Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(F)c(N)cc2oc(=O)[nH]c12
Solvent: CCO
Product: Cc1c(F)c(NCc2ccccc2)cc2oc(=O)[nH]c12
Reaction time: 15 h
Yield: 85.7 %

Procedure:
A mixture of 6-amino-5-fluoro-4-methyl-2-benzoxazolone (Example 7 0.43 g, 2.40 mmoles) and benzaldehyde (0.26 g, 2.40 mmoles) in ethanol (2 ml) was refluxed for 2.5 hours. After cooling, the precipitated product was collected and washed with cold ethanol. To a mixture of the precipitate (0.63 g) and ethanol (8 ml) was added portionwise sodium borohydride (300 mg) at room temperature under stirring. Stirring continued for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (1:4 by volume) to give the title compound (0.56 g). Recrystallization from methanol gave 0.44 g (68%) of the title compound as pale orange needles: m.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[N:7]3[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[C:16](=[O:17])[C:5]([C:6]=23)=[CH:4][CH:3]=1.C>[OH-].[Na+]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[N:7]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16](=[O:17])[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)N(C)CC2C
Agent: [Na+]
Agent: [OH-]
Product: CC1CN(C)c2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
A mixture of 13.8 g of ethyl 10-chloro-2,3-dihydro-1,3-dimethyl-7-oxo-1H, 7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate and 600 ml of three percent sodium hydroxide solution is heated on a steam bath for five hours. The solution is treated with decolorizing charcoal, filtered and neutralized to pH 7 with acetic acid. The product is separated by filtration, washed with water and recrystallized from N,N-dimethylformamide to provide yellow crystals of 10-chloro-2,3-dihydro-1,3-dimethyl-7-oxo-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylic acid, m.p. 243°-245° C. Analysis: Calculated for C14H13ClN2O3 : %C, 57.5; %H, 4.5; %N, 9.6. Found %C, 58.0; %H, 4.3; %N, 9.7.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:23]([O:24]C)=[CH:22][C:10]2[S:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:9]=2[CH:8]=1.O>ClCCl>[OH:6][C:7]1[C:23]([OH:24])=[CH:22][C:10]2[S:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:9]=2[CH:8]=1
Reactant: COc1cc2cc(C3=NNC(=O)CC3C)sc2cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1cc2cc(O)c(O)cc2s1
Yield: 93.7 %

Procedure:
Boron tribromide (1.55 ml) was added to a stirred solution of 4,5-dihydro-6-(5,6-dimethoxy-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (1.14 g) in dichloromethane (200 ml). After 2 hours the orange solution was cooled in ice, and water (40 ml) was added. The dichloromethane was then evaporated off under reduced pressure and the residual suspension was filtered to give 4,5-dihydro-6-(5,6-dihydroxy-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (0.97 g) as a yellow solid. Crystallisation from dichloromethane:methanol and diethylether gave 4,5-dihydro-6-(5,6-dihydroxybenzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone. m.p. >270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][N:15]=[C:16]=[S:17]>C(#N)C>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)Nc1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 65.3 %

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) and methyl isothiocyanate (1.1 g.) were stirred in acetonitrile (60 ml.) at room temperature for 15 hours, and then the mixture was refluxed under heating for 3 hours. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from methanol to give yellow prisms of 5-methylthioureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.62 g.). m.p. 191°-194° C.
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[CH:10]=[C:6]2[C:5]([CH2:13][O:14]C2CCCCO2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH:13]([C:5]1[C:6]2[N:7]([N:8]=[C:9]([S:11][CH3:12])[CH:10]=2)[C:2]([I:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: CSc1cc2c(COC3CCCCO3)ccc(I)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSc1cc2c(C=O)ccc(I)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
The compound of Example 101 (665 mg, 1.64 mmol) containing inseparable isomers was dissolved in methanol (15 mL). To this solution, p-toluenesulfonic acid (31.2 mg) was added and the mixture was stirred at room temperature for 2 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting solid product was dissolved in dichloromethane (20 mL). To this solution, activated manganese dioxide (1.37 g) was added and the mixture was sonicated at room temperature for 3 hours. Subsequently, the mixture was filtered through Celite and the filtrate was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1) afforded the title compound as a yellow powder (333 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]3)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:21]=1.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)(=[O:11])=[O:12])=[CH:7][C:6]=2[CH:21]=1
Reactant: O=CN1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1cc2cc(Cl)ccc2o1)N1CCNCC1
Yield: 150.2 %

Procedure:
To a solution of 1-(5-chlorobenzofuran-2-sulfonyl)-4-formylpiperazine (405 mg) in ethanol (15 ml) was added concentrated hydrochloric acid (1 ml), and the mixture was heated for 30 minutes under reflux. The solid obtained by concentration was washed with ethyl acetate and dried to give a colorless solid of the title compound (312 mg).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([N:15]([CH3:25])[C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[OH-].[Na+]>C(O)C>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([N:15]([CH3:25])[C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
17β-Acetoxy-4-methyl-4-aza-androst-5(6)-en-3-one (3.373 g, 9.763 mmol) is dissolved in ethanol (50 mL). Concentrated sodium hydroxide (6M, 25.0 mL) is added and the reaction is stirred at room temperature for 4 ½ hours. The reaction is partitioned between brine (10.0 mL) and EtOAc (100 mL). The layers are separated and the organic layer washed with brine (2×100 mL), saturated NH4Cl (100 mL), dried over MgSO4, filtered and evaporated to give a crude reaction product as a yellow solid. This is purified by dissolving in methanol and evaporating until the formation of large crystals is seen. The crystals are washed in acetone and dried overnight at reduced pressure (0.3 mm Hg) to give 17β-hydroxy-4-methyl-4-aza-androst-5(6)-en-3-one of very good purity (1.8119 g, 5.9712 mmol). Yield: 61%. m.p. 188° C.-192° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:19])[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:19][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanol and DBU in dioxane. ES-MS m/e (%): 286 (M{81Br}+H+, 99), 284 (M{79Br}+H+, 100), 258 ([M{81Br}+H—CH2═CH2]+, 52), 256 ([M{81Br}+H—CH2═CH2]+, 50).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:5][O:6][C:16]=1[NH2:17])=[O:18]
Reactant: ON=C(Cl)c1ccccc1Cl
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2Cl)noc1N
Yield: 88.4 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-chloro-N-hydroxybenzimidoylchloride (8.00 g, 42.10 mmol), methylcyanoacetate (5.22 g, 52.63 mmol) and sodium methoxide (4.55 g, 84.20 mmol), a white solid required compound (9.40 g, 37.21 mmol, 88%) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=[N:2]1.[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1>>[Cl:29][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[NH:6][C:5]4[NH:1][N:2]=[CH:3][C:4]=4[CH:8]=3)=[O:11])[CH3:30])[N:16]=2)[CH:27]=[C:26]([F:28])[C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc2cn[nH]c2[nH]1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc2cn[nH]c2[nH]1
Yield: 18.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h), starting from 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid (0.280 mmol, 0.042 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.215 mmol, 0.080 g). The crude product was purified by preparative HPLC. 0.0164 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.29 (d, 3H), 4.27-4.34 (m, 1H), 4.36-4.43 (m, 1H), 4.50-4.60 (m, 1H), 6.75-6.79 (m, 2H), 7.58 (s, 1H), 7.60-7.65 (m, 1H), 7.69 (d, 1H), 7.79-7.82 (m, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[CH2:30]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(=O)O
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: C=C(C)C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 56 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and methacrylic acid using Method E (56% yield). HPLC: 98%, RT=4.345 min. MS: m/z=423 [M+H]+, RT=4.33 min. 1H-NMR (DMSO-d6), 1H), 8.51 (s, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.73 (d, 1H), 7.42-7.33 (m, 4H), 7.19 (d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.79 (d, 1H), 5.80 (s, 1H), 5.51 (s, 1H), 1.94 (s, 3H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:23])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:43][C:44]1[CH:49]=[C:48](I)[CH:47]=[CH:46][C:45]=1[N:51]1[C:55]([CH3:56])=[N:54][N:53]=[N:52]1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:23])/[C:13](/[C:48]1[CH:47]=[CH:46][C:45]([N:51]2[C:55]([CH3:56])=[N:54][N:53]=[N:52]2)=[C:44]([Cl:43])[CH:49]=1)=[CH:14]/[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCCC1
Reactant: Cc1nnnn1-c1ccc(I)cc1Cl
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A mixture of zinc dust (980 mg, 15 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (280 mg, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (162 mg, 1.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (1.54 g, 5 mmol) in dry tetrahydrofuran (3 mL). The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in dry tetrahydrofuran (12 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.28 g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 45-50° C. for 20 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 mL), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylic acid methyl ester (1.29 g, 85%) as a yellow oil: EI-HRMS m/e calcd for C19H23ClN4O2 (M+) 374.1509, found 374.1509.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5]C1CCCCO1.C(O)(=O)C(O)=O>CO>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([OH:5])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(F)cccc1OC1CCCCO1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: Cc1c(O)cccc1F
Temperature: 60 °C
Yield: 73 %

Procedure:
The 5.0 g (23.78 mmol) of 2-(3-fluoro-2-methylphenoxy)tetrahydro-2H-pyran was dissolved in 120 mL of methanol followed by addition of 3.21 g (35.67 mmol) of oxalic acid. The mixture was heat to 60° C. for 2 hours. The volatiles were removed in vacuo while maintaining a bath temperature of <29° C. to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (1:9). Concentration of the desired fractions afforded 2.19 g (73%) of a pale yellow oil, which later solidified upon standing: 1H NMR(CDCl3/400 MHz) 2.16 (d, 3H, J=2.0 Hz), 5.17 (s, 1H), 6.57 (d, 1H, J=8.4 Hz), 6.64 (t, 1H, J=8.8 hz), 7.00 (dd, 1H, J=8.4, 14.8 Hz); HRMS (EI+) m/z calcd for (C7H7FO) 126.0481, found 126.0470.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](\[C:17]2[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:19][CH:18]=2)/[C:21]([OH:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccc(Br)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
Aryl Bromide AB1 was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100 mL) was added 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) and piperidine (2 mL). After overnight refluxing, the mixture was cooled down to r.t. To the slurry thus formed, toluene was added (10 mL). Filtration gave (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]1[CH2:13][C@H:12]([C:14](=O)[CH2:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)[C@H:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[OH-].[Na+].CC1CCCO1>C(#N)C.[Cl-].[Na+].O>[CH2:1]([N:8]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:9]1[CH2:10][C@@H:11]([CH3:37])[C@@H:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][NH:23][C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)[C@H]4C[C@@H](N(Cc5ccccc5)Cc5ccccc5)C[C@H]4C)cnc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CC#N
Solvent: O
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 40 °C
Reaction time: 42 h
Yield: 66.9 %

Procedure:
To a 250 mL round-bottomed flask 1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (11.2 g, 17.51 mmol) in acetonitrile (60 ml) was added. The mixture was cooled with an ice bath and TFA (2.70 ml, 35.0 mmol) and TFAA (24.46 ml, 175 mmol) was added. The resulting mixture was warmed and stirred at about 40° C. for about 42 h. The reaction was then cooled in an ice bath and quenched with methanol (7 mL). After warming to ambient temperature and stirring for about 1 h, it was poured into ethyl acetate (100 mL) and aqueous sodium carbonate (10% w/v, 200 mL). The layers were separated and the organic layer concentrated. The residue was dissolved in THF (120 ml) and 2N sodium hydroxide (35.0 ml, 70.0 mmol) was added. The reaction mixture was warmed to about 60° C. and stirred for about 16 h. After cooling to ambient temperature, 2-methyl-tetrahydrofuran (100 mL) and brine (100 mL) were added and the layers separated. The aqueous layer was extracted with 2-methyl-tetrahydrofuran (50 mL) and the combined organic layers washed with brine (50 mL). The organic layer was concentrated, dissolved in EtOH (100 mL) and treated with charcoal (500 mg) for about 1 h. The charcoal was filtered off and the ethanol removed under reduced pressure. The residue was taken up in CHCl3 (50 mL) warmed to about 50° C. and heptane (50 mL) was added. After cooling to ambient temperature, the product was collected, washed with 1:2 CHCl3:heptane (30 mL) and dried in a vacuum oven to afford (1S,3S,4R)-N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine as a tan solid (5.1 g, 67%) 1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 8.52 (s, 1H), 7.60 (s, 1H), 7.44-7.29 (m, 8H), 7.22 (t, J=7.2 Hz, 2H), 6.84 (d, J=3.4 Hz, 1H), 3.86 (dd, J=17.6, 8.8 Hz, 1H), 3.77-3.59 (m, 4H), 3.41-3.17 (m, 2H), 2.64-2.53 (m, 1H), 2.32-2.06 (m, 3H), 1.49-1.30 (m, 1H), 0.40 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([CH3:19])[CH:17]=[CH:18][C:11]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([CH3:19])[CH:17]=[CH:18][C:11]=12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Cn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1ccc2c(Nc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)ccnc21

Procedure:
200 mg (0.78 mmol) of 2-fluoro-N1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 169 mg (0.82 mmol) of 4-chloro-6-pyridin-4-ylpyrimidine-2-amine are suspended in 5 ml of water. 84 μl (1.01 mmol) of a 37% strength hydrochloric acid solution are then added, and the mixture is heated under reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off, washed with a little water and then dissolved in DMSO and purified by preparative RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[O:33]([NH2:35])[CH3:34].O>C(Cl)Cl>[CH3:34][O:33][NH:35][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CON
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CONC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A warm solution of 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid (2.03 g; 7 mmol) in CH2Cl2 (100 mL) is treated with 1,1'-carbonyl-diimidazole (1.75 g; 11 mmol) and the mixture is stirred at room temperature for 5.0 minutes when a clear solution is obtained. The solution is then treated with methoxylamine hydrochloride (1.50 g; 18 mmol) and the reaction mixture stirred at room temperature for 108 hours. It is then decomposed with water, extracted with CH2Cl2, dried over Na2SO4 and then evaporated to dryness to give a solid. Fractional recrystallization of the crude product from a mixture of toluene-CH2Cl2 gives off-white crystalline solid (1.27 g; 55.8%); mp 177°-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[C:20]#[C:21][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[C:20]#[C:21][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12
Reactant: Cn1ncc2c(Br)cncc21
Reactant: C[Si](C)(C)C#Cc1cc(N)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(C#Cc3cc(N)ccc3F)cncc21
Temperature: 80 °C

Procedure:
In an adaption of GP 3c, 1000 mg of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (Intermediate 2.1, 4.7 mmol, 1 eq), 1590 mg 4-fluoro-3-trimethylsilanylethynyl-phenylamine (7.69 mmol, 1.63 eq.), 165 mg dichlorobis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2) (0.24 mmol, 5 mol %) and 179 mg copper (I) iodide (0.94 mmol, 0.2 eq.) were dissolved in 8 mL THF (0.2 M) and treated with 16.5 mL tetra-n-butylammonium fluoride solution (1.0 M in THF, 16.5 mmol, 3.5 eq.). The resulting mixture was heated to 80° C. in a Biotage Initiator microwave oven for 30 min. Extractive work-up delivered the crude product which was used without further purification.