Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([CH3:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=1[CH:9]=O)C.[BH4-].[Na+].P(Br)(Br)[Br:23]>C(O)(=O)C>[Br:23][CH2:4][C:5]1[O:6][C:7]2[C:14]([CH3:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=2[CH:9]=1
Reactant: CCOC(COc1c(C)cc(F)cc1C=O)OCC
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(F)cc2cc(CBr)oc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A stirred solution of 20 (350 mg, 1.30 mmol) in acetic acid (10 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product (300 mg) was dissolved in THF (5 mL). NaBH4 (78 mg, 2.02 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvents were evaporated off in-vacuo. The crude residue (260 mg) was dissolved in toluene (20 mL) and the solution was cooled to 0° C. PBr3 (135 μL, 1.44 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 21 (200 mg, 36%). 1H NMR (500 MHz, CDCl3): δ: 7.03 (1H, d, J=7.50 Hz, H-4), 6.88 (1H, t, J=9.80, H-5), 6.75 (1H, s, H-3), 4.69 (2H, s, 2-CH2), 2.54 (3H, s, CH3).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[S:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[S:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=S)Nc1ccc(Br)cc1
Agent: Cl
Product: O=c1c(=NNC(=S)Nc2ccc(Br)cc2)c(=O)c2ccccc12

Procedure:
ninhydrin, 4-(4-bromophenyl)-thiosemicarbazide hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.O.NN>C(O)C.Cl[Fe](Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2F)cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccncc2F)cc1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a refluxing mixture of 3-fluoro-4-(4-nitrophenyl)pyridine (2.23 g), trichloroiron (130 mg) and activated carbon (1.12 g, 50 wt % of the starting material) in ethanol (74 mL) was added dropwise hydrazine hydrate (1.6 g), and the mixture was stirred for 3 hours. The insoluble materials were removed by filtration in hot and washed with ethanol. Most of ethanol was removed in vacuo, and to the residue was added water. Resulting solid was collected by filtration, and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:2) to afford 4-(3-fluoropyridin-4-yl)aniline (1.36 g) a pale orange solid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:17](Br)[CH:18]=[CH2:19]>CO.CN(C)C=O>[CH2:19]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH:18]=[CH2:17]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium hydroxide (8.0 gm, 0.2 ml) in methanol (170 mL) was added dropwise to a solution of 6-hydroxybenzothiazole-2-sulfonamide (23.0 gm, 0.1 mol) and allyl bromide (10.0 mL, 0.12 mol) in dry dimethylformamide (100 mL). This mixture was stirred at room temperature for 16-20 hours and then poured into hydrochloric acid-ice water. The precipitate was collected by filtration, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. This residue was triturated with methylene chloride and the crystalline product was collected. (wt. 9.9 gm), m.p. 184°-187° C. A sample was recrystallized from 1,2-dichloroethane, m.p. 193°-195° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=4)[C:11]4[N:16]=[CH:15][S:14][C:12]=4[N:13]=3)[CH2:4]2)=[O:34])=[CH:31][N:30]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(N)nc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 6-aminonicotinic acid (40 mg, 0.27 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 5 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with a mixture of CH2Cl2 and methanol (100:1→15:1) to give 6-amino-N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)nicotinamide (40 mg, 33%). 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 8.81 (s, 1H), 8.475-8.46 (m, 1H), 8.27-8.25 (m, 2H), 7.60-7.25 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.47-6.39 (m, 3H), 4.54-4.52 (m, 1H), 3.76-3.58 (m, 10H), 2.34-2.04 (m, 2H). LC-MS: 247 [M/2+H]+, 493 [M+H]+, 491 [M−H]−, tR=1.22 min. HPLC: 95.20% at 214 nm, 95.06% at 254 nm, tR=5.64 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)=[O:16])[CH3:2].I[C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][N:41]=[C:42]([NH2:43])[C:35]=12>>[NH2:43][C:42]1[C:35]2[C:36](=[N:37][CH:38]=[CH:39][C:34]=2[C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15]([NH:14][C:5]3[CH:6]=[C:7]([C:10]([F:11])([F:13])[F:12])[CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:16])=[CH:19][CH:20]=2)[NH:40][N:41]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1n[nH]c2nccc(I)c12
Product: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2ccnc3[nH]nc(N)c23)cc1

Procedure:
1-(2-Ethoxy-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea is coupled, by Suzuki reaction, with 4-iodo-1H-pyrazolo[3,4-b]pyrid-3-ylamine according to the preparation of Example 6. A yellow powder of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-ethoxy-5-trifluoromethylphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:46])([CH3:45])[C@@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:22]1[C:23]3[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][C:24]=3[O:25][C:21]=1[C:20]2([CH3:44])[CH3:43])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[CH3:53][N:54](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([SiH2:5][O:6][C:7]([CH3:45])([CH3:46])[C@@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:22]1[C:23]3[CH:29]=[CH:28][C:27]([C:53]#[N:54])=[CH:26][C:24]=3[O:25][C:21]=1[C:20]2([CH3:44])[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(OS(=O)(=O)C(F)(F)F)ccc4c2C3=O)O1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(C#N)ccc4c2C3=O)O1
Temperature: 200 °C

Procedure:
Trifluoro-methanesulfonic acid 8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6 dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester (Compound Z14, 24 mg) was dissolved in DMF (0.5 mL), added with zinc (II) cyanide (8.2 mg) and palladium tetrakistriphenylphosphine (2.0 mg), and the mixture was stirred under heating at 200° C. for 20 min with microwave irradiation. To the reaction mixture, ethyl acetate was added and the organic layer was washed with saturated brine. Thereafter, the organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (15 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of the product from Example 1A (1.0 g, 3.05 mmol) in anhydrous THF (30 ml) at 0° C. was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at 50° C. overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gm, 81% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH:28]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])[CH3:29]>>[OH:26][CH2:27][CH:28]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])[CH3:29]
Reactant: CC(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1-methyl-ethyl)-amide (example B.16) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 65%). MS (ISP) 570.2 [(M+H)+]; mp 225–226° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[N:9]=[C:8]([O:14][CH3:13])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: Cc1c(Cl)c(Cl)nc(Cl)c1C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)c(C#N)c(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a slurry of 2,5,6-trichloro-4-methyl-nicotinonitrile (11.0 g, 49.67 mmol, Tetrahedron, 1977, 33, 113-117) in MeOH (125 ml) is added sodium methoxide solution (25% wt. in MeOH)(11.92 ml, 52.15 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, then room temperature for 1 hour. The reaction is quenched by the addition of water (300 ml) and a thick, white precipitate is formed. An additional 200 ml of water is added and the mixture is stirred at 0° C. for 10 minutes. The precipitate is collected by filtration and dried (vacuum oven for 16 hours at 60° C.) to give the title compound as an off-white solid (10.05 g, 93%). Mass (m/z): 217.0 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:29]=[C:26]([CH:27]=[O:28])[C:25]([OH:30])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([CH:29]=1)[CH:27]=[O:28]
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.87 g, 9.6 mmol) in DMF (20 mL) was added 5-chlorosalicylaldehyde (1.65 g, 10.5 mmol), potassium carbonate (2.64 g, 19.2 mmol) and potassium iodide (1.59 g, 9.6 mmol). The resulting mixture was heated to 100° C. for 12 hours. The reaction was cooled, diluted with saturated aqueous brine and extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. Purification via chromatography on silica gel (15% EtOAc/Hexanes) gave the title compound 3.40 g, 85% yield.)
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccc(C(F)(F)F)cc2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc(C(F)(F)F)cc2)C1=O
Yield: 75.9 %

Procedure:
A solution of Example 139B (0.262 g) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with 95%water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.172 g, 78%).
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([O:3][CH2:4][CH3:5])=[O:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNc1cc(C(F)(F)F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
Dissolve 2-(Carbethoxy)methylamino-4-trifluoromethylbenzonitrile (2.34 g, 8.6 mmol) in tetrahydrofuran (40 mL) and add dropwise with stirring to a solution of potassium tert-butoxide (9.46 mL of a 1M tetrahydrofuran solution) under a nitrogen atmosphere at 0° C. The reaction was allowed to warm to room temperature. After 3 hour, dilute with ethyl acetate, rinse with water, saturated sodium chloride, dry magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography to yield the 3-amino-2-carbethoxy-6-trifluoromethylindole (1.22 g, 52%); mp 204°-210° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Li]C1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:34]=2)[CH:32]=[O:33])=[CH:23][CH:22]=1>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:32]([C:31]2[CH:34]=[C:27]([O:26][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:37][CH:36]=3)[CH:28]=[CH:29][C:30]=2[CH3:35])[OH:33])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: COc1ccc(COc2ccc(C)c(C=O)c2)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C)c(C(O)c3ccc(Br)cc3[N+](=O)[O-])c2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,4-dibromo-2-nitro-benzene (5.89 g, 21.00 mmol) in THF (300 ml) was added a solution of PhLi (1.8 M in cyclohexane/diethyl ether 7:3, 12.8 ml, 23.1 mmol) at −110° C. The mixture was stirred at the same temperature for 1 h. Compound 502 (4.45 g, 17.4 mmol) in THF (100 ml) was dropwise added to the mixture. The reaction mixture was then allowed to warm to −78° C. and stirred at the same temperature for 4 h. Afterwards, the reaction mixture was quenched with saturated aqueous solution of NH4Cl. the aqueous phase was extracted once with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 5:1), furnishing a reddish foam.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[N:17]=[C:16]([C:19](O)=[O:20])[CH:15]=[CH:14][C:13]=2[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[N:17]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:15]=[CH:14][C:13]=2[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (0.66 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A80. A solution of 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (256.9 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B80. Solution B80 was added to Solution A80 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-methanesulfonamide (93.2 mg, 30%) as a white solid: MS (ESI) M+1=445.1.
Reaction SMILES: [CH2:1]([C:12]#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:14]([NH:17][CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>C(=S)=S>[CH:14]([N:17]1[CH2:18][CH2:19][N:20]=[C:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH3:12])([CH3:16])[CH3:15]
Reactant: CC(C)NCCN
Reactant: CCCCCCCCCCCC#N
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NCCN1C(C)C
Yield: 81.4 %

Procedure:
18.324 g of Undecyl cyanide, 15.12 g of N-isopropylethylenediamine and 0.5 ml of carbon disulfide were heated at 125° C. for 24 hrs. and worked up as mentioned under Example 23, followed by distillation at 150° C./1.2 mm gave 21.93 g (82.3%) of the product.
Reaction SMILES: Br[C:2]1[S:11][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[S:11][C:5]3[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=3[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCc2cc(Br)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c(s2)C(=O)NCC3)cc1
Yield: 82.9 %

Procedure:
Combine 2-bromo-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (1.024 g, 4.42 mmol), 4-methoxyphenyl boronic acid (0.671 g, 4.42 mmol), Na2CO3 (0.94 g, 8.83 mmol), in water (10 mL), dimethoxyethane (75 mL) and CH3OH (50 mL). Purge with nitrogen for 5 min. Add Pd(PPh3)4 (0.153 g, 0.1325 mmol) and reflux the resulting mixture overnight. Cool the reaction to RT and dilute with water (100 mL). Extract with EtOAc (3×100 L), and concentrate. Treat the residue with EtOAc (40 mL), collect the solid and wash with EtOAc (20 mL) and Et2O (2×20 mL) to give the title compound (0.950 g). Concentrate the filtrate and purify the resulting residue by chromatography to give additional product (0.140 g). The overall yield is 1.090 g (95%). MS/ES m/z 260.0 [M+H]+.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]2[O:12][C:13]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:15]2[C:14]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=3[O:12][C:11]3[CH:23]=[CH:24][C:8]([CH3:7])=[CH:9][C:10]=3[CH:16]=2)[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(C)ccc1O2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
A solution of 11.35 ml. of titanium (IV) chloride in 135 ml. of benzene is added dropwise with stirring and cooling at 20°-25° C. to a solution of 30 g. of 10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one and 80 ml. of N-ethoxycarbonylpiperazine in 300 ml. of benzene. Then, the mixture is stirred for 4 hours at reflux and cooled. The cooled mixture is poured into a solution of 12 g. of sodium bicarbonate in 300 ml. of water. The precipitated titanium dioxide is removed by filtration and washed well with benzene. The filtrate is washed four additional times with water. The aqueous phases are extracted again with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated in vacuo, and there is obtained 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Br:15]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CBr)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at −10° C. was added carbon tetrabromide (CBr4) (7.17 g, 21.6 mmol). The resulting mixture was stirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portion-wise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g), 1H NMR (400 MHz, CDCl3) δ4.6 (s, 2 H) 7.5 (dd, J=8.3, 1.6 Hz, 1 H) 7.8 (m, 2 H).