Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].[Br:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[Br:33][C:34]1[CH:35]=[N:36][C:37]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:30])[N:6]=2)=[N:38][CH:39]=1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 45.8 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (1.00 g) in anhydrous THF (10 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 195 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (1.12 g) in dimethylacetamide (3 ml). After stirring for 1 hr, the reaction mixture was partitioned between ethyl acetate (100 ml) and saturated ammonium chloride solution (100 ml). The organic fraction was washed with brine (100 ml), followed by drying over magnesium sulfate, filtering and concentration under reduced pressure. Purification of the residue by preparative HPLC on a Phenomenex Magellen column using a 0.1M ammonium acetate:acetonitrile gradient (95:5 to 50:50 over 5 minutes) afforded the title compound as a white solid (625 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH:20]=[N:19]1>>[OH:9][CH2:8][C:6]1[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:25]([NH:24][CH2:23][C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)=[O:42])=[CH:28][CH:29]=2)[N:7]=1
Reactant: Cn1cc(CNC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1

Procedure:
The preparations of [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (1.00 g, 4.10 mmol) and 3-[(1-methylpyrazol-4-yl)methyl]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea were described earlier.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([O:18][C:29](=[S:30])[N:28]([CH3:32])[CH3:27])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(OC(=S)N(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (10 g, 37.3 mmol) in dioxane (157 ml) is added 4-dimethylaminopyridine (476 mg, 3.9 mmol), triethylamine (10 mL, 78.6 mmol), and dimethylthiocarbamoyl chloride (6.1 g, 49.1 mmol). The reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using 20% ethyl acetate in hexanes to give dimethyl-thiocarbamic acid O-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yl)ester (12.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:14]([NH2:17])(=[S:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:14]1[S:16][CH:12]=[C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=2)[N:17]=1
Reactant: CC(N)=S
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 80 %

Procedure:
A solution of 3-bromo-(4-nitrophenyl)-ethanone (2.5 mmol) and thioacetamide (3 mmol) in N,N-dimethylformamide (20 mL) was heated at 65° C. for 8 h. Ethyl acetate (40 mL) was added and the solution was washed with water (3×20 mL). The product was purified by crystallization from ether to give the title product (80%). ESMS [M+H]+: 221.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of Cul and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CC1c2c(c3cc(Cl)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (220 mg, μmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite and Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 6-chloro-9-((4-chlorophenyl)ethynyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (88 mg). 1H NMR (CDCl3) FREE BASE 7.51-7.43 (m, 4H), 7.39-7.36 (d, 1H), 7.30-7.22 (m, 2H), 4.05-3.97 (q, 1H), 3.24-2.80 (m, 4H), 2.60 (s, 3H), 1.68-1.58 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33](Cl)=[C:32](OC)[CH:31]=[C:30](OC)[C:29]=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=N[C:50]2[CH:51]=CC=[CH:54][C:49]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCN(C2C=CC(NC(C3C4N=CC=NC=4C(C4C5C(=CC=CC=5)C=CC=4)=CC=3)=O)=CC=2)CC1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33]5[C:32](=[CH:54][CH:49]=[CH:50][CH:51]=5)[CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)nc2)CC1
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 72 h at it and using 3 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2.4 equiv) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 489.1 [M+H]+; tR=3.73 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 9:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.C(=O)(O)[O-].[Na+]>[CH3:29][CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1)[CH3:32]
Reactant: CC(C)=O
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A solution of 1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 0.77 mmol), acetone (0.10 mL, 1.4 mmol), sodium cyanoborohydride (0.10 g, 1.51 mmol) and acetic acid (6 drops) in methanol (4 mL), sealed in a well-stoppered round-bottomed flask, was stirred at 60° C. for 16 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (3×25 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (14:1) afforded 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 64%) as a colorless foam: 1H NMR (300 MHz, CD3OD) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.14-7.05 (m, 3H), 6.44 (s, 1H), 6.32 (s, 1H), 4.81 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H), 4.99 (t, J=8.7 Hz, 2H), 3.74 (dd, J=14.0, 7.2 Hz, 1H), 3.65 (dd, J=14.0, 7.1 Hz, 1H), 3.02-2.91 (m, 4H), 2.77 (septet, J=6.6 Hz, 1H), 2.30-2.18 (m, 2H), 2.00-1.84 (m, 1H), 1.81-1.71 (m, 2H), 1.50-1.34 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CD3OD) δ180.3, 163.2, 162.9, 144.1, 134.1, 123.0, 124.8, 124.6, 121.6, 121.4, 120.0, 110.5, 93.7, 81.7, 73.5, 59.2, 56.2, 49.5, 49.4, 46.6, 36.0, 30.7 (2C), 29.9, 18.3, 18.3; MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:12]/[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(/C=C/[N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 10.3 g (80 mmol) 5-methyl-2-thiophenecarboxaldehyde (commercially available) and 13.5 mL nitromethane in 160 mL methanol was cooled to −5° C. A 50% sodium hydroxide solution (80 mL) was added drop wise maintaining the temperature between 5 and 10° C. (formation of a yellow precipitate). After complete addition the mixture was stirred at 10° C. for 1 h. The suspension was poured onto an ice-cold solution of HCl 37% (340 mL) and water (560 mL). The crude product separated as a yellow solid, which was filtered and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on a silica eluting with a gradient formed from heptane and ethyl acetate. Evaporation of the product fractions yielded 6.9 g (51%) of the title compound as yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27](B(O)O)=[CH:26][N:25]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[CH:26]=[N:25][C:24]([Cl:23])=[CH:29][C:28]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ncc1B(O)O
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: Cc1cc(Cl)ncc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 2-chloro-4-methylpyridine-5-boronic acid following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.40 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10].[CH2:18]([O:20][C:21]#[CH:22])[CH3:19]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]1[C:11]([CH2:15][CH2:16][CH3:17])([CH2:8][CH2:9][CH3:10])[C:12](=[O:13])[CH:19]=1)[CH3:22]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: C#COCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)C(=O)C=C1OCC
Reaction time: 48 h
Yield: 66.6 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (29 ml) was added dropwise at room temperature to a well-stirred solution of di-n-propylacetyl chloride (13.9 g, 85.8 mmol) and ethyl ethynylether (15 g, 40% solution in hexanes, 85.7 mmol) in toluene (120 ml. The reaction was warmed to 60° and stirred for 48 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a brown oil (11.2 g, 57.1 mmol, 67%). δH (CDCl3, 300K) 5.02 (1H, s), 4.32 (2H, q, J 7.1 Hz), 1.69-1.61 (4H, m), 1.45-1.40 (4H, m), 1.02 (6H, t, J 7.3 Hz). m/z (ES+, 70V) 197.1 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=2)[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(OC(=O)c4ccc(F)cc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Dissolve the compound of Example 3 (111 mg, 0.21 mmol) in dichloromethane (2 mL). Add 4-fluorobenzoyl chloride (30 μL, 0.25 mmol) dropwise. After stirring for 10 minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate (10 mL) and extract with dichloromethane (10 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%) to give 99 mg of the title compound (73%): mass spectrum (ion spray): m/z=640.3 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Cl[Sn](Cl)(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:34])[O:28][N:27]=2)=[CH:22][CH:21]=1.[N+](C)([O-])=O>C(Cl)Cl>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:31]([C:30]3[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[N:27][O:28][C:29]=3[CH3:34])=[O:32])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C(=O)c3c(-c4ccc(F)cc4)noc3C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.5 %

Procedure:
To a stirred solution of 1.75 g (10 mmol) methyl indole-6-carboxylate (commercially available) in 15 mL of dry CH2Cl2 under argon at 0° C. was added 1.41 mL (12 mmol) of SnCl4 in one portion. After removing the ice-bath, the mixture was stirred for 40 min at room temperature and then 2.39 g (10 mmol) of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid chloride (Prepared from the corresponding acid according to: J. Agric. Food Chem. 1995, 43, 219-228.) in 5 mL of CH2Cl2 was added at 0° C. followed by the addition of 15 mL of nitromethane in one portion. The mixture was stirred for 15 minutes at 0° C., after which 50 mL of ice-water was added to quench the reaction. The organic phase was separated and the aqueous solution was extracted with CH2Cl2 (2×20 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, and evaporated to give 3.5 g of crude product (purity ˜30%, LCMS) as brown semi-solid. The crude product was further washed with ethyl acetate to give 0.85 g of the title compound in 23% yield as a light-yellow powder. (m/e): 379.2 (MH+; 100%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(CCN(CCN(C)C)C)C.C([Li])CCC.CN([CH:38]=[O:39])C>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:38]=[O:39])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
A mixture of Intermediate 368.1 (7.5 g, 29.5 mmol) and PMDTA (7 mL) in THF (50 mL) was cooled to −78° C. 1.6 M n-butyl lithium (21 mL, 32.4 mmol) was added dropwise and the mixture was stirred for 40 min at −60° C. The mixture was cooled to −78° C. and added DMF (4.6 mL, 59 mmol) before allowing the mixture to warm to 23° C. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O and brine, passed through a 2″ SiO2 plug eluting with EtOAc/Hex (95/5), dried (Na2SO4) and concentrated to afford 7 g of Intermediate 368.2. 1H NMR (400 MHz, CDCl3) δ ppm 0.21 (s, 6H) 0.97-1.03 (m, 9H) 1.21 (t, J=7.69 Hz, 3H) 2.59 (q, J=7.76 Hz, 2H) 6.99 (dd, J=8.13, 2.42 Hz, 1H) 7.20-7.29 (m, 1H) 10.30 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CCO
Product: Clc1cc(N2CCNCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
18 g 3,4,6-trichloro-pyridazine and 34 g piperazine are suspended in 100 ml of ethanol and stirred for 30 minutes at ambient temperature. The precipitated solid is suction filtered. 500 ml of water are added to the mother liquor and the precipitated product is suction filtered. 14 g product are obtained as a solid. M.p=111-115° C.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:10]([OH:17])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:17][C@H:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:9]2)=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Yield: 61.9 %

Procedure:
In the manner of Example 4, the reaction of 0.6 g (0.0027 mole) of trans-3-phenylmethyl-1-indanol (96% trans, 4% cis) and 0.704 g (0.0027 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (which may be prepared by method disclosed in U.S. Pat. No. 4,238,505, Example 7) in the presence of 0.214 g (0.0027 mole) of pyridine and 50 mL of toluene gave 0.75 g of trans-3-phenylmethyl-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44]Br)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: OC1CCC1
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(COC2CCC2)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of cyclobutanol (0.009 mL, 0.115 mmol) in 0.26 mL DMF, cooled to 0° C., was added sodium bis(trimethylsilyl)amide dropwise. After stirring for 5 min, a solution of 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine (13.5 mg, 0.023 mmol) in 0.25 mL DMF was added and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine. Drying, solvent evaporation and flash chromatography (15-55% EtOAc/hexanes) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(cyclobutoxymethyl)-N-methyl-N-(methylsulfonyl)benzenamine. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 7.27 (m, 3H), 7.06 (m, 2H), 5.09 (bs, 1H), 4.47 (s, 2H), 4.05 (m, 1H), 3.57 (d, J=13.6 Hz, 1H), 3.43 (m, 1H), 3.38 (s, 3H), 2.90 (s, 3H), 2.24 (m, 2H), 2.02 (m, 2H), 1.73 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H).