Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ClC(OCC)=O.[BH4-].[Na+].O>C1COCC1>[F:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(F)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cncc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.9 %

Procedure:
To a solution of 5-fluoronicotinic acid (1.0 g, 7.09 mmol) in THF (10 mL) was added TEA (0.9 mL, 7.73 mmol), followed by ethyl chloroformate (0.6 mL, 7.73 mmol) at 0° C. The reaction was stirred at room temperature 2 h; then it was filtered. The residue was washed with a small amount of THF. The filtrate was chilled to 0° C. and sodium borohydride (0.67 g, 17.73 mmol) was added, followed by dropwise addition of water (5 mL). The reaction was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, and concentrated to give a crude product which was used purified by a silica gel chromatography to give (5-fluoropyridin-3-yl)methanol (197 mg, 21.8% yield) as a colorless oil. LCMS retention time 0.375 min; LCMS MH+ 128.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:19][C:20]([F:30])([F:29])[C:21](OCC(F)(F)F)=[O:22]>C1COCC1>[C:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][C:21](=[O:22])[C:20]([F:30])([F:29])[F:19])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a suspension of 60% NaH (2.2 g, 55 mmol; washed with hexanes) in THF (250 mL) at 0° C. was added dropwise tert-butyl acetoacetate (8.0 g, 50.6 mmol) over a period of 15 min. The mixture was stirred for 15 min. and a homogenous solution solution resulted. A solution of 2.5M n-BuLi in hexanes (20.5 mL, 51 mmol) was added dropwise. After stirring for 15 min., 2,2,2-trifluoroethyl trifluoroacetate (11 g, 56 mmol) was added and the mixture was stirred for 30 min., quenched with HOAc, diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (anhydrous MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (10:1), then hexanes:EtOAc (4:1) provided 5 g of title compound as a red-brown oil.
Reaction SMILES: Br[C:2]1[S:20][C:5]2[N:6]=[C:7]([CH3:19])[N:8]=[C:9]([CH2:10][N:11]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:36][CH2:35][C:32]3([CH2:34][CH2:33]3)[CH2:31][CH:30]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[O:17]=[S:14]1(=[O:18])[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[C:4]3[CH:3]=[C:2]([C:29]4[CH2:36][CH2:35][C:32]5([CH2:34][CH2:33]5)[CH2:31][CH:30]=4)[S:20][C:5]=3[N:6]=[C:7]([CH3:19])[N:8]=2)[CH2:12][CH2:13]1
Reactant: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(Br)sc2n1
Reactant: CC1(C)OB(C2=CCC3(CC2)CC3)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(C3=CCC4(CC3)CC4)sc2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a mixture of 6-bromo-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (200 mg), 4,4,5,5-tetramethyl-2-(spiro[2.5]octa-5-en-6-yl)-1,3,2-dioxaborolane (185 mg), and dioxane (4 mL) were added Pd2dba3 (25 mg), dicyclohexyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (50 mg), K3PO4 (340 mg), and water (200 μL), followed by heating and stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by a basic silica gel column (hexane/EtOAc) to obtain 4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methyl-6-(spiro[2.5]octa-5-en-6-yl)thieno[2,3-d]pyrimidine (167 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]([C@H:9]([C:14](=[O:36])[NH:15][C@H:16]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:35])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:6]([OH:8])=[O:7])=[O:4].[Li+].[OH-]>C(O)C>[C:3]([CH:5]([C@H:9]([C:14](=[O:36])[NH:15][C@H:16]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:35])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:6]([OH:8])=[O:7])([OH:4])=[O:2]
Reactant: COC(=O)C(C(=O)O)[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R,10S)-2-Methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanoic acid was taken up in ethanol (25 mL) and then 1N LiOH (0.3 mL, 3 eq) was added dropwise. The resulting homogeneous solution was stirred at room temperature for 3 hrs. Most of the ethanol was removed under reduced pressure at 30° C. Then water (5 mL) and ethyl acetate (30 mL) was added and with stirring, 4N HCl was added until pH=2. The ethyl acetate layer was further washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purified by reverse phase HPLC to give 47 mg of (3R,10S)-2-carboxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, as a white solid, MS: 484.5 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:40]=[CH:41][CH:42]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([O:37]CC)=[O:36])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:40]=[CH:41][CH:42]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([OH:37])=[O:36])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Ethyl 5-{3-{3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy}phenoxy}-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate, (8.00 g, 0.013 mole) was dissolved in ethanol, (150 ml) and water (50 ml) and sodium hydroxide (0.520 g, 0.013 mole) dissolved in water (5 ml) was added. The solution was stirred at room temperature for 5 hours. The reaction was neutralized with dilute hydrochloric acid and excess ethanol evaporated in vacuo. The aqueous solution was extracted with EtOAc, (three times), then chloroform (three times), and the organic extracts combined, dried (MgSO4), and evaporated in vacuo to a pale yellow foam. Trituration with diethyl ether gave a white solid which was filtered off and dried in vacuo to yield 92% of the title compound, mp (EtOH) 100°-2° C. (dec). νmax (mull) 1515, 1590, 1615, 3390 cm-1 δ(DMSOd6) 1.81 (2H, m, CH2), 2.50 (10H, m, piperazinyl+ CH2), 3.45 (2H, s, CH2N--) 3.70 (3H, s, OCH3), 3.89 (2H, t, J 6 Hz, OCH2), 4.75 (1H, bs, OH, exchangeable D2O), 5.35 (2H, s, N--CH2), 6.40 (2H, m, aromatics), 6.67 (1H, dd, J2, 8 Hz, aromatic), 7.00 (4H, ABq, Δν 84 Hz, J 9 Hz, C6H4OCH3), 7.19 (1H, t, J 8 Hz, aromatic) 7.32 (4H, ABq, Δν 17 Hz, J 8.5 Hz, --C6H4 --Cl). Mass spec. Observed mass 547.2342, theoretical mass 547.2350 (C31H34ClN5O5 --CO2).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:34][CH3:35])=[N:12][N:13](CC4C=CC=CC=4)[C:14]=3[NH:15][S:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:34][CH3:35])=[N:12][NH:13][C:14]=3[NH:15][S:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1nn(Cc2ccccc2)c(NS(=O)(=O)/C=C/c2ccccc2)c1-c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: COc1n[nH]c(NS(=O)(=O)CCc2ccccc2)c1-c1ccc2c(c1)OCO2
Yield: 97.6 %

Procedure:
(E)-N-[4-(1,3-benzodioxol-5-yl)-1-benzyl-3-methoxy-1H-pyrazol-5-yl]-2-phenyl-1-ethenesulfonamide (1.2 g) (Preparation 57) was dissolved in acetic acid (50 ml). Under an atmosphere of nitrogen, Pearlmann's catalyst (JM type 91, 200 mg) was added and the reaction was stirred for 24 h under 2 bars of hydrogen at 50C. The reaction mixture was filtered on a short pad of Celite® and concentrated under reduced pressure. To the oily residue was added water (dichloromethane (200 ml). The phases were separated, the organic phase washed with a 10% aqueous solution of sodium bicarbonate (2×100 ml). The aqueous phase was then extracted with dichloromethane (2×10 ml), the combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a colourless oil (0.96 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:39])[C:9]2[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([O:24]C3CCCCO3)[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1.CC(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:39])[C:9]2[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:20][N:21]([OH:24])[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1
Reactant: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: CC(=O)O
Solvent: O
Product: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Yield: 21 %

Procedure:
[(2R)-3-(2-{6-[[(2-Amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (110 mg, 0.19 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature for 2 days. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide N-[(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino}-2-chloro-5-fluoro-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]-N-hydroxyformamide (20 mg, 21%). LCMS: (M+H)+: 501.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].CN(C)CCN(C)C.C([Li])CCC.[Si:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][C:46](=[O:49])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>O1CCCC1>[Si:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:48][CH2:47][C:46]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=3[O:12][CH2:13][O:14][CH3:15])([OH:49])[CH2:45][CH2:44]2)=[CH:41][CH:42]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)cc1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.3 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 1-bromo-2,4-bis(methoxymethoxy)benzene (277 mg, 1.00 mmol) and anhydrous tetrahydrofuran (5 ml). The stirred solution was cooled to −78° C. and N,N,N′,N′-tetramethylethylene diamine (0.32 ml, 2.10 mmol) was added followed by dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol, 2.40M solution in cyclohexanes). The resulting solution was stirred for 40 min at −78° C., then 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (304 mg, 1.00 mmol) was added via syringe as a solution in anhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30 min at −78° C., then allowed to warm to room temperature over 3 hr. The reaction was quenched with aqueous hydrochloric acid (5 ml, 0.10M), then poured into a separating funnel containing ethyl acetate (50 ml) and water (10 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 3:7, v/v) furnishing the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (6H, s), 1.63 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 2.56 (2H, m), 2.70 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s), 5.24 (2H, s), 6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H, d), 7.05 (2H, d), 7.33 (1H, d).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[N:23]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Cc1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
To a flask containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.50 g, 6.85 mmol) and 2-chloro-4-methylpyrimidine (1.01 g, 7.87 mmol) were added dioxane (69 mL) and methanesulfonic acid (0.51 mL, 7.87 mmol). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 4-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (1.23 g, 3.95 mmol, 58% yield).
Reaction SMILES: [CH3:1][CH:2]([CH:25]([CH3:28])[CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:24])=[CH:11][N:12]3[C:19](=[O:20])[C:18]([C:21](O)=[O:22])=[CH:17][N:16]=[C:13]32)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[C:42]1([CH:48]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][NH2:57])[CH2:51][CH2:50]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:58]1([CH:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:49]2[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][NH:57][C:21]([C:18]3[C:19](=[O:20])[N:12]4[CH:11]=[C:10]([CH3:24])[C:9]5[C:14]([C:13]4=[N:16][CH:17]=3)=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH:25]([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:8]=5)=[O:22])[CH2:53][CH2:54]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)O)cnc3c2c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)NCCN4CCN(C(c5ccccc5)c5ccccc5)CC4)cnc3c2c1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirred mixture containing 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (455 mg), triethylamine (0.174 ml) and dry dichloromethane (70 ml) was added slowly ethyl chloroformate (0.12 ml) at 0° C. under an inert atmosphere. After being stirred for 2 hours, a solution of 2-(4-diphenylmethyl-1-piperazinyl)-ethylamine (359 mg) in dry dichloromethane (10 ml) was added dropwise to the reaction mixture at 5° C. After stirring was continued for 12 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel with chloroform-methanol. The eluate was concentrated in vacuo to give residue, which was recrystallized from chloroform-ether to give N-[2-(4-diphenylmethylpiperazin-1-yl)ethyl]-7-methyl-10-(2,3-dimethylpentanoylamino)-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxamide (0.59 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1.N>>[Cl:34][C:29]1[CH:28]=[C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-bromo-2-chloro-1-fluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). mp 153-156° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02-7.07 (m, 4H), 7.59 (m, 1H), 7.65-7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI/NH3) m/z 487 (M+H)+, 504 (M+NH4)+. Anal. calc. for C24H17ClF2N2O3S.0.25H2O: C, 58.65; H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8])[CH3:2].Cl.[CH2:14](O)[CH3:15]>>[NH2:12][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: CCO
Reactant: CCc1ccc(C(=O)O)c(N)c1
Agent: Cl
Product: CCOC(=O)c1ccc(CC)cc1N

Procedure:
A mixture of 59.4 gm. of 4-ethylanthranilic acid and 1,000 cc. of ethanol is saturated with dry hydrogen chloride gas and then refluxed overnight. The reaction mixture is then concentrated in vacuo and the residue taken up between ether and sodium bicarbonate solution. The ether extract is dried and concentrated in vacuo to give ethyl 2-amino-4-ethylbenzoate as an oil (characterized by IR and NMR).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCC2=Nc2cc([N+](=O)[O-])ccc2N1Cc1ccccc1
Solvent: CCOCC
Product: O=C1[C@H]2CCC[C@H]2Nc2cc([N+](=O)[O-])ccc2N1Cc1ccccc1
Yield: 89 %

Procedure:
Employing 9-benzyl-6-nitro-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized by substantially the same procedure as in Reference Example 15. Yield 89%. m.p.174°-176° C. (diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9](N)(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14]S(O)(=O)=O>>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([Cl:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1Br
Product: Nc1c(Br)cc(S(=O)(=O)Cl)cc1Br
Temperature: 0 °C

Procedure:
A solution of 15 g. of 4-amino-3,5-dibromobenzenesulfonamide in 45 ml. of chlorosulfonic acid is heated on a steam bath at 95° C. for 2 hours. The reaction mixture is cooled and poured onto 400 ml. of ice/water mixture. The resultant precipitate is filtered, dissolved in methylene chloride, and the methylene chloride solution is dried, filtered and evaporated to dryness, affording 4-amino-3,5-dibromobenzenesulfonylchloride, m.p. 153°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C

Procedure:
3-Fluoro-4-nitrophenol (Fluorochem) (10 g, 64 mmol) was dissolved in butan-2-one (60 ml) and treated with potassium carbonate 16.6 g (120 mmol) at 40° C. for 10 minutes. The resulting suspension was cooled to 0° C., treated with methyl iodide (7.5 ml, 120 mmol), heated to 40° C. for three hours and concentrated in vacuo to 20 ml. The mixture was poured into dichloromethane (35 ml), filtered and the filtrate evaporated to give 3-fluoro-4-nitroanisole, as a white solid (8.0 g, 73%). An analytically pure sample was obtained by recrystallization from aqueous ethanol (4:1); mp 47°-49° C.; ir 1608 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6](COCC[Si](C)(C)C)[C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#[N:2]>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#[N:2]
Reactant: COC(=O)c1ccc(C)c(-c2c(C#N)cnn2COCC[Si](C)(C)C)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C)c(-c2[nH]ncc2C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-methylbenzoate (compound 256.3, 1.9 g, 5.11 mmol) in triethylsilane (4 mL) and trifluoroacetic acid (8 mL). The resulting solution was stirred for 4 h at room temperature, then concentrated under reduced pressure. The pH of the residue was carefully adjusted to 7-8 with aqueous sodium bicarbonate (sat.), then the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (20/1) as eluent to obtain the title compound as a white solid (600 mg, 49%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH2:60])[CH2:59][CH2:58]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:68])([F:67])[F:66])[CH:45]=1>CN(C=O)C>[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH:60][C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)=[O:34])[CH2:58][CH2:59]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:66])([F:67])[F:68])[CH:45]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(C)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
28 μL (0.20 mmol) of TEA and 118.8 mg (0.30 mmol) of HATU were added to a solution of 27.7 mg (0.20 mmol) of 6-methylpicolinic acid in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 112 μL (0.81 mmol) of TEA and 100 mg (0.20 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred overnight at RT. The reaction mixture was purified by chromatography (reversed phase).