Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13]CC2CCCCC2)[C@H:11]([CH2:21][CH2:22][C:23]2([C:33]([O:35]CC)=[O:34])[S:28](=[O:30])(=[O:29])[CH2:27][CH2:26][CH2:25][S:24]2(=[O:32])=[O:31])[O:10][C:9]1([CH3:39])[CH3:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].O1[CH2:47][CH2:46]OCC1>>[C:1]([N:8]1[C@@H:12]([CH2:13][CH:47]2[CH2:46][CH2:13][CH2:12][CH2:11][CH2:21]2)[C@H:11]([CH2:21][CH2:22][C:23]2([C:33]([OH:35])=[O:34])[S:28](=[O:29])(=[O:30])[CH2:27][CH2:26][CH2:25][S:24]2(=[O:31])=[O:32])[O:10][C:9]1([CH3:39])[CH3:38])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCOC(=O)C1(CC[C@@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CCC2CCCCC2)S(=O)(=O)CCCS1(=O)=O
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CCC2(C(=O)O)S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Reaction time: 3 h

Procedure:
A mixture of 1 g of 2-[2-((4S,5S)-3-BOC-4-cyclohexylethyl-2,2-dimethyl-5-oxazolidinyl)-ethyl]-2-ethoxycarbonyl-1,3-dithiane 1,1,3,3-tetroxide, 50 ml of dioxane and 20 ml of 2 N NaOH (aqueous) is stirred at 20° for 3 h. The usual working up gives 2-[2-((4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl)-ethyl]-2-carboxy-1,3-dithiane 1,1,3,3-tetroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>C[O-].[Na+].CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2cc(Cl)c(Oc3ccc(Cl)cc3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2c1=O
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere in a flame-dried flask at room temperature and with magnetic stirring, 0.921 g (0.003 mol) of 7-chloro-6-(4-chlorophenoxy)quinazolin-4(3H)-one was slurried in 3.0 ml of 1.1N sodium methoxide. After 15 minutes, 1.00 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate in 10 ml of methanol was added dropwise. After 2 hours, the reaction mixture was evaporated under reduced pressure, and the residue treated with water. The aqueous solution was extracted three times with 75 ml of dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the title compound: yield 1.28 g (76%); m.p. 138°-141° C. H-NMR(CDCl3) 1.3 to 1.9 (m, 4H), 2.6-3.4 (m, 6H), 3.3 (s, 3H), 4.9 (s, 2H), 4.5-6.2 (m, 5H), 7.1 (q, 4H), 7.6 (s, 1H), 7.8 (d, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].CC(C)([O-])C.[K+].I[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH:30]3[CH3:32])=[O:28])[N:25]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH:30]3[CH3:32])=[O:28])[N:25]=2)[N:22]=1
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Reactant: Cc1ccc(O)cc1N
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4C)cn3n2)cc1N
Yield: 56 %

Procedure:
Using 3-amino-4-methylphenol (1.08 g, 8.77 mmol), N,N-dimethylformamide (30.0 mL), potassium tert-butoxide (1.02 g, 9.13 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.5 g, 7.31 mmol) and potassium carbonate (0.51 g, 3.65 mmol), and in the same manner as in Example 216, the title compound (1.38 g, 56%) was obtained as a brown powder.
Reaction SMILES: C(N1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1)(=O)C.C(NC1C=CC(N)=C(OC)C=1)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=3)[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=2)=[C:11]([O:38][CH3:39])[CH:10]=1)([CH3:5])[CH3:7]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(C)=O)C4)cc3OC)ncc2C(F)(F)F)c1
Agent: COc1cc(NC(C)C)ccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC(C)C)cc3OC)ncc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
As shown in Scheme 2, a mixture of intermediate 1 of Scheme 2 (16 mg) and N1-isopropyl-3-methoxybenzene-1,4-diamine (15 mg, prepared from WO 2006/021548) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50° C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the title compound (8 mg) as a TFA salt. 1H-NMR (DMSO-d6, 400 MHz) δ 10.12 (s, 1H), 8.49 (br, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.71 (br, 1H), 7.47 (d, J=6.4 Hz, 1H), 7.23 (m, 3H), 6.44 (dd, J=10.0, 16.8 Hz, 1H), 6.23 (m, 2H), 5.91 (m, 1H), 5.75 (dd, J=1.6, 10.0 Hz, 1H), 5.21 (m, 1H), 3.68 (s, 3H), 1.10 (d, J=6.0 Hz, 1H); calculated mass for C24H25F3N6O2: 486.2. found: 486.9 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
4-Bromophenol (5.0 g, 29.0 mmol) was dissolved in N,N-dimethylformamide (150 ml), and imidazole (4.09 g, 60.0 mmol, 2.0 eq.) was added to the mixture, tert-Butyldimethyl silyl chloride (4.36 g, 29.0 mmol, 1.0 eq.) was slowly added to the above mixture and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 8.15 g of the title compound (yield: 97.8%).
Reaction SMILES: C([O:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:26]([O-:28])=[O:27])=[C:9]([N:19]3[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[CH:20]3)[CH:10]=2)[N:5]=1)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C)C)(C)C>ClCCl>[N+:26]([C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:4](=[O:3])[NH:5]2)=[CH:10][C:9]=1[N:19]1[CH:23]=[C:22]([CH2:24][O:25][C:36](=[O:37])[NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]=[CH:20]1)([O-:28])=[O:27]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of the compound of Example 1 (50.0 mg, 129 μmol) in dichloromethane (2 ml) was added phenyl isocyanate (46.2 mg, 388 μmol), and the mixture was stirred overnight at room temperature. Diisopropyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and air-dried. These were dissolved into acetic acid (5 ml) and concentrated hydrochloric acid (1 ml) was added, which was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was washed with water and ethyl acetate in sequence and then air-dried, thereby obtaining 41.0 mg of title compound as yellow powder. Yield 71%.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)(O)[O-].[Na+].Cl[C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48]>ClCCl.C1(C)C=CC=CC=1>[CH:50]([O:49][C:47](=[O:48])[NH:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4](=[O:5])[N:6]([CH3:8])[CH3:7])([CH3:52])[CH3:51]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)OC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C

Procedure:
45 mg (0.08 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 1.0 mL dichloromethane and 1.0 mL of a saturated aqueous solution of sodium bicarbonate was added. The biphasic solution was cooled to 0° C. in an ice bath and, while stirring vigorously, 161 μL (0.161 mmol) of 1 M isopropyl chloroformate in toluene was added. The reaction was allowed to stir in the ice bath and allowed to warm to room temperature overnight (16 hours). The layers were separated and the organic layer was washed twice with water. The organic layer was then dried over sodium sulfate and concentrated. MS: m/z 645.1 (M+H+).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 77.6 %

Procedure:
A mixture of 70 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione, 400 mg of p-toluenesulfonyl chloride, 1 ml of 4-dimethylaminopyridine and 0.9 ml of pyridine was heated under reflux for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 50% hydrochloric acid and then with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (19/1)] to give 52 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. The 1H-NMR spectrum of this compound was the same as that of the compound produced in Example 1.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([OH:13])[CH:12]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:13][CH2:17][CH2:18][Cl:19])[CH:12]=1
Reactant: COc1ccc(Br)cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OCCCl
Temperature: 70 °C
Reaction time: 5 h
Yield: 103.4 %

Procedure:
To 1.2 L of N,N-dimethylformamide solution containing 159 g (0.79 mol) of 5-bromo-2-methoxyphenol (see WO 01019785) were added 340 g (2.37 mol) of 1-bromo-2-chloroethane and 120 g (0.868 mol) of potassium carbonate, and the mixture was stirred at 70° C. for 5 hours. Then, 220 g (1.53 mol) of 1-bromo-2-chloroethane and 80 g (0.58 mol) of potassium carbonate were additionally added thereto twice by dividing them to two portions during the reaction, and the mixture was further stirred for 7 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The organic layer after separation was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 217 g of the title compound as a dark brownish solid substantially quantitatively.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O>C(O)C>[OH:3][N:2]=[CH:4][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NO
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
Hydroxylamine hydrochloride (4.3 grams, 0.062 mole) was added to a cold solution of 5-formyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (7 grams, 0.031 mole) in absolute ethanol (40 ml.). The reaction mixture was stirred in the cold for thirty minutes, then at room temperature for 16 hours. The reaction mixture was then poured over ice-water, and the precipitated product was separated, dried, and recrystallized from toluene, yielding 3 grams of 5-(hydroxyiminomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester, m.p., 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 505.23 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([C:19]1[C:18](=[O:28])[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC(=O)O)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl bromoacetate (341 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) and cesium carbonate (998 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted by adding ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure. Dichloromethane (15 ml) and TFA (0.59 ml) were added to the residue at room temperature. The reaction mixture was stirred at room temperature for two hours. TFA (1.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. TFA (4.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->17:3 (v/v)] to give 320 mg of the title compound as a solid.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][N:19]([CH:20]([CH3:23])[CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.64 g) in methanol (20 ml) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (540 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.44 g, 82%) as a pale-yellow powder.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH:5]1[N:10]([N:11]([CH3:24])[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9](=[O:25])[CH2:8][N:7]([S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:6]1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)Cl>[ClH:39].[ClH:1].[Cl:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:26]([N:7]1[CH2:8][C:9](=[O:25])[N:10]([N:11]([CH3:24])[CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:5]([CH2:4][NH:3][C:47](=[O:49])[CH3:48])[CH2:6]1)(=[O:27])=[O:28])[CH:38]=[CH:37]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CN
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-(aminomethyl)-4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-2-piperazinone dihydrochloride (0.14 g) obtained in Example 113, triethylamine (0.16 ml) and methylene chloride (3 ml) was combined with acetic anhydride (0.043 ml) with stirring at room temperature and then stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.12 g) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)c(C)cc1O
Solvent: ClCCl
Product: COc1cc(Br)c(C)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxy-5-methylphenol (500 mg, 0.002 mol), phenylboronic acid (0.70 g, 0.0058 mol), TEA (1.9 mL, 0.014 mol), cupric acetate (0.67 g, 0.0037 mol) and DCM (30 mL) were added to a 100 mL oven dried flask and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.27 (s, 3H), 3.79 (s, 3H), 6.84 (s, 1H), 6.88-6.96 (m, 2H), 7.00-7.08 (m, 1H), 7.15 (s, 1H), 7.23-7.33 (m, 2H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCCCCO
Solvent: O
Solvent: c1ccncc1
Product: C#CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of 9.81 g. (0.10 moles) of 5-hexyn-1-ol, 33.5 g. (0.12 moles) of triphenylmethyl chloride, and 200 ml. of dry pyridine is refluxed for 60 minutes. The cooled mixture is poured into water and extracted with ether. The extract is washed successively with water, ice-cold N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The extract is dried with magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on Florisil to give an oil, ν max. 3290 (acetylenic hydrogen), 1600, 1072, and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[C:15]([OH:17])(=[O:16])[CH3:14].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[CH:2]=1
Reactant: Nc1ccc(C(=O)O)c(-c2ccccc2)c1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Reaction time: 0.17 h
Yield: 186.5 %

Procedure:
3-Pyridinecarboxaldehyde (1.2 mL, 12.8 mmol) and 4-amino-2-phenylbenzoic acid hydrochloride (3.2 g, 12.8 mmol), prepared in Example 190A, were dissolved in 100 mL 1% acetic acid in methanol. After stirring for 10 minutes, NaBH3CN was added, and stirring was continued for 18 hours. The reaction was evaporated to dryness under reduced pressure and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with brine, and dried over Na2SO4 to give 4-(3-Pyridylmethylamino)-2-phenylbenzoic acid acetic acid salt (4.35 g, 90%) of the title compound. MS m/e 305 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 4.41 (s, 2H), 6.45 (d, J=3 Hz, 1H), 6.60 (m, 1H), 7.15-7.90 (m, 10H), 8.48 (m, 1H), 8.60 (m, 1H).