Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH3:13])CCCCC)[CH3:3].C[C:15]([CH3:17])=[O:16].[OH:18]S(O)(=O)=O.O=[Cr](=O)=O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O>[CH3:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:13])[CH2:3][CH2:17][C:15]([OH:18])=[O:16]
Reactant: CC(C)=O
Reactant: CCCCC[C@H](C)CCC=C(C)C
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC[C@H](C)CCC(=O)O
Temperature: 0 °C
Yield: 74 %

Procedure:
Compound 162 (7.97 g, 43.7 mmol) was dissolved in acetone (214 mL) and cooled to 0° C. Jones reagent (CrO3/H2SO4) (2.7 M, 95 mL) was added dropwise, and the reaction allowed to warm to room temperature over 18 hours. The reaction was poured on to water/Na2SO4 (200 mL), and the aqueous layer extracted with ethyl acetate (4×100 mL). The combined organics were dried over MgSO4, filtered, and rotovapped to give an oil. The crude oil was chromatographed on silica eluting with hexanes to give 163 as an oil (5.56 g, 74%). 1H NMR (400 MHz, CDCl3) δ2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); MS APCI m/z 170.9 (M−1, 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7](=[O:8])[C:6]2=[CH:16][CH:17]=1.O>CO.[BH4-].[K+]>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:6]([CH:7]([OH:8])[N:9]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:10]2=[O:11])=[CH:16][CH:17]=1.[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:16][CH:17]=1)[C:7](=[O:8])[N:9]([CH2:12][CH:13]([CH3:14])[CH3:15])[CH:10]2[OH:11]
Reactant: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2cc(C(F)(F)F)ccc2C1O
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 160.8 %

Procedure:
5-Trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are prepared as described in Example 1, starting with 14.9 g of 4-trifluoromethyl-N-isobutylphthalimide in 300 cm3 of methanol and 2.96 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and then cooled to a temperature in the region of 0° C. and 100 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted 3 times with 200 cm3 of ethyl acetate. The organic extracts are combined, washed with 300 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 12.07 g of 5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.64, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH:2]=1.[Cl:18][C:19]1[C:20]2[CH:28]=[C:27]([N:29]([CH3:31])[CH3:30])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[ClH:18].[CH3:30][N:29]([CH3:31])[C:27]1[N:26]=[CH:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:9]=[CH:10]4)[C:20]=2[CH:28]=1
Reactant: Nc1ccc2c(cnn2Cc2cccnc2)c1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Product: CN(C)c1cc2c(Nc3ccc4c(cnn4Cc4cccnc4)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(3-Pyridylmethyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.50(1H,s), 9.90(1H,s), 8.65(1H,d), 8.60(2H,m), 8.25(1H,s), 8.14(1H,s), 7.91(1H,d), 7.75(2H,m), 7.70(1H,s), 7.50(1H,m), 5.80(2H,s), 3.20(6H,s); m/z (M+1+) 397.
Reaction SMILES: C([O:9][CH2:10][CH3:11])(=O)CC(OCC)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[NH2:19].[OH2:20]>[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[NH:18]1[C:11](=[O:20])[C:10](=[O:9])[NH:19][C:13]2[N:12]=[CH:17][CH:16]=[CH:15][C:14]1=2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O
Reactant: Nc1cccnc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Product: O=c1[nH]c2cccnc2[nH]c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Ytterbium(III) triflate [Yb(OTf)3] (853 mg, 1.38 mmol) and diethyl malonate (7.5 mL, 55.0 mmol) were added to pyridine-2,3-diamine (3.00 g, 27.5 mmol) and the mixture was stirred at 80° C. for 2 hours. After water was added to the reaction mixture, the resulting solid was collected by filtration, washed with ethanol and dried under reduced pressure. Thus, pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione (3.58 g, yield: 80%) was obtained.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.B.N1C=CC=CC=1C>CO.CC(O)=O>[CH:16]1([NH:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Agent: B
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccn1
Product: C(#Cc1ccc(NC2CCCC2)nc1)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
5-Phenylethynyl-pyridin-2-ylamine (100 mg, 0.515 mmol), cyclopentanone (77 mg, 0.927 mmol) and 2-picoline borane (85 mg, 0.927 mmol) were dissolved in 5.5 ml MeOH:AcOH (10:1 v/v) and stirred for 48 hours at 40° C. MeOH was then evaporated and the residue was acidified to pH 1 with 6 ml 10% HCl. The resulting white suspension was stirred for 2 hours. The mixture was extracted with dichloromethane and brine. The pH of the aqueous layer was adjusted to 12 by addition of conc. NaOH and the mixture was extracted twice with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silicagel (heptane/ethyl acetate 100:0→50:50 gradient). The desired compound was obtained as a light yellow solid (70 mg, 53%), MS: m/e=263.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20]Cl)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(CCl)CC2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C1CCN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CC1

Procedure:
2-Chloro-5-(4-chloromethylpiperidinosulfonyl)benzoic acid (0.5 g.) is dissolved in 10 ml. of 5N sodium hydroxide and refluxed for one hour. 10 ml. of water is then added and the mixture is acidified with concentrated hydrochloric acid. The precipitated solid is chromatographed on a 10 g. silica gel column with a developing solvent system of 1:7 benzene:hexane containing 5% acetic acid. 2-Chloro-5-(4-methylenepiperidinosulfonyl)benzoic acid, m.p. 157°-160° C., is isolated from the first fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25](SC)[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.Cl[C:35]1C=CC=C(C(OO)=O)C=1.[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25]([S:45]([CH3:35])(=[O:49])=[O:47])[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(SC)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(S(C)(=O)=O)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethyl-phenyl)-2-methylthiopyrazolo[1,5-a]pyrimidine (compound obtained in Reference Example A5; 11.0 g) in methylene chloride (400 mL) was added m-chloroperbenzoic acid (16.5 g) at 0° C., and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise an aqueous sodium thiosulfate solution at 0° C. under stirring, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the resultant crude product was washed with ethanol to give 6-(2-chlorophenyl)-3-ethoxycarbonyl-7-(4-trifluoromethylphenyl)-2-methylsulfonylpyrazolo[1,5-a]pyrimidine (10.7 g, yield: 91%) as a powder.
Reaction SMILES: O.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.N>CN(C=O)C>[CH2:19]1[O:20][CH:16]([CH2:15][CH2:14][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:17][CH2:18]1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: BrCCC1OCCO1
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCC2OCCO2)cc1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
A mixture of sodium 4-toluenesulphinate monohydrate (37.2 g, 0.19 mole) and 2-(2-bromoethyl)-1,3-dioxolane (20 ml, 0.17 mole) in dry DMF (100 ml) was stirred at room temperature for 64h, resulting in a homogenous solution. This was poured into ice/water (1 liter) containing conc. ammonia solution (100 ml) and stirred vigorously until a white precipitate formed. The solid was filtered off, washed with water, dried and recrystallised from propan-2-ol/ether to give the title compound (D24) as a white solid (28.7 g, 66%) m.p. 78°-80° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([S:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=4[CH:32]=3)(=[O:30])=[O:29])[CH2:24][C:23]2=[O:41])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:33]2[CH:32]=[C:31]([S:28]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[C:23](=[O:41])[CH2:24]3)(=[O:30])=[O:29])[S:35][C:34]=2[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1

Procedure:
Trifluoroacetic acid (4 mL) is added to a solution of 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.0 mmol) in CH2Cl2 (15 mL). After 1 h the reaction is concentrated and the residue is dissolved in CH2Cl2 and washed with Na2CO3, dried (MgSO4) and concentrated to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one. 1H NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 3H), 7.46 (dd, 1H), 3.86 (dd, 2H), 3.45 (s, 2H), 3.23 (d, 2H), 3.07 (d, 2H), 2.54 (dt, 2H), 2.39 (s, 1H), 1.83-1.75 (m, 1H), 1.56 (d, 2H), 1.24-1.11 (m, 2H); MS (Ion spray) 428 (M+H)+.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]([C:21]([O:23]C)=O)=[C:19]([N:29]=[CH:30]N(C)C)[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:20]([C:21]([OH:23])=[C:7]([C:6]#[N:8])[CH:30]=[N:29]2)=[CH:25][C:26]=1[O:27][CH3:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF at −78° C. was added a 3.51 ml of acetonitrile in 20 ml of THF during 10 min. After stirring at −78° C. for 30 min, the mixture was treated with 10 g of methyl 4-benzyloxy-2-(dimethylaminomethyleneamino)-5-methoxybenzoate in 20 ml of THF during 5 min. After 15 min at −78° C. the stirred mixture was warmed to 0° C. for a further 30 min. It was then treated with 5 ml of acetic acid, warmed to 25° C. and stirred for 30 min. The mixture was evaporated to dryness, and diluted with aqueous sodium bicarbonate. The resulting off-white solid was filtered, washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile was obtained as an off-white solid, dec>255° C.; mass spectrum (electrospray, m/e) M+H 307.
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[S:14])[NH:8][CH:7]2[CH3:15]>CC(C)=O.C(OCC)C>[IH:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:1])[NH:8][CH:7]2[CH3:15]
Reactant: CC1NC(=S)Nc2ccc(Cl)cc21
Reactant: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: CSC1=Nc2ccc(Cl)cc2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Methyl iodide (0.30 ml, 4.86 mmol) was added to a suspension of 6-chloro-4-methyl-3,4-dihydro-1H-quinazoline-2-thione (345 mg, 1.62 mmol) in acetone (4.8 ml). The mixture was stirred for 2 hours (r.t.), diluted with diethyl ether and the title compound (538 mg, 94%) was isolated from the reaction mixture by filtration.
Reaction SMILES: [NH2:1][C:2]1(O)[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][NH:3]1.N/[C:11](=[CH:16]\[CH3:17])/[C:12](OC)=[O:13].C(O)(=[O:20])C>C(Cl)(Cl)Cl.O>[Br:8][C:5]1[CH:6]=[C:7]([OH:20])[C:2]2[N:3]([CH:4]=1)[C:12](=[O:13])[CH:11]=[C:16]([CH3:17])[N:1]=2
Reactant: C/C=C(\N)C(=O)OC
Reactant: NC1(O)C=CC(Br)=CN1
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(=O)n2cc(Br)cc(O)c2n1

Procedure:
When a mixture of 189.0 g of 2-amino-5-bromo-2-pyridinol and 130.0 g of methyl 2-aminocrotonate is heated for 4 hours at an internal temperature of about 150°, a solid reaction product is formed. This solid is suspended in 2 liters of chloroform and 240 ml of water, and 20% aqueous acetic acid is added to adjust the aqueous phase to pH 5.5. The chloroform solution is separated, washed with saturated aqueous sodium chloride, dried, and concentrated to give 180.5 g of 7-bromo-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Reaction SMILES: [C:1]([C@H:3]1[C@H:7](O[Si](C)(C)C)[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:26])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C@H:3]1[C@@H:7]([F:26])[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)[C@H](O[Si](C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)[C@@H](F)C1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl trans-3-cyano-4-[(trimethylsilyl)oxy]-1-pyrrolidinecarboxylate (1.0 g, 3.52 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.90 mL, 7.40 mmole). After 3 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.51 g, 67%) as a colorless oil: LC-MS (ES) m/e 215 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F-].[K+]>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a solution of 1-bromo-4-nitro-benzene (2.02 g, 10 mmol) in toluene (20 mL) is added palladium tetrakis triphenylphosphine (1.156 g, 1 mmol), 4-t-butyl phenyl boronic acid (3.56 g, 20 mmol), and potassium fluoride (1.74 g, 30 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At the reflux temperature, water (5 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is, diluted with ethyl acetate and Celite® is added, followed by water. This mixture is then filtered through a pad of Celite®. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified by flash column chromatography, eluting with ethyl acetate/hexanes to afford 1.8 g of the product as a yellow solid. 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH3:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccccc1C(C)c1ccccc1OC
Agent: [Li]C
Solvent: CI
Solvent: CCOCC
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethane (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed. After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22].[CH3:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[CH:37]([NH2:39])[CH2:36][CH2:35]2>>[F:15][C:16]1[CH:17]=[C:18]([S:24]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:39][CH:37]2[C:38]4[C:34](=[CH:33][CH:32]=[CH:31][C:30]=4[O:29][CH3:28])[CH2:35][CH2:36]2)=[N:9]3)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1cccc2c1C(N)CC2
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)c4cc(F)c(F)c(F)c4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=500.0 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,4,5-trifluorobenzenesulfonyl chloride and rac-7-methoxy-indane-1-ylamine.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]Cl)=[O:24]>CC(C)=O.O>[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28][NH:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:24]
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 55.7 %

Procedure:
4.5 g of sodium iodide and 6.63 g of dry sodium carbonate are added to a solution of 4.03 g of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine and 6.41 g of 2-methoxycarbonylamino-6-methyl-benzyl chloride in 400 ml of dry acetone, and the mixture is heated under reflux for 6 h. After cooling to RT, 400 ml of water are added and the acetone is distilled off in a water jet vacuum. The aqueous residue is then extracted three times with each time 200 ml of ethyl acetate. The combined organic extracts are washed with 300 ml of water, dried over magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (toluene/dioxan=9:1 as eluent). The fractions with Rf =0.2 are concentrated and then recrystallized from diisopropyl ether. 4.71 g (56%) of the title compound of m.p. 136°-138° C. are isolated.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 48.1 %

Procedure:
Using the general method of Example 233 Part B except that the reaction was run at ambient temperature, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.00 g, 7.1 mmol) was reacted with methanesulfonyl chloride (1.65 mL, 21.3 mmol) to provide 1.23 g of N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a light yellow solid, m.p. 133.2-134.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)[C@H](CC(C)C)Nc1sncc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](Nc1sncc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A solution composed of methyl N-(4-bromoisothiazol-5-yl)leucinate (98 mg, 0.32 mmol) in methanol (1.5 mL) at 0° C. was treated with a 2.0 M solution of lithium hydroxide (1.0 mL, 2.0 mmol). The mixture was stirred rapidly at rt for 6 h and then recooled to 0° C. prior to acidification to pH 5.5with 2.0 M hydrochloric acid in water. The reaction vessel contents were poured into water, extracted with ethyl acetate (3×) and the combined organics were washed with saturated sodium chloride solution and dried (Na2SO4). Concentration in vacuo gave 92 mg of N-(4-bromoisothiazol-5-yl)leucine as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.Cl[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[F:13][C:4]1[CH:3]=[C:2]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:6][C:5]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)Cl
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-1-(methylsulfonylmethyl)benzene (2 g, 7.487 mmol) in dimethylformamide (11 mL) were added ethyl 2-chloropropionate (1.24 mL, 9.733 mmol), manganese (822 mg, 14.974 mmol) and (2,2′-bipyridine)nickel(II)-dibromide (196 mg, 0.524 mmol). Trifluoroacetic acid (4 drops) was added. The reaction mixture was stirred overnight at 60° C. After cooling down to room temperature, the mixture was hydrolyzed by 1N HCl (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo. The crude product was purified by CC (eluent: ethyl acetate/cyclohexane (1:1)) to give ethyl 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoate (966 mg, 45%).