Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].COC1C=CC(C[N:31]2[N:35]=[N:34][C:33]([C:36](Cl)=[O:37])=[N:32]2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:36]([C:33]1[N:32]=[N:31][NH:35][N:34]=1)=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ccc(Cn2nnc(C(=O)Cl)n2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate 8-1 in DCM (8 ml) at room temperature is added 2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl chloride and followed by TEA (Intermediate 22: 0.293 ml, 2.100 mmol). The reaction is stirred at room temperature for 5 min. The reaction is quenched by brine and is extracted with DCM. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (15% to 40% EtOAc/Heptane). The obtained residue in TFA (5 ml, 64.9 mmol) is heated at 80° C. for 0.5 hours. The reaction is concentrated under reduced pressure to give (R)-4-(3′-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyric acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH:7]([S:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:41]3[CH:42]=[CH:43][C:38]([C:28]4[C:29]5[O:30][C:31]6[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=6[C:33]=5[CH:25]=[CH:26][CH:27]=4)=[CH:39][CH:40]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COC(=O)[C@@H]1CC(Sc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)[C@@H]1CC(Sc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 4-(4′-bromophenylsulfanyl)-N-tert-butoxycarbonyl-proline methyl ester (416 mg, 1 mmol), (4-Dibenzofuran-4-yl-phenyl)boronic acid (302 mg, 1.05 mmol), Pd(PPh3)4 (52 mg, 5% mol) in toluene (10 mL) and ethanol (2.5 mL) was heated until the solution became clear and subsequently treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) to give 4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfanyl)-N-tert-butoxycarbonyl-proline methyl ester (410 mg, 73%). 1H NMR (CDCl3), δ 8.01 (m, 3H), 7.95 (d, J=6 Hz, 1H), 7.73 (d, J=7 Hz, 2H), 7.62 (m, 4H), 7.41 (m 5H), 4.37-4.28 (m, 1H), 4.01 (m, 1H), 3.76 (s, 3H), 3.69 (m, 1H), 3.42 (m, 1H), 2.67 (m, 1H), 2.07 (m, 1H), 1.44 (s, 9H). LCMS 580 (M++1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:39][CH:38]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccc([C@H](C)Nc3nccc(-n4cnc5ccccc54)n3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (28.9 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (55 μL) was added followed by 4-methoxyaniline (62 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 18 h then directly eluted on silica gel column (1-4% MeOH:CH2Cl2) to yield 19.7 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.45 (br s, 1H); 8.37 (d, J=5.5 Hz, 1H); 7.99 (s, 1H); 7.88 (s, 1H); 7.80 (d, J=6.2 Hz, 1H); 7.75 (d, J=7.5 Hz, 1H); 7.62 (d, J=7.8 Hz, 1H); 7.49 (m, 3H); 7.33 (m, 2H); 6.90 (d, J=8.9 Hz, 2H); 6.77 (d, J=5.5 Hz, 1H); 5.87 (br s, 1H); 5.26 (br s, 1H); 3.81 (s, 3H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 465.2 (M+1).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH:23]1([C:26]2[C:27]([NH:35][C@@H:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][C@@H:37]3[OH:45])=[N:28][C:29]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][N:31]=2)[CH2:25][CH2:24]1>>[Br:1][C:30]1[N:31]=[C:26]([CH:23]2[CH2:24][CH2:25]2)[C:27]([NH:35][C@H:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][C@@H:37]2[OH:45])=[N:28][C:29]=1[CH:32]1[CH2:33][CH2:34]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)cnc1C1CC1
Product: O[C@H]1Cc2ccccc2[C@@H]1Nc1nc(C2CC2)c(Br)nc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.89–1.03, 1.27–1.30, 1.71–1.75, 2.36–2.39, 3.05–3.09, 3.25–3.30, 4.72–4.75, 5.45–5.46, 7.26–7.33; MS (ESI+) for C19H20BrN3O m/z 386 (M+H)+.
Reaction SMILES: [Br:1]C1CC(=O)NC1=O.[O:9]=[C:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[NH:15][C:14]=2[CH:13]=[CH:12][NH:11]1>CN(C=O)C>[CH3:26][O:25][C:23]([C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:10](=[O:9])[NH:11][CH:12]=[C:13]([Br:1])[C:14]=3[NH:15][C:16]=2[CH:17]=1)=[O:24]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1cc[nH]c(=O)c12
Reactant: O=C1CC(Br)C(=O)N1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(Br)c[nH]c(=O)c12
Reaction time: 4 h

Procedure:
Bromosuccinimide (0.633 g, 3.56 mmol) was quickly added to a stirred mixture of methyl 1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (0.783 g, 3.23 mmol) in DMF (20 mL) at room temperature. The reaction was exothermic and turned brown. The reaction mixture was stirred for four hours. at room temperature. LC-MS showed complete conversion to the desired product mass. The reaction mixture was poured in to 200 ml water with stirring, then filtered. The residue was washed with water, then slurred in hot methanol, and filtered. The residue was then dried under vacuum overnight to give Methyl-4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate as a light brown solid. [0.898 g, 2.80 mmol, 87% yield]. The product had an HPLC Retention Time=2.703 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 320.86, 322.86
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH3:16][N:17]([CH3:19])[NH2:18]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[CH:6][CH:5]=[C:4]2[NH:1][C:2]([NH:18][N:17]([CH3:19])[CH3:16])=[O:3])=[CH:9][CH:10]=1
Reactant: CN(C)N
Reactant: COc1ccc2cccc(N=C=O)c2c1
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(NC(=O)NN(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude title compound of Step C (5.8 g) in toluene (85 mL) was cooled to 0° C. under N2. While stirring the reaction solution, 1,1-dimethylhydrazine (2.5 mL) was added and the mixture was allowed to warm to room temperature. After stirring for 30 min at room temperature, a precipitate formed. Filtration afforded 5.1 g of the title compound of Step D as a white solid melting at 152-153° C. 1H NMR (CDCl3): δ 8.48 (br s,1H), 7.89 (d,1H), 7.77 (m,1H), 7.58 (d,1H), 7.34 (t,1H), 7.17 (m,2H), 5.72 (br s,1H), 3.93 (s,3H), 2.72 (s,6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]1)([CH3:5])[CH3:4].N1C=CN=C1.Cl[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]1)([CH3:5])[CH3:4])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccc(=O)n(C(C)(C)CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of methyl 1-(1-hydroxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2000 mg, 8.88 mmol), 1H-imidazole (1.51 mg, 22.2 mmol), and chloro-tert-butyldimethylsilane (1405 mg, 9.32 mmol) in DMF (10 mL) was stirred overnight at 23° C. The mixture was partitioned between CH2Cl2 and 5% NaHCO3. The organic was dried over MgSO4 and reduced to an oil under reduced pressure from toluene. MS (ESI pos. ion) m/z (MH+): 340. Calc'd exact mass for C17H29NO4Si: 339.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].O[NH:38]/[C:39](=[N:56]\[H])/[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:56]=[C:39]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43]4)[N:38]=2)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:22]
Reactant: [H]/N=C(\NO)c1ccc2[nH]c(CCC(=O)OCC)cc2c1
Reactant: COc1cc(C(=O)O)cnc1OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
EDCI (182 mg) and HOBT (145 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinecarboxylic acid (100 mg) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 hour followed by addition of ethyl 3-{5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (196 mg). The resulting mixture was stirred at room temperature for 2 hrs followed by addition of TBAF (495 mg). The reaction vessel was sealed and heated in Biotage Initiator to 120° C. for 2 hrs. After cooling the reaction, THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoate (D118) (35 mg). MS (ES): C24H26N4O5 requires 450; found 451.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[F:22][C:23]1[CH:24]=[C:25]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[CH2:29][NH:30][S:31]([CH3:34])(=[O:33])=[O:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH:17][C:36](=[O:37])[CH:35]([C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:23]([F:22])[CH:24]=3)[CH3:39])=[CH:14][CH:13]=[C:12]([C:18]([F:20])([F:21])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1)c1ccc(CNS(C)(=O)=O)c(F)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.104 g, 3.632 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (1 g, 3.632 mmol) in tetrahydrofuran (28 mL) was added 1-hydroxybenzotriazolhydrate (0.49 mL, 3.632 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.166 g, 3.632 mmol) and N-ethyldiisopropylamine (1.852 mL, 10.896 mmol) and the reaction mixture was allowed to stir for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (eluent:ethyl acetate/cyclohexane 2:1) to afford a white solid (example 16) (605 mg, 30%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([S:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[NH:29])=[CH:24][C:23]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: Cc1c(Oc2ccc(C#N)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Solvent: CCOCC
Product: Cc1c(Oc2ccc(C(=N)Sc3ccccc3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[6-(4-cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (TFA salt, 109 mg, 0.21 mmol) and thiophenol (27 μl, 0.21 mmol) in Et2O (1 mL) was stirred in an ice-bath under HBr atmosphere for 30 min. The crude compound was used for the next step without further purification. Exact mass calculated for C27H29FN4O4S 524.19, found 525.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α-Bromo-p-chloroacetophenone (4.64 g) in acetonitrile (50 ml) was treated with 1,2,4-triazole (1.4 g) followed by triethylamine (2 g). The mixture was stirred at room temperature for two hours and refluxed for one hour. The solvent was removed under reduced pressure and the residue was treated with water to give a yellow solid which was filtered, washed with water and dried. Crystallisation from ethanol-petroleum ether (60°-80°) gave α-1,2,4-triazol-1-yl-p-chloroacetophenone as cream coloured plates. Analysis:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:15].[Na+].[OH-].[Na+].Cl[O-].[Na+]>O.CO>[CH2:1]([C:8]1[CH:13]=[C:12]([I:15])[CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(I)cc1Cc1ccccc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
6.87 g of 2-benzylphenol, 7.2 g of sodium iodide and 1.7 g of sodium hydroxide were added to 60 ml of methanol and while stirring in an ice bath, 50 ml of an aqueous 5% sodiumhypochlorite solution was added dropwise to the mixture over 30 minutes. The temperature was slowly returned to room temperature and the stirring was continued overnight. Water was added to the reaction mixture, which then was extracted with ethyl acetate, washed with brine and then dried over anhydrous magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 10.1 g of the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:27]=[CH:26][C:10]([O:11][C:12]3[C:17]4[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=4[CH:15]=[C:14]([C:23](O)=[O:24])[CH:13]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>>[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:23]([C:14]2[CH:13]=[C:12]([O:11][C:10]3[CH:9]=[CH:8][C:7]([C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[CH:27][CH:26]=3)[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[CH:15]=2)=[O:24])=[N:30]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)cc2O1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 15, from 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (35c) (598 mg, 1.63 mmol) and 1-methyl-3-aminopyrazole (236 mg, 2.43 mmol) to give a white solid (315 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H) 7.65 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.02 (dd, J=9.85, 1.26 Hz, 2 H) 6.98 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.19-4.30 (m, 2 H) 3.81 (s, 3 H) 2.89 (s, 2 H) 2.32-2.40 (m, 2H) 1.49 (s, 6 H); LCMS for C25H26N4O4 m/z 447.20 (M+H)+; Anal. Calcd. for C25H26N4O4.0.31 H2O: C, 65.38; H, 6.02; N, 12.20. Found: C, 65.37; H, 5.85; N, 12.38.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=[O:29])[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:3]=12.C[Si](C)(C)[CH2:37][CH2:38]C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:29])[C:37]#[CH:38])[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[C:3]=12
Reactant: C[Si](C)(C)CCC(=O)O
Reactant: COc1cc(C#Cc2nn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N1CC[C@H](n2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)C1
Reaction time: 8 h

Procedure:
The crude product (16 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 2 as an intermediate, 3-(trimethylsilyl)propionic acid (10 mg), HATU (28 mg) were dissolved in DMF (0.5 ml). DIPEA (31 μl) was added thereto, followed by stirring overnight. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a white solid (0.7 mg). Table 1 shows the physical properties thereof.
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7]1)[C:3](=[O:5])[CH3:4]>C(O)C.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH2:7]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C1CCN(c2ccc(N)cc2)C1
Reaction time: 3 h

Procedure:
A suspension of N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (3.5 g) and palladium(II) hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was vigorously stirred under a hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C)C.Cl.O.[OH-].[Na+].C[C:28](C)=[O:29]>>[CH:8]1([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:4][CH:28]=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(OCC)C(c1ccccn1)C(C)C1CCCCC1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CCC(CC1CCCCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Pyridyl-3-cyclohexyl-butyraldehyde diethyl acetal (650 mg) was dissolved in acetone (10 mL), treated with HCl (a solution of 2.5 mL concentrated HCl and 7.5 mL water) and the reaction was stirred at room temperature overnight. 1N sodium hydroxide (30 mL) was then added and the neutralized reaction mixture was extracted with ethyl acetate (2 times). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 4-cyclohexyl-3-(2-pyridyl)-butyraldehyde (480 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CO)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 78.1 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoate (712 mg, 2.15 mmol) in THF:MeOH:H2O (2:1:1; 8 mL) and NaOH (344 mg, 8.60 mmol) to afford 510 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 8.08-8.05 (t, J=8.0 Hz, 1H), 7.36-7.33 (m, 2H), 4.90 (t, 1H), 4.29-4.28 (d, J=6.0 Hz, 2H), 3.38 (m, 2H), 1.06 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: O=C(O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.012 mole) in dimethylformamide is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled and stirred at room temperature for 15 minutes. 5-Aminotetrazole monohydrate (1.24 g, 0.012 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled, and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.1 g, 34%), m.p. above 300.