Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:28]=[O:29]>N1C=CC=CC=1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29])[CH3:36]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and ethyl 3-Isocyanatopropionate (0.016 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.4, 173.8, 161.0 (dd), 158.0, 157.8 (dd), 151.1, 141.0, 138.7, 136.1, 135.0, 132.7, 132.2, 128.8, 127.4 (dd), 126.0 (dd), 122.6, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 61.7, 36.7, 35.8, 19.7, 14.5
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.606 g of 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.063 g of 60% oily sodium hydride was added,-followed by stirring at room temperature for 1 hour. 0.253 ml of ethyl 2-bromoisobutyrate was added, followed by stirring in an oil bath (bath temperature 80° C.) for 17 hours. After cooling, 0.063 g of 60% oily sodium hydride and 0.253 ml of ethyl 2-bromoisobutyrate were added, followed by stirring in an oil bath (bath temperature 80° C.) for 3 hours. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 0.38 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 5 ml of ethyl acetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration; the residue was powdered from diethyl ether, collected by filtration, and dried, to yield 0.342 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19]I>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[NH:17])[S:16][CH3:19])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(N)=S)CC1
Solvent: CO
Product: CSC(=N)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 1.19 g of (trans-4-thioureido-cyclohexyl)-carbamic acid tert-butyl ester and 0.41 ml of methyliodide in 50 ml of MeOH is stirred at RT. From the mixture obtained solvent is evaporated and [trans-4-(2-methyl-isothioureido)-cyclohexyl]-carbamic acid tert-butyl ester in the form of a hydrolodide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19]2)=[O:17])[CH:10]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)ncn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(C)=O)C2)ncn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]amide (compound #16A) (110 mg, 0.352 mmol) was dissolved in 5 ml of anhydrous dichloromethane, cooled to 0° C. and 4-N,N-dimethylaminopyridine (90 mg, 0.70 mmol) and acetic anhydride (54 mg, 0.53 mmol) were added simultaneously. The reaction mixture was stirred for 3 hours at room temperature, treated with crushed ice and partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate and concentrated to provide 1-acetyl-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #20A) (105 mg, 84.13%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:18]1[C:24]2[CH2:23][NH:22][C:25]3[CH:26]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:4]=2[CH:3]=[CH:2][CH:19]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 5,11-dihydro-10-dibenz [b,e][1,4]diazepine 1.9 g of 4-[(2-methylbenzoyl) amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2N HC1, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and the solvent removed to give a residue. The residue is chromatographed on a silica gel column using 1:4 ethyl acetatehexane to give 1.8 g of the desired product as a solid, m.p. 68°-71° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[F:11][CH:12]([F:15])[CH2:13]I>>[F:11][CH:12]([F:15])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: FC(F)CI
Reactant: Cc1cc(O)ccc1C=O
Product: Cc1cc(OCC(F)F)ccc1C=O
Yield: 67.4 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 2,2-difluoro-1-iodoethane (153 mg, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 4-(2,2-difluoroethoxy)-2-methylbenzaldehyde (54 mg, 68%). Used without further characterization.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1>>[O:32]1[C:36]2([CH2:41][CH2:40][N:39]([C@H:23]3[CH2:24][C@@:25]4([CH3:26])[C@@H:20]([CH2:19][CH2:18][C@@H:17]5[C@@H:27]4[CH2:28][CH2:29][C@@:13]4([CH3:14])[C@H:15]5[CH2:16][C@H:11]([N:8]5[CH2:9][CH2:10][C:5]6([O:1][CH2:2][CH2:3][O:4]6)[CH2:6][CH2:7]5)[C@@H:12]4[OH:31])[CH2:21][C@@H:22]3[OH:30])[CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 80.1 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-17β-hydroxy-5α-androstane is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to obtain the title compound in a yield of 80.1%, m.p.: 180°-182° C.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([N:16]=[C:17]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O>CO>[CH3:1][O:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:16][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: C1CCOC1
Reactant: O=C(O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Product: COC(=O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a 0° C. THF (700 mL) solution of compound 1 (133 g, 0.3 mol) was added carbonyldiimidazole (55.3 g, 0.34 mol). After the addition was complete, the resultant solution was allowed to warm to room temperature and stirred for 45 min. Anhydrous methanol (100 mL) was added. The solution was stirred for 16 h and concentrated. The residue was triturated with ether (400 mL). The supernatant was separated. The process was repeated with two more portions of ether (2×200 mL). The ether phases were combined, washed with H2O, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/1:1) to afford 130 g (95%) of the title product, mp 36°-39° C.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:6][N:5]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[CH:8]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-Ethylisoxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B28) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10].C(OC([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:38]([C@H:33]3[CH2:34][CH2:35][CH2:36][CH2:37][NH:32]3)=[O:39])[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10]
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1F)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1F)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a stirred solution of the (R)—N-(1-(2,4-dichlorophenyl)ethyl)-2-fluoro-5-(piperazin-1-yl)aniline (0.085 g, 0.23 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.053 g, 0.23 mmol) in DMF (1.5 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.075 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-70% ethyl acetate in hexanes) to afford the desired product (0.080 g, 0.14 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.Br[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:11])[N:9]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:10]=[C:4]2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(CBr)cn1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12

Procedure:
Using the procedure described in Example 274, 7-chloro-8-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one prepared as described in Example 273 was reacted with 5-(bromomethyl)-2-(trifluoromethyl)pyridine to give the title compound, 7-chloro-8-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)methyl-[1,2,4]triazolo[4,3-b]pyridazin-3 (2H)-one.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(I)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(I)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford title compound. HPLC: RT=10.87 min. MS (ESI+): mass calcd. for C23H17ClI2N4O5S2, 782.80; m/z found, 783/785 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.31 (s, 1H), 8.37 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.09 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55 (d, J=2.0, 1H), 7.35-7.33 (m, 2H), 7.00-6.94 (m, 2H), 6.46 (d, J=7.1, 1H), 4.97-4.91 (m, 1H), 3.82 (s, 3H), 3.21-3.10 (m, 2H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[CH3:32][NH:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:38][CH:37]=1)=[O:35].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:42](=[O:43])[CH:41]=[CH:40][C:39]3[CH:45]=[CH:46][C:36]([C:34](=[O:35])[NH:33][CH3:32])=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Reaction time: 3 h
Yield: 116.1 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg), 4-(methylcarbamoyl)cinnamic acid (20.9 mg) and 1-hydroxybenzotriazole (22.6 mg) in N,N-dimethylformamide (0.6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27.4 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-[4-(methylcarbamoyl)cinnamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (73 mg) as colorless amorphous.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](O)=[O:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]([CH3:31])=[CH:27][C:28]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:29]
Reactant: CC(C)=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=C(C)C
Yield: 76.3 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcrotonic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 77%) as crystals.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46]CC)=[O:45])=[CH:39][CH:38]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2coc(C(C)(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (320 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (181 mg, yield 59%) as colorless prism crystals. melting point: 104-106° C.
Reaction SMILES: [CH3:1][C:2]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]([O:12][Si:13]([CH3:14])([CH3:15])[CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]/[CH:4]=[CH:5]/[Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: C#CCC(C)(CCCCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 25 °C

Procedure:
A solution of 30 g of 4-methyl-4-trimethylsilyloxy-1-decyne, 150 mg of azobisisobutyronitrile, and 35 ml of tri-n-butyltin hydride was magnetically stirred under an argon atmosphere at 130°-135° C. for about 2 hours (exothermic), then cooled to ambient temperature. The product was distilled to provide 60 g of (E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-decene (b.p. 156°-158° at 0.03 mm).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:10][C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1])(=[O:13])[CH3:12]
Reactant: COCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Product: COCCC1=C(OC(C)=O)CCC1

Procedure:
The subject compound is prepared from 2-(2-methoxyethyl)cyclopentan-1-one (Example 895) and acetic anhydride by the procedure of Example 10. The product is an oil, b.p. 60°C. (0.2 mm.)
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3]1.[CH3:9][NH:10][CH3:11]>>[CH3:9][N:10]([CH3:11])[CH2:4][CH2:3][CH:2]([S:6]([OH:5])(=[O:8])=[O:7])[CH3:1]
Reactant: CNC
Reactant: CC1CCOS1(=O)=O
Product: CC(CCN(C)C)S(=O)(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2,4-butanesultone (1.27 g, 8.9 mmol) was added to an ice-chilled solution of dimethylamine (40% w/w in water). The solution was stirred at 0° C. for 4 hours. The solvent was evaporated in vacuo until complete dryness. The solid was washed with acetone (50 mL), collected by filtration and dried in vacuo. 1H NMR (D2O, 500 MHz) δ ppm 3.18 (t, 2H, J=8.1 Hz), 2.85 (m, 1H), 2.76 (s, 6H), 2.09 (m, 1H), 1.81 (m, 1H), 1.17 (d, 3H, J=7.3 Hz). 13C (D2O, 125 MHz) δ ppm 55.65, 53.05, 42.88, 26.72, 14.81. ES-MS182a (M+1).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CN2CCCCC2)C1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CN3CCCCC3)C2)c2ccccc21
Yield: 39 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(piperidin-1-yl)methyl]-pyrrolidin-1-yl]ethanamine in a yield of 39% of theory. Colourless crystals, m.p. 168°-169° C. (acetonitrile).