Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:3][CH:2]=1.[NH2-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11])[CH3:25]
Reactant: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reactant: CCI
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccncc1)c1ccccc1C(=O)N1CCCCC1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 22.4 g of 1-[2-(4-pyridinylamino)benzoyl]piperidine (Example 1b) in 45 ml of dimethylformamide was added dropwise to a suspension of sodium amide (from 4.8 g of 50% oil suspension, washed free of oil) in 115 ml of dimethylformamide. The mixture was stirred for one hour, and then 6.5 g of ethyl iodide was added dropwise. The reaction mixture was stirred for two hours, then filtered and concentrated in vacuo. The residue was partitioned between water and ether and the ether-soluble material recovered (15.2 g). The latter was recrystallized from ethyl acetate--pentane to give 13 g of 1-{2-[ethyl-(4-pyridinyl)amino]benzoyl}piperidine, m.p. 123°-124° C.
Reaction SMILES: C([C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#N.[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[C:5]1([C:4]2[NH:26][N:25]=[N:24][C:3]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccc2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate (100 mg) taken in dry DMSO (2 ml) added sodium azide (0.2 g) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using MeOH: CH2Cl2 (1:9) as an eluent to afford tert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[NH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[CH:26][C:25]=1[O:32][CH3:33]>CN(C=O)C>[F:30][C:29]1[C:28]([F:31])=[CH:27][CH:26]=[C:25]([O:32][CH3:33])[C:24]=1[CH2:23][N:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7]([C:5]([NH:4][CH2:3][CH2:2][F:1])=[O:6])=[CH:8]1
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: O=C(NCCF)c1c[nH]c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
See FIG. 17(a). In a 50 mL round-bottomed flask N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.1 g, 0.48 mmol) was DMF (10 mL) to give a colourless suspension. the reaction mixture was cooled to 0° C. and potassium carbonate (0.200 g, 1.45 mmol) and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene (0.114 g, 0.48 mmol) was added then the RM was stirred at 80° C. for 4 h. The reaction was monitored by LCMS. DMF was concentrated under vacuao, added water and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated to give crude product. The crude material was purified on reverse phase preparative HPLC system to get 1-(2,3-difluoro-6-methoxybenzyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.060 g, 34.2%). ES+MS m/z: 364 (M+1) 1H NMR (DMSO-d6, 300 MHZ): δ ppm 8.90 (br. s., 1 H ), 8.50 (d, J=4.3 Hz, 1 H ), 8.02-8.15 (m, 2 H ), 7.30-7.52 (m, 2 H ), 6.92 (d, J=8.7 Hz, 1 H ), 5.53 (s, 2 H ), 4.63 (t, J=4.4 Hz, 1 H ), 4.47 (t, J=4.8 Hz, 1 H ), 3.86 (s, 3 H ), 3.74 (d, J=5.3 Hz, 1 H ), 3.65 (d, J=5.3 Hz, 1 H ).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]([C:8]1[C:9](=[O:21])[N:10]([CH3:20])[C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[NH2:7].C(N(CC)CC)C>O1CCOCC1>[CH3:20][N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[N:17]=[C:8]([NH:6][NH:7][C:1](=[O:4])[CH2:2][CH3:3])[C:9]1=[O:21]
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)NNc1nc2cc(OC)ccc2n(C)c1=O

Procedure:
Propionyl chloride (2.63 g., 28.4 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (4.5 g., 23.7 mmol) and triethylamine (2.87 g., 28.4 mmol) in 250 ml. of dioxane and stirred at room temperature for four days. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried at 80° C. under high vacuum. The material is then recrystallized from ethanol, filtered and dried at 80° under high vacuum overnight to yield purified product.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(C)CC(=O)O
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (8 mg, 26%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methoxybutanoic acid
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.[CH2:42](O)C>>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH:20]=3)[CH3:42])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCO
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)c(-c2ccc(N(C)Cc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (148 mg) in ethanol (2.8 mL) was added 2N aqueous sodium hydroxide solution (695 μL) at room temperature, and the mixture was stirred for 5 hr. The mixture was further stirred at 50° C. for 2 hr, and the reaction mixture was cooled to 0° C. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (128 mg) as a colorless gummy substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[CH:6][C:5]=1[OH:13])[CH2:2][CH3:3].I[CH3:15].[H-].[Na+]>CN(C=O)C>[CH3:15][O:13][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1ccc(CCC)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(CCC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
To a solution of 2,5-dipropylphenol (3.50 g, 19.6 mmol) and iodomethane (3.70 mL, 58.8 mmol) in DMF (65 mL) at 0° C. was added sodium hydride (1.60 g, 39.2 mmol, 60% dispersion in oil) in two portions. The resulting mixture was stirred at 0° C. for 10 min and then at room temperature for 14 h. After being quenched with water, the mixture was extracted in hexanes (3×100 mL) with 50% saturated brine (50 mL). Flash chromatography with silica gel (100% hexanes) afforded the title compound as a colorless liquid (3.70 g, 97% yield): 1H NMR (300 MHz, CDCl3) δ 0.95 (two overlapping triplets, 6H), 1.60 (m, 4H), 2.55 (m, 4H), 3.81 (s, 3H), 6.66 (s, 1H), 6.70 (d, 1H, J=7.5 Hz), 7.02 (d, 1H, J=7.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.[Cl-].[Na+].O>[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCC2=O)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-benzofuran-3-one (1.01 g, 6.73 mmol) in dry dichloromethane (18 mL) was added imidazole (0.458 g, 6.727 mmol) followed by tert-butyldiphenylchlorosilane (1.72 mL, 6.73 mmol) at room temperature. The mixture was stirred overnight and poured into brine. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, evaporated in vacuo and the residue was purified by column chromatography (ethylacetate:hexane; 1:9) to give the 6-(tert-butyl-diphenyl-silanyloxy)-benzofuran-3-one as slightly yellow oil (1.34 g, 52%). 1H NMR (CDCl3, 400 MHz) 1.21 (s, 9H), 4.54 (s, 2H), 6.40 (s, 1H), 6.55 (dd, J=1.6, 8.0 Hz, 1H), 7.38-7.50 (m, 7H), 7.67 (m, 4H).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C(Cl)CCl.[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23](O)=[O:24])([CH3:18])([CH3:17])[CH3:16].[OH-].[NH4+]>ClCCl>[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23]([NH2:2])=[O:24])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(C(N)=O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 96.1 %

Procedure:
1-hydroxybenzotriazole (225 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) were added sequentially to compound 50.3 (750 mg, 1.5 mmol) in dichloromethane (25 mL). The resulting mixture was stirred for 1 h before ammonium hydroxide (25% in water, 630 mg, 4.5 mmol) was added dropwise. The reaction was quenched after 30 min. with water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.1 (720 mg) as a white solid. MS ESI (pos.) m/e: 500 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.68 (1H, s); 7.57-7.48 (3H, m); 7.29-7.25 (2H, m); 7.0-6.97 (2H, d, J=6.8 Hz); 5.14 (2H, s); 3.91-3.88 (1H, m); 3.19-3.13 (1H, m); 2.60-2.55 (1H, m); 1.4 (9H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:20][CH3:21])=[CH:6][CH:5]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:19][C:17]1[CH:16]=[CH:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=3)[C:11]([CH2:20][CH3:21])=[N:12][C:13]=2[CH:18]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1nc2cc(O)ccc2n1-c1ccc(CCBr)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1-c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A mixture of 1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ol (step 1, 200 mg, 0.58 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.7 mmol) and imidazole (47 mg, 1.45 mmol) in DMF (5 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 119 mg (45%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.20 (2H, d, J=8.4 Hz), 7.10 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=2.3 Hz), 6.72 (1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.3 Hz, 8.6 Hz), 3.45 (2H, t, J=7.4 Hz), 3.07 (2H, t, J=7.4 Hz), 2.56 (2H, q, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz), 0.79 (9H, s), 0.05 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[N:6][CH:7]=1.[C:29]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl>>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][N:26]([CH3:29])[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc3n2C)C1
Yield: 81 %

Procedure:
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (57 mg, 0.14 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54.5 mg, 81%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.72 (d, J=1.7 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 7.14 (dd, J=8.3, 1.8 Hz, 1H), 4.80-4.72 (br m, 1H), 4.46-4.34 (m, 1H), 3.96-3.86 (m, 1H), 3.75 (s, 3H), 3.65-3.55 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 405 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.0 min.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCNC4)n3)ccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCN(CCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 4-bromobutyl acetate. The protecting group is cleaved off as described by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][N:2]2[CH:3]=[C:4]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]3)[CH:5]=[N:1]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCN1CCCC1
Agent: Cl
Product: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 1-(2-chloroethyl)pyrrolidine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 1-(2-chloroethyl)pyrrolidine hydrochloride, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (45%). LCMS (ES+) 292 (M+H)+, RT 1.81 minutes (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.C(O)(=O)C(O)=O.[CH2:18]([NH:20][NH2:21])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:21][N:20]2[CH2:18][CH3:19])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CN1CCCC1=O
Product: CCn1ncc2c(F)cc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzaldehyde (1000 mg, 4.5 mmol) in NMP (10 mL) was added ethyl hydrazine oxalate (747 mg, 5.0 mmol). The reaction mixture was stirred at r.t. for 72 h. The reaction mixture was heated under reflux for 15 h. After being cooled at r.t., the reaction mixture was partitioned between heptane and water. The aqueous layer was extracted with heptane. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-20% EtOAc in heptanes) to afford 6-bromo-1-ethyl-4-fluoro-1H-indazole as a light yellow oil (902 mg, 84%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)=[O:23])=[CH:26][CH:27]=1)([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(C)C(=O)OC)cc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(C)(Br)C(=O)OC)cc3)cc2)cc1
Yield: 45 %

Procedure:
A mixture of MOPPP (see Example 20d; 1.1 mmole) in dry CCl4 (10 ml) with N-bromosuccinimide (1.8 mmole) and a catalytic quantity of azo-isobutyronitril (5 mg) was heated for 24 hours. After cooling, the reaction mixture was purified directly by column chromatography (silica gel eluted with hexane/chloroform). MBOPP was recrystallised from hexane as fine needles (yield 45%; mp 104°-5° C.). The results of IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]([CH3:35])([CH3:34])[C:8]([NH:10][CH2:11][CH:12]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH:13]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)=[O:9])(=O)C.O>C(O)C>[Cl:33][C:28]1[CH:27]=[C:26]([CH:13]2[CH:12]([CH2:11][NH:10][C:8](=[O:9])[C:7]([OH:6])([CH3:35])[CH3:34])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(=O)OC(C)(C)C(=O)NCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)C(C)(C)O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
2 M Aqueous sodium hydroxide solution (0.3 mL) was added dropwise to a solution of tert-butyl (6SR,7RS)-7-({[2-(acetyloxy)-2-methylpropanoyl]amino}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (130 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccsc1Br
Temperature: 23 °C
Yield: 94.6 %

Procedure:
Tert-butyl thien-3-ylcarbamate (37 g, 0.19 mol) and N-bromosuccinimide (33 g, 0.19 mol) were combined in carbon tetrachloride (900 mL) and heated at reflux for 3 h. At this time, the mixture was cooled to 23° C. and filtered. The filtrate was washed with water (5×900 mL) to remove succinimide, dried (Na2SO4), and concentrated in vacuo to give the title compound (50 g, 96%, m.p. 68-70° C.) as a tan solid which was pure enough for further use.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10]1>ClC(Cl)C>[I:1][C:13]1[S:9][CH:10]=[N:11][C:12]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ncsc1I
Yield: 86 %

Procedure:
1033 mg (4.59 mmol) of N-iodosuccinimide are introduced into a solution of 800 mg (3.99 mmol) of tert-butyl N-(1,3-thiazol-4-yl)carbamate in 40 ml of dichloroethane, and the reaction mixture is heated under reflux for 2 h. After cooling, the mixture is washed twice with water and with saturated sodium thiosulfate solution. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8/2 to 1/1), giving 1.19 g (3.43 mmol, 85%) of tert-butyl N-(5-iodo-1,3-thiazol-4-yl)carbamate as white crystals after crystallisation from diethyl ether; ESI-MS: m/e: 327 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH:29]1[CH2:37][CH2:36][CH2:35][C@H:30]1[C:31]([NH:33][CH3:34])=[O:32]>>[CH3:34][NH:33][C:31]([C@@H:30]1[CH2:35][CH2:36][CH2:37][N:29]1[C:24](=[O:26])[CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:10][CH:11]=2)[CH2:18][CH2:19]1)=[O:32]
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Reactant: CNC(=O)[C@@H]1CCCN1
Product: CNC(=O)[C@@H]1CCCN1C(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with H-Pro-NHMe, using general method C, to give (S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic acid methylamide. White solid. MS 533.3 ([M+H]+)