Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:30]=[CH:29][NH:28][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24](O)=[O:25])[C:18](=[O:27])[CH2:17][CH2:16]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:46][C:41]2C=C[CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55]CN(C(C)C)C(C)C.CNN(CC)NC>CN(C=O)C>[CH:1]1([NH:5][C:6]2[C:7]3[CH:30]=[CH:29][NH:28][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([NH:46][CH2:41][CH2:40][N:45]([CH3:44])[CH3:55])=[O:25])[C:18](=[O:27])[CH2:17][CH2:16]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Agent: CCN(NC)NC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid 4 mg, 0.01 mmol) in DMF (0.3 mL) was added HATU, DIPEA and N,N-dimethylaminoethylamine. After stirring for 1 h at room temperature, it was then purified by prep HPLC to give 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)-N-(2-(dimethylamino)ethyl)acetamide (MS calcd for C25H32N8O2 476.3. found [MH] 477.0; UV 205.1, 304.5 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]2OC(C)(C)C(C)(C)O2)[CH:3]=1.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=C[N:29]=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][N:29]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH2:8])[CH:31]=1
Reactant: CC1(C)OC(c2cc(Cl)ccc2N)OC1(C)C
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
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: O
Solvent: COCCOC
Product: Nc1ccc(Cl)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-chloro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzenamine (300 mg, 1.17 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (15 mL), N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide (432 mg, 1.20 mmol, 1.00 equiv), a solution of sodium carbonate (636 mg, 6.00 mmol, 5.00 equiv) in water (3.0 mL), and Pd(PPh3)4 (138 mg, 0.12 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 85° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined, and washed with brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1). The product was obtained as 260 mg (55%) of a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1)#[N:2].Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.8 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(7-cyano-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (1.1 g, 2.8 mmol) in chloroform (15 ml) was added 4N HCl in 1,4-dioxane (15 ml) and the reaction stirred at rt for 45 mins. Toluene was then added and the solution was evaporated, dissolved in MeOH and treated with Amberlyst A21 basic resin for 30 m until pH of the solution is basic. The resine was filtered off and the solvent removed; the residue was subjected to column chromatography on silica gel eluting with 0-15% 2M ammonia in methanol-DCM to afford the desired compound (0.82 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:25]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:28]=[CH:27][N:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Clc1cc(-c2ccccc2)ccn1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (5.96 g, 19.28 mmol), 2-chloro-4-phenylpyridine (4.39 g, 23.13 mmol), tris(dibenzylideneacetone)palladium(0) (0.353 g, 0.386 mmol) and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.8 g, 1.951 mmol) were charged into a 500 mL 2-neck flask. Potassium phosphate tribasic (12.26 g, 57.8 mmol) was then dissolved in 45 mL of water. This solution was charged into the reaction mixture. The reaction mixture was degassed with nitrogen then was heated to reflux overnight. The reaction mixture was cooled to room temperature. The toluene layer was separated and was dried over magnesium sulfate. These organics were filtered and concentrated under vacuum. The crude product was passed through a silica gel column using 70-99% toluene/heptanes followed by 5-15% ethyl acetate/toluene. Some of the impure product fractions were columned on silica gel using 5-15% ethyl acetate/DCM. All the clean product fractions were combined yielding 2-methyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.3 g, 15.76 mmol, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH:41]=[CH2:42])=[N:9]2)=[CH:5][CH:4]=1.B1C2CCCC1CCC2.[OH:54]O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42][OH:54])=[N:9]2)=[CH:43][CH:44]=1
Reactant: C=Cc1nn(Cc2ccc(OC)cc2)c2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c12
Reactant: OO
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of N-(4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.357 g, 0.60 mmol) in THF (5 mL) was added a 0.5 M solution of 9-BBN (3.60 mL, 1.80 mmol) in THF. The reaction was stirred for 18 hours at room temperature. The reaction was cooled in an ice bath, and then was quenched by addition of 2N aqueous NaOH (3 mL). After stirring for 10 minutes in the ice bath, 30% aqueous hydrogen peroxide (0.577 mL, 6.00 mmol) was added. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was partially purified by Biotage Flash 40, eluting with 30% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, then neat EtOAc. The resulting solid was further purified by preparative TLC, eluting with 5% MeOH (containing 7N NH3) in DCM. The product was obtained as a waxy, white solid (179 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.49 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.75 (m, 1H), 7.46 (m, 2H), 7.32 (d, J=9 Hz, 2H), 7.27 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 6.17 (d, J=6 Hz, 1H), 5.57 (s, 2H), 4.09 (m, 2H), 3.76 (s, 3H), 3.36 (t, J=6 Hz, 2H), 2.76 (s, 1H), 1.80 (m, 2H), 1.63 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]#[N:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(N=NC(C#N)=C2NC(C)(C)Cc3ccccc32)cc1

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia), thionyl chloride and DMF are mixed and stirred slowly. An excess of thionyl chloride is removed from the mixed solvent by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:16])[CH:12]=[CH:13][C:14]#[N:15]>C(O)C>[NH2:15][C:14]1[CH2:13][CH:12]([CH:11]([CH3:16])[CH3:10])[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: CC(C)C=CC#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC(C)C1CC(N)=NN1c1ccccc1

Procedure:
A 0.31 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 6.3 g. of phenylhydrazine is added followed by 5.5 g. of 4-methyl-2-pentenonitrile. The reaction mixture is refluxed for 16 hours. The solvent is removed in vacuo, water is added to the residue and the mixture is extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and evaporated to give a gum. The gum is chromatographed on a column containing 400 g. of a synthetic magnesium silicate absorbent. The column is eluted first with protions of 21/2% acetone-hexane and 5% acetone-hexane to remove exteraneous colored material, then with portions of 25% and 10% acetone-hexane to remove the product. The product cuts are evaporated to give 2.7 g. of a dark gum which solidifies on standing. This material is recrystallized twice from ether-hexane to give 1.7 g. of the product of the Example as tan crystals, m.p. 115°-117° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:10]C)(=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[C:12](#[N:14])[CH3:13].Cl>O.C1(C)C=CC=CC=1.CS(C)=O>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:10])[CH2:13][C:12]#[N:14]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)CC#N
Temperature: 82 °C

Procedure:
In the reaction apparatus described in Example 4 were placed 40.5 g (0.75 mol) of sodium methoxide, 58.1 g (0.50 mol) of methyl pivalate, 30.8 g (0.75 mol) of acetonitrile, and 58.1 g of dimethyl sulfoxide (relative dielectric constant at 20° C.: 48.9) under nitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6 hours. After the reaction was complete, 400 mL of toluene was added to the reaction mixture. To the mixture were added 56.7 mL (0.68 mol) of hydrochloric acid (12 mol/L) and 100 mL of water, keeping the temperature of the resulting mixture at 30° C. or lower. After the reaction mixture became to have pH 2.0, the mixture was extracted with 3 portions of 100 mL toluene. The toluene portions were combined and washed with 30 mL of an aqueous saturated sodium hydrogen carbonate solution and then dried over magnesium sulfate. The toluene solution was filtered and then analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that the following products were produced:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](OC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1ccccc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 12.5 g (50 mmol) (E,E)4,8,12-trimethyl-trideca-3,7,11-trienoic acid (isomeric purity of 95%) [K. Ishihara et al., J. Am. Chem. Soc. 2002, 124, 3647-3655] in 100 ml MTBE were added at r.t. 8.4 g (50 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.5 g DMAP. After stirring for 15 min, 10.5 g (51 mmol) DCC is added, during which the temperature raised to 35° C. The reaction mixture was stirred for 4 h at 35° C., cooled to room temperature and filtered. The resulting solution was concentrated in vacuo to a volume of ca. 50 ml and filtered over 100 g of silicagel. The product was eluted with ca. 600 ml hexane/MTBE 1:1. Concentration of the combined fractions in vacuo and drying of the product in high vacuo (50° C./0.08 Torr) afforded 19.8 g (98%) of (E,E)-4,8,12-Trimethyl-trideca-3,7,11-trienoic acid (S)-methoxycarbonyl-phenyl-methyl ester (2) in form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].BrC[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Br:1])[CH3:26]
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Br
Temperature: 65 °C

Procedure:
A mixture of 11.6 g of 7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, 17.5 g of ethyl bromoacetate, 13.3 g of potassium carbonate and 100 ml of dimethylformamide is heated at 65° C. for 5 hr. The reaction mixture is poured into water and the mixture is extracted with ether. The ether extracts are washed, dried and evaporated to afford ethyl{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6yl]oxy}acetate, mp 130°-131° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[S:5][C:6]=1[CH3:7].FC1(F)OC2C=C(C)C(C3N=C[C:25]([NH:28][C:29](=O)[C:30]4[CH:35]=[CH:34]C=CC=4F)=[N:26]C=3)=CC=2O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(#N)C.O>[CH3:7][C:6]1[S:5][C:4]2[CH2:8][CH2:9][CH2:10][CH2:11][C:3]=2[C:2]=1[C:30]1[CH:35]=[CH:34][C:25]([NH2:26])=[N:28][CH:29]=1
Reactant: Cc1sc2c(c1Br)CCCC2
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1sc2c(c1-c1ccc(N)nc1)CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Palladium tetrakis-triphenylphosphine (12 mg, 10 μmol) was added to a degassed solution of bromide 239 (46 mg, 0.2 mmol) and boronate 11 (88 mg, 0.4 mmol) in dioxane:acetonitrile:water (9:9:2, 1.5 mL) and potassium phosphate (63 mg, 0.3 mmol). The resulting mixture was heated under argon at 90° C. with stirring for 4 hours. The mixture was then cooled, extracted with dichloromethane (3×10 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 240 (32 mg, 66%) as an oil: LRESIMS m/z 245.1 [M+H]+, calcd. for C14H17N2S1 245.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1.O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH2:8][Br:11])[CH:7]=1
Reactant: COc1ncc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: COc1ncc(CBr)cc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromo-2-methoxy-5-methyl-pyridine (4.0 g, 19.8 mmol), N-bromosuccinimide (4.45 g, 23.8 mmol), and azobisisobutyronitrile (0.163 g, 0.99 mmol) were combined in benzene (40 mL) and stirred overnight at 80° C. The reaction was stirred for another 24 hours at 80° C., and then additional N-bromosuccinimide (1.8 g, 10.1 mmol), and azobisisobutyronitrile (catalytic) were added. After stirring for another 2 hours at 80° C., the mixture was diluted with H2O and extracted with CH2Cl2. The residue was purified by silica gel chromatography to give 3-bromo-5-bromomethyl-2-methoxy-pyridine.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH2:5][OH:6].Cl[CH2:16][C:17](OCC)=[O:18]>C1COCC1>[F:14][C:9]1[CH:8]=[C:7]([CH:4]2[NH:3][C:17](=[O:18])[CH2:16][O:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CCOC(=O)CCl
Reactant: NC(CO)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at 0° C. was added a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (7.51 mmol, 1.3 g) in 20 THF dropwise via an addition funnel and after 30 min ethyl chloroacetate was added dropwise via syringe. The orange colored reaction mixture was stirred for 2 hours at 0° C. and then for 2 hours at 35° C. The solvent was removed and the 5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick yellow oil (0.5 g). 1H NMR showed that the product was about 85% pure and any attempts to purify it further by column chromatography were not successful. It was used in the next reaction as described below without further purification.
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:8]=1)[CH:2]=[CH2:3].P(=O)(O)(O)O.[OH2:30]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][N:4]2[C:1]3[C:21](=[CH:22][CH:23]=[CH:3][CH:2]=3)[CH2:20][CH:19]2[CH3:24])=[O:30])=[CH:8][C:9]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reactant: O
Agent: O=P(O)(O)O
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 4 h

Procedure:
A mixture of 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine (36.6g, 0.1 mole) and orthophosphoric acid, 85% (100 ml) was stirred at 60° for a period of 4 hours. Dilution with water gave crude 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline which was purified by recrystallization from isopropanol-n-hexane (60:40).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][S:24][CH3:25])=[O:10].[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:13][C:12]=3[CH2:22][CH2:23][S:24][CH3:25])=[O:10])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CSCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CSCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3S (m/e) 424, obsd 425 (M+H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:22]([F:37])[C:23](F)=[C:24]([C:26]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[N:27][OH:28])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:46][S-:47].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OC(=O)C)C>[CH3:44][C@@H:42]1[CH2:43][N:38]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([C:29]4[CH:34]=[N:33][C:32]([S:47][CH3:46])=[CH:31][N:30]=4)=[N:27][O:28][C:23]=3[C:22]=2[F:37])[CH2:39][C@H:40]([CH3:45])[O:41]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)c3cnc(Cl)cn3)c(F)c2F)C[C@H](C)O1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cnc(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
1-{5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}-1-(5-chloropyrazin-2-yl)-N-hydroxymethanimine (Intermediate 200, 400 mg, 0.61 mmol) in DMF (5 mL) was treated with sodium thiomethoxide (45.3 mg, 0.61 mmol) at room temperature, the mixture was stirred at room temperature for 10 min. K2CO3 (5 eq) was added and the mixture was heated to 100° C. for 1 hour. The reaction mixture was diluted with ethylacetate (20 ml). Organic layer washed with water and brine, then dried over sodium sulfate, filtered, and the filtrate was concentrated, purified by silica gel column chromatography (Hexanses/EtOAc, gradiant) to give the desired product (97 mg, 39.0%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][O:13][CH3:14].Cl.CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
10 g of 6-chloro-pyridine-2-carboxylic acid are dissolved in 50 ml of thionyl chloride and heated under reflux for 3.5 h. The solution is cooled and freed from excess thionyl chloride under reduced pressure. The crude product is taken up in 60 ml of methylene chloride and treated with 7.22 g of N,O-dimethyl-hydroxylamine•hydrochloride. 25 ml of NEt3 in 30 ml of CH2Cl2 are added while cooling with ice and the solution is stirred at RT for 1.5 h., the suspension is filtered and the filtrate is washed with dilute sodium hydroxide solution and saturated sodium chloride solution and dried. After concentration of the solution 13.12 g of 6-chloro-pyridine-2-carboxylic acid methoxy-methyl-amide are obtained as the crude product. 6.7 g of this amide in 40 ml of THF are added dropwise at −78° C. to a solution of 40 ml of n-BuLi (1.6M in hexane) and 15 g of 1,4-dibromobenzene in 140 ml of THF. The solution is stirred at −78° C. for 2 h. and at 0° C. for 1 h. and then treated with 60 ml of 2M HCl. The phases are separated, the inorganic phase is extracted with 50 ml of ether and the organic phases are washed with sat. NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified over silica gel with ethyl acetate:hexane (6:1) and recrystallized from ethyl acetate/hexane. There are obtained 6.75 g of (4-bromo-phenyl)-(6-chloro-pyridin-3-yl)-methanone, m.p 127.4° C., MS: m/e 295 (M, 1Br).