Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[C:23]([O:25]C)=[O:24].[OH-].[Li+]>O1CCCC1.CO>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C@H:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@@H:11]([C:23]([OH:25])=[O:24])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3.3 g (15 mmol) of the product of Step B in 200 mL of 3:1 tetrahydrofuran/methanol was added 50 mL (50 mmol) of 1N aqueous lithium hydroxide solution and the resulting solution was stirred at ambient temperature for 16 h, then concentrated and acidified with 100 mL of 1N aqueous hydrochloric acid. The resulting mixture was extracted with three 100-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid and saturated aqueous brine (100 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as a colorless foamy solid that was used without further purification. LC/MS 382.4 (M+23).
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=1.C([BH3-])#N.[Na+]>>[CH3:21][C@@H:20]1[N:22]([C:23]2[N:28]=[C:27]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[CH:30]3)[CH:26]=[CH:25][N:24]=2)[CH:44]([C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)[N:17]2[C@H:16]1[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH2:19][CH2:18]2
Reactant: O=Cc1cccnc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H]1[C@@H]2CN(C(=O)Nc3cccc4ccccc34)CCN2C(c2cccnc2)N1c1nccc(-n2cnc3ccccc32)n1

Procedure:
The title compound was prepared from 2-[1-(4-(N-naphth-1-yl-carbamoyl) piperazin-2-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 18.2 mg), 3-pyridinecarboxaldehyde (23.7 mg), and sodium cyanoborohydride (4.6 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 582.2 (M+1).
Reaction SMILES: [H-].[Na+].C([N:11]1[CH2:28][CH2:27][CH:15]2[N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH:14]2[CH2:13][CH2:12]1)[CH:19]([OH:26])[CH2:18][CH2:17]3)(=O)C1C=CC=CC=1.I[CH3:30]>CN(C=O)C>[CH3:30][O:26][CH:19]1[C:20]2[C:25]3=[C:24]([CH:14]4[CH2:13][CH2:12][NH:11][CH2:28][CH2:27][CH:15]4[N:16]3[CH2:17][CH2:18]1)[CH:23]=[CH:22][CH:21]=2
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN2c3c1cccc3C1CCNCCC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
NaH (60% dispersion in mineral oil, 0.50 g, 1.2 mmol) was added to a solution of 10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-ol (0.20 g, 0.58 mmol) in DMF (5.0 mL) at 0° C. under N2. After 30 min, iodomethane (0.040 mL, 0.64 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1 h and then allowed to warm to room temperature prior to extracting with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/heptanes (2:1) to give 0.16 g (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 7.46-7.30, 6.94, 4.51, 4.22-4.03, 4.01-3.79, 3.65-3.41, 3.29, 3.12, 3.04, 2.90, 2.82, 2.34, 2.08; IR (drift) 1631, 1493, 1477, 1459, 1422, 1370, 1359, 1324, 1292, 1267, 1098, 1085, 786, 748, 706 cm−1; HRMS (FAB) calcd for C23H24N2O2+H 361.1916, found 361.1913.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:51][C:52]1([CH3:59])[C:56]([CH3:58])([CH3:57])[O:55][BH:54][O:53]1>C1COCC1>[CH3:28][C:24]1([CH3:27])[O:25][C@H:26]2[C@@H:19]([O:18][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20]([B:54]3[O:55][C:56]([CH3:58])([CH3:57])[C:52]([CH3:59])([CH3:51])[O:53]3)=[C:21]([CH2:29][O:30][C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@H:22]2[O:23]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(B1OC(C)(C)C(C)(C)O1)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a 25 mL round-bottom 3-neck flask equipped with nitrogen inlet/outlet, stir bar, and thermocouple with temperature controller was charged 0.2806 g of compound 8 (0.353 mmol, 1.0 eq) and 3 mL tetrahydrofuran (10 V). The reaction was cooled to 0° C. To this solution was added 0.653 mL (0.847 mmol, 2.4 eq) of isopropylmagnesium chloride lithium chloride complex, 1.3 M in THF slowly over 15 minutes. The reaction was stirred at 0° C. for 1 hour. HPLC assay indicated formation of intermediate. 0.128 mL of 4,4,5,5 tetramethyl-1,3,2 dioxaborolane (0.884 mmol, 2.5 eq) was added to the reaction. An HPLC assay after 1 hour at 0° C. indicated that the reaction was completed. The reaction was quenched with saturated aqueous ammonium chloride solution (3V). The ice bath was removed and the reaction warmed to room temperature. The reaction was charged with DI water (3V) and ethyl acetate (6V). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (6V). The organic phases were combined and washed with brine (3V) and dried over MgSO4. The resulting mixture was filtered. The filtrate was concentrated to dryness by the rotary evaporator. Obtained 0.098 grams as a white solid, (35% yield), 80 A % purity of [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (compound 9c-2).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16]C1C=CC=CC=1CCl.[Mg].C(OCC)(=O)C(OCC)=O>>[Cl:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: ClCc1ccccc1Cl
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1Cl
Yield: 74 %

Procedure:
The title compound was prepared as described for B4 using 2-chlorobenzyl chloride (1.250 g, 7.76 mmol), magnesium (0.208 g, 8.54 mmol), diethyl oxalate (2.269 g, 15.53 mmol). The product was isolated in the form of colorless oil in 74% yield and use instantly in next step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[CH:24][C:23]([C:34](Cl)=[O:35])=[N:22]1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:34]([C:23]1[CH:24]=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[N:21]([CH2:20][C:19]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:17]([Cl:16])[CH:18]=2)[N:22]=1)=[O:35]
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: CC1CCCCC1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(C(=O)NC3CCCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 1 ml of 2-methylcyclohexylamine, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. The compound is purified by chromatography on silica using a DCM/MeOH mixture (98/2; v/v) as the eluent to give 0.27 g of the expected product. M.p.=165° C.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])C.[C:18]1(=[O:25])[CH:23]=[CH:22][C:21](=[O:24])[CH:20]=[CH:19]1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]([C:5]2[C:20]3[CH:19]=[C:18]([OH:25])[CH:23]=[CH:22][C:21]=3[O:24][CH:4]=2)=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Reactant: O=C1C=CC(=O)C=C1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3ccc(O)cc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.7 %

Procedure:
A suspension of enaminone 12 (2 g, 8.43 mmol) and compound benzoquinone Q-4 (910 mg, 8.43 mmol) in acetic acid was stirred at room temperature under an atmosphere of N2 for 5 h. The precipitate that formed was filtered, washed with water, and dried under high vacuum to afford compound 13 (1.2 g, 47%) as an off-white solid. TLC Rf=0.5 (petroleum ether-EtOAc, 7:3); 1H NMR (DMSO-d6) δ 9.43 (s, 1H), 8.59 (s, 1H), 7.57-7.43 (band, 4H), 7.12 (d, J=8.3 Hz, 1H), 6.86 (dd, J=9.0 Hz, 2.6 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (ES) m/z 299 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: Cc1cccnc1C(=O)CBr
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncccc2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-3-methylpyridine hydrobromide (Preparation is described in Example 73).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][CH:42]=[C:43]([CH:46]=2)[C:44]#[N:45])O1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:39]4[CH:40]=[N:41][CH:42]=[C:43]([CH:46]=4)[C:44]#[N:45])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cncc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 29.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (24 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)nicotinonitrile (6.27 mg, 30%). 1H-NMR (MeOD): 2.04 (d, 1H), 2.20 (m, 1H), 3.06 (m, 3H), 5.24 (d, 0.3H), 5.82 (d, 0.7H), 7.01 (m, 1H), 7.36 (m, 6H), 7.50 (m, 1H), 8.29 (m, 1H), 8.70 (m, 1H), 8.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (30.0 mg, 0.068 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 31.8 mg, 0.136 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (39.1 mg, 0.204 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (27.5 mg, 0.204 mmol), N-ethyl-N-isopropylpropan-2-amine (0.061 ml, 0.340 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature for 48 hours. Then the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (27.3 mg, 61.1%). LRMS (APCI pos) m/e 658 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.42 (m, 2H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.21-7.66 (m, 7H), 6.58 (s, 1H), 6.30 (m, 1H), 4.18 (m, 2H), 3.68 (m, 2H), 2.62 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[CH2:1]([N:5]([C:29]([C:24]1[NH:25][C:26]([CH2:27][CH3:28])=[C:22]([Cl:21])[N:23]=1)=[O:30])[CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CN(c2nc(C)c(C(=O)OCC)s2)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)OCC)s2)C1
Yield: 79.4 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-[3-(n-butylamino)azetidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (230c) (98 mg, 0.33 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (58 mg, 0.33 mmol), WSC hydrochloride (190 mg, 0.99 mmol), 1-hydroxybenzotriazole (46 mg, 0.33 mmol) and N-methylmorpholine (0.07 mL, 0.66 mmol), to obtain 119 mg of the title compound as a white solid (79%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.[OH:16][C@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C@H:17]([OH:16])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:24]2)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2c(Cl)nc(Cl)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(Cl)nc3cc(C(=O)O)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2,4-dichloroquinazoline-7-carboxylic acid (0.45 g, 1.9 mmol) in CH2Cl2 (20 mL) was added (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (0.37 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol). The reaction mixture was stirred overnight at room temperature and then purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 to obtain 2-chloro-4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylic acid (0.58 g, 77%). LC/MS: m/z 407.3 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([N:22]=[C:23]=[O:24])=[CH:16][C:15]=2[O:14]1>C1C=CC=CC=1>[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([NH:22][C:23]([NH:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:24])=[CH:16][C:15]=2[O:14]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(NCCc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyphenylethylamine (0.25 g, 1.5 mmol) and 3,4-methylenedioxyphenyl isocyanate (0.25 g, 1.5 mmol) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0078B (0.43 g, 85%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (100 mg) in CHCl3 (3 mL) was treated with Et3N (0.090 mL), N-(tert-butoxycarbonyl)-D-phenylalanine (122 mg), EDCI (89 mg) and HOBt (62 mg). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was washed with 1 N aqueous NaOH solution (2 mL×2) and brine (2 mL). The organic layer was dried and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(tert-butoxycarbonyl)-D-phenylalanyl}aminomethyl]piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([N:28]([CH3:30])[CH3:29])(=[O:32])=[O:31])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-dimethylsulfamoyl-benzoic acid (CAS: 37088-27-0; BE 620741) (64%, light yellow foam, MS (m/e): 468.1 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)[CH:3]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+]>O1CCOCC1>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:17]([OH:21])[OH:18])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1
Reactant: CN(C)C1CCN(c2cc(Br)ccn2)CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2cc(B(O)O)ccn2)CC1
Yield: 125.9 %

Procedure:
In a Schlenck vessel 1-(4-bromopyridin-2-yl)-N,N-dimethylpiperidin-4-amine (1.55 g, 5.45 mmol) was treated with bis(pinacolato)diboron (1.65 g, 6.50 mmol), potassium acetate (1.6 g, 16.3 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.22 mg, 0.24 mmol) and dioxane (20 ml) as a solvent according to the method described in Preparation 174a to give 1.71 g (85% yield) of the title compound that was used in the next synthetic step without further purification. Purity 90%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH2:14][CH:13]3[N:10]([C:11](=[O:17])[CH:12]3[CH2:15][CH3:16])[C:9]=2[C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pt]=O>[N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH2:14][CH:13]3[N:10]([C:11](=[O:17])[CH:12]3[CH2:15][CH3:16])[C:9]=2[C:18]([OH:20])=[O:19])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)CC12
Agent: O=[Pt]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)O)=C(Sc3ccncc3)CC12
Reaction time: 4 h
Yield: 56.2 %

Procedure:
54 mg of p-nitrobenzyl 3-(4-pyridylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Example 17 was dissolved in a mixture of 2 ml of dioxane and 2 ml of a 0.1 M phosphate buffer (pH 7.0). Then, 54 mg of platinum oxide was added, and the reaction was performed at room temperature for 4 hours in a Paar reducing apparatus (hydrogen pressure 4 kg/cm2). The catalyst was removed by filtration. The filtrate and the wash liquid were combined and concentrated under reduced pressure to about 2/3 of the original amount. To the resulting solution was added 2.5 g of sodium chloride, and further water was added to make the total amount 50 ml. The solution was charged on a column of Diaion HP-20AG (1.1×20 cm), and eluted with 300 ml in total of an aqueous solution of acetone having a concentration gradually varying from 0 to 30% by a concentration gradient method. The eluate was fractionated into 5 g fractions. The fractions were screened by high-velocity liquid chromatography, and fractions having an ultraviolet absorption at λmax 303 nm were collected, and lyophilized to afford 20.7 mg (yield 56.8%) of the captioned product.