Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[OH-].[Na+].C([C:8]1[C:9]([Br:19])=[N:10][S:11][C:12]=1[NH:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])(=O)C.S(=O)(O)[O-].[Na+].Cl>O1CCOCC1>[Br:19][C:9]1[C:8]([Br:1])=[C:12]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[S:11][N:10]=1
Reactant: CC(=O)c1c(Br)nsc1NC(=O)C1CC1
Reactant: BrBr
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1snc(Br)c1Br)C1CC1
Yield: 55 %

Procedure:
Add bromine (118.3; mL, 2.30; mol) over 1; hour to a cooled aqueous solution of sodium hydroxide (3.77; M, 2.44; L, 9.21; mol) at 0° C. and stir 15; min. To this solution, add a solution of cyclopropanecarboxylic acid (4-acetyl-3-bromo-isothiazol-5-yl)-amide (155.7; g, 0.51; mol) in 1,4-dioxane (856.3; mL, 10.03; mol) over 100; min maintaining the temperature below 5° C. Stir for 1.5; hour maintaining the internal temperature below 10° C. Add an aqueous solution of sodium bisulfite (77.8; mL, 0.377; mol), stir for 5; min and add 12; M hydrochloric acid (390.1; mL, 4.60; mol) over 15; minutes maintaining the temperature below 25° C. Hold the mixture without stirring for 10; min then remove the supernatant, filter the remaining suspension, wash the recovered solid twice with water (200; mL) and dry under vacuum to give the title compound as a yellow solid (91.21; g, 55%). MS (m/z): 325, 327, 329; (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:4]=1[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:13](=[O:15])[CH3:14])=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0° C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm a to 25° C. The reaction mixture was stirred at 25° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtrated and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CC(C)([O-])C.[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:38]=[CH:37][C:29]3[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[S:32][C:28]=3[CH:27]=2)[CH:23]=[CH:22][N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([C:20]1[CH:25]=[C:24]([C:26]2[CH:38]=[CH:37][C:29]3[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[S:32][C:28]=3[CH:27]=2)[CH:23]=[CH:22][N:21]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)c3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N(C)S(=O)(=O)c4ccc(C)cc4)c3)cc2s1
Reaction time: 0.08 h

Procedure:
A microwave vial equipped with a stir bar was charged with n-methyl-p-toluenesulfonamide (0.26 g, 1.4 mmol) in DMF (3 ml). Then sodium t-butoxide (0.270 g, 2.8 mmol) was added to the mixture and allowed to stir 5 minutes. Then palladium(II) acetate (0.013 g, 0.057 mmol), N-(6-(2-chloropyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.173 g, 0.57 mmol) and Xantphos (0.010 g) was added to the mixture. The vial was capped and placed into a CEM Microwave for 20 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product peaks. The mixture was diluted with DMSO and purified by reverse-phase HPLC. This gave N-(6-(2-(N,4-dimethylphenylsulfonamido)pyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.010 g, 3.9% yield) as a tan solid. MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for C22H20N4O3S2: 452. 1H NMR (300 MHz, DMSO-d6): 2.03 (s, 3H), 2.37 (s, 3H), 3.24 (s, 3H), 7.32-7.42 (d, 2H), 7.44-7.73 (m, 6H), 7.80 (s, 1H), 8.14 (s, 1H), 8.29 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[N:24]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CCOc1cccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of 3-bromo-4-nitro-1H-indazole (1.5 g, 6.20 mmol) in DMF (0.5M, 12 mL) was added potassium carbonate (1.71 g, 12.4 mmol) at ambient temperature. After 15 minutes, 2-(chloromethyl)-6-ethoxypyridine hydrochloride (1.29 g, 6.20 mmol) was added. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated and diluted with ice-water (300 mL). Precipitated solids were collected by filtration, washed with water and dried under high vacuum overnight to provide 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (1.21 g, 52% yield).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.O1CCCC1.[Si:33]([O:50][CH2:51][C:52]1[S:56][C:55]([CH:57]=[O:58])=[N:54][N:53]=1)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:33]([O:50][CH2:51][C:52]1[S:56][C:55]([C:57](=[O:58])[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:54][N:53]=1)([C:46]([CH3:47])([CH3:48])[CH3:49])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(C)[Si](OCc1nnc(C=O)s1)(c1ccccc1)c1ccccc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (141 mg) in a mixed solvent of ethanol (1 mL) and tetrahydrofuran (1 mL) were added 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazole-2-carbaldehyde (171 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (12.1 mg) and triethylamine (24.4 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (168 mg, yield 57%) was obtained as white crystals from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:13][C:12]([F:14])([F:15])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)cc1
Yield: 96.4 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 2, 1-(2-nitro-vinyl)-4-trifluoromethyl-benzene (I-4a: 2.5 g, 11.52 mmol) was reacted with LAH (856 mg, 23.04 mmol) in dry THF (50 mL) to afford 2.1 g of the product (96.77%).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16](O)([CH3:19])([CH3:18])[CH3:17]>FC(F)(F)C(O)=O>[C:16]([C:5]1[NH:6][C:7]2[C:12](=[CH:11][C:10]([C:4]([CH3:12])([CH3:5])[CH3:3])=[CH:9][C:8]=2[C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=1[CH2:3][C@@H:2]([C:13]([OH:15])=[O:14])[NH2:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(C)(C)C)c2[nH]c(C(C)(C)C)c(C[C@H](N)C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tryptophan (4.00 g, 19.59 mmol), trifluoroacetic acid 98% (60 ml) and tert-butanol (15.54 g, 209.66 mmol) were mixed. The reaction mixture was stirred at room temperature for 48 hours. The trifluoroacetic acid was evaporated. The residue was suspended in 40 ml distilled water, and the pH adjusted to neutral with addition of sodium hydrogen carbonate. The crude product was obtained by filtration. Crystallisation from 50% ethanol affored the product as a white powder (85-90% pure).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:12]([O:16][C:17]([N@:19]1[CH2:21][CH:20]1[CH3:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:22])[CH2:21][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1CN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)c2occc2c1
Product: C[C@@H](Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Yield: 45.5 %

Procedure:
Beginning with 0.94 gm (4.4 mMol) 5-fluoro-7-bromobenzofuran and 0.63 mg (4 mMol) (S)-(+)-N-tert-butoxycarbonyl-2-methylaziridine, 0.534 gm (46%) of the desired compound were prepared essentially as described in Example 10.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCN1CCC(N)CC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(NC(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.0 Grams of N-acetylsulphanilyl chloride were added in portions to a stirred, ice cooled, mixture of 4.7 grams of 4-amino-1-n-butyl piperidine and 6.3 grams of sodium bicarbonate in 75 milliliters of water and 35 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, washed with water, and dried to give 4.2 grams of the title compound. Melting Point 174°-175°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[O:26]=[C:27]([CH3:31])[C:28](O)=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[C:28]([OH:29])[C:27](=[O:26])[CH3:31]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: CC(=O)C(=O)O
Product: CC(=O)C(O)=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2-oxopropionic acid by the method of Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:19][C:20]#[N:21])[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N+:22]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1)([O-])=O>>[C:20]([CH2:19][C:13]1([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:25]4[CH:38]=[CH:37][C:28]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:27][CH:26]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1)#[N:21]
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CC(C#N)C1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(OCCN5CCCC5)cc4)n3)cn2)CC(C#N)C1

Procedure:
The cis- and trans-isomers of the titled compound were prepared as a racemic mixture according to the procedure described in example 306, using 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-cyclobutanecarbonitrile and 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine as starting materials. First isomer retention time 1.055 min, LCMS (M+H) 469.4. Second peak retention time 1.072 min, LCMS (M+H) 469.4.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[Mg].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)c1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc([Si](C)(C)C)cc2)cc1

Procedure:
C-1) A Gringnard reagent consisting of 0.2 mol of 4-trimethylsilylchlorobenzene and 0.2 mol of magnesium was prepared in tetrahydrofuran, mixed with 0.2 mol of 4-methylbenzaldehyde and subjected to Oppenauer oxidation reaction to obtain 4-methyl-4'-trimethylsilylbenzophenone represented by the following chemical structural formula: ##STR19## The reaction product was actually used in the form of a 15% solution in isopropyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([N:36]=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)nc3N21
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture consisting of 0.20 g (0.54 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, 91 μl (0.54 mmol) benzophenone imine, 73.0 mg (0.76 mmol) sodium tert-butoxide, 5.6 mg (0.01 mmol) tris(dibenzylideneacetone)dipalladium chloroform complex and 10.1 mg (0.02 mmol) R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene in 3 ml toluene was stirred at reflux for 1 h. The reaction mixture was cooled to room temperature, poured into 10% aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (2:1) as eluant to afford the product as a yellow foam (94.3%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:16][CH3:17]>C(O)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:1](=[O:3])[CH3:2])=[CH:11][C:10]=1[O:16][CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)ccc1Br
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (13 mL) is added to an ice-cold solution of 4-bromo-3-methoxy-phenylamine (25.0 g) in acetic acid (100 mL). The mixture is stirred for 1 h and then diluted with ice-cold water (500 mL). The precipitate is separated by filtration, washed with water and dried at 60° C. to give the product.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O>O>[CH2:7]([C:6]1[O:14][C:12]([C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:10][C:11]=1[CH:12]=[O:14])[CH3:8]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Product: CCc1oc(-c2ccccc2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 137.4 %

Procedure:
To a solution of (2-ethyl-5-phenylfuran-3-yl)methanol (5.9 g) obtained by the above-mentioned reaction in methylene chloride (30 mL) was added Dess-Martin reagent (14.8 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane) to give the title compound (4.8 g, 83%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:20])([CH3:19])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:19])([CH3:20])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[S:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)(=[O:37])=[O:36])=[CH:21][CH:22]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc3c(c2)C(=O)NCC3(C)C)c1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
To a stirred solution of 7-(4-chloro-benzylamino)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (20 mg, 0.06 mmol) and pyridine (12 μl, 0.14 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (25 mg, 0.14 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative HPLC (Method A) to afford the title compound as a colourless solid (15 mg, 21%). HPLC retention time 4.07 min. Mass spectrum (ES+) m/z 459 (M+H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:4]=1.FC(F)(F)C1C=C(C2C=CC([N+]([O-])=O)=CC=2)N=C(SC)N=1.[N+](C1C=CC(C(=O)CC(=O)C(F)(F)F)=CC=1)([O-])=O.FC(F)(F)C1C=CC(B(O)O)=CC=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1COCC1.S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(C(F)(F)F)nc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [Cu+2]
Agent: [Pd]
Agent: CSc1nc(-c2ccc([N+](=O)[O-])cc2)cc(C(F)(F)F)n1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(C(F)(F)F)nc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 52 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
4-Trifluoromethyl-6-(4-nitrophenyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine. A solution of 4-trifluoromethyl-2-methylsulfanyl-6-(4-nitrophenyl)-pyrimidine (1.25 g, 4.0 mmol, prepared from 1-(4-nitrophenyl-4,4,4-trifluorobutane-1,3-dione according to Green et al. WO 200138311 A2), 4-trifluoromethylphenylboronic acid (0.95 g, 5.0 mmol), trifurylphosphine (140 mg, 0.60 mmol), and copper (II) 2-thiophenecarboxylate (1.05 g, 5.0 mmol) were combined in 25 mL of dry THF and heated to 52° C. The catalyst tris(dibenzyl-ideneacetone)dipalladium(0)-chloroform adduct (100 mg) was then added in three portions over 3 h, and the solution was then allowed to stir at 50° C. for 12 h. Concentration and chromatography (Biotage, 4:1 hexane/DCM) furnished 0.67 g (41%) of the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=8 Hz, 2H), 8.41 (s, 4H), 8.03 (s, 1H), 7.80 (d, J=8 Hz, 2H); EIMS 414.1 (M+H); mp 162° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:25][CH:26]([CH2:31]OS(C)(=O)=O)[C:27]([O:29][CH3:30])=[O:28]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: COC(=O)C(C)COS(C)(=O)=O
Product: COC(=O)C(C)Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Yield: 38.6 %

Procedure:
Following the general method as outlined in Example 6 Step 1, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 683 mg; 2.00 mmol) and methyl 2-methyl-3-((methylsulfonyl)oxy)propanoate (588 mg; 3.00 mmol), 341 mg (39%) of the title compound was obtained as a colorless oil after purification by a silica gel chromatography (petroleum ether/EtOAc=3/1 to 2/1).
Reaction SMILES: C([NH:4][C@H:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:6][CH:7]([CH3:9])[CH3:8])(=O)C.N>Cl>[N:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C@@H:5]([NH2:4])[CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)N[C@@H](CC(C)C)c1ccccc1N1CCCCC1
Agent: Cl
Agent: N
Product: CC(C)C[C@H](N)c1ccccc1N1CCCCC1

Procedure:
1 g (3.47 mMol) of N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine (melting point: 128-133° C.; ee=99.4%] are refluxed in 10 ml of concentrated hydrochloric acid for 5.5 hours, then cooled and poured into a mixture of concentrated ammonia and ice. The mixture is extracted twice with ethyl acetate, the organic phase is washed with water, dried and filtered and then evaporated down in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]3([CH2:27][CH2:26][C:18]4(OCC(C)(C)C[O:19]4)[CH2:17][CH2:16]3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]3([CH2:27][CH2:26][C:18](=[O:19])[CH2:17][CH2:16]3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: Cl
Solvent: CC(C)=O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
A solution of 3-[(S)-1-(4-bromo-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one (0.75 g), aqueous hydrochloric acid (5 mL), and acetone (10 mL) is stirred at room temperature overnight. The acetone is then evaporated, and the residue is diluted with saturated aqueous K2CO3 solution and extracted with ethyl acetate. The combined extracts are washed with water and brine, dried (MgSO4), and concentrated to give the crude title compound that is used without further purification. Yield: 0.70 g (ca. 65% pure); Mass spectrum (ESI+): m/z=366/368 (Br) [M+H]+.