Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6](N1C2C=CC(Br)=CC=2N(CC2C3C(=CC=CC=3C)N(C)C=2)C1=O)[CH2:7][CH2:8][CH3:9])[CH3:2].NC1SC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(Br)ccc21
Agent: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In a dry pressure bottle, 3-[5-bromo-3-(1,4-dimethyl-1H-indol-3-ylmethyl) 2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (200 mg, 0.390 mmol) was dissolved in 50% Toluene/NMP (10 ml). To the solution, 2-amino thiazole (59 mg, 0.585 mmol), Cesium carbonate (191 mg, 0.585 mmol), 2(dicyclohexylphosphino)biphenyl (14 mg, 0.040 mmo), tris (dibenzyledeneacetone)-dipalladium (0) 99 mg, 0.010 nmol) were added. The bottle was then purged for 5 minutes by passing a slow stream of argon through the mixture while stirring. As the bottle was ready to be capped, the argon flow was increased. After capping, the reaction vessel was then immersed in an oil bath heated to 100° C. for 18 hours. An aliquout was removed and checked by TLC. The cooled reaction mixture was then diluted with Ethyl Acetate (200 ml) and washed with water 3 times. The organic phase was again washed with 1N HCl (200 ml), followed with brine. The collected organic phase was dried over MgSO4, filtered and evaporated to dryness to give an oil, which was purified by flash Chromatography, eluded with 30% to 50% ethyl acetate in Hexanes in 30 minutes to give 205 mg (35%) of 3-[3-1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-5-phenylamino-2,3-dihydro-benzoimidazol-1-yl]hexanoic acid Ethyl ester. LCMS (ESMS): m/z 524.65 (M+H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture of acetic anhydride (80 mL), 4-(methylthio)benzaldehyde (9.81 g, 61.2 mmol), 4-chlorophenylacetic acid (12.03 g, 70.5 mmol), and triethylamine (7.49 g, 7.42 mmol) was heated to reflux for 7 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow solid separated from the solution which was isolated by filtration and air dried to afford the desired acid. The acid was recrystallized from toluene (9.59 g, 51%): mp 185°-187° C. 1H NMR (CDCl3) 300 MHz 7.91 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17-7.35 (m, 3H), 7.03 (d, 2H), 7.00 (d, J=8.7 Hz, 2H), 2.44 and 2.36 (s, 3H). Mass spectrum: M+H=305.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:11]([F:29])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[C:11]([F:29])[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N(Cc3ccccc3)Cc3ccccc3)cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 15B (4 g, 8 mmol) in methanol (100 mL) was added 10% palladium on carbon (400 mg). The mixture was stirred at room temperature under hydrogen for 16 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound. MS: 314 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]([N:9]([CH3:21])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][OH:35].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18](=[O:20])[N:31]([CH2:32][CH2:33][CH2:34][OH:35])[CH3:30])[CH2:16][CH2:17]2)[CH3:21])=[CH:22][CH:23]=1
Reactant: CNCCCO
Reactant: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.02 g (3.00 mmol) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid in 30 mL of CH42Cl2 was treated at RT with 2 drops of DMF, followed by 0.28 mL (3.30 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 15 mL of CH2Cl2 and added to a solution of 0.80 g (9.00 mmol, 3 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (4) 338-340 (1986)]and 2.09 mL (15.00 mmol, 5 eq) of Et3N in 12 mL of CH2Cl2 at 0° C. The reaction was kept at RT for 1 h then partitioned between Et2O (×3)/ aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 90 g silica gel (EtOAc:CH2Cl2 1:1 to 4:1) gave 0.95 g (77%) of pure trans-(2-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 411 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:9]([C:23]([NH2:25])=[O:24])[CH2:8]1)=[O:6])[CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41](N)([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>CN(C=O)C>[C:41]([NH:25][C:23]([C@@H:9]1[CH2:8][N:7]([C:5]([O:4][C:2]([CH3:26])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH2:11][N:10]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:24])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(N)=O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 9.90 g (27.16 mmol) of 4-(1,1-dimethylethoxy-carbonyl)-1-(phenylmethoxycarbonyl)-piperazine-2(S)-carboxamide dissolved in 75 mL of DMF and cooled to 0° C. were added 5.73 g (29.88 mmol) of EDC, 4.03 g (29.88 mmol) of HOBt, 3.14 mL (29.88 mmol) of t-butylamine, and finally 4.16 mL (29.88 mmol) of triethylamine. The reaction mixture was stirred for 18 hours and the reaction volume was concentrated under reduced pressure. The residue was then diluted with 600 mL of EtOAc and washed with 10% HCl (2×75 mL), saturated NaHCO3 (1×75 mL), water (3×75 mL) and brine (1×50 mL), dried over MgSO4 and concentrated to a solid. This solid was triturated with EtOAc: hexane (1:2) and filtered to provide the title compound as a white solid; mp 134°-135° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S([O:16][CH2:17][C:18](F)([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:28][CH:18]1[CH2:17][O:16][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:19]1
Reactant: O=S(=O)(OCC(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 2.6 g of 2,2-difluoropropane-1,3-diyl bis(trifluoromethanesulfonate) and 10 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-25% ethyl acetate in hexanes) gave the product as white crystalline solid. MS (m+1)=197.1; 1H NMR (400 MHz, CDCl3) 9.82 (s, 1H), 7.45 (m, 2H), 7.05 (d, 1H), 5.1 (doublet of mutliplets, JHF=58 Hz, 1H), 4.5 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.OO.[OH-].[Na+].Cl.[CH2:36]1COCC1>O>[OH:2][C:3]1[CH:12]=[C:7]2[C:6](=[C:5]([CH3:36])[CH:4]=1)[O:11][CH:10]([C:13]([F:15])([F:14])[F:16])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(B3OC(C)(C)C(C)(C)O3)cc(OC)c2OC1C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(O)cc(C)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
The ethyl 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.62 g, 3.92 mmole) was dissolved in THF (25 mL) and cooled to 0° C. (ice bath). Hydrogen peroxide (0.67 g, 5.88 mmole) followed by 2.5 N sodium hydroxide (1.57 mL) was added dropwise and the resulting solution was stirred for 3 hours. The contents were poured into water (40 mL) and acidified using 2.4 N HCl to pH around 1 and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to flash chromatography (silica gel) and eluted with 0-100% EtOAc/hexanes to give yellow solid (0.84 g, 71%). GCMS m/z 302.0 (M+). LCMS m/z 303.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.59 (s, 1H), 6.60 (s, 1H), 6.51 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 2.17 (s, 3H), 1.31 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][N:5]=[CH:6][C:7]=1[N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[H][H]>[Pd].O>[CH3:15][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:16])[CH:2]=1
Reactant: [H][H]
Reactant: CN(c1ccccc1)c1cn[nH]c(=O)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(c1ccccc1)c1cn[nH]c(=O)c1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(methyl-phenyl-amino)-2H-pyridazin-3-one (158.7 mg, 0.67 mmol), water (10 mL), and a 2N aqueous solution of sodium hydroxide (0.37 mL) was treated with 10% palladium on carbon (15.8 mg, 10% weight of 4-chloro-5-(methyl-phenyl-amino)-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook overnight. The resulting reaction mixture was filtered through a pad of diatomaceous earth and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solution was acidified to pH 1-2 with a 1N aqueous hydrochloric acid solution and then extracted into methylene chloride (2×25 mL). Thin layer chromatography indicated the presence of starting material. The reaction was re-exposed to the same hydrogenation conditions. The reaction was hydrogenated (50 psi) for 2 d. After this time, the resulting reaction mixture was filtered through a pad of diatomaceous earth and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solution was acidified to pH 1-2 with a 1N aqueous hydrochloric acid solution and then extracted into methylene chloride (3×25 mL). The combined organics were dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 24 g, 50-100% ethyl acetate/hexanes) afforded 5-(methyl-phenyl-amino)-2H-pyridazin-3-one (75.8 mg, 56%) as a yellow solid.
Reaction SMILES: Br[CH:2]([C:7](=O)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].N[C@H](C(O)=O)CC.[CH:17]1([N:20]([CH:42]2[CH2:44][CH2:43]2)[C:21]([C:23]2[N:39]([CH2:40][CH3:41])[C:26]3=[N:27][C:28]([NH:35][C:36]([NH2:38])=[S:37])=[C:29]4[N:33]=[CH:32][N:31]([CH3:34])[C:30]4=[C:25]3[CH:24]=2)=[O:22])[CH2:19][CH2:18]1>C(O)C>[CH:42]1([N:20]([CH:17]2[CH2:18][CH2:19]2)[C:21]([C:23]2[N:39]([CH2:40][CH3:41])[C:26]3=[N:27][C:28]([NH:35][C:36]4[S:37][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH3:8])[N:38]=4)=[C:29]4[N:33]=[CH:32][N:31]([CH3:34])[C:30]4=[C:25]3[CH:24]=2)=[O:22])[CH2:43][CH2:44]1
Reactant: COC(=O)C(Br)C(C)=O
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Agent: CC[C@H](N)C(=O)O
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)OC)s3)nc21
Temperature: 65 °C
Yield: 84 %

Procedure:
Methyl 2-bromo-3-oxobutanoate (213 mg, 1.094 mmol, prepared following the procedure described by Abu T. Khan et al. in Tetrahedron Letters 2006, 47, 2751-2754) was added to a suspension of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 290 mg, 0.730 mmol) in ethanol (5 ml) and the reaction mixture was heated at 65° C. for 2 h. LC/MS shows completion of reaction (reaction remained as suspension all the time). The reaction mixture was concentrated to remove ethanol, and taken up in dichloromethane. The solution was washed with saturated sodium bicarbonate and the aqueous layer was back extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography using an automated ISCO system (40 g column, eluting with 0-5% methanol/dichloromethane) to afford methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-methylthiazole-5-carboxylate (301 mg, 0.610 mmol, 84% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=O>C1C=CC=CC=1>[C:17]([CH:21]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:7][O:8]1)([CH3:20])([CH3:18])[CH3:16]
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: CC(C)(C)C=O
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)COC(C(C)(C)C)OC1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and 2,2-dimethylpropanal were reacted, using benzene as solvent, to give, after separation by column chromatography, r-2-(tert-butyl)-t-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, m.p. 50°-52°; and r-2-(tert-butyl)-C-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, m.p. 85°-87°. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.II.[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>O.C1(C)C=CC=CC=1>[C:31]([CH2:32][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:30][CH3:29])=[O:34]
Reactant: COC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Methylbromoacetate (314 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with toluene (2×500 ml). The combined organic layers were washed with brine and concentrated under vacuum to yield 4-((carbomethoxy)methoxy)benzaldehyde as an oily material (385 g, Y=97%, P=99%).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:21]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][C:8]([O:10][CH3:21])=[O:9]
Reactant: CO
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc(OC)c(OC)c1

Procedure:
To a 50 mL round bottom flask equipped with an electromagnetic stirrer and a drying tube, 15 mL of anhydrous methanol was added. The solution was cooled on an ice-sodium chloride bath to minus 10° C., and 2 mL of SOCl2 was added slowly. The reaction mixture was allowed to react for an hour at room temperature. Then 2.25 g of 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid (prepared according to a method disclosed in J. Med. Chem. 1996, 39, 3238) was added. The reaction mixture was allowed to react for 3 hours at room temperature, and then refluxed for 40 minutes. After the solution was evaporated to remove the solvent, 100 mL of CHCl3 and saturated NaHCO3 were added, and the layers were separated. The organic layer was washed successively with 30 mL of water and saturated brine, dried over anhydrous MgSO4, filtered, evaporated, and purified by column chromatography to give 1.9 g of oil-like products. 1H NMR (CDCl3): δ 6.77-6.88 (m, 3H), 4.34 (t, 1H, J=5 Hz), 3.85 (s, 3H), 3.82 (s, 3H), 3.64 (s, 3H), 2.61 (d, 2H, J=5 Hz), 1.83 (t, 2H, J=6 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>ClCCl>[CH3:17][S:18]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:20])=[O:19]
Reactant: OCCc1ccccc1Br
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccccc1Br
Reaction time: 72 h

Procedure:
9.8 g of 2-(2-bromophenyl)ethanol and 4.7 cm3 of pyridine are dissolved under an inert atmosphere in 200 cm3 of dichloromethane at a temperature close to 20° C. The reaction mixture is cooled to a temperature close to 0° C. and 4.55 cm3 of methanesulfonyl chloride are introduced dropwise. The stirring is continued for 72 h, during which time the medium is allowed to gradually climb back up to a temperature close to 20° C. 100 cm3 of a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction mixture. Stirring is continued for 10 min. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 18 g of brown oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane to 90% dichloromethane/10% ethyl acetate gradient). After concentrating the fractions under reduced pressure, 12.9 g of 2-(2-bromophenyl)ethyl methanesulfonate are obtained in the form of a colorless oil.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:21][N:22]([CH3:25])[CH:23]=O>C(O)C.C(C1C=CC=CC=1N1CCNCC1)#N>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1)[CH2:3][N:16]1[CH2:17][CH2:23][N:22]([C:25]2[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=2[C:12]#[N:13])[CH2:21][CH2:15]1
Reactant: CN(C)C=O
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Agent: N#Cc1ccccc1N1CCNCC1
Solvent: CCO
Product: N#Cc1ccccc1N1CCN(C[C@@H](O)COc2cccc(-c3noc4ncccc34)c2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=456.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[N:11]([CH3:14])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: Clc1ncnc2[nH]c(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Br)cc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (122 mg, 0.53 mmol), prepared as in reference 1, in THF (5 mL) at 0° C. is added NaH (31.8 mg, 0.80 mmol, 60% dispersion in oil) portion wise and the reaction mixture is warmed to room temperature for 1 hour. Methyl iodide (103 μL, 1.59 mmol) is added and the mixture is stirred overnight. The reaction is quenched with water and extracted three times with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, and concentrated. Flash column chromatography of the crude product using 1% MeOH in DCM yielded 100 mg of 6-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (77%); 1H NMR (500 MHz, DMSO) δ 8.64 (s, 1H), 6.96 (s, 1H), 3.79 (s, 3H); LC-ESMS observed [M+H]+ 245.9 (calculated for C7H5BrClN3 244.9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:5][CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]([CH3:17])([CH3:16])[C:11]#[C:12][CH2:13]CO)=[O:8].[H-].[Na+].CI.O.CN(C)[CH:31]=[O:32]>CCCCCC.C(OCC)(=O)C>[Cl:23][C:21]1[CH:20]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:22]=1)[O:5][CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]([CH3:16])([CH3:17])[C:11]#[C:12][CH2:13][O:32][CH3:31])=[O:8]
Reactant: CN(C)C=O
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCOC
Reaction time: 2 h

Procedure:
2-(3,5-Dichlorophenoxy)-N-(1-hydroxymethyl-4-methylpent-2-yn-4-yl)butyramide (prepared as described in Example 2; 1.54 g) in dry N,N-dimethylformamide (20 ml) was added dropwise over 5 minutes to a suspension of sodium hydride (0.28 g, 80% dispersion in mineral oil) in dry N,N-dimethylformamide (2 ml) under an atmosphere of nitrogen at ambient temperature. The mixture was stirred for 2 hours and methyl iodide (0.71 g) in dry N,N-dimethylformamide (5 ml) was added over 1 minute at ambient temperature. The mixture was stirred for 2 hours and stored at ambient temperature for 18 hours. Water was added and the mixture extracted with ethyl acetate (three times). The extracts were combined, washed with water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; hexane/ethyl acetate, 4:1 by volume) to give the required product (0.44 g) as a colourless solid, mp 103-104° C.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate, to give the desired product as a yellow oil (48%).