), and Acetone (15 mL, 0.20 mol). The reaction mixture was heated at 50° C. for 4 hr, filtered and concentrated to afford title product (670 mg, 51%) LCMS 163 (M+H).
Reaction SMILES: [CH2:1]1CCCCC1.Cl[C:8]([C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=1[F:23])([CH3:13])[C:9]([F:12])([F:11])[F:10].C[Al](C)C>CCCCCC>[F:23][C:15]1[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([F:20])[C:14]=1[C:8]([CH3:1])([CH3:13])[C:9]([F:12])([F:11])[F:10]
Reactant: COc1cc(F)c(C(C)(Cl)C(F)(F)F)c(F)c1
Reactant: C1CCCCC1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Yield: 97 %

Procedure:
To a cyclohexane (100 ml) solution of 2-(1-chloro-2,2,2-trifluoro-1-methylethyl)-1,3-difluoro-5-methoxybenzene (8.84 9, 32.2 mmol) was added 1.0 M hexane solution of trimethylaluminum (129 ml, 129 mmol) at room temperature and the mixture was stirred under reflux condition for 4 hours. Then, the reaction was quenched with 2 N-hydrochloride aqueous solution and the product was extracted with hexane which was dried over sodium sulfate, filtration and evaporation to furnish 7.9 g (97% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH:40]1([Zn+])[CH2:42][CH2:41]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15]([CH:40]5[CH2:42][CH2:41]5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: [Zn+]C1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1c(C1CC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Yield: 21.3 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50.0 mg, 0.078 mmol) in THF (1 mL) in a 2.0 mL heavy-walled sealed microwave tube under N2 was added cyclopropylzinc(II) bromide (0.5 M solution in THF, 0.219 mL, 0.109 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol). The reaction mixture was heated to 70° C. for 2 h, quenched with saturated NaHCO3 and filtered by vacuum filtration through Celite®. The Celite® was washed with EtOAc (2×5 mL). The filtrate was extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (10 mL), dried over MgSO4, filtered by vacuum filtration. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound as a amber oil (9.2 mg). LCMS m/z=554.6 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[C:5]1[C:6]2[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1.[I-].[Na+]>CC(C)=O>[CH3:15][N:14]1[C:6]2[C:5]3[N:10]([CH2:4][CH:2]([CH3:1])[N:3]=3)[C:9]([CH3:11])=[N:8][C:7]=2[C:12]([CH3:16])=[N:13]1
Reactant: Cc1nc(N2CC2C)c2c(n1)c(C)nn2C
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1=Nc2c(C)nn(C)c2C2=NC(C)CN12
Yield: 57.5 %

Procedure:
The above aziridine (4.4 g, 0.02 mol) in 50 ml of acetone is stirred under reflux with 3.5 g of sodium iodide for three hours and evaporated in vacuo. The residue is partitioned in 150 ml of methylene dichloride and 50 ml of 20% aqueous sodium carbonate solution. The organic layer is separated, dried (MgSO4) and evaporated in vacuo. The resulting solid is recrystallized from acetonitrile to give 2.5 g of the title compound, mp 169°-172° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl[CH2:15][C:16]12[CH2:23][CH2:22][CH2:21][N:20]1[CH2:19][CH2:18][CH2:17]2>>[N:20]12[CH2:21][CH2:22][CH2:23][C:16]1([CH2:15][N:3]([C:4]1[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:2])[CH2:17][CH2:18][CH2:19]2
Reactant: O=CNc1cccc2ccccc12
Reactant: ClCC12CCCN1CCC2
Product: O=CN(CC12CCCN1CCC2)c1cccc2ccccc12

Procedure:
The procedures described in Example 2 were repeated except that N-formyl-1-naphthylamine (1.83 g, 10.7 mmol ) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 2.30 g, 11.7 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (3.02 g, 95.9%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22](Br)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:42]4[CH:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[N:39][N:38]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:46]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(Br)c4c(N)ncnn34)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1

Procedure:
Using the procedure described in step 4 of Example 80, the product from step 3 above and Intermediate C were converted to the title compound. 1H NMR (CD2Cl2) 1.50 (s, 9H), 1.60 (m, 1H), 1.80 (m, 2H), 2.80 (m, 3H), 4.10-4.30 (m, 3H), 5.60 (s, 2H), 5.80 (br, 2H), 7.00 (s, 1H), 7.10-7.50 (m, 9H), 7.80 (m, 2H), 7.90 (m, 2H), 7.95 (s, 1H), 8.10 (s, 1H); LC-MS [M+H]+=600.1, RT=3.55 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:31]=[CH:30][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:26]C(=O)C)[CH:17]=[C:18]([C:20]5[O:21][C:22]([CH3:25])=[CH:23][CH:24]=5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:31]=[CH:30][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:26][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])[CH:17]=[C:18]([C:20]5[O:21][C:22]([CH3:25])=[CH:23][CH:24]=5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(C)o2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: Cc1ccc(-c2cc(NS(=O)(=O)C3CC3)cc(-n3cnc4cc(-c5cnn(C)c5)ccc43)c2)o1

Procedure:
The compound was prepared from the compound of Example 73 using the procedures of Example 74 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, CD3OD): δ 8.5 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.9 (s, 1H), 7.6-7.7 (m, 4H), 7.5 (s, 1H), 6.8 (d, 1H), 6.2 (s, 1H), 4.0 (s, 3H), 2.4 (s, 3H), 1.0-1.5 (m, 4H). LC-MS (ESI): Calculated mass: 473.55; Observed mass: 474.0 [M+H]+ (rt: 1.382 min).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13](=[O:23])[CH:12](C(OCC)=O)[C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13](=[O:23])[CH2:12][C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C1C(=O)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O
Agent: Cl
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from ethyl 1-(1H-benzo[d]imidazol-5-yl)-2,4-dioxo-5-(2,3-difluorophenyl)pyrrolidine-3-carboxylate (which may be prepared in accordance with the procedure described for Intermediate 6; 0.082 g, 0.205 mmol) and 5 N aqueous hydrochloric acid (3 ml) according to the method described in Method 1, step 3.
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:23])=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:5])C.[OH-].[Na+]>CO.O>[C:4]([C:6]([CH3:23])=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1cn(-c2cccnc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=Cc1cn(-c2cccnc2)c2ccccc12)C(=O)O

Procedure:
A solution of 1.1 g of 3-[2-(ethoxycarbonyl)-prop-1-enyl)-N-(3-pyridyl)indole, and 0.288 g of sodium hydroxide in 10 ml of methanol and 10 ml of water is heated under reflux for 2 hours, cooled and evaporated. The resulting oil is redissolved in 10 ml of ice water and is neutralized with 0.59 ml of concentrated hydrochloric acid. The resulting solid is filtered and dried to yield 3-(2carboxyprop-1-enyl)-N-(3-pyridyl)indole, m.p. 213°-215°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1)[CH3:2].[C:16]([O:20][C:21](=[O:42])[CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:22]/[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:42])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CSc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Yield: 78.6 %

Procedure:
A solution of 2.24 g of (4-formyl-phenylsulfanyl)-acetic acid ethyl ester and 4.72 g of (triphenylphosphoranylidene)-acetic acid tert-butyl ester in 50 ml of dichloromethane was kept at 20° for 15 h. The solvent was evaporated in vacuo and the remaining oil was chromatographed on silica gel using dichloromethane/hexane (1:1) as eluent to give 2.53 g of (E)-2-[4-(2-tert-butoxycarbonyl-vinyl)-phenylsulfanyl]-acetic acid ethyl ester as a colorless oil. To a solution of this material in 20 ml of tetrahydrofuran were added 8 ml of 2N aqueous sodium hydroxide, and the mixture was stirred for 2 h at 20°. The clear solution was diluted with 20 ml of ethyl acetate and then extracted with 30 ml of water. The aqueous layer was cooled with ice, acidified to pH 2.8 by the addition of 3N HCl, and the mixture was extracted with 60 ml of ethyl acetate. The organic layer was dried over sodium sulfate, evaporated in vacuo, and the residue was crystallized from ethyl acetate/hexane to give 1.78 g (E)-2-[4-(2-tert-butoxycarbonyl-vinyl)-phenylsulfanyl]-acetic acid as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:35])=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][C:26]=1[CH3:35])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(OC(C)C)ncc1Br
Product: Cc1cc(OC(C)C)ncc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-isopropoxy-4-methyl-pyridine (Intermediate 28) in analogy to Example 1a): MS (ISP): 453.1 and 455.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.Cl.[N:47]1([CH2:53][C:54]([NH2:56])=[O:55])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:50]3[CH2:51][CH2:52][N:47]([CH2:53][C:54]([NH2:56])=[O:55])[CH2:48][CH2:49]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1
Yield: 78.8 %

Procedure:
rac-(4S*,5R*)-2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (110 mg, 0.2 mmol) was added to the mixture of triethylamine (140 uL, 1.0 mmol) and 2-piperazin-1-yl-acetamide dihydrochloride (52 mg, 0.24 mmol, Matrix Scientific) in 3 mL of dichloromethane at 0° C. The mixture was allowed to react for 16 h then concentrated to dryness under reduced pressure. Purification of the crude residue by flash column chromatography (40 g of silica gel, eluting with a gradient of 5 to 100% of 9:1 ethyl acetate-methanol and ethyl acetate) provided 105 mg of rac-2-{4-[(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][N:18]3[C:19](=[O:29])[CH2:20][C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:26][C:27]3=[O:28])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Product: Cc1ccc(Cl)cc1N1CCN(CCN2C(=O)CC3(CCCC3)CC2=O)CC1
Temperature: 160 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
A mixture of 1-(5-chloro-2-methylphenyl)piperazine (20 mg, 0.095 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (17.3 mg, 0.043 mmol, 49%): ESI-MS m/z 404 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([F:34])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:9]=[C:8]2Br)=[O:4].[S:35]1[C:39](B(O)O)=[CH:38][C:37]2[CH:43]=[CH:44][CH:45]=[CH:46][C:36]1=2.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:34])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:39]1[S:35][C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[CH:38]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c(Br)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Temperature: 55 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of 515 mg of 3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl ester obtained in Production Example II-13-e in 7.5 ml dimethylformamide were sequentially added 267 mg of 2-benzo[b]thiopheneboronic acid, 1 ml of an aqueous solution of 291 mg of potassium fluoride, 30 mg of 2-(di-tert-butylphosphino)biphenyl and 12 mg of palladium(II) acetate, and the mixture was stirred at 55° C. for 1 hour. The reaction mixture was ice-cooled, and then the precipitated crystals were collected by filtration. The resulting crystals were dissolved in a mixture solution of ethyl acetate and tetrahydrofuran, and the mixture was sequentially washed with water, half-saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 504 mg of a crude coupling product. A total of 350 mg of the resulting crude coupling product was suspended in 4 ml of methylene chloride, 2 ml of trifluoroacetic acid and 0.1 ml of triisopropylsilane were added, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution and it was extracted with 50 ml of ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9), to give 154 mg of the title compound as pale yellow crystals.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13]([NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)C(C)C)(C)C.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13](=[CH:12][CH:11]=1)[NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][N:19]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Combine 5-benzyloxytryptamine hydrochloride (1 g, 3.3 mmol), phthalic anhydride (.56 g, 4.0 mmol) and N,N-diisopropylethylamine (0.86 g, 6.6 mmol) in 25 mL anhydrous pyridine and reflux for 1 hour, cool to room temperature and treat with 4 g 3 Å molecular sieves. Refluxing was continued for 60 hours then the mixture was filtered. Concentrate under vacuum to give a residue which is mixed with 25 mL CHCl3 and filtered to give a solid. Purification of the filtrate by chromatography on silica gel eluting with 1% MeOH in CHCl3 to give an additional amount of title compound: ISMS 397 (M+1); Analysis for C25H20N2O3 0.3H2O C7H8: calcd: C, 75.09; H, 5.25; N, 6.82; found: C, 75.00; H, 5.22; N, 6.96.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:21])[CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:9].[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>C(Cl)Cl>[CH2:14]([N:13]([S:22]([Cl:25])(=[O:24])=[O:23])[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A solution of triethylamine (2.0 ml, 14.4 mmol) and N-benzylglycine ethyl ester (2.25 ml, 12.0 mmol) in methylene chloride (5 ml) was added to a solution of sulfuryl chloride (0.96 ml, 12.0 mmol) in methylene chloride (30 ml) at -78° C. The reaction mixture was stirred at -78° C. for 4 h and then concentrated. Ether (75 ml) was added and the resulting precipitate was filtered. The organic layer was washed with 1M HCl and brine, dried over MgSO4 and concentrated in vacuo to give ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate as a colorless oil (69%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][C:15](O)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][C:15]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Nc1ncc(-c2cnn(CCC(=O)O)c2)cc1-c1nc2ccccc2s1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(-c2cnn(CCC(=O)N3CCCC3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-propionic acid (7.0 mg, 0.013 mmol), pyrrolidine (9 mg, 0.1 mmol), TBTU (8.24 mg, 0.0257 mmol), DIPEA (0.02 mL, 0.1 mmol), and DMF (2 mL, 0.02 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.85 (q, J=6.4 Hz, 2H), 1.88-1.96 (m, 2H), 2.92 (t, J=6.6 Hz, 2H), 3.39 (q, J=7.1 Hz, 4H), 4.49 (t, J=6.6 Hz, 2H), 7.39-7.44 (m, 1H), 7.47-7.52 (m, 1H), 7.81 (s, 1H), 7.94-7.97 (m, 2H), 8.00 (d, J=7.8 Hz, 1H), 8.12 (d, J=2.3 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H). MS (ES+): m/z=419.13 (100) [MH+]. HPLC: tR=2.99 min (ZQ3, polar—5 min).