Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH:19]2[CH2:21][CH2:20]2)[CH3:18])[C:11]=1[NH2:22].[C:23](OCC)(=[O:27])[C:24]([CH3:26])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:22]=[C:24]([CH3:26])[C:23](=[O:27])[N:16]([C@@H:17]([CH:19]3[CH2:20][CH2:21]3)[CH3:18])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2ncnc(N[C@H](C)C3CC3)c2N)c(Cl)c1
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: COc1ccc(-c2ncnc3c2nc(C)c(=O)n3[C@H](C)C2CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (5 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 565a). 1H NMR (300 MHz, CDCl3) δ ppm 9.04 (s, 1 H), 7.45 (d, J=8.42 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.98 (dd, J=8.42, 2.56 Hz, 1 H), 4.26 (m, 1 H), 3.91 (s, 3 H), 2.54 (d, J=7.32, 3 H), 2.18 (m, 3 H), 0.87 (m, 2 H), 0.45 (m, 2 H), 0.26 (m, 1 H). MS (AP) 371.3 [(M+H)+, 100].
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>C1COCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2nc(NCC(F)(F)F)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 10 h
Yield: 115.4 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2,2,2-trifluoroethanamine (10.06 mL, 102.0 mmol) and the reaction mixture was stirred for 10 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum to give 6-methoxy-2-(2,2,2-trifluoroethylamino)quinoline-3-carbaldehyde SLA 41066 as an orange solid (2.22 g, >100% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]#[CH:44])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:44]#[C:43][CH2:42][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[S:17][C:10]=12
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CCN1CCN(C)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 70.8 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A, 29.2 mg, 0.211 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.56), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (36 mg, 69%). HPLC: 100% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm, m/z 602 (M+1) detected; 1H NMR (CDCl3, 400 MHz) δ 10.18 (s, 1H), 8.64 (s, 1H), 8.47 (d, J=5 Hz, 1H), 7.77 (m, 1H), 7.56 (s, 1H), 7.44 (m, 2H), 7.26 (m, 2H), 7.04 (m, 2H), 6.51 (d, J=5 Hz, 1H), 3.60 (s, 2H), 2.4-2.8 (m, 8H), 2.32 (s, 3H), 1.77 (m, 2H), 1.63 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[NH2:5].[NH:14]1[CH2:21][CH2:20]C[C@H:15]1[C:16](O)=[O:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O1CCOCC1.[Cu]I>[O:17]1[CH2:16][CH2:15][N:14]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)[CH:8]=2)[NH2:5])[CH2:21][CH2:20]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Nc1cc(N2CCOCC2)cc(-n2cccn2)c1
Temperature: 120 °C
Reaction time: 96 h
Yield: 149.3 %

Procedure:
The mixture of 3-bromo-5-(1H-pyrazol-1-yl)aniline (200 mg, 0.84 mmol), morphoine (0.22 mL, 2.52 mmol), proline (39 mg, 0.34 mmol), CuI (33 mg, 0.17 mmol) and K3PO4 (540 mg, 2.52 mmol) in 10 mL DMSO was stirred at 120° C. in a sealed tube for 4 days. It was diluted with dioxane, filtered through celite, concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate 3-morpholino-5-(1H-pyrazol-1-yl)aniline (124 mg).
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5](=[O:47])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:45])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:46])=[CH:11][CH:12]=1)C.C(OCC)(=O)C.S(=O)(=O)(O)[O-].[K+]>CO.O1CCCC1>[CH3:2][O:4][C:5](=[O:47])[CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:45])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:46])=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)o1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CCC(=O)OC)o2)c(C)c1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Magnesium (24.3 mg, 1.0 mmol) was added to a solution of (E)-3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-acrylic acid ethyl ester (Example 5-(1); 64.5 mg, 0.10 mmol) in methanol (2 mL) and tetrahydrofuran (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for two hours. Ethyl acetate and a potassium bisulfate aqueous solution were added to the reaction mixture to separate the layers. Then, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1) to give the title compound (48 mg, 76%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]2[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[N:14]=2)[CH:8]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]3[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[N:14]=3)[CH:8]=2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(C(F)(F)F)c4)c(C(N)=O)s3)c2)CC1
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 0.1289 g (0.295 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.48b), 6.5 mL of dichloromethane, 0.1 mL (0.892 mmole) of 1-methyl piperazine and 0.3321 g (1.489 mmole) of sodium triacetoxyborohydride was stirred for 16 hours. The mixture was quenched by the addition of 1 mL of saturated ammonium chloride, 1 mL of water and 5 mL of dichloromethane, followed by the addition of 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane. The mixture was stirred for 45 minutes and then diluted with 75 mL of dichloromethane and 5 mL of water. The aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 1:99-20:80) to give 0.127 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(3-trifluoromethylphenyl)-thiazole-5-carboxylic acid amide (VI.48c) as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:23]1[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1.03 g, 5.39 mmol) was dissolved in dichloromethane (20 mL), and added with tert-butyl-piperazine-1-carboxylate (1 g, 5.39 mmol). The reaction solution was cooled to 0° C., and slowly added with NaBH(OAc)3 (1.6 g, 7.55 mmol), followed by stirring for 3 hours at room temperature. The reaction mixture was added with water, and subjected to extraction with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:7 (v/v)) to obtain the title compound (1.9 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:9][O:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14].[CH3:17][O:18][C:19](=[O:22])[C:20]#[CH:21]>CO>[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH:21][C:12](=[C:13]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:14])[C:11]([O:10][CH3:9])=[O:16]
Reactant: NCC1CCOCC1
Reactant: C#CC(=O)OC
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCOCC1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 4-aminomethyltetrahydropyran (1.02 g, 8.9 mmol) and 3-oxo-butyric acid methyl ester (1.15 mL, 10.6 mmol) in MeOH (40 mL) was refluxed for 2 h. Propynoic acid methyl ester (1.2 mL, 13.3 mmol) was added, and the resulting mixture was refluxed for 48 h. After cooling to r.t., the solvent was evaporated, and the crude oil was recrystallized from MeOH to give 2.39 g of the title compound as an off-white solid. MS: (+) m/z 298.33 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[CH2:12]([O:14][CH2:15][CH2:16]Cl)[CH3:13]>>[CH2:12]([O:14][CH2:15][CH2:16][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])[CH3:13]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CCOCCCl
Product: CCOCCn1c(CC)nc2ccccc21
Yield: 80 %

Procedure:
1-(2-Ethoxyethyl)-2-ethyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-ethylbenzimidazole was used instead of benzimidazole, and an equimolar amount of 2-chloroethyl ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 80%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N.O=[Si]=O>CO.[Ni]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN1Cc2cc(Oc3cccc(C#N)c3)ccc2N=C1NC(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Agent: O=[Si]=O
Solvent: CO
Product: CCCN1Cc2cc(Oc3cccc(CN)c3)ccc2N=C1NC(=O)OC(C)(C)C

Procedure:
A mixture of [6-(3-cyano-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0197 mol) in a solution of ammonia in methanol (250 mL) was hydrogenated at 14° C. with Raney nickel (1 g) as a catalyst. After uptake of H2 gas (2 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated to yield the title compound as a residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[NH:13][N:12](COCC[Si](C)(C)C)[NH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCN1NC=C(Nc2cccc(F)c2)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: NCCN
Product: Fc1cccc(Nc2cn[nH]n2)c1
Temperature: 90 °C

Procedure:
To N-(3-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-amine 7e (50 mg, 0.16 mmol) was added ethane-1,2-diamine (50 mg, 55.6 μL, 0.83 mmol) and tetrabutylammonium fluoride (424 mg, 478 μL, 1.62 mmol) and the mixture was heated to 90° C. in a microwave for 2 h. The mixture was diluted with EtOAc and water and the organic was washed with water, brine and then dried (MgSO4) and concentrated. Material was purified by Fractionlynx to afford the title compound I-45 as a white solid (10 mg, 35%). 1H NMR (500 MHz, d6-DMSO) δ 14.19 (1H, s), 9.02 (1H, s), 7.39 (1H, d), 7.17-7.27 (2H, m), 6.99-7.06 (1H, m), 6.52-6.61 (1H, m). MS m/z: 179.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([Cl:13])(=[O:12])=[O:11].[N:14]1C=CC=CC=1.C(OC(=O)N[CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[C:41]3[O:40][CH:39]=[CH:38][C:37]=3[CH:36]=[C:35]([NH2:42])[CH:34]=2)[CH2:29][CH2:28]1)(C)(C)C>C(Cl)Cl>[ClH:13].[NH2:14][CH:31]1[CH2:32][CH2:27][CH2:28][CH2:29][N:30]1[C:33]1[C:41]2[O:40][CH:39]=[CH:38][C:37]=2[CH:36]=[C:35]([NH:42][S:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:12])=[O:11])[CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: c1ccncc1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(N2CCCCC2N)c2occc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxy-5-methylbenzenesulfonyl chloride (80.0 mg, 0.36 mmol) and pyridine (219 mL) were added to tert-butyl[1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. N-deprotection and conversion into the hydrochloride salt was performed by treatment with 2 M HCl in ether. This furnished 59.0 mg (47%) of the title product. HPLC 100%, RT: 1.731 (System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.70-1.76 (m, 2H) 2.05 (d, J=10.05 Hz, 2H) 2.20 (s, 3H) 2.76 (t, J=11.46 Hz, 2H) 3.19-3.21 (m, 1H) 3.65 (d, J=12.56 Hz, 2H) 3.87 (s, 3H) 6.58 (d, J=1.88 Hz, 1H) 6.81 (d, J=2.20 Hz, 1H) 6.89 (d, J=1.88 Hz, 1H) 7.04 (d, J=8.48 Hz, 1H) 7.32 (dd, J=8.48, 2.20 Hz, 1H) 7.51 (d, J=2.20 Hz, 1H) 7.86 (d, J=1.88 Hz, 1H) 8.35 (d, J=3.45 Hz, 3H) 9.65 (s, 1H). LC-MS 416 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH:34]=O)=[CH:29][CH:30]=2)[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:28]3[CH:27]=[C:26]4[C:31]([CH2:32][CH2:33][C:24](=[O:23])[NH:25]4)=[CH:30][CH:29]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CC5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To 20 mL of a chloroform solution containing 176 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 102 mg of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde, 34 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 200 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=100:1] to give 178 mg of 7-methoxy-1-(2-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[F:23].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=2)[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1ccc(F)c(Cl)c1)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 23.9 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 69a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 24%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.Br[C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CC(O)CC.CN(C)C(=O)C>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCN(c2nccs2)CC1

Procedure:
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 228 is suspended in 2-butanol (5 ml), and thereto are added 2-bromothiazole (113 μl) and N,N-diisopropylethylamine (131 μl), and the mixture is heated under reflux for 24 hours. To the reaction solution are added 2-bromothiazole (57 μl) and N,N-dimethylacetamide (2 ml), and the mixture is further heated under reflux for 24 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then ethyl acetate) to give 3-[[1-(2-thiazolyl)piperidin-4-yl]-carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (38 mg). This product is further treated with hydrogen chloride in dioxane to give the title compound (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[CH3:24][C:25]([CH3:40])([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1)=[O:29])[CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:37](=[O:38])[CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([C:28]([O:27][C:25]([CH3:26])([CH3:24])[CH3:40])=[O:29])[CH2:31][CH2:32]4)[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1Cc2cccnc2C(N2CCNCC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cccnc2C(N2CCN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 30.1 %

Procedure:
(8-Chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-piperazine (531 mg, 1.14 mmol), 1-(1,1-dimethylethoxycarbonyl)-4-piperidine-acetic acid (570 mg, 2.3 mmol), EDCl (439 mg) and HOBT (311mg) were dissolved in DMF (8 ml), and NMM (4 ml) was added. The reaction mixture was stirred at 20° C. for 20 hours and then water (100 ml) was added, and the resulting tan suspension was extracted with EtOAc (2×30 ml). The EtOAc phase was then washed with Na2CO3 (30 ml), dried over Na2SO4, filtered, and evaporated. The product was chromatographed over silica gel in CH2Cl2, and the column was eluted with CH2Cl2 and with CH2Cl2 /MeOH (95:5). The resulting purer material (0.75 g) was rechromatographed over silica gel in hexane/acetone (85:15) and eluted with increasing amounts of acetone (finally 30%). The product was rechromatographed on silica gel to afford the title compound (0.19 g), m.p. 86-98° C.; found: C, 64.64; H, 7.39; N, 12.12; calcd. for C30H40ClN5O3 : C, 65.03; H, 7.28; N, 12.64; HRMS: calcd. 554.2898; found 554.2891.
Reaction SMILES: [O:1]=[C:2]([NH:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:15]=2[CH:14]=1)[CH2:3][NH:4]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:14]1[C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[O:17][C:16]=2[CH:25]=[CH:26][C:13]=1[NH:12][C:2](=[O:1])[CH2:3][NH2:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 72.2 %

Procedure:
A solution of tert-butyl [2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.10 g) in 1:1 trifluoroacetic acid:dichloromethane (5 mL) was stirred at room temperature for 30 min and then concentrated to provide N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (52 mg) as its trifluoroacetic acid salt. MS (ESI) m/z 259 ([M+H]+).