Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=S)[CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1cccc(N=C=S)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add m-tolyl isothiocyanate (69 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and recrystallize from toluene/EtOAc. Suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) ppm 2.38 (s, 3 H) 6.90 (d, J=7.58 Hz, 1 H) 7.26 (t, J=7.77 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.43 (s, 1 H) 7.56-7.65 (m, 3 H) 7.82 (d, J=8.59 Hz, 1 H) 8.01 (dd, J=8.53, 1.33 Hz, 1 H) 8.27 (s, 1H); MS m/z=436.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]=1[N+:22]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]=1[NH2:22]
Reactant: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1N
Yield: 85.5 %

Procedure:
[4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.28 g, 0.80 mmol) and Na2S2O4 (1.12 g, 6.42 mmol) were treated substantially as described in Part E of Example 9 to give 0.22 g (84%) 4-(2-chloro-4-methoxy-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 321.8 [(M+H)+, 72].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][C:19]1[S:20][C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:22]([CH3:24])[N:23]=1>O1CCCC1>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[S:25]([C:21]2[S:20][C:19]([CH3:18])=[N:23][C:22]=2[CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CNc1ccc(OC)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)S(=O)(=O)c2sc(C)nc2C)cc1
Temperature: 0 °C
Yield: 16.7 %

Procedure:
Under nitrogen in a flame-dried round-bottomed flask fitted with a dropping funnel, stir bar and condensor, was added N-methyl-p-anisidine (1.0 grams, 7.29 mmol) in 30 mL of anhydrous tetrahydrofuran (THF). To this was added triethylamine (1.01 mL, 7.29 mmol) and the flask was cooled to 0° C. with an ice bath. Next, 2,4-dimethyl-5-thiazolesulfonyl chloride (1.54 grams, 7.29 mmol, Maybridge Chem. Co.) in 20 mL of THF was added dropwise and the reaction allowed to stir at 25° C. overnight. The reaction was quenched by pouring it slowly into 200 mL of saturated aqueous sodium bicarbonate and extracting the crude product with dichloromethane (CH2Cl2). After drying the organic extracts over magnesium sulfate (MgSO4), the solvent was removed in vacuo to a dark brown oil. Chromatography on silica gel, eluting with hexanes:ethyl acetate (EtOAc) (4:1), gave 380 mg of pale brown oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.Cl.[NH2:9][OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.Cl>O>[N:9](=[CH:2][C:3]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:5])[OH:10]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: COc1ccc(N)cc1
Reactant: NO
Agent: Cl
Solvent: O
Product: COc1ccc(NC(=O)C=NO)cc1
Temperature: 60 °C
Yield: 85.2 %

Procedure:
Chloral hydrate (9.6 g) was dissolved in 200 mL water containing 83 g sodium sulfate. The solution was warmed to 60° C., a solution of 11.4 g hydroxylamine hydrochloride in 50 mL water was added and the mixture was held at 60° C. In a separate flask, 6.4 g 4-anisidine and 4.3 mL concentrated hydrochloric acid in 80 mL of water and was warmed to 80° C. The first solution was added to the second and the resulting mixture was refluxed for 2 minutes, cooled slowly to room temperature, and then cooled in an ice bath. The tan precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 8.6 g (85% yield) of N-(2-hydroximinoacetyl)anisidine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH3:38])[CH:32]=3)=[C:25]([F:39])[CH:24]=2)=[C:13]([NH:15][CH2:16][C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH3:38])[CH:32]=3)=[C:25]([F:39])[CH:24]=1)[C:17](=[O:18])[CH2:16][NH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1cc(SCc2ccccc2)ccc1Nc1cc(F)c(-c2ccc(Cl)c(C)c2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1N1C(=O)CNc2cc(SCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a microwave vial was added, ethyl 2-((5-(benzylthio)-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)phenyl)amino)acetate (2.00 g, 3.54 mmol) followed by DCM (11.80 ml) and TFA (2.73 ml, 35.4 mmol). The vial was placed in the microwave for 30 min at 80° C. Solvent was removed in vaccuo and sodium bicarbate solution was added. The solution was extracted with DCM and organics dried over MgSO4, filtered and removed solvent in vaccuo. Used 6-(benzylthio)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (1.43 g, 2.76 mmol, 78% yield) without further purification. m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH2:8].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18]1[C:22]([C:23](Cl)=[O:24])=[C:21]([CH3:26])[O:20][N:19]=1>>[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH:8][C:23]([C:22]1[C:18]([C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[N:19][O:20][C:21]=1[CH3:26])=[O:24]
Reactant: COC(=O)CCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: Cl
Product: COC(=O)CCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 103.9 %

Procedure:
Methyl-4-aminobutanoate hydrochloride (668 mg, 4.34 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.19 g, 4.35 mmol) were converted to 1.60 g of the title compound by the procedure of Preparation 1 except that the residue was not treated with hexanes. (100%). EA calculated for: C16H16N2O4ClF: C, 54.17; H, 4.55; N, 7.90. Found: C, 54.41; H, 4.58; N, 7.78. MS(FD) m/z 355 (M+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:32])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C[Sn](C)(C)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>O1CCCC1.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>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH:3]=2)=[O:32])=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(I)c2)cc1
Reactant: C[Sn](C)(C)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(-c3nccs3)c2)cc1
Yield: 19.5 %

Procedure:
A mixture of 10 g of N-[3-iodophenyl)-4-(tetradecyloxy)benzeneacetamide, 4.96 g of 2-(trimethylstannyl)thiazole, and 638.62 mg of dichlorobis(triphenylphosphine)palladium (II) in 100 ml of tetrahydrofuran is refluxed under argon for 6 hours. The solvent is evaporated and the residue is partitioned between chloroform and 1N sodium hydroxide. The organic layer is dried and evaporated to a yellow solid residue. The residue is purified by chromatography on silica gel using chloroform. A total of 3.5 g of starting material is recovered as well as impure product which is crystallized from hexane:carbon tetrachloride to give 1.8 g of the desired product as a tan solid, m.p. 128°-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:54]([O:61][CH2:62][CH2:63][CH2:64]O)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Si:54]([O:61][CH2:62][CH2:63][CH2:64][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([C:57]([CH3:58])([CH3:59])[CH3:60])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 53.4 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (136 mg, 0.519 mmol), 3-(tert-butyldimethylsilyloxy)propanol (0.111 mL, 0.519 mmol) and 40% DEAD-toluene solution (0.237 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-[3-(tert-butyldimethylsilyloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (58.6 mg, yield 53%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[OH2:6].[NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(C)CN)OCC
Agent: Cl
Product: CC(CN)CP(O)O
Product: O
Temperature: 25 °C

Procedure:
A solution of 6.0 g of ethyl 3-amino-2-methylpropyl(diethoxymethyl)phosphinate in 30 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 7 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 10 ml of water under reduced pressure. The crude product is dissolved in 50 ml of dry ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-methylpropylphosphonous acid monohydrate, m.p. 96°-100° C. 31 p=+25.8 pp, (D2O).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][NH:6][C:7](=[O:10])[CH:8]=[CH2:9].[CH3:14][Cl:15]>O>[Cl-:15].[C:7]([NH:6][CH2:5][C:4]([CH3:12])([CH3:11])[CH2:3][N+:2]([CH3:14])([CH3:1])[CH3:13])(=[O:10])[CH:8]=[CH2:9]
Reactant: CCl
Reactant: C=CC(=O)NCC(C)(C)CN(C)C
Solvent: O
Product: C=CC(=O)NCC(C)(C)C[N+](C)(C)C
Product: [Cl-]

Procedure:
Into a vigorously stirred 80° C. solution of 376 g N-(3-dimethylamino-2,2-dimethylpropyl)-acrylamide (TEMAPA of Example 1) in 320 g water, there was introduced over a period of 3.5 hours under a working pressure of 0.4 bar 103 g methyl chloride. An aqueous solution of the quaternary product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:16]1([N+:22]#[C-:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:24]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>Cl(O)(=O)(=O)=O>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:23]([NH:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Nc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2NC2CCCCC2)cc1

Procedure:
Compound (7) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of 4-acetamidobenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])(O)[CH3:10])=[CH:4][CH:3]=1.[C:13](#[N:15])[CH3:14].S(=O)(=O)(O)[OH:17].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:15][C:13](=[O:17])[CH3:14])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CC(C)(O)Cc1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)NC(C)(C)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
A solution of 3.5 g (15.4 mmol) of 1-(4-bromophenyl)-2-methyl-propan-2-ol in 20 ml of glacial acetic acid was treated with 630 mg (15.4 mmol) of acetonitrile and cooled in ice. 10 ml of concentrated sulfuric acid was added slowly and the mixture stirred for 72 hours. The mixture was poured into 300 ml of ice/water and neutralised with potassium carbonate. The product was extracted with diethyl ether (2×250 ml). The combined organic phases were dried over magnesium sulfate, filtered and evaporated. The product was purified by recrystallisation from diethyl ether/hexane to give 3.3 g (80%) of N-[2-(4-bromophenyl)-1,1-dimethyl-ethyl]acetamide as a white solid. [Mass spectrum (ESI) MH+ =270].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.[S:28]([O:33]C)([O:31][CH3:32])(=[O:30])=[O:29]>C(Cl)Cl>[CH3:32][O:31][S:28]([O-:33])(=[O:30])=[O:29].[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([CH3:32])=[CH:12][CH:11]=[CH:10]2
Reactant: COS(=O)(=O)OC
Reactant: COC1(c2cc(F)cc(OCc3ccc4ncccc4c3)c2)CCOCC1
Solvent: ClCCl
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc[n+]4C)c3)c2)CCOCC1
Product: COS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]quinoline (1.835 g), dimethyl sulphate (0.52 ml) and methylene chloride (25ml) was stirred and heated to reflux for 16 hours. The mixture was cooled to ambient temperature and the precipitate was filtered off to give 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]-1-methylquinolinium methyl sulphate (1.9 g) in 77% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:7]1[CH:6]=[CH:5][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=1)([O-:4])=[O:2]
Reactant: O=C1CCCCc2ccccc21
Reactant: O=[N+]([O-])O
Product: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen, to fuming nitric acid (60 ml) was added 6,7,8,9-tetrahydrobenzocyclohepten-5-one (20 g) on ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was poured into ice water (200 ml). The precipitates were collected by filtration and dissolved into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][CH:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:48][N:47]=[N:46][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][CH:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.26 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) and toluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 46%).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].CC1C=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.CI>C(OCC)C>[CH2:3]([C:1]1[CH:2]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH3:4]
Reactant: Cc1ccc2ccccc2n1
Reactant: [Li]C(C)CC
Solvent: CCOCC
Solvent: CI
Product: CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
sec-Butyllithium (1.3 M in cyclohexane, 19.3 mL, 25.1 mmol, 1.2 eq.) was added dropwise to a 0° C. solution of 2-methylquinoline (2.84 mL, 3.0 g, 21.0 mmol, 1.0 eq.) in dry diethyl ether (75 mL). After the addition was complete the cooling bath was removed and the mixture was stirred at r.t. for 1.5 h. The reaction mixture was cooled to 0° C. and methyl iodide (1.96 mL, 4.46 g, 31.4 mmol, 1.5 eq.) was added dropwise. After the addition was complete the cooling bath was removed and the reaction was stirred at r.t. for 3 h. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure which gave the crude product (4.82 g) as an orange oil. The crude product was purified by column chromatography (SiO2, 1:5 ethyl acetate-cyclohexane) which yielded the product (3.03 g, 92% yield) as a clear yellow oil; 1H NMR (500 MHz, CDCl3) δ 1.41 (t, J=7.5 Hz, 3H, CH3), 3.01 (q, J=7.5 Hz, 2H, CH2), 7.31 (d, J=8.5 Hz, 1H, Ar), 7.48 (t, J=7.5 Hz, 1H, Ar), 7.68 (t, J=7.5 Hz, 1H, Ar), 7.77 (d, J=8.0 Hz, 1H, Ar), 8.04 (d, J=8.5 Hz, 1H, Ar), 8.07 (d, J=8.5 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[OH:21])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(CC2CCCC2=O)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C[C@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 710 mg (2.48 mmoles) of the title product of Example 5 in 25 ml of ethanol was added dropwise a solution of 188 mg (4.97 mmoles) of sodium borohydride in 3 ml of water. After 30 minutes, acetic acid was added, most of the ethanol was evaporated, the residue was partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer was further extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue using 15% ethyl acetate/hexane as eluent gave the title cis isomer (105 mg) and the title trans isomer (155 mg) as colorless oils. The structures were supported by 1H NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH:12]([NH:14][C:15]3[C:16]([CH3:27])=[N:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[NH:14][CH:12]([CH3:13])[CH2:11][CH2:10][C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc5c(c4)OCO5)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using (3-benzo[1,3]dioxol-5-yl-1-methyl-propyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21](Cl)(=[O:23])=[O:22])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:23])=[O:22]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1Sc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2Sc2ccccc2)c1Br
Yield: 83 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole (192 mg, 1.1 mmol) and 3-phenylthio-thiophene-2-sulfonyl chloride (300 mg, 1.0 mmol). Purification by column chromatography using 10% MeOH/CHCl3 yielded 358 mg (83%) of the pure sulfonamide as a brown oil.