Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH3:35])[C:22]=3[NH:23][C:24]([O:26][C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])=[O:25])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.[OH-].[Li+]>C1COCC1>[CH3:35][N:21]1[C:22]([NH:23][C:24]([O:26][C@@H:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28])=[O:25])=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[N:19]=[N:20]1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3nnn(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)nnn1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (from Example 1, 120 mg, 0.30 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)acetate (130 mg, 0.45 mmol), X-PHOS (43 mg, 0.09 mmol), palladium acetate (10 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.90 mmol) were combined in 5 mL of toluene. Deionized water (1 mL) was added and the mixture was degassed with argon for 2 minutes. The mixture was sealed and stirred at 100° C. for 2 hrs. The mixture was extracted with ethyl acetate and water, washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (12 g silica gel, 0% to 70% ethyl acetate in hexanes) to give {4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid ethyl ester as an amorphous powder (70 mg, 48.3% yield). LC/MS calcd for C28H28N4O4 (m/e) 484.0, obsd 485.1 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=7.2 Hz, 3H), 1.53-1.76 (m, 3H), 3.69 (s, 2H), 3.95 (s, 3H), 4.21 (q, J=7.2 Hz, 2H), 5.93 (m, 1H), 6.40 (br s, 1H), 7.31-7.49 (m, 7H), 7.56-7.66 (m, 4H), 7.80 (d, J-6.8 Hz, 2H). {4′-[1-Methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid ethyl ester (60 mg, 0.124 mmol) was dissolved in 3 mL of THF and lithium hydroxide solution (0.5 N, 1.0 mL) was added. The mixture was stirred at room temperature for 3 hrs. TLC indicated complete consumption of the starting material. The mixture was concentrated and dissolved in water (8 mL). The clear solution was treated with hydrochloric acid (1N, 0.6 mL). The mixture was filtered and the white solid was dried to give {4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid (51 mg, 90.2% yield). LC/MS calcd for C26H24N4O4 (m/e) 456.0, obsd 457.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) ppm 1.12-1.32 (m, 0.6H), 1.59 (br, 2.4H), 3.64 (s, 2H), 3.89 (s, 3H), 5.80 (br m, 1H), 6.96-7.54 (m, 7H), 7.61-7.74 (m, 4H), 7.80 (d, J=7.6 Hz, 2H), 9.54 and 9.95 (br s, 1H), 12.38 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([NH:23][CH:20]2[CH2:22][CH2:21]2)[N:3]=1
Reactant: NC1CC1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-6chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (425 mg, 1.5 mmol), cyclopropylamine (Aldrich, 1.4 mL), and ethanol (4 mL) were refluxed for 3 hours. To the cooled solution was added 1N sodium hydroxide (1.5 mL). The residual oil left on evaporation of volatiles under vacuum was chromatographed on silica gel. Title compound was eluted with methanol: ethyl acetate/15:85 as a white solid foam which solidified to white powder in methanol-acetonitrile (309 mg, 68%); m.p. 174°-176° C.; mass spectrum (Cl, CH4) 305 (M+1); 1H-NMR (DMSO-d6) δ: 7.79 (s, 1, H-8); 7.25 (d, J=2.9 Hz, 1, NH), 5.79 (s, 2, NH2), 4.90-4.75 (m, 1, CH--N), 4.73 (d, J=4.0 Hz, 1, OH), 4.63 (t, J=5.3 Hz, 1, CHOH), 4.08-4.00 (m, 1, CHO), 3.58-3.38 (m, 2, CH2O), 3.05-2.95 (m, 1, CH--NH), 2.35-2.20 (m. 1, CH), 2.18-2.0 (m, 1, 1/2CH2), 2.0-1.9 (m, 2, methylene), 1.7-1.5 (m, 1, 1/2CH2), 0.70-0.50 (m, 4, 2CH2 of cyclopropyl); [α]20589 +7.72°, [α]20578 +7.87°, [α]20546 +8.77°, [α]20436 +14.4°, [α]20365 +20.1° (c=0.66, methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18](Br)=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18]([CH3:21])=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Br)csc2C2CN(Cc3ccccc3)CC12
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Temperature: 22 °C
Yield: 97 %

Procedure:
A solution of the product from step e) (2.4 g, 6.89 mmol) in dioxane (34.5 ml) was treated with Pd(dppf)2Cl2 (337 mg, 0.41 mmol) and a 2M solution of dimethylzinc in toluene (6.89 ml, 13.78 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (20 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) and passed through a plug of silica-gel using 50:50 hexanes:EtOAc to give the subtitle compound (1.9 g, 97%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:14][CH3:15])=[C:7](I)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[C:16]([C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1)#[CH:17]>CC#N.CCN(CC)CC.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>[CH3:15][O:14][C:6]1[C:7]([C:17]#[C:16][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: C#Cc1cncn1C
Reactant: COc1ccc(I)c(OC)c1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cncn2C)c(OC)c1OC(C)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a stirred solution of 3-acetoxy-2,4-dimethoxy-iodobenzene (250 mg, 0.776 mmol) and 5-ethynyl-1-methyl-1H-imidazole (100 mg, 1.09 mmol) in dry MeCN (3 ml) and dry NEt3 (1 ml) was added Pd(Ph3P)2Cl2 (20 mg, 3.7 mol %) and the reaction vessel was evacuated and backfilled with N2 (g) three times. Copper (I) iodide (15 mg) was added and the reaction was heated to 60° C. and stirred overnight. The resulting dark solution was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc) to give the product as a tan solid (130 mg, 56%). 1H-NMR (300 MHz, CDCl3) δ 7.45 (br s, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.30 (br s, 1H), 6.68 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].C1CCCCC=1>CCO.[Pd]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1cccc(N)c1C#N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(=O)CC.C(Cl)Cl>[CH3:37][O:38][CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)c4cccc(OC)c4)nn23)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(S)-1-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 223; 20.3 mg) was suspended in 2-butanone (2 ml). Thereafter, potassium carbonate (69.4 mg) and 2-methoxyethyl bromide (47.2 μl) were added to the suspension, and the obtained mixture was stirred at 80° C. for 5 hours. Thereafter, the reaction solution was diluted with methylene chloride (5 ml), and the resultant product was then washed with 1 M hydrochloric acid (5 ml×3), saturated sodium bicarbonate (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (10.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.[In].[C:28](O)(=O)[CH3:29].C(OC)(OC)(OC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]3[N:24]=[C:28]([CH3:29])[O:23][C:16]=3[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Agent: COC(C)(OC)OC
Agent: [In]
Solvent: c1ccccc1
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Yield: 61.9 %

Procedure:
The title compound was prepared following the procedure described for step-4 of Intermediate-55 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (0.320 g, 0.840 mmol), benzene (6 mL), indium (0.386 g, 3.363 mmol), acetic acid (0.505 g, 8.40 mmol) and trimethyl orthoacetate (0.812 g, 2.96 mmol) to afford 0.195 g of the desired product. 1HNMR (DMSO-d6): δ 2.63 (s, 3H), 3.88 (s, 3H), 7.439-7.46 (m, 3H), 7.71 (s, 1H), 9.0-10.0 (s, 1H), 11.60 (s, 1H); MS [M+H]+: 375.34.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[CH3:34].C(C1C=CC(S([N:48]2C3C=C(C#N)C=CC=3NC3N=C(C(F)(F)F)C=CC=3[CH2:49]2)(=O)=O)=CC=1)(C)(C)C>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[C:33]([CH3:34])=[C:2]([C:49]#[N:48])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Reactant: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Product: Cc1c(C#N)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2

Procedure:
The title compound was prepared from 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 63) according to the procedure described for intermediate 54. Racemic mixture: LC/MS: m/e 501.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.63 (1H, d), 7.47 (1H, d), 7.19 (2H, d), 7.13 (1H, d), 7.00 (2H, d), 5.20 (1H, d), 4.45 (1H, d), 2.65 (3H, s), 1.25 (9H, s). The racemic mixture was separated into individual enantiomers via chromatography on a Chiracel OD column eluting with 15% EtOH in hexanes at 8.0 mL/min. The faster eluting enantiomer E1 has a retention time of 9.77 min. The slower eluting enantiomer E2 has a retention time of 12.04 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:34][CH:35]([NH2:38])[CH2:36][OH:37]>C(Cl)(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH:35]([CH3:34])[CH2:36][OH:37])[N:7]=3)=[C:16]3[N:11]([N:12]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:14][CH2:15]3)[N:10]=2)=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Reactant: CC(N)CO
Solvent: ClC(Cl)Cl
Product: CC(CO)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCN3C(=O)OCc2ccccc2)n1

Procedure:
A solution of phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Example 4, Step C) (390 mg, 0.84 mmol) and DL-2-amino-1-propanol (2.62 mL, 3.36 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by medium pressure liquid chromatography using 10-80% ethyl acetate in hexanes as eluant to give 150 mg of the title compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:26][NH:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:26][N:27]([CH2:28][CH3:29])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Reactant: CCNCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5 g, 0.023 mol) and potassium carbonate (9.9 g, 0.0717 mol) in DMF (75 mL) was stirred for 20 min at RT. Cyclopentylmethyl ethyl amine (4.25 g, 33.0 mmol) was then added and the reaction was refluxed for 8 h. After cooling the reaction to RT, water (500 mL) was added to the reaction mixture and extracted with ethyl acetate (3×400 mL) and the combined organic layers were dried and concentrated. The residue was purified by silica gel (100-200 mesh) column chromatography. Elution with 10% ethyl acetate in hexanes gave the pure product as a colorless, gummy mass (76%).
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26]/[C:27](/[C:31]([F:34])([F:33])[F:32])=[CH:28]/[C:29]#[N:30]>CC(O)C>[C:1]([C:3]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:7]=3[CH:6]=2)[C:28]([C:29]#[N:30])=[C:27]([C:31]([F:34])([F:33])[F:32])[NH:26][C:23]=1[CH3:24])#[N:2]
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#C/C=C(/N)C(F)(F)F
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C(F)(F)F)N1

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}-benzamide (Example 4A) and 329 mg (2.41 mmol) (2E)-3-amino-4,4,4-trifluorobut-2-enenitrile [CAS Reg.-No. 33561-24-9; prepared following A. W. Lutz, U.S. Pat. No. 3,635,977 and also C. G. Krespan, J. Org. Chem. 34, 42-45 (1969)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 171 mg (63% of th.) of the racemic title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([CH3:27])[NH:19]CC2C=CC=CC=2)[CH2:14][CH2:13]1.[H][H]>[Pd].CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([CH:18]([CH3:27])[NH2:19])[CH2:16][CH2:17]1
Reactant: CC(NCc1ccccc1)C1CCN(CC2COc3ccccc3O2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(N)C1CCN(CC2COc3ccccc3O2)CC1
Yield: 80.4 %

Procedure:
A mixture of 13.2 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-α-methyl-N-(phenylmethyl)-4-piperidinemethanamine and 160 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 8 parts (80.4%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-α-methyl-4-piperidinemethanamine as an oily residue (intermediate 83).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:20]([C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][N:27]=[CH:28]2)(=[O:22])=[O:21])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=O)(C)(C)C.[ClH:33].CO>>[ClH:33].[CH:28]1[C:29]2[C:24](=[C:23]([S:20]([N:12]([CH2:13][CH2:14][C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10][CH2:9][NH2:8])(=[O:22])=[O:21])[CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCc1cccs1)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCN(CCc1cccs1)S(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 3 (238 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (202 mg) as white powdery solid.
Reaction SMILES: [O:1]1[CH2:6][C:2]1([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].O>C(O)C>[CH3:5][C:4]1[O:1][CH:6]=[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: C#CCC1(c2ccccc2)CO1
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccccc2)co1
Temperature: 23 °C
Yield: 75.9 %

Procedure:
To a solution of 0.5 g HgSO4 in 30 mL of 2N HgSO4 was added 4.74 g (30 mmol) of 4,5-epoxy-4-phenyl-1-pentyne in 30 mL of absolute ethanol over a 5 minute period. The reaction mixture was refluxed for 0.25 hour and cooled to 23° C. After addition to 150 mL of H2O the mixture was extracted with hexanes three times. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Sublimination (90° C. at 15 mmHg) of the solid gave 3.6 g (76%) of 2-methyl-4-phenylfuran as a solid (m.p. 89°-91° C.) which was homogeneous by spectroscopic considerations; IR (KBr) 1599, 1545, 1440, 742 cm-1 ; 1HNMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.50 (d, 2H, J=9.0 Hz), 7.38 (t, 2H, J=9.0 Hz), 7.28 (t, 1H, J=9.0 Hz), 6.33 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Si](OCC)(OCC)(OCC)OCC.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:12]3[CH:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[C:2]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: COc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Temperature: 135 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and ethyl 2-(2-oxocyclopentyl)acetate (2.05 g, 12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridinum p-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135° C. for 4 h. After cooling to 120° C., DIEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual ethyl 2-(2-oxocyclopentyl)acetate. The mixture was dissolved in DCM (80 mL) and cooled to 0° C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z=260.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.05-2.14 (m, 1H), 2.50 (dd, J=16.8, 11.2 Hz, 1H), 2.68-2.86 (m, 4H), 3.48-3.58 (m, 1H), 4.16-4.24 (m, 2H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 8.4 (s, 1H).