Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:14][C:13]=1[CH:25]=[O:26].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:25]([OH:26])[C:13]3[CH:14]=[C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][C:12]=3[F:11])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 170.0 mg, 0.86 mmol) in methanol (7.0 mL) were added propane-1-sulfonic acid (4-fluoro-3-formyl-phenyl)-amide (672, 220.0 mg, 0.90 mmol) and potassium hydroxide (0.50 g, 0.0089 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1N HCl to pH=5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound (673, 55.0 mg, 14.0%). MS (ESI) [M+H+]+=442.1, 444.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.I[CH2:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:23][CH3:24])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cncc(Cl)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate (0.20 g, 0.64 mmol) in tetrahydrofuran (3 mL) at −70° C. was added iodoethane (0.26 mL, 3.2 mmol) and NaHMDS (1M solution in THF; 1.3 mL, 1.3 mmol). The reaction mixture was warmed to room temperature. Iodoethane (0.26 mL, 3.2 mmol) and NaHMDS (1M solution in THF; 1.3 mL, 1.3 mmol) were added. The reaction mixture was stirred at 65° C. After 18 h, the reaction was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with EtOAc (3×25 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)(ethyl)amino]piperidine-1-carboxylate as a yellow solid. LRMS (ESI) calculated for C16H25ClN4O2 [M+Na]+, 363.2; found 363.1.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[CH3:3][CH:2]([O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)CCCC(C)Br
Product: COc1ccc(OC(C)CCCC(C)C)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-methoxy-phenol to obtain p-[(1,5-dimethyl-hexyl)-oxy]-anisole (boiling point = 170°-172°C/1.0 mmHg);
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1)#[N:2].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:28][CH:27]=3)[CH:10]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 89.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano benzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.55 g (1.48 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.316 g, 1.48 mmol) were used to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.3 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.1 (2H, s), 7.22 (1H, s), 7.44 (1H, s), 7.66 (2H, d), 7.88 (4H, m), 8.28 (1H, d).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[CH3:34])=[O:12].[Cu][C:36]#[N:37]>CN1C(=O)CCC1.[NH4+].[OH-].[Cu]I>[C:36]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[CH3:34])=[O:12])#[N:37]
Reactant: N#C[Cu]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1C#N
Yield: 39.4 %

Procedure:
A solution of 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (20 mg, 0.037 mmol), copper(i) cyanide (3.35 mg, 0.037 mmol) and copper(i) iodide (7.13 mg, 0.037 mmol) in NMP (1 mL) was stirred 10 min at 150° C. in microwave with cooling. Poured in NH4OH solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (20% EtOAc in CH2Cl2) gave the title compound 7-cyano-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 43b (7 mg, 38.9%). NMR (400 MHz, DMSO-d6) 2.31 (s, 3H), 7.33 (d, J=8.2 Hz, 1H), 7.58-7.69 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.94-8.00 (m, 2H), 8.06 (m, 1H), 8.95 (d, J=2.3 Hz, !H), 9.06 (d, J=2.3 Hz, 1H), 10.41 (s, 1H), 10.77 (s, 1H). (m/z)=481 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH:29]C(OC(C)(C)C)=O)=[CH:24][C:23]=1[CH3:37].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([CH3:37])[CH:24]=2)[N:29]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1cc(NNC(=O)OC(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1Cl
Yield: 44921.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.0 g, 0.003 mmol), tert-butyl 2-(4-chloro-3-methylphenyl)hydrazinecarboxylate (Intermediate-105, 1.500 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.38 (s, 3H), 4.45 (d, J=5.4 Hz, 2H), 7.53 (d, J=9.3 Hz, 2H), 7.67 (s, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.92 (s, 1H), 10.08 (t, 1H), 12.61 (s, 1H); MS (m/z): 445.31 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH:31]=1)[CH:29]=O)(=[O:3])[CH3:2].[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH2:29][N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:33]2)[CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(C=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CN3Cc4ccccc4C3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a mixed solution of the above 5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde 83 (325 mg), 2,3-dihydro-1H-isoindole (98 mg), acetic acid (82 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (219 mg). The mixture was stirred at room temperature for 3 hours, and cooled to 0° C. A saturated aqueous sodium hydrogen carbonate solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene 84 (234 mg) as a colorless solid. APCI-Mass m/Z 574/576 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])C)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[O-].[Na+].S(=O)(O)[O-:17].[Na+].Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:17])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 1-(2,3-dihydrobenzofuran-5-yl)ethanone (4.0 g, 25 mmol) and sodium hypochlorite [160 mL of a 6.0% aqueous solution, (Clorox brand of bleach)] at 55° C. is stirred for 1 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persists. Hydrochloric acid (80 mL of a 1.0 N aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3.93 g (97%) of 2,3-dihydrobenzofuran-5-carboxylic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.0-10.3, 8.00, 6.87, 4.72, 3.31.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([NH:1][C:2]3[CH:17]=[CH:16][C:5]4[N:6]([C:9]5[CH:10]=[CH:11][C:12]([NH:15][C:27]([C:23]6[CH:22]=[C:21]7[C:26](=[CH:25][CH:24]=6)[NH:18][CH:19]=[CH:20]7)=[O:29])=[CH:13][CH:14]=5)[CH:7]=[N:8][C:4]=4[CH:3]=3)=[O:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc(-n2cnc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(Nc1ccc(-n2cnc3cc(NC(=O)c4ccc5[nH]ccc5c4)ccc32)cc1)c1ccc2[nH]ccc2c1

Procedure:
Compound 564 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)benzimidazole and indole-5-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.19; found: 511.07.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCOCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[O:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OC1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 175.5 %

Procedure:
4-nitro-1H-pyrazole (0.15 g, 1.3 mmol), tetrahydro-2H-pyran-4-ol (0.14 g, 1.3 mmol), DIPAD (0.35 g, 1.7 mmol), PPh3 (0.42 g, 1.6 mmol) were dissolved in THF (5 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/petroleum ether=6/1) to give 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.45 g). 1H NMR (500 MHz, CDCl3): δ 8.19 (s, 1H), 8.10 (s, 1H), 4.38 (m, 1H), 4.16-4.12 (m, 2H), 3.57-3.53 (m, 2H), 2.17-2.05 (m, 4H).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1>O1CCOCC1.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>[CH:1]([C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)=[CH2:2]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ncc(C(=O)OCC)s1
Temperature: 100 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of tributyl(vinyl)stannane (0.92 mL, 3.14 mmol) and ethyl 2-bromothiazole-5-carboxylate (0.38 mL, 2.54 mmol) in dioxane (33 mL) is added Pd(PPh3)2Cl2 (182 mg, 0.26 mmol) at room temperature. After stirring at 100° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl 2-vinylthiazole-5-carboxylate (418 mg). HPLC retention time=0.45 minutes (condition B); MS (m+1)=184.1; 1H NMR (400 MHz, CD3OD) δ ppm 1.37 (t, J=7.2 Hz, 3 H) 4.35 (q, J=7.1 Hz, 2 H) 5.71 (d, J=10.9 Hz, 1 H) 6.24 (d, J=17.4 Hz, 1 H) 6.93 (dd, J=17.4, 10.9 Hz, 1 H) 8.29 (s, 1 H)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH3:7])[CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO>[CH3:11][O:9][C:8]([CH:4]1[CH2:3][CH:2]([OH:1])[CH2:6][N:5]1[CH3:7])=[O:10]
Reactant: CN1CC(O)CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1CC(O)CN1C

Procedure:
4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid (0.27 g, 1.85 mmol) was dissolved in 5 ml methanol at room temperature and (trimethylsilyl)diazomethane (2M solution in hexane) was added until solution become yellow. The mixture was concentrated down to afford crude 4-hydroxy-1-methyl-pyrrolidine-2-carboxylic acid methyl ester, which was converted to 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-1-methylpyrrolidine-2-carboxylic acid following the same procedure as for the preparation of (1R,2R)-2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH2:19][CH2:18]1.C[Al](C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:26])[CH2:19][CH2:18]1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Reactant: COC(=O)CCN1CCOCC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCN1CCOCC1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 160 °C

Procedure:
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) and methyl 3-morpholinopropanoate (63 μL, 0.39 mmol) in toluene (2.5 mL) was added a 2M solution of trimethylaluminum in toluene (0.22 mL, 0.43 mmol). The resulting solution was heated twice for 5 min at 160° C. in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO4. After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5 mg (14%) of the title compound (LCMS RT=5.54 min, MH+ 352.0)
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C1CN2CCC(CC2)N1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a stirred solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 □L of H2O, 200 □L of 15% aqueous NaOH, and 600 □L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)(c1ccnc(Cl)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (175 mg, 0.958 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in diethyl ether, 0.380 mL, 1.15 mmol) dropwise. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)-1-cyclopropylethanol (115 mg, 0.579 mmol, 60% yield). MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.2, 1H), 7.43 (d, J=5.2, 1H), 3.43 (s, 1H), 1.52 (s, 3H), 1.26 (m, 1H), 0.60 (m, 1H), 0.50 (m, 1H), 0.40 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:22][O:23][CH2:24][CH2:25][C:26](Cl)=O.C(N(CC)CC)C>>[CH3:22][O:23][CH2:24][CH2:25][C:26]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCn1c(CCOC)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate (23.0 g, 88.6 mmol, prepared in Parts A and B of Example 34) was treated according to the method described in Part A of Example 12. The addition of methoxypropionyl chloride (12.97 g, 106.3 mmol) was carried out at 0° C., and the reaction was stirred at ambient temperature for two hours. The reaction with triethylamine (49.4 g, 354 mmol) was heated at reflux for four hours. After the work-up procedure, 28.6 g of ethyl 5-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoate were obtained as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (311 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow oil (320 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CN1CCN(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with 1-methylpiperazine to give (2S)-1-(tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7-2.05 (m, 4H), 2.1-2.25 (m, 1H), 2.32 (s, 3H), 2.35-2.5 (m, 4H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H), 3.3-3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum: M+H+ 242.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NCC1C=CC(O)=C(OC)C=1.Cl.[OH:27][C:28]1C=C(C=CC=1)CN.C(N(CC)CC)C>>[CH3:28][O:27]/[CH:14]=[C:5]1/[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]2[C:4]/1=[CH:3][CH:2]=[CH:11][CH:10]=2
Reactant: NCc1cccc(O)c1
Reactant: COc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CO/C=C1/C(=O)NC(=O)c2ccccc21

Procedure:
Using the procedure described for the preparation of (4Z)-6-bromo-4-{[(4-hydroxy-3-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione, 0.25 g (78% yield) of off-white solid is obtained from 0.2 g (0.98 mmol) of (4E)-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione and 0.2 g (1.08 mmol) of 4-methoxy]-3-hydroxyl-benzylamine hydrochloride, and 0.3 mL (2.94 mmol) of triethylamine: mp 192-193° C.; 1H NMR (DMSO-d6) δ 10.97 (s, 1H), 10.60 (m, 1H), 9.04 (s, 1H), 8.62 (d, J=9 Hz, 1H), 7.98 (d, J=6 Hz, 1H), 7.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.17 (t, J=6 Hz, 1H), 6.91 (d, J=6 Hz, 1H), 6.78 (m, 2H), 4.56 (d, J=4.5 Hz, 2H), 3.75 (s, 3H); MS (ESI) m/z 325.1 (M+H)+1.