Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[H][H].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>ClCCCl.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[CH:15]([OH:20])[C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: -30 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrine hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -30° C., a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. On raising the temperature of the resulting suspension from -30° C. to room temperature over 2 hours, 87 ml of hydrogen gas was generated. Thereafter, a solution of 0.39 g (1.2 mmoles) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane was added to this suspension at room temperature, and then stirring was carried out for 23 hours. Thereafter, 6 ml of 2M hydrochloric acid was added, followed by stirring for 2 hours. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. By gas-chromatographic analysis, it was found that the conversion was 96.4%, and the composition of the reaction product was: E-form alcohol, 98.3% and Z-form alcohol, 1.7% (Z-form alcohol was produced through isomerization of the ketone compound to the Z-form, followed by reduction of the carbonyl group).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:37][CH:36]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-amide as a white solid. (Yield 35 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:33])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C#N)CC1

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (723 mg) described in Preparation Example 189 and pyrrolidin-2-one (196 μL) and by the reaction and treatment in the same manner as in Example 20262, the title compound (668 mg) was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:47][CH2:48][C@@H:49]1[O:53][C:52](=[O:54])[N:51]([C:55]2[CH:60]=[CH:59][C:58]([C:61]3[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=3)=[C:57]([F:68])[CH:56]=2)[CH2:50]1>CN(C=O)C>[F:68][C:57]1[CH:56]=[C:55]([N:51]2[CH2:50][C@H:49]([CH2:48][NH:47][C:18](=[O:20])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH:10]=[O:11])=[CH:22][CH:21]=3)[O:53][C:52]2=[O:54])[CH:60]=[CH:59][C:58]=1[C:61]1[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C=CC(=O)NC[C@H]2CN(c3ccc(C4=NNC(=O)CS4)c(F)c3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (0.169 ml, 0.972 mmol) is added to 4-formylcinnamic acid (0.057 g, 0.324 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.129 g, 0.340 mmol) in DMF (2 ml) and is stirred for 20 minutes at room temperature. 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.100 g, 0.308 mmol) is added and stirring is continued at room temperature overnight. The reaction mixture is partially evaporated under vacuum and the residue is diluted with water (5 ml). The resulting precipitate is filtered and dried under vacuum to give crude product used directly in the next step (0.076 g, 51%). MS (m/z): [M+H]+=483.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1cccc(C=O)c1
Product: CCOC(=O)C=Cc1cccc(C)c1
Yield: 87.8 %

Procedure:
3-Methylbenzaldehyde (12.0 g, 100 mmol) and mono-ethyl malonate (15.5 ml, 130 mmol) were reacted as described under General Procedure A to furnish the title compound (16.7 g, 88%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=16.0 Hz, 1H), 7.34-7.18 (m, 4H), 6.42 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:18]=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH3:22][C:23]([CH3:25])=O>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:18]=[C:23]([CH3:25])[CH3:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2N=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)=NN1CC(c2ccc(F)cc2)c2cc(C)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
3-(4-Fluorophenyl)-5-methyl-1-nitrosoindoline (1.2 g, 0.00468 mol) was dissolved in acetone (60 mL). To this was added saturated ammonium chloride solution (6.0 mL) and the reaction mixture was cooled to 0° C. Zinc dust (1.2 g, 0.0187 mol) was added portionwise over 30 min. at 0° C. After the addition, the reaction mixture was stirred for 1 h at RT. After completion of reaction (monitored by TLC), the reaction mixture was filtered through Celite, solvent was removed under reduced pressure and the residue purified by column chromatography (8% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.78 g, 60% yield).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][N:32]1[C@@H:25]([CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: COC(=O)C(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCN1[C@@H](C)c1ccccc1
Reaction time: 9.5 h
Yield: 78.1 %

Procedure:
Methyl (RS)-2,5-dibromovalerate (24.5 g) and toluene (19.8 g) were added to a 49% aqueous potassium carbonate solution (53.3 g), and heated to 80° C. (S)-α-methylbenzylamine (12.0 g) was added dropwise to the mixture obtained above at that temperature, and was stirred at that temperature for 9.5 hours. Water (33.9 g) was added to the reaction mixture, and then the organic layer was separated from the resulting mixture. Separated organic layer was washed with water, a 1% aqueous hydrochloric acid solution and water in this order, and concentrated under reduced pressure. Thus, N-[(S)-α-methylbenzyl]-(RS)-proline methyl ester (16.3 g) was obtained in a yield of 77.8%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][N:11]=1)=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=1)=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCCc3scnc3C)cc([N+](=O)[O-])c2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 18 h
Yield: 45.5 %

Procedure:
10% Palladium on carbon (0.20 g) was added under an argon atmosphere to a solution of methyl 2-[3-nitro-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylate (1.05 g, 1.7 mM) in ethyl acetate (50 ml)/ethanol (50 ml). Hydrogen gas was introduced and the reaction mixture stirred vigorously for 18 hrs before filtering through diatomaceous earth, concentration in vacuo and replacement of the catalyst (80 mg). After stirring under hydrogen gas for a further 18 hrs a final catalyst change was carried out, after which the crude aniline was purified on silica gel (1% to 4% MeOH/DCM) to give the title compound as a colourless solid (0.43 g, 60%); 1H NMR δ (d6-DMSO): 2.36 (s, 3H), 3.18 (dd, 2H), 3.88 (s, 3H), 4.12 (dd, 2H), 5.32 (bs, 2H), 6.33 (m, 1H), 6.79 (m, 2H), 8.30 (m, 2H), 8.81 (s, 1H), 8.88 (m, 1H), 10.90 (bs, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[N:4][N:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][Cl:11].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[ClH:11].[Cl:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[N:5]([CH3:12])[N:4]=[C:3]2[C:2]=1[C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:16]=[C:13]2[NH2:14]
Reactant: Cn1nc(C#N)c(Br)c1CCCCCl
Reactant: Nc1ccccc1B(O)O
Agent: Cl
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Temperature: 115 °C

Procedure:
The method described in Part F of Example 46 was used to couple 4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile (16.0 g, 60.0 mmol) and 2-aminophenylboronic acid hydrochloride (20.8 g, 0.120 mol). After the mixture was heated at 115° C. for 24 hours, it was cooled to ambient temperature and filtered through a plug of silica gel (eluting with 3:2 chloroform/methanol). The filtrate was concentrated under reduced pressure and dissolved in ethanol (300 mL). Hydrogen chloride (45 mL of a 4 M solution in ethanol) was added to the solution, and the reaction was heated at reflux for two hours and then cooled to ambient temperature. A precipitate formed and was isolated by filtration and washed with ethanol to provide 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride. The filtrate was concentrated under reduced pressure and the resulting solid was dissolved in dichloromethane and water. The pH of the solution was raised to 14 using 50% aqueous NaOH while keeping the temperature at 0° C. by adding ice. The layers were separated, the aqueous layer was extracted with additional dichloromethane, the organic layers were combined, dried over Na2SO4, filtered and concentrated to a dark yellow oily solid. The residue was purified by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine. This solid was purified as light tan crystals, mp 188-189° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(Cl)CCl.CCOC(C)=O>[OH:1][C:2]1[C:3]([C:8](=[S:20])[NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=S)c1ncccc1O
Yield: 69.1 %

Procedure:
A stirred solution of 3-hydroxypicolinamide (1.35 g, 9.75 mmol) and Lawesson's reagent (2.37 g, 5.85 mmol) in dry ClCH2CH2Cl (12 mL) was heated to reflux under nitrogen for 5 hr. At ambient temperature, the mixture was diluted with EtOAc (50 mL), washed with half-saturated aq. NaCl (30 o5 mL) containing NaHCO3 (840 mg) and with brine (20 mL). After drying over MgSO4 and filtration, the filtrate was concentrated in vacuo to give a brown solid, which was subject to flash chromatography on silica gel CH2Cl2 as eluent) to provide 3c (623 mg, 42%) as a greenish yellow solid after crystallization from EtOAc/hexane. mp 152.0°-153.0° C.; IR (KBr) 3372, 3259, 2464, 1626, 1458, 1317 cm-1 ; 1H NMR (DMSO-d6) δ 7.33 (1H, dd, J=8.6 and 1.0 Hz, Ar), 7.46 (1H, dd, J=8.6 and 4.3 Hz, Ar), 8.07-8.10 (1H, m, Ar), 8.15(1H, s, NH), 8.49 (1H, s, NH), 12.76 (1H, s, OH); FABMS m/z 154 (M+); Anal. Calcd for C6H6N2OS: C, 46.74; H, 3.92; N, 18.17. Found: C, 46.83; H, 3.89; N, 17.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:23]=[C:11]3[N:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25]1[C:29]([CH:30]=O)=[C:28]([CH3:32])[O:27][N:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:24][C:25]1[C:29]([CH2:30][N:20]2[CH2:19][CH2:18][N:17]([C:13]3[N:14]=[C:15]([NH2:16])[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:23]=[C:11]4[N:12]=3)[CH2:22][CH2:21]2)=[C:28]([CH3:32])[O:27][N:26]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3cccc(F)c3)nn12
Reactant: Cc1noc(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4cccc(F)c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3Fluoro-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 3,5-dimethyl-isoxazole-4-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 6.9-7.25 (m, 3 H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 424 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>ClCCl>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To a suspension of potassium carbonate (7.06 g, 50 mmol, 1.50 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (9.98 g, 34.05 mmol) in dichloromethane (50 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (13.8 g, 37.8 mmol, 1.10 equiv.) in dichloromethane (50 mL) at room temperature. After 3 h at this temperature, the solids were filtered off and water was added to the filtrate. The mixture was extracted with dichloromethane and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diethyl ether to yield the title compound (10.1 g, 52%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.[CH3:28][O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:32]=1Br.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(OCC)C.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>[CH3:28][O:29][C:30]([C:31]1[C:32]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[C:33]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)=[O:41]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Heat the mixture of propane-2-sulfonic acid {2-[4-{4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide(662 mg, 1.65 mmol), 2-bromo-3-nitro-benzoic acid methyl ester (390 mg, 1.5 mmol), Na2CO3(2M, 2.2 mL, 4.5 mmol) and Pd(PPh3)4 (260 mg, 0.26 mmol) and 15 ml of 1,4 dioxane under N2 to 80° C. overnight. After cooling to room temperature, dilute with diethyl ether (200 mL). Wash with water, saturated aq. sodium chloride, and dry over MgSO4. Remove solvent and purify by flash chromatography (Silica gel-hexane/EtOAc) to provide 6-nitro-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (250 mg). MS (m/e): 478.7(M+1).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[CH3:19][O:20][C:21]([C:23]1[N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=[C:26]([CH:28]=[O:29])[CH:27]=1)=[O:22]>O.CC(C)=O>[CH3:19][O:20][C:21]([C:23]1[N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=[C:26]([C:28]([OH:3])=[O:29])[CH:27]=1)=[O:22]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(C=O)cn1S(C)(=O)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cn1S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
The Jones reagent was made up in 1.00-mol batches by dissolving 100 g of CrO3 in a minimum of distilled water. Sulfuric acid (87 mL) was added and more water (200 mL total) was then added to effect solution of precipitated CrO3. The final volume was 350 mL (2.86 M with respect to CrO3). To a solution of 4-formyl-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (700 mg, 3.03 mmol) in acetone (5 mL) was added the Jones reagent at 10° C. dropwise until a persistent orange color was observed. The reaction mixture was stirred for additional 20 minutes, and then the orange color was removed by the addition of isopropyl alcohol. After dilution with water (20 mL) the solution was extracted with CHCl3 (3×30 mL). The combined organic layers were washed once by water and then extracted to aqueous NaHCO3 solution (60 mL). The NaHCO3 solution was acidified by concentrated HCl to pH 2 and the resulting white precipitate was collected by filtration and washed with cold water. The crude product was dried on the oil pump for the next step without further purification (600 mg, 80%). 1H NMR (500 MHz, DMSO-d6) δ12.87 (s, 1H), 7.91 (s, 1H), 7.30 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H) ppm. MS (ES+): m/e=248.1 (M+H); LC/Method A/2.38 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:44][C:45]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1ccc(NS(C)(=O)=O)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.2 mmol) was treated with N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (100 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 50 mg (35% yield) of the title compound as a yellow oil. Purity 98%.