Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([OH:26])[C:23]([OH:25])=[O:24].[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34].Cl.C(Cl)Cl>N1C=CC=CC=1>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:33]([C:29]1[O:28][CH:32]=[CH:31][CH:30]=1)=[O:34])[C:23]([OH:25])=[O:24]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(6S,9S,10S,11S,13S,16R,17R)-9,11-Epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (5 g) is dissolved in pyridine (15 mL) and cooled to 0° C. 2-Furoyl chloride (1.82 g) is added and the reaction mixture is stirred at room temperature. After 2 hours, the reaction mixture is added dropwise to a vigorously stirred solution of 6M HCl. DCM is added, the phases are separated and the organic phase is washed with water and brine. After drying over magnesium sulphate, evaporation affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 6.30 (1H, dd), 6.5 (2H, m), 6.55 (1H, d), 7.20-7.65 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)CCC(=O)O
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
Compound 2 (0.25 g, 1 eq.) was suspended in CH2Cl2 (12.5 ml, C=0.1M). Triethylamine (0.26 ml, 1.5 eq.) was added to the solution which was then stirred for 10 minutes. After stirring 4-dimethylamino pyridine (0.015 g, 0.1 eq.) and succinic anhydride (0.125 g, 1 eq.) were added and the reaction left to stir for 16 hours at room temperature. The reaction mixture was then shaken with 3×20 ml portions of hydrochloric acid (2M), the aqueous washings were subsequently extracted with 3×20 ml portions of diethyl ether. The DCM portion was discarded and the ether layers were combined and dried over anhydrous MgSO4, filtered and evaporated to yield a white solid 3 (0.199 g, 60% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[N:9][CH:8]=[CH:7][N:6]2[C:21]=1[C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[N:9][CH:8]=[CH:7][N:6]2[C:21]=1[C:22]([OH:26])([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCCC(=O)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Reactant: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The resulting 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (220 mg, 0.63 mmol) was dissolved in tetrahydrofuran (2 mL), then a 0.90M propylmagnesium bromide solution in tetrahydrofuran (3.6 mL, 3.2 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:5) to give the title compound (150 mg) as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>CS(C)=O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCNCC2)cc1
Temperature: 95 °C
Yield: 93.5 %

Procedure:
Potassium carbonate (20.7 g, 0.15 mol) was added to a solution of 4-fluorobenzonitrile (12.1 g, 0.1 mol) and piperazine (25.8 g, 0.3 mol) in dimethylsulfoxide (75 ml) and heated at 95° C. for 20 hours. The reaction was cooled and poured into water (1100 ml) and extracted into dichloromethane (4×400 ml). The organic solution was dried and the solvent removed in vacuo to yield 4-cyanophenylpiperazine (17.5 g, 93.6% yield):
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:34][C:35]1[C:36]([F:45])=[C:37]2[C:43]([NH2:44])=[CH:42][NH:41][C:38]2=[N:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:34][C:35]1[C:36]([F:45])=[C:37]2[C:43]([NH:44][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:11])=[CH:42][NH:41][C:38]2=[N:39][CH:40]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
2-Phenylpropanoic acid (653 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide (384 mg, 48.8% yield) was obtained as a solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([O:52][Si](C(C)(C)C)(C)C)[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([CH:70]([CH3:72])[CH3:71])([CH:67]([CH3:69])[CH3:68])[CH:64]([CH3:66])[CH3:65])[CH2:5][C:4]1=[O:73])[CH3:2]>CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([CH:64]([CH3:66])[CH3:65])([CH:70]([CH3:72])[CH3:71])[CH:67]([CH3:69])[CH3:68])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O[Si](C)(C)C(C)(C)C)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-t-butyldimethylsilyloxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone is treated with p-toluenesulfonic in methanol as in Example 67 to yield 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-hydroxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[CH3:16][S:17]SC>C1COCC1>[CH3:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[S:17][CH3:16]
Reactant: COc1ccc(Br)c(C)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To the cold (−78° C.) solution of 2-bromo-5-methoxy toluene (8 g, 0.04 mol) in dry THF (80 mL) under inert atmosphere, butyl lithium solution (1.6M solution in hexane; 36.8 mL, 0.058 mol) was added dropwise and the mixture was stirred for 1 h at same temperature. Dimethyl disulphide (7.7 mL, 0.08 mol) was then added dropwise and the reaction mixture was allowed to warm to room temperature over a period of 2 h. The reaction mixture was quenched with sat. ammonium chloride solution and extracted in diethyl ether. The combined organic extracts were washed with water and brine and dried. The solvent was evaporated in vacuo to yield 6.5 g of 2-methyl-4-methoxy thioanisole, which was used as such in Step 2 MS m/z 168 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Si:6]([O:13][CH2:14][C:15](=[O:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([OH:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: c1cscn1
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (2.98 ml, 3.88 mmol) was dissolved in THF (4 mL). Thiazole (0.252 ml, 3.52 mmol) in THF (2 mL) was added slowly. After 1 h, 1-(tert-butyldimethylsilyloxy)-2-propanone (0.816 ml, 423 mmol) in THF (2 mL) was added and the reaction was stirred for 3 h at room temperature. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel column chromatography (5%-10% EtOAc:hexanes) afforded 1-{[tert-butyl(dimethyl)silyl]oxy}-2-(1,3-thiazol-2-yl)propan-2-ol (383 mg, 40%) as a yellow oil. MS ESI: [M+H]+ m/z 274.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Na].[CH:23]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:28][CH2:29][O:30][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: OCCC1CCCC1
Agent: [Na]
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(OCCC2CCCC2)c2[nH]c(C(F)(F)F)nc12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the sodium salt of 2-cyclopentylethanol to obtain 4-(2-cyclopentylethoxy) -7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 397.3.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].II.[I:22]([O-])(=O)=O.[K+].O>S(=O)(=O)(O)O>[I:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17]
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=C(N1CCCc2ccc([N+](=O)[O-])cc21)C(F)(F)F
Agent: II
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(N1CCCc2c(I)cc([N+](=O)[O-])cc21)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
A solution of 7-nitro-1-trifluoroacteyl-1,2,3,4-tetrahydroquinoline (D4) (2 g, 7.3 mmol) in conc. sulfuric acid (10 ml) was cooled to 0° C. and treated with iodine (1.11 μg, 4.4 mmol) and potassium iodate (0.625 g, 2.9 mmol). The reaction was stirred at 0° C. for 3 h then room temperature for 2 h. The reaction mixture was slowly poured into water (150 ml) at 0° C. and extracted with DCM. This was washed with aq. sodium metabisulfite and water then dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by column chromatography gave the title compound (420 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.59 (m, 2H), 3.86 (m, 2H), 2.90 (t, 2H), 2.17 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]2[CH2:15][C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:18])=[CH:11][C:12]=3[OH:17])[O:7]2)=[CH:4][CH:3]=1.C(O[C:25](=[O:27])[CH3:26])(=O)C>S(=O)(=O)(O)O.O>[C:2]([O:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]2[CH2:15][C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:18][C:25](=[O:27])[CH3:26])=[CH:11][C:12]=3[O:17][C:6](=[O:7])[CH3:5])[O:7]2)=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: O=C1CC(c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C2CC(=O)c3c(OC(C)=O)cc(OC(C)=O)cc3O2)cc1

Procedure:
4',5,7-Trihydroxyflavanone (10.5 g) was stirred with acetic anhydride (50 ml) and sulphuric acid (5 drops) for 2 hr at room temperature, then poured into iced water. The product was extracted into ether and the extracted washed with water, followed by sodium bicarbonate solution. 4',5,7-Triacetoxyflavanone was obtained on evaporation of the ether, and this was dissolved in a mixture of tetrahydrofuran (250 ml) and ethanol (250 ml). Sodium borohydride (1.2 g) was added over 5 min, and the solution stirred for 30 min. Further borohydride (1.8 g) was then added and stirring continued for a further 30 min. The solution was acidifed by cautious addition of glacial acetic acid (8 ml). The solvent was evaporated off and the residual oil extracted into chloroform, washed with water, dried and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].S(=O)(=O)(O)O.[CH2:29](O)CC>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH3:29])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCCO
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 3, 300 mg) obtained in Example 3 in 1-propanol (6 ml), concentrated sulfuric acid (0.3 ml) was added and the mixture was stirred under reflux for 50 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: ethyl acetate/hexane=1/5) and desired fractions were concentrated under reduced pressure. The residue was purified by column chromatography on octadecylsilica (ODS) (eluent: methanol/water=4/1) and then crystallized from diisopropyl ether to yield propyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 23, 60 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][C:31](B(O)O)=[C:26]3[CH:25]=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]4[N:23]([S:20]([C:17]5[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=5)(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]=34)[CH:3]=[C:4]([NH2:12])[C:5]=2[CH:6]=[N:7]1
Reactant: Cn1ncc2c(N)cc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B(O)O)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)c5cnn(C)c5c4)ccnc32)cc1
Temperature: 100 °C

Procedure:
6-Bromo-1-methyl-1H-indazol-4-amine (300 mg), {1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}boronic acid (482 mg), tripotassium phosphate (845 mg) and Pd(dppf)Cl2 (97 mg) were added to 1,4-dioxane (7 ml) and water (3.5 ml). The reaction mixture was heated in the microwave at 100° C. for 15 min. After this time the reaction mixture was partitioned between water (20 ml) and DCM (20 ml). The organic layer was extracted then put through hydrophobic frits. The solvent was removed to afford a crude mixture. The residue was purified by column chromatography on silica (100 g) eluting with a gradient of 0-100% ethyl acetate:cyclohexane. Fractions containing desired product were combined and concentrated in vacuo to afford the title compound, 312 mg as an orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:15])=[CH:10][N:9]=1.[Cl-].[NH4+]>>[F:15][C:11]1[C:12]([NH2:14])=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ncc1F
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(N2CCOCC2)ncc1F

Procedure:
Morpholine (3 ml) was added to 2-chloro-5-fluoropyridin-4-amine (262 mg) obtained in the 2nd step, followed by microwave irradiation (Initiator™, 235° C., 2 hours, 2.45 GHz, 0-240 W). A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with a saturated ammonium chloride aqueous solution and saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure and a light brown solid of 5-fluoro-2-morpholinopyridin-4-amine (311 mg) was thus obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[CH:10](=O)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[CH:10](=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9])[CH3:11]
Reactant: N#CCc1cccnc1
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC=C(C#N)c1cccnc1
Temperature: 20 °C
Reaction time: 30 h

Procedure:
A mixture of 57 g of 3-pyridineacetonitrile, 23.3 g of acetaldehyde and 0.5 g of cesium carbonate were dissolved in 1 liter of ethanol. The solution was stirred at 20° C. for 30 hours, then partitioned between 2 liters of water and 1 liter of ether. The aqueous phase was extracted with three 1 liter portions of ether and then 500 ml of ethyl acetate. All organic layers were combined, dried and the solvent removed at reduced pressure giving an orange oil. This oil was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1), giving a pale yellow oil which was crystallized from methylene chloride-hexane, giving α-ethylidene 3-pyridineacetonitrile as white needles, mp 46°-47° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[N:30]=1)=[O:36]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cccc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3), was reacted with 6-aminopicolinic acid methyl ester and HBTU at 80° C. 17 h to give the title compound as a white solid. MS (m/e)=528.3 [M+H+].
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O.CCOCC>C1COCC1>[C:14]([O:13][C:12](=[O:18])[NH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([Br:19])[CH:6]=2)[NH:1][CH2:2]1)([CH3:15])([CH3:17])[CH3:16]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Reaction time: 0.25 h
Yield: 1863.5 %

Procedure:
To a solution of 1A (2.7 g, 10.9 mmol) in THF (50 mL) at RT was added dropwise a solution of pyridinium tribromide (3.83 g, 0.41 mmol) in THF (50 mL). After addition, the reaction mixture was stirred for 15 min, then water (60 mL) and ether (60 mL) added. The aqueous layer was separated, and extracted with EtOAc (2×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 50%) in hexane to give the title compound (2.5 g, 70% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[S:11]C#N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[SH:11]
Reactant: Cc1cc(SC#N)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(S)c(C)c(C)c1O
Temperature: 0 °C
Yield: 103.4 %

Procedure:
2,3,5-Trimethyl-4-hydroxyphenylthiocyanate (2 g, 10.35 mmol) was dissolved in 100 mL of anhydrous ether containing 25 mL of anhydrous tetrahydrofuran. This solution was added dropwise over 1 h to 100 mL of anhydrous ether containing LiAlH4 (0.9 g, 24 mmol) at room temperature. After a further hour at 20° C., the unreacted LiAlH4 was destroyed by cooling the heterogeneous mixture to 0° C. and adding moist ether (50 mL), H2O (50 mL), and 1 N HCl (50 mL). A further 50 mL of water was added and the organic phase was separated and washed with water (2×50 mL), NaHCO3 solution (2×50 mL), water (2×50 mL), and saturated NaCl (50 mL). The organic phase was dried over anhydrous MgSO4 and filtered and the solvent removed under reduced pressure. Silica gel column chromatography with 5% ethyl acetate in hexane gave 1.8 g (90%) of 2,3,5-trimethyl-4-hydroxybenzenethiol as a white powder, mp 86° C. [Lit.1 mp 86° C.].