Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]>[NH2:26][C:25]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])=[O:15])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOC(=O)COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)COc1ccc(N)c(OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
A mixture of 2-trimethylsilanylethyl (3-benzyloxy-4-nitrophenoxy)acetate (5.0 g) and 5% Pt/C (500 mg) in EtOAc (50 mL) is hydrogenated at 1 atm for 3 h. The catalyst is filtered off through Celite and the solvent removed under reduced pressure to afford the title compound: 1H NMR (CDCl3)δ 7.31 (m, 5H), 6.73 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 6.29 (dd, J=8.6, 2.8 Hz, 1H), 5.01 (s, 2H), 4.45 (s, 2H), 4.94 (m, 2H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(3-aminophenyl)acetamide (36 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 44 mg (40%). 1H-NMR: 10.46 (s, 1H), 9.97 (s, 1H), 8.08 (m, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.11-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.0 Hz, 2H), 2.04 (s, 3H), 1.67-1.59 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:16][C:17]#[N:18]>C1COCC1.CCCCCC.CCOCC>[C:17]([CH2:16][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)#[N:18]
Reactant: C1=Cc2ccccc2C1
Reactant: N#CCCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC1=CCc2ccccc21
Temperature: 25 °C

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: COC([C:5]1[N:6]([NH:11][C:12]([NH:14][C:15](=[O:22])C2C=CC=CC=2)=[S:13])[CH:7]=[C:8]([Br:10])[CH:9]=1)=O.[OH-].[Na+].O.C(O)(=O)C>CCOCC.C(O)C>[Br:10][C:8]1[CH:9]=[C:5]2[N:6]([CH:7]=1)[NH:11][C:12](=[S:13])[NH:14][C:15]2=[O:22]
Reactant: COC(=O)c1cc(Br)cn1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(=S)[nH]n2cc(Br)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Into a 500 mL beaker, 1-(3-Benzoyl-thioureido)-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (31.20 g, 0.08162 mol) and 2.00 M of Sodium hydroxide in Water (164 mL, 0.327 mol) were added. The mixture was heated at 85° C. for 75 minutes. The reaction was cooled to RT. The solid was dissolved with Ethanol (100 mL). Acetic acid (18.8 mL, 0.332 mol) was added at 0° C. and stirred for 30 minutes. The solid was filtered and washed with cold EtOH (50 mL) to afford a white solid. The white solid was stirred in Et2O (300 mL) for 20 minutes. The solid was filtered and washed with Et2O (200 mL) to give 6-Bromo-2-thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one as a white solid. The white solid was dried under vacuum over night (11.6, 57%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16]([N:18]1CCCC1)=[O:17])(=N)=[O:3].BrC1C=CC=CC=1>>[CH3:14][O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]2[SH:2](=[O:3])([CH3:1])[NH:18][C:16](=[O:17])[NH:15][C:6]=2[CH:7]=1
Reactant: COc1cc(NC(=O)N2CCCC2)c(S(C)(=N)=O)cc1OC
Solvent: Brc1ccccc1
Product: COc1cc2c(cc1OC)[SH](C)(=O)NC(=O)N2

Procedure:
A solution was prepared from 42.8 g. of S-methyl-S-[2-(pyrrolidinylcarbonylamino)-4,5-dimethoxyphenyl]sulfoximine and 1 l. of bromobenzene. The reaction mixture was heated to reflux temperature for three hours, and was then cooled and filtered. The filter cake was dissolved in 700 ml. of chloroform. The chloroform solution was cooled and 6,7-dimethoxy-1-methyl-1H-1,2,4-benzothiadiazine-3(4H)-one-1-oxide formed in the above reaction crystallized therefrom. The crystalline material melted at 326°-328° C. (91 percent yield).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(NCC=C)C=C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: C=CCNCC=C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 203 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and diallylamine (11.4 ml) is added thereto at the temperature within 20 min, the above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The above mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.9 g). The yield is about 73.1%.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>CCOCC.C1COCC1.II>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of 2.3 g of magnesium and 0.01 g of iodine in 20 ml of ether is heated to reflux, a solution of 26 g of 1-bromo-2-trifluoromethylbenzene in 20 ml of ether is added dropwise and the resulting mixture is refluxed for 60 minutes. A solution of 9 g of 5-chloro-1H-indole-2,3-dione in 40 ml of THF is then added and refluxing is continued for 30 minutes. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with ether, the organic phase is washed with 1N NaOH solution and with water, and dried over Na2SO4, and the solvent is evaporated off under vacuum. 5.3 g of the expected product are obtained after crystallization from heptane, m.p.=205–208° C.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:19])[CH:12]=[CH:13][CH:14]([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8][CH:7]1[CH:6]([OH:20])[CH2:5][CH2:4][CH2:3]2.N1C=CN=C1.Cl[Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29]>CN(C)C=O>[CH3:1][C:2]12[CH:10]([CH:11]([CH3:19])[CH:12]=[CH:13][CH:14]([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH2:9][CH2:8][CH:7]1[CH:6]([O:20][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:5][CH2:4][CH2:3]2
Reactant: CC(C)C(C)C=CC(C)C1CCC2C(O)CCCC12C
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1CCCC2(C)C(C(C)C=CC(C)C(C)C)CCC12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.95 g of [1R-[1α[1R*,4S*-(E)],3aβ,4α,7aα]]-octahydro-7a-methyl-1-(1,4,5-trimethyl-2-hexenyl)-1H-inden-4-ol 1 is introduced into 220 ml of dimethylformamide [H. H. Inhoffen et al. Chem. Ber. 91, 781 (1958)], 5.33 g of imidazole and 10.78 ml of chlorotriethylsilane are added, and it is stirred for 24 hours at room temperature. It is quenched with sodium chloride solution, extracted with ethyl acetate, the organic phase is washed with sodium chloride solution and dried on sodium sulfate. After the solvent is removed, the residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby 14.6 g of title compound 2 is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.Br[CH2:34]C=C(C)C>>[CH3:6][C:7]([CH3:34])=[CH:2][CH2:1][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1F
Reactant: CC(C)=CCBr
Product: CC(C)=CCn1ncc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(F)cc2)c1=O
Yield: 30 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 1-bromo-3-methyl-2-butene in place of 4-fluorobenzyl bromide, to provide the title compound (yield: 50 mg, 30%). mp 134–136° C. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J=7.5 Hz, 2H), 5.48 (t, J=6 Hz, 1H), 6.96 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.85 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 414 (M+H)+. Anal. calc. for C21H20FN3O3S: C, 61; H, 4.87; N, 10.16. Found: C, 60.98; H, 4.66; N, 9.95.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[CH:15][C:8]=12.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:8]=12
Reactant: O=[N+]([O-])O
Reactant: Clc1ccnc2[nH]ccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Into concentrated sulfuric acid (150 mL) was added 4-chloro-1H-pyrrolo[2,3-b]pyridine (50.0 g) in portions while maintaining the internal temperature of the mixture below 10° C. (Note: exothermic upon addition). A mixture of concentrated nitric acid (30.0 mL) and concentrated sulfuric acid (60.0 mL) was added slowly while maintaining the internal temperature of the mixture below 10° C. (Note: exothermic upon addition). The reaction mixture was stirred at 0° C. for 30 min. Cold water (750 mL) was added slowly while maintaining the internal temperature below 20° C. (Note: exothermic upon addition). The resulting solid was collected by filtration and washed with a pH 7 buffer solution, water, and then acetonitrile. The product was collected by filtration and dried in a vacuum oven at 50° C. overnight to give the 52 g (92% yield) of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine as an light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.5 (s, 1H), 8.91 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 148.0, 145.7, 134.7, 132.5, 127.2, 120.9, 110.0. HRMS calcd. For C7H3ClN3O2 [M-H]−: 199.9919, found 199.9921.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-:37].[Na+]>CC(C)=O>[I:37][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12
Yield: 30 %

Procedure:
Diphenylmethyl 3-chloromethyl-7β-(2'thienylacetamido)-ceph-3-em-4 -carboxylate (7.858 g., 14.5 mmole) was dissolved in acetone and reacted with sodium iodide (7.8 g., 50 mmole) in acetone (100 ml.) in the dark for 90 minutes. At the end of this time the solution was filtered and poured into water (750 ml.) containing sodium chloride and sodium thiosulphate. The oil was extracted with ether (4×), and the organic layer washed once with water and twice with brine, and dried and evaporated to a foam, which was crystallised from ethyl acetate (16 ml.) to give the title compound. The mother liquors were washed with sodium thiosulphate, water and brine, and were dried and evaporated to a foam (2.75 g., impure title compound, approx. 30% yield). Yield of crystalline material 60%, m.p. 155-161°C (decomp.), [α]D28 =86.3° (c 0.73; tetrahydrofuran), λmax. (ethanol) 290 nm. (ε 8,400), νmax. (Nujol) 1773 (β-lactam), 1717 (CO2R), and 1670 and 1520 cm.-1 (-CONH-), N.M.R. (deuterochloroform) τ5.70 (2-proton broad singlet) (CH2I) (Found: C, 51.6; H, 3.7; I, 19.7; N, 4.3; S, 10.2. C27H23IN2O4S2 requires C, 51.3; H, 3.7; I, 20.1; N, 4.4; S, 10.2), RF 0.65 (Kieselgel G, benzene-ethylacetate=5:1) (T.L.C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:26]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:30]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-vinylbenzoate (0.42 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0 mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.24 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.26 g) as a crude product.
Reaction SMILES: C([SnH2][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1)(C)(C)C.I[C:17]1[CH:18]=[C:19](/[CH:23]=[CH:24]/[CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[I-].[F-].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:26][CH2:25]/[CH:24]=[CH:23]/[C:19]1[CH:18]=[C:17]([C:6]2[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc([SnH2]C(C)(C)C)on1
Reactant: OC/C=C/c1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(/C=C/CO)c2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
The tributyltin reagent from Example 1C (665 μL, 1.83 mmol) was added under nitrogen atmosphere to a mixture of alcohol from Example 1B (433 mg, 1.66 mmol), tris(dibenzylideneacetone)-dipalladium(0) (76 mg, 0.083 mmol), tri-2-furylphosphine (39 mg, 0.166 mmol), and cupper(I) iodide (32 mg, 0.166 mmol) in DMF (7 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. Aqueous potassium fluoride was added to the mixture and the resulting suspension was filtered through celite and washed with ethyl acetate. The filtrate was taken up in ethyl acetate and water. The organic phase was washed with brine (×3), dried (MgSO4), filtered and concentrated under reduced pressure and purified by flash chromatography on silica gel with hexane/ethyl acetate (1:1) to provide the titled compound (353 mg). MS (ESI(+)) m/e 291 (M+18)+; 1H NMR (500 MHz, DMSO-d6) δ 8.05(t, J=1.7 Hz, 1H), 7.80 (dt, J1=1.7 Hz, J2=7.5 Hz, 1H), 7.60 (dt, J1=1.7 Hz, J2=7.5 Hz, 1H), 7.57 (s, 1H), 7.51(t, J=7.5 Hz, 1H), 6.63–6.59 (m, 2H), 4.94 (t, J=5.4 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.19–4.14(m, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-]>>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])=[CH:9][C:8]=1[CH3:32])[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid as a mixture of two diastereomeric racemates as colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2Cl)[C:16]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:20][C:21]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2.[NH4+].[OH-]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2[NH:30][C:27]2[CH:28]=[CH:29][C:21]([CH3:20])=[C:22]3[C:26]=2[NH:25][CH:24]=[CH:23]3)[C:16]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(N)c2[nH]ccc12
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cncc(C#N)c2Nc2ccc(C)c3cc[nH]c23)cc1OC
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A solution of 5-(3,4-dimethoxyphenyl)-4-chloronicotinonitrile (120 mg, 0.44 mmol) and 4-methyl-7-aminoindole (77.8 mg, 0.52 mmol) in ethanol (2.5 mL) was heated at the reflux temperature for 24 h and cooled to room temperature. The reaction mixture was treated with aqueous NH4OH and concentrated in vacuo, and the residue was purified by flash column chromatography (ethyl acetate/CH2Cl2 5% to 25%) to provide a 48 mg (29%) of 5-(3,4-dimethoxyphenyl)-4-[(4-methyl-1H-indol-7-yl)amino]nicotinonitrile 530 as an off white solid. HPLC retention time: 9.0 min.(g); MS: 385.3 (M+H); and HRMS: 385.1659.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:23]([F:26])([F:25])[F:24])=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][C:16]([C:23]([F:24])([F:26])[F:25])=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(cc(C(F)(F)F)c3cccnc23)-c2cc(Cl)ccc21
Yield: 8.6 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 282) (340 mg, 0.85 mmol), t-butyl nitrile (0.15 ml, 1.27 mmol) and AcOH:THF (3.4 ml: 3.4 ml) gave the title compound (28 mg, 9%) after purification by column chromatography with DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [CH3:1][N:2](C(C1CCCN1S(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)=O)[C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[S:4].O1CCCC1.CO.[OH-].[Na+]>O>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[S:4]
Reactant: CN(C(=O)C1CCCN1S(=O)(=O)c1ccc2ccccc2c1)C(=S)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Yield: 94.2 %

Procedure:
1.05 g of (-)-N-methyl-N-[1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl]-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide, 40 ml of tetrahydrofuran, 40 ml of methanol, 120 mg of sodium hydroxide and 3 ml of water are treated in the same manner as described in Example 148-(2). 600 mg of (-)-N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide are obtained. Yield: 94.2%.