Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C([Sn]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(CCCC)CCCC)CCC.O>CN(C=O)C>[CH3:15][CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCC(C)Oc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(C)Oc1ccc(-c2cccs2)cc1
Temperature: 100 °C
Reaction time: 68 h
Yield: 44.4 %

Procedure:
Tetrakistriphenylphosphinpalladium(0), (20.45 g, 17.70 mmol) is suspended in anhydrous DMF (400 mL) in a 2000 mL 3-necked flask with magnetic stirrer and condenser under an argon atmosphere. To this, 1-bromo-4-(1-methyl-hexyloxy)-benzene (240.00 g, 884.96 mmol) and tri-n-butylstannylthiophene (330.24 g, 884.96 mmol) are added. The resulting solution is stirred at 100° C. for 68 hours. After cooling to room temperature the mixture is poured into water (2000 mL) and divided into two portions of the same volume. Extraction with n-hexane (3×300 mL) results in two layers and an emulsion between those two layers. The organic layers are separated, combined, washed with diluted sodium chloride solution (2×400 mL) and dried (MgSO4). After removal of solvent by rotary evaporation most of the byproducts are removed by distillation (p=10−3 millibar, maximum temperature Tmax=130° C.). The residue is subjected to filtration using a layer of SiO2 (30×10 cm) and n-hexane as eluent. After removal of solvent, a yellowish oil (107.88 g, about 44%) with sufficient purity for synthetic purposes is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (2.28 mmoles, 0.54 g-see Example 35) and pyrrolidine (5.26 mmole, 0.375 g.) were dissolved in THF and stirred at room temperature. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and concentrated to yield 0.583 g of 5-(2-Cyanophenyl)-2(1-pyrroidinomethyl)-1H-benzimidazole.
Reaction SMILES: [BH4-].[Li+].[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]2[N:11]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=3[CH3:24])[C:12](=O)[CH:13]([CH3:14])[C:5]=12.Cl.[OH-].[Na+]>O1CCCC1>[Cl:23][C:19]1[CH:18]=[C:17]([CH3:24])[C:16]([N:11]2[C:6]3=[N:7][C:8]([CH3:10])=[CH:9][C:4]([NH2:3])=[C:5]3[C:13]([CH3:14])=[CH:12]2)=[C:21]([CH3:22])[CH:20]=1
Reactant: Cc1cc(N)c2c(n1)N(c1c(C)cc(Cl)cc1C)C(=O)C2C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Yield: 56 %

Procedure:
To a suspension of lithium borohydride (11.6 g) in tetrahydrofuran (50 mL) was added a solution of 4-amino-1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (33.7 g) in tetrahydrofuran (100 mL) was added. The mixture was stirred at reflux for 1 hour. After cooling with ice-cooling bath, a 6M HCl aqueous solution was added slowly. The solution was made to alkaline (pH=9) with 4 M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=3:1) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) as a solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[N:12]=[C:11]1[CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1.[Cl:33]CCl.[ClH:36]>CO>[ClH:33].[ClH:36].[NH:23]1[CH2:24][CH2:25][CH:20]([C:11]2[N:10]([CH2:9][CH2:8][OH:7])[CH:14]=[C:13]([CH2:15][C:16]([F:18])([F:17])[F:19])[N:12]=2)[CH2:21][CH2:22]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CC(F)(F)F)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: CO
Product: OCCn1cc(CC(F)(F)F)nc1C1CCNCC1
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (3.12 g, 6.76 mmol), dichloromethane (88 mL), and methanol (35 mL). Add hydrogen chloride (17.3 mL, 10.2 eq) (4 M in dioxane) slowly. Stir overnight under nitrogen. Concentrate in vacuo to give 2-(2-(piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethanol dihydrochloride (2.37 g, 100%). MS (ES) m/z=278 [M]+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]([NH:9][C@H:10]1[CH2:27][C:26]2=[CH:28][N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:29])=[O:8])(=O)C.[NH4+].[OH-]>CO>[SH:4][CH2:5][CH:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]([NH:9][C@H:10]1[CH2:27][C:26]2=[CH:28][N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:29])=[O:8]
Reactant: CC(=O)SCC(CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(CS)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the less polar stereoisomer of (10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide (50 mg, 0.106 mmol) in 10 mL of methanol at 0° C. under argon was added 0.5 mL concentrated NH4OH. The reaction mixture was stirred from 0° C. (ice-bath was removed after addition of NH4OH) to room temperature and further stored at room temperature for 1 hour. Excess methanol was removed under reduced pressure to give a white solid residue. The residue was partitioned between ethyl acetate (30 mL) and 0.1 NHCl (15 mL). The organic layer was washed with brine (15 mL), dried (MgSO4), and evaporated to dryness. The solid residue was stirred in 50% ether/pet. ether and filtered to yield the more polar stereoisomer of (10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]-nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as a white powder, 41 mg (90%) m.p. 224° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([S:25]([CH3:24])(=[O:27])=[O:26])[S:25]([CH3:24])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(Benzyloxy)-3-nitropyridine (14 g, 69.8 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0° C. Then added TEA (29.2 ml, 209.6 mmol, 3 eq), followed by the addition of potassium carbonate (9.96 g, 69.8 mmol, 1 eq) at 0° C. and stirred for 15 minutes. Methane sulfonyl chloride (20 g, 174 mmol, 2.5 eq) was added slowly at 0° C. to the above mixture and stirred for 14 h. After the completion of reaction, monitored by TLC, the reaction mixture was diluted with water and organic layer was separated. Water layer was extracted twice with 200 ml of dichloromethane, and the combined dichloromethane mixture was washed with water (500 ml) and brine (500 ml). The organic solution was concentrated under vacuum to yield the pure product. Yield: 19.5 g (78%). 1HNMR (400 MHz, DMSO-d6): δ 3.47 (S, 6H), 5.35 (s, 2H), 7.32 (d, J=5.76 Hz, 1H), 7.40-7.49 (m, 3H), 7.51 (t, J=4.12 Hz, 2H), 8.52 (d, J=5.68 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[CH3:35][N:36]([CH3:44])[C@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:43][C@@H:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C@@H:37]4[N:36]([CH3:44])[CH3:35])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CN(C)[C@H]1CCCC[C@H]1O
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@@H]4N(C)C)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-cis-2-(dimethylamino)cyclohexanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(F)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>Cl>[CH2:1]([N:8]1[C:16]([OH:25])=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)CNc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Thus obtained 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine was added to concentrated hydrochloric acid (10 ml), and the mixture was stirred for 8 hours at 100° C. The mixture was neutralized in an ice bath with 5% sodium hydroxide solution (pH 7) and the solvent was removed. To the residue were added methanol (30 ml) and sulfuric acid (1 ml), and the mixture was refluxed for 4 hours. After being neutralized (pH 6) in an ice bath with saturated sodium hydrogencarbonate solution, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography and the obtained compound was washed with methanol to give the captioned compound (0.02 g) as a white solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21](O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 3.04 g of vanillin, 3.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 5.24 g of triphenylphosphine. The thus prepared solution was mixed with 4.00 g of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hours. After concentrating the resulting reaction solution, the thus obtained residue was purified by subjecting it to silica gel column chromatography using an ethanol/chloroform mixture as an elution solvent. In this way, 5.0 g of the title compound was obtained in an oily form.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:35][C@H:36]1[CH2:53][C@@:51]2([CH3:52])[C@@H:47]([CH2:48][CH2:49][C@@H:50]2O)[C@H:46]2[C@@:37]1([F:57])[C@:38]1([CH3:56])[C:43]([CH2:44][CH2:45]2)=[CH:42][C:41](=[O:55])[CH:40]=[CH:39]1)(=[O:34])[CH3:33].[C:58]1([SH:64])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:32]([O:35][C@H:36]1[CH2:53][C@@:51]2([CH3:52])[C@@H:47]([CH2:48][CH2:49][C@H:50]2[S:64][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@H:46]2[C@@:37]1([F:57])[C@:38]1([CH3:56])[C:43]([CH2:44][CH2:45]2)=[CH:42][C:41](=[O:55])[CH:40]=[CH:39]1)(=[O:34])[CH3:33]
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1C[C@]2(C)[C@H](Sc3ccccc3)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a magnetically stirred solution of triphenylphosphine (1.05 g) in dry tetrahydrofuran (15.0 ml) maintained at 0° C. was added diethylazodicarboxylate (0.488 ml) and the mixture was stirred at 0° C. for thirty minutes. To this stirred solution at 0° C. was added dropwise, a mixture of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (362 mg, 1 mmole) and thiophenol (0.276 ml) dissolved in 5.0 ml of tetrahydrofuran. The solution was added over a ten minute period and then the reaction mixture stirred for 1 hour at 0° C., followed by 5.5 hours at room temperature. TLC (silica gel, 7:3 chloroform:ethyl acetate) indicated very little reaction taking place so the mixture was refluxed under nitrogen for 48.0 hours, followed by quenching in water and extraction with chloroform (4×50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulfate and evaporated to a yellow oil. This was dissolved in a mixture of chloroform and hexane (8:2) and preadsorbed on silica gel. Flash chromatography was performed and the desired product was successfully eluted with (9:1) chloroform:hexane. The product-containing fractions were pooled, evaporated to an oil, taken up in hot ethyl acetate and evaporated to a yellow crystalline material which was vacuum dried.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[I:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(I)c1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)cccc1I

Procedure:
A solution of 2-iodo-6-methyl-benzoic acid (3.42 g, 13 mmol) in dichloromethane (25 mL) was treated with oxalyl chloride (7.5 mL, 15 mmol) and dimethylformamide (several drops) followed by treatment with methanol (30 mL) and triethylamine (2.78 mL, 20 mmol). Workup afforded 2-iodo-6-methyl-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=O)C>Cl>[NH2:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(NC(C)=O)c(OCCN2CCCCC2)c(OC)c2occc12
Agent: Cl
Product: COc1c(N)c(OCCN2CCCCC2)c(OC)c2occc12

Procedure:
A solution of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-piperidinoethoxy benzofuran were brought to reflux for 10 hours in 200 ml of 2 N hydrochloric acid. Then it was neutralized with concentrated soda, extracted with ethyl acetate, the solvent was evaporated, the residue was taken up again in acetone and 30 ml of 7 N hydrochloric ethanol were added. It was filtered and recrystallized in ethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[NH:16][N:15]=1)=[O:13])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:51][CH3:52]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH2:51][CH3:52])[N:15]=1)=[O:13])[CH3:2]
Reactant: CCBr
Reactant: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(CC)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-9-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.065 g, 0.11 mmol) in DMF (1.1 mL), Cs2CO3 (0.073 g, 0.22 mmol) and bromoethane (0.008 mL, 0.11 mmol) were added. The mixture was stirred at room temperature for 12 h, solvent was removed under vacuo, then DCM (10 mL) was added and the organic phase washed with water (2×15 mL). The organic fraction was, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: DCM/MeOH95/5) provided 30 mg (30%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5].C(Cl)Cl.[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=O)[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]>C1COCC1>[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23](/[CH:26]=[N:1]/[O:2][CH2:3][C:4](=[O:5])[NH:6][CH3:7])[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]
Reactant: CNC(=O)CON
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 15 h
Yield: 76.9 %

Procedure:
To a solution of 2-aminooxy-N-methyl-acetamide (1.71 g, 16.4 mmol) obtained in Step B in a mixed solvent of methylene chloride (50 ml) and THF (25 ml) was added 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (3.94 g, 8.20 mmol) obtained in Step F of Example 1 at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (40 ml) was added to the resultant residue to precipitate a solid, which was filtered and washed with methylene chloride. The resultant solid was dried under reduced pressure to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoylmethoxyimino-methyl]-benzamide (3.57 g, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([O:17][C:18]([F:27])([F:26])[CH:19]([F:25])[O:20][C:21]([F:24])([F:23])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([O:17][C:18]([F:27])([F:26])[CH:19]([F:25])[O:20][C:21]([F:23])([F:24])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a mixture of 1.32 g of methyl 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylate and 15 ml of methanol was added 5 ml of a 2N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was washed with methyl tert-butyl ether. The aqueous layer was adjusted to pH 2 by an addition of 6N hydrochloric acid and then extracted with methyl tert-butyl ether two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.18 g of 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Li]CCCC.CCCCCC.CN([CH:29]=[O:30])C1C=CC=CC=1>CCOCC>[S:9]1[C:8]([CH:29]=[O:30])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2s1
Temperature: -15 °C
Reaction time: 1.75 h
Yield: 73.1 %

Procedure:
To a solution of thianaphthene (1.45 g, 10.5 mmol (97% pure)) in anhydrous Et2O (20 mL) at -15° C. was added dropwise a 1.6M solution of n-BuLi in hexane (9.9 mL, 15.7 mmol). The mixture was stirred at -15° C. (1.75 h) and at 25° C. (15 min). After recooling to -15° C., anhydrous N-methylformanilide (1.6 mL, 12.7 mmol) (distilled from CaH2) was added dropwise and the mixture was heated at reflux (30 min). The reaction mixture was quenched by addition of a mixture of 3N HCl (9 mL) and ice chips (20 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (3×75 mL). The combined organic layers were washed with 1N HCl (3×40 mL), saturated aq. NaHCO3 (40 mL), dried (MgSO4), and evaporated to dryness. The residue was dissolved in EtOH (3 mL) and mixed with saturated aq. NaHSO3 (15 mL). The resulting mixture was allowed to stand for 30 min and the crystalline bisulfite addition product was collected by filtration, washing with Et2O (50 mL) and dried in a vacuum desicator. The yellow solid was dissolved in warm H2O (30 mL) and cooled to 0° C. Saturated aq. Na2CO3 was added and the mixture was stirred at 25° C. for 15 min. Filtration, washing with H2O and drying afforded benzo[b]thiophene-2-carboxaldehyde as an amorphous solid (1.25 g, 7.68 mmol) in 73% yield.