Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:29]([C@H:38]([CH2:51][O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:39]C(=O)C1C=CC([N+]([O-])=O)=CC=1)[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][O:11][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(N(CC)CC)C.F.F.F.C(N(CC)CC)C>CO>[CH2:1]([O:8][C@H:9]([C@@H:29]([C@H:38]([CH2:51][O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[OH:39])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OC(=O)c1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
Compound 6 (110 g, 138.54 mmole) was dissolved in methanol (500 mL) and sodium methoxide (11 g, 204.0 mmole, 1.5 eq.) was added and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ether and water. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried in vacuo for 3 hrs and dissolved in dry THF under nitrogen. Triethylamine (TEA) (100 mL, 0.752 mole, 5 eq.) was added followed by triethylamine trihydrofluoride (TREAT.HF) (220 mL, 1.38 mole, 10 eq.) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue partitioned between ether and water. The ether layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (40% ethyl acetate in hexane) to give 51 g of compound 7 in 90% yield (reported literature yield 81%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[C:2]1([CH:1]=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2ccccc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nccc2ccccc12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In 1,4-dioxane (20 ml) was dissolved 1-methylisoquinoline (300 mg, 2.10 mmol). To the resulting solution was added selenium dioxide (323 mg, 2.91 mmol), followed by heating under reflux for 1.5 hours under a nitrogen gas stream. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (5:1, v/v) eluate fractions, 1-isoquinolinecarbaldehyde (252 mg, 77%) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:3]=[O:4].FC(F)(F)C1C=CC(SC(C)[CH2:27][CH:28]=[O:29])=CC=1.[C:33]1(C)C=CC=CC=1>>[OH:4][CH:3]([CH:2]([CH3:1])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=1)[CH2:33][C:28](=[O:29])[CH3:27]
Reactant: CC(C=O)CSc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccccc1
Reactant: CC(CC=O)Sc1ccc(C(F)(F)F)cc1
Product: CC(=O)CC(O)C(C)CSc1ccc(C(F)(F)F)cc1
Yield: 71.1 %

Procedure:
The same procedure as in Production example 27 was repeated except that 59.6 g of a toluene solution containing 41.6% of 2-methyl-3-(4-trifluoromethylphenylthio)propanal was used in place of the toluene solution containing 3-(4-trifluoromethylphenylthio)butanal. Thus, 36.67 g of crude 4-hydroxy-5-methyl-6-(4-trifluromethylphenylthio)-2-hexanone were obtained (purity: 59.3%, yield: 71.1%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]([O-])([O-:13])=[O:12].[K+].[K+].Cl>C(OCC)(=O)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(O)c(C(=O)O)c1

Procedure:
4-Isopropylphenol (2.7 g, 19.83 mmol) and K2CO3 (5.48 g, 39.7 mmol) were heated to 150° C. under an atmosphere of carbon dioxide. The cooled residue was suspended in ethyl acetate and acidified with 2N hydrochloric acid. The organic layer was separated and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound which was used in the next step without further purification. 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: COc1cc(N)ccc1Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-chloro-3-methoxyaniline (1.57 g, 10.0 mmol) in methanol (27 ml) were added acetic acid (3 ml), N-(tert-butoxycarbonyl)-L-prolinal (2.40 g, 12.05 mmol) and sodium cyanoborohydride (1.56 g, 24.1 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=70:30) to yield a light yellow oil (2.31 g, 68%); MS (ISP): 341.0, 342.9 ((M+H)+.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1>>[CH2:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: O=Cc1ccc(O)cc1
Product: CCCCOc1ccc(C=O)cc1

Procedure:
4-Butoxybenzaldehyde was prepared according to the method of Example 1, part a, except using 1-bromobutane instead of benzylbromide and using 4-hydroxybenzaldehyde instead of 4-hydroxyacetophenone.
Reaction SMILES: [OH:1][C@H:2]([CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4](OCC)=[O:5].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[C:11]([O:10][CH2:9][C@@H:2]([OH:1])[CH2:3][CH2:4][OH:5])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
In ethanol (10 ml) was dissolved (S)-ethyl 3-hydroxy-4-trityloxybutanoate (0.37 g, 0.975 mmol). Sodium borohydride (0.238 g, 6.29 mmol) was added to the solution and the solution was stirred at room temperature over night. Acetic acid was added to neutralize the solution. The solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried on magnesium sulfate, filtered, and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-1-trityloxy-2,4-butanediol (0.28 g, yield 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Li+].[OH-].C1COCC1.CO.Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(COC(=O)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccco3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 36.5 %

Procedure:
4-Methoxybenzyl 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-2a) (750 mg, 1.4 mmol) was stirred a 2/2/1 mixture of aqueous 2N LiOH/THF/MeOH (45 mL) at ambient temperature for 3 hours. The solution was acidified with aqueous 1N aq HCl to a pH of ˜3 (ca. 100 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (9 mL) and purified by reverse phased HPLC (5-95% ACN in H2O gradient: 40 minutes) in three-3 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in absolute ethanol and evaporated (4×, 20 mL) to provide pure 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (205 mg, 36%) as a white solid. M.p. 151-152° C. 1H NMR (DMSO-d6, 400 MHz): δ 3.71 (s, 3H), 4.24 (s, 2H), 4.27 (s, 2H), 6.14 (d, 1H, J=3.2 Hz), 6.26 (m, 1H), 6.87 (d, 2H, J=9.2 Hz), 7.14 (d, 2H, J=8.8 Hz), 7.41 (s, 1H), 7.89 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8.4 Hz), 13.48 (bs, 1H). MS 400 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (417 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][N:6]([CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH3:7].[C-:22]#[N:23].[K+]>O.CO>[CH3:1][N:2]([CH3:3])[C:12]1([C:22]#[N:23])[CH2:13][CH2:14][C:9]([CH2:8][N:6]([CH3:7])[CH3:5])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:11]1
Reactant: CNC
Reactant: [C-]#N
Reactant: CN(C)CC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)CC1(c2ccccc2)CCC(C#N)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
40% aqueous dimethylamine solution (12.8 mL, 21.1 mmol) was added in drops to a mixture of 4N hydrochloric acid (5 mL) and methanol (3 mL) with ice cooling. The title compound of step 6 (4.89 g, 21.1 mmol) and KCN (3.30 g, 50.7 mmol) were then added one after the other. The mixture was stirred for 3 d at RT. For work up the batch was mixed with water (10 mL) and extracted with diethyl ether (3×20 mL). The ether phase was concentrated to low volume in a vacuum, the residue was taken up in CH2Cl2, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1([CH2:32][CH2:33][NH:34][S:35]([C:38]2[S:39][C:40](Cl)=[CH:41][CH:42]=2)(=[O:37])=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][CH2:33][NH:34][S:35]([C:38]2[S:39][C:40]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:41][CH:42]=2)(=[O:36])=[O:37])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCN1CCOCC1)c1ccc(Cl)s1
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (example B.38) (155 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (51 mg, 16%). MS (ISP) 630.1 [(M+H)+]; mp 219° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+].[CH3:36]I.Cl>C(O)C>[CH3:36][S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(SC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.68 g) in ethanol (10 ml) containing 1N-NaOH (3.0 ml) was added methyl iodide (0.24 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with dilute hydrochloric acid to give crystals. The crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate afforded colorless prisms (0.31 g, 44%), m.p. 207–208° C. (decomp.).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14].CC[N:19](C(C)C)C(C)C.O>C(Cl)Cl.C1COCC1>[Cl:12][C:8]1[C:9]([Cl:11])=[CH:10][CH:2]=[C:3]2[C:4]([O:6][C:13](=[O:14])[NH:19][C:7]=12)=[O:5]
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
2-Amino-4,5-dichloro-benzoic acid (1.5 g, 7.28 mmol) was dissolved in 1:1 DCM/THF (20 mL) and cooled to 0° C. Phosgene (20% in toluene, 5.4 mL, 8.00 mmol) and Hünig's base (2.54 mL, 14.6 mmol) were added and the reaction was stirred overnight and warmed slowly to rt. The mixture was poured into water and extracted with DCM (3×) and EtOAc (2×). The combined organic layers were dried (MgSO4), and concentrated to provide the product as a white solid (1.6 g, 92%). HPLC: RT=8.10 min. MS (ESI−): mass calcd. for C8H3Cl2NO3, 232.0; m/z found, 231 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 11.95 (s, 1H), 8.10 (s, 1H), 7.32 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:22][C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C[C@@H]1OCCN(C2C3C(C4C=C(C=CC=4)C#N)=CNC=3N=CN=2)C1>>[Br:1][C:2]1[C:10]2[C:9]([N:25]3[CH2:26][CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: C[C@H]1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Agent: C[C@H]1CN(c2ncnc3[nH]cc(-c4cccc(C#N)c4)c23)CCO1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1

Procedure:
5-Bromo-4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (P3) was reacted with the hydrochloride salt of (3S)-3-methylpiperidine according to the method described for preparation of 3-{4-[(2S)-2-methylmorpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile (6) in Example 6. In this case, purification was effected via silica gel chromatography (Eluent: 5:1 petroleum ether/ethyl acetate), providing the product as a white solid. Yield: 4.3 g, 9.6 mmol, 92%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:9]1[CH2:11][CH2:10]1)=[N:5][CH2:6][C:7]#[N:8])C.CC(C)([O-])C.[K+].C(OCC)=O>C1COCC1.CCOCC>[CH:9]1([C:4]2[O:3][CH:1]=[C:6]([C:7]#[N:8])[N:5]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=NCC#N)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC=O
Product: N#Cc1coc(C2CC2)n1
Temperature: -10 °C
Reaction time: 3 h
Yield: 23.2 %

Procedure:
To a solution of N-cyanomethyl-cyclopropanecarboximidic acid ethyl ester (4.54 g, 14.9 mmol) in THF (10 mL) at −10° C. were added potassium tert-butoxide (1.67 g, 14.9 mmol) and ethyl formate (1.2 mL, 14.9 mmol) successively. After being stirred at −10° C. for 3 h, the reaction mixture was left in the refrigerator overnight and then diluted with ether. The precipitated brown solid was filtered and dried under vacuum. The vacuum-dried solid was added to boiling acetic acid (45 mL) and refluxed for 2 min. The reaction mixture was cooled to room temperature, diluted with water, and adjusted to pH 7 by adding 1 N sodium hydroxide. The reaction mixture was extracted with ether (2×1 L). The combined organic fractions were dried (MgSO4), filtered, and concentrated. The crude brownish solid was chromatographed (silica gel, 0-50% EtOAc in Hexane, detection KMnO4 spray, Rf=0.3 in 10% EtOAc/Hexane) to give 2-cyclopropyl-oxazole-4-carbonitrile as a colorless liquid (463 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[O:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1.Cl.CO>CN(C)C=O.C(OCC)(=O)C.CO>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[O:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: NC(=O)c1cc(Cl)cnc1N
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccc(C(F)(F)F)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-5-(trifluoromethyl)furan (0.30 g), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate. The obtained crystals were dissolved in aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was treated by silica gel chromatography (ethyl acetate 100%→ethyl acetate:methanol=5:1) to give a yellow solid. The obtained solid was dissolved in methanol, and 2N hydrochloric acid-methanol solution (0.3 ml) was added. The solvent was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate to give the title compound (45 mg).
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.C(O)C.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:23]=1
Reactant: Cc1ccnc(Oc2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccnc(Oc2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yloxy)phenyl)guanidine (0.2 g) in dichloromethane (2 ml) and ethanol (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure. To the residue was added 20% ethanol in ethyl acetate (20 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methylpyridin-2-yloxy)-phenyl)guanidine dihydrochloride (125 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C1CCCCC1.C(O[B:44]1[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]1)(C)C>C1COCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[C:27]([B:44]6[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3ccccc34)cc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan (11.55 g, 32.0 mmol) and THF (200 ml), a solution of sec-butyllithium 1.4 M in cyclohexane (30.9 ml, 43.3 mmol) at −78° C. was slowly added. The resulting mixture was stirred at −78° C. for 2 hours before adding 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.81 ml, 48.1 mmol) by syringe. The reaction solution was allowed to gradually warm to room temperature and stirred for 14 h. The reaction was quenched with methanol (MeOH) and the solvent was removed in vacuo. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulfate, then filtered, before the solvent was evaporated. The crude product was purified by column chromatography on silica gel with a heptane/DCM/EtOAc (75/20/5 to 40/50/10, v/v/v) eluent and recrystallization from toluene yielded 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:18][C:3]1[C:2]([NH2:1])=[CH:11][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of methyl 3-amino-5-morpholino-2-nitrobenzoate, prepared as described in Example 26, step c (19.2 g, 68.3 mmol) and Pd/C (1.9 g) in MeOH (500 mL) in an autoclave under an atmosphere of H2 (4 atm) were stirred at room temperature for 3 h, When TLC analysis indicated complete consumption of starting material, the mixture was filtered and the filtrate was concentrated in-vacuo to afford the desired product as a brown solid (13.9 g, 80.1%). 1H NMR (300 MHz, DMSO-d6): δ ppm 6.62 (d, 1H, J=2.4 Hz), 6.54 (d, 1H, J=2.4 Hz), 5.84 (s, 2H), 4.75 (s, 2H), 3.76 (s, 3H), 3.70 (t, 4H, J=4.8 Hz), 2.85 (t, 4H, 4.8 Hz). LC-MS: m/e=252.1 [M+1]+.