Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH:48][C:49]1([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:52][NH:51][CH2:50]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:51]1[CH2:52][C:49]([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])([OH:48])[CH2:50]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CNC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reaction time: 0.17 h
Yield: 105 %

Procedure:
3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (200 mg, 0.559 mmol), prepared using procedures similar to those described in WO 2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred at ambient for 10 minutes and then triethylamine (0.078 mL, 0.559 mmol) was added. After a further 20 minutes, 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (143 mg, 0.559 mmol), prepared using similar procedures to those described in Example 22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added and the mixture was stirred for 15 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic portion was washed with 5% lithium chloride and twice with saturated sodium bicarbonate, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-80% ethyl acetate in hexanes) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (368 mg, 0.587 mmol, 74% yield): 1H NMR (400 MHz, CDCl3): 8.73 (br m, 1H), 8.62 (br s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.43-7.39 (m, 1H), 7.20-7.12 (m, 2H), 4.38-4.21 (m, 2H), 4.16-4.01 (m, 2H), 4.01-3.88 (m, 1H), 3.44-3.30 (m, 1H), 2.98-2.83 (m, 1H), 2.00-1.88 (m, 1H), 1.71-1.50 (m, 6H), 1.44 (s, 9H); MS (EI) for C25H30FIN4O4: 597 (MH+).
Reaction SMILES: [O:1]1[CH2:24][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:23])[NH:10]2.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]1>C(O)(C)C>[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:30]3)=[C:6]3[C:11]=2[NH:10][C:9](=[O:23])[CH2:8][CH2:7]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCc2c(OCC3CO3)ccc(OCc3ccccc3)c2N1
Reactant: CC(C)COC(=O)NC1CCNCC1
Solvent: CC(C)O
Product: CC(C)COC(=O)NC1CCN(CC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)CC1
Yield: 76.2 %

Procedure:
5-(2,3-epoxypropoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril (130 mg) was dissolved in isopropanol (10 mL) and isobutyl 4-piperidylcarbamate (80 mg) was added. The mixture was then heated under reflux for 20 hours with stirring. After completion of the reaction, the isopropanol was evaporated under reduced pressure. The residue was then purified by flash chromatography (AcOEt/MeOH-99:1) to yield 160 mg of the title compound, 8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 386.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[I-:28].[Na+]>[Cu]I>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:28])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 82 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (979 mg) described in Preparation Example 110, sodium iodide (650 mg) and copper(I) iodide (205 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (886 mg) was obtained.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(OC(N1CCNCC1)=O)(C)(C)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]=C=O)=[CH:48][CH:47]=1>C(Cl)Cl.C(N(CC)CC)C>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:5])=[CH:48][CH:47]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccnc2c1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc2c1

Procedure:
4-Chloro-7-methylquinoline [obtained from 3-toluidine following the protocol of Krogstad et. al. (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR ([D]6-DMSO), δ 2.55 (s, 3H), 7.60 (m, 1H), 7.75 (d, 1H), 7.90 (s, 1H), 8.10 (d, 1H), 8.80 (d, 1H)) (0.80 g, 4.5 mmol) and 1-tert-butoxycarbonylpiperazine (3.35 g, 18 mmol) are reacted according to method A yielding 475 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-methylquinoline. After cleaving the Boc group with trifluoroacetic acid (1.8 mL) in CH2Cl2 (1.8 mL), the piperazine is treated with 4-fluorophenyl isocyanate and triethylamine (0.245 mL) according to method C yielding the title product.
Reaction SMILES: [C:1]1([S:7]([C:10]([C:13]([S:16](F)(=[O:18])=[O:17])([F:15])[F:14])([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>ClCCCl>[CH2:20]([NH:27][S:16]([C:13]([F:15])([F:14])[C:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([F:12])[F:11])(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)S(=O)(=O)c1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)S(=O)(=O)c1ccccc1

Procedure:
Added to a solution of 1,2-dichloroethane (5 ml), containing the PhSO2CF2CF2SO2F (325 mg, 1 mmol) prepared according to the method from example 4, was freshly distilled benzylamine (550 μl, 5 mmol). The mixture was stirred and heated at 50° C. for 20 h until the disappearance of PhSO2CF2CF2SO2F (monitored by TLC and 19F NMR/CDCl3). After returning to ambient temperature, an aqueous solution of HCl (10%) was added to the reaction medium. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over MgSO4. After filtration and evaporation of the solvents, the residue was purified by chromatography over silica gel (pentane to pentane/AcOEt:4/1). The sulfonamide product was obtained in the form of a white solid (340 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[CH3:18][O:19][NH2:20].C(OCC)(=O)C>C(O)(=O)C>[CH3:18][O:19][N:20]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:7][Br:8]
Reactant: CON
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CON=C(CBr)c1ccc(Cl)cc1

Procedure:
50.3 g of 4-chlorophenacyl bromide in 300 ml of glacial acetic acid are stirred with 23 g of sodium acetate and 21.6 g O-methylhydroxylamine hydrochloride for 2 hours at 70° C. 150 ml of ethyl acetate are added to the mixture, which is then extracted by washing several times with water and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo. Crystallisation from hexane yields 4-chlorophenacyl bromide O-methyloxime having a melting point of 57 to 60° C.
Reaction SMILES: [O:1]=[C:2]([NH:6][C:7](=[O:16])[C:8]([NH:10][C:11](=[O:15])[CH2:12][CH2:13]Cl)=[O:9])[CH2:3][CH2:4]Cl.C(N(CC)CC)C>C(Cl)Cl>[O:15]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:2](=[O:1])[CH:3]=[CH2:4])=[O:16])[CH:12]=[CH2:13]
Reactant: O=C(CCCl)NC(=O)C(=O)NC(=O)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(=O)C(=O)NC(=O)C=C
Yield: 4.6 %

Procedure:
To a suspension of N,N'-bis(1-oxo-3-chloropropyl) ethanediamide (3.0 g; 11 mmol) in methylene chloride (40 ml), triethylamine (2.82 g; 28 mmol) was added, and the resultant mixture was stirred at room temperature for 2 hours. The precipitated solid was collectd and washed with water to give N,N'-bis(1-oxo-2-propenyl)ethanediamide (0.1 g). Yield, 4.6%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1)=[CH2:29])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Br)c3)C[C@@H]2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Temperature: 90 °C
Yield: 45.1 %

Procedure:
The product from Example 64A (107 mg, 0.29 mmol) and tributyl-(1-ethoxyvinyl)stannane (157 mg, 0.43 mmol) were combined in a 100 mL conical flask with toluene (4 mL). Tetrakis(triphenylphosphine)palladium(0) (19.7 mg, 0.017 mmol) was added, and the mixture was heated under nitrogen at 90° C. for 22 h. The black mixture was cooled to room temperature, applied to a column of silica gel and eluted with hexanes-EtOAc (1:1) to provide the titled compound as an amber gum (contaminated with triphenyl phosphine oxide, 47 mg, 47% pure, 21% yield). MS(DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][C:4]1[C:21]([O:22][CH3:23])=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=O)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].Cl.[NH2:28][OH:29].C(=O)(O)[O-].[Na+].O>CO.C(OCC)(=O)C>[S:1](=[O:26])(=[O:25])([O:3][C:4]1[C:21]([O:22][CH3:23])=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])/[C:13](=[N:28]/[OH:29])/[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: COc1cc2c(cc1OS(N)(=O)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OS(N)(=O)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)/C(=N/O)CC[C@@H]12
Yield: 74.9 %

Procedure:
A suspension of 570 mg of 2-methoxy-17-oxo-estra-1,3,5(10)-trien-3-yl sulfamate, 365 mg of hydroxylamine hydrochloride and 441 mg of sodium bicarbonate in 8 ml of methanol was stirred under reflux for one hour. Then, it was mixed with 30 ml each of water and ethyl acetate. After phase separation, the aqueous phase was extracted twice more with 15 ml each of ethyl acetate. The combined organic phases were first washed with 15 ml of 0.5N HCl and then with saturated NaCl solution, dried on sodium sulfate and concentrated by evaporation in a rotary evaporator. The crude product was purified by flash chromatography (toluene/ethyl acetate 3:1). 444 mg (73%) of 2-methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-yl sulfamate (17) was obtained as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([OH:18])([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl.C(O)C>[C:19]([O:18][C:12]1([C:15]([OH:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)OC1(C(=O)O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
A mixture of 9.4 g 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid, hydrochloride, 3.62 g (35 mmol) acetic anhydride, 11.89 mL pyridine in 40 mL DCM was stirred for 1 h at room temperature. KHSO4 (10%) and ethanol were added and filtered. The filtrate was evaporated and the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 4.2 g (52%) of the title compound as light yellow solid. MS (m/e): 278.1 [(M+H)+].
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[C:3]([CH:15]=O)[C:2]=1[CH:17]=O.[CH2:19]([C:23]#[N:24])[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[C:21]([C:20]1[C:19]([C:23]#[N:24])=[CH:15][C:3]2[C:2](=[CH:1][C:14]3[C:5]([CH:4]=2)=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=3)[CH:17]=1)#[N:22]
Reactant: N#CCCC#N
Reactant: O=Cc1cc2cc3ccccc3cc2cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc2cc3cc4ccccc4cc3cc2cc1C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.5 g of anthracene-2,3-dialdehyde (E. Mallonli et al., Synthesis 1980, page 689), 1.8 g of succinodinitrile, 3 g of K2CO3 and 250 ml of dimethyl sulfoxide is heated with stirring at 60°-70° C. for 30 minutes. It is then cooled to 15° C. and 50 ml of water are added. The precipitate which has been deposited is filtered off and is sublimed at 300° C. Yield 485 mg (12%), λmax : 772 nm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29]Cl)[CH3:27].N>C(OCC)C.O.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCOCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a mixture of diisopropylamine (2.1 mL, 15 mmol) and tetrahydrofuran (30 mL) was dropped n-butyl lithium (2.4 M n-hexane solution, 5.0 mL, 12 mmol) at −78° C., which was stirred for 30 minutes at the same temperature. Tributyl tin hydride (3.3 mL, 12 mmol) was dropped at the same temperature followed by stirring for 40 minutes under ice-cold conditions. The reaction mixture was cooled to −78° C. and chloromethyl ethyl ether (1.1 mL, 12 mmol) was dropped into the reaction mixture. The reaction mixture was gradually warmed to room temperature followed by additionally stirring at room temperature for 3 hours. The reaction mixture was distributed among water (100 mL), saturated aqueous ammonia (50 mL) and diethyl ether (100 mL). The organic layer was separated followed by washing with sat. NaCl and concentrating under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=30:1) to obtain the title compound (2.8 g, 65%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(C=O)cc2)cc1

Procedure:
This compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and 4-formylbenzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as an off-white solid; MS m/e 407 (M+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])[CH:6]=[CH:7][CH:8]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of ethyl (RS)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was shaken on a Parr hydrogenator at 50 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (43 mg, 94%), which was used without further purification.
Reaction SMILES: [F:1][CH:2]1[CH:9]([CH2:10][C:11]([O:13]C)=[O:12])[CH2:8][CH:7]2[NH:15][CH:3]1[CH2:4][O:5][CH2:6]2.Br[CH2:17][C:18]1[NH:23][C:22]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[N:21][C@@H:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[Cl:36])[C:19]=1[C:37]([O:39][CH3:40])=[O:38]>>[Cl:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[C@H:20]1[C:19]([C:37]([O:39][CH3:40])=[O:38])=[C:18]([CH2:17][N:15]2[C@H:3]3[C@@H:2]([F:1])[C@H:9]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][C@@H:7]2[CH2:6][O:5][CH2:4]3)[NH:23][C:22]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[N:21]1
Reactant: COC(=O)CC1CC2COCC(N2)C1F
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl
Product: COC(=O)C1=C(CN2[C@H]3COC[C@@H]2[C@@H](F)[C@H](CC(=O)O)C3)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl

Procedure:
The title compounds were prepared in analogy to Example 86 starting from methyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (100 mg) and methyl (4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 88a (208 mg). The crude product was purified by silica gel chromatography first, and then by preparative HPLC to give Example 101 and Example 102.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[N:51]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:52]4[N:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnn1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnn1
Yield: 52 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridazin-3-ylmethanamine, the title compound was obtained as a colorless solid in 52% yield: mp 222-225° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.15 (dd, J=4.8, 1.6 Hz, 1H), 8.67 (t, J=5.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.35 (m, 2H), 7.24-7.18 (m, 2H), 4.69 (d, J=5.7 Hz, 2H), 4.44 (s, 2H), 4.05-4.00 (m, 2H), 3.50-3.45 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([N:21]([CH3:31])[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:24])=[O:23])[CH:20]=1)[NH:17][C:16]([C:32]1[S:33][CH:34]([CH2:37][C:38](O)=[O:39])[CH2:35][N:36]=1)=[CH:15]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[OH:6][CH:4]1[CH2:5][N:2]([C:38](=[O:39])[CH2:37][CH:34]2[S:33][C:32]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][CH3:7])=[CH:20][C:19]=4[N:21]([CH3:31])[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:24])=[N:36][CH2:35]2)[CH2:3]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)N4CC(O)C4)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
A mixture of azetidin-3-ol hydrochloride (80 mg), triethylamine (75 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 min. (2-{5-(2-Methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol (100 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (140 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-95:5, volume ratio) to give the title compound (80 mg, yield 29%) as a colorless amorphous solid.