Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:34])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8][CH3:9].Cl.[Cl:36]CC1N=C(N(C2C=C(Cl)C(OC)=C(Cl)C=2)C)C2C(=CC=CC=2)N=1.C([O-])([O-])=O.[K+].[K+].C1(=O)NC(=O)C2=CC=CC=C12.[K]>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[ClH:1].[ClH:36].[NH2:23][CH2:22][C:14]1[N:13]=[C:12]([N:11]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=2)[CH3:34])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: COc1c(Cl)cc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl
Reactant: COc1c(Cl)cc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1NC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(N(C)c2nc(CN)nc3ccccc23)cc1Cl
Temperature: 50 °C

Procedure:
2-{4-[(3,5-Dichloro-4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A mixture of (2-chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine hydrochloride (521 mg, 1.24 mmol), K2CO3 (401 mg, 2.90 mmol) and potassium phthalimide (312 mg, 1.68 mmol) in DMF (7 mL) was heated at 50° C. for 4 h. EtOAc and DCM were added and this was washed with water then 50% satd NaCl then satd NaCl. The organic layer was dried (MgSO4), filtered through a pad of silica with an EtOAc wash then most of the solvents were removed on a rotary evaporator. The remaining solvent was removed from the crystalline material that had formed and the product was washed with two portions of EtOAc then suspended in hexanes, collected by filtration and washed with hexanes. The title compound was obtained as a paleyellow microcrystalline solid (373 mg; 61%). 1H NMR (CDCl3) δ 7.96-7.91 (m, 2H), 7.79-7.40 (m, 3H), 7.60 (m, 1H), 7.16-7.06 (m, 2H), 7.04 (s, 2H), 5.16 (s, 2H), 3.90 (s, 3H), 3.30 (s, 3H); LC-MS (ESI+; 493 ([M+H]+)).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[NH:3][C:4]([CH:6]1[CH2:12][CH2:11][CH:10]2[CH2:13][N:7]1[C:8](=[O:19])[N:9]2[O:14][S:15]([OH:18])(=[O:17])=[O:16])=[O:5].[Na].FC(F)(F)C(O)=O>>[CH3:1][NH:2][NH:3][C:4]([CH:6]1[CH2:12][CH2:11][CH:10]2[CH2:13][N:7]1[C:8](=[O:19])[N:9]2[O:14][S:15]([OH:18])(=[O:17])=[O:16])=[O:5]
Reactant: CN(NC(=O)C1CCC2CN1C(=O)N2OS(=O)(=O)O)C(=O)OC(C)(C)C
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: CNNC(=O)C1CCC2CN1C(=O)N2OS(=O)(=O)O
Yield: 58.1 %

Procedure:
Sodium tert-butyl 1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate (100 mg, 0.24 mmol) of Example 18 was deprotected with trifluoroacetic acid, and purified by octadecyl silica gel column chromatography to afford 41 mg of the title compound (yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[O:33]1[CH:37]=[CH:36][C:35]([CH:38]([NH2:40])[CH3:39])=[N:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:33]1[CH:37]=[CH:36][C:35]([CH:38]([NH:40][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH3:39])=[N:34]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccon1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.3 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and 1-isoxazol-3-yl-ethylamine hydrochloride (crude from Step 3, 81 mg, 0.41 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.26 ml, 1.49 mmol) and HATU (95 mg, 0.25 mmol). The yellow solution was stirred at room temperature for 48 h. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 115 mg (95%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-isoxazol-3-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: [CH:1]1([NH:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH:1]1([N:9]([OH:10])[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ONC1CCCCCCC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N(O)C1CCCCCCC1

Procedure:
Using the general method of Compound 36 Part C, cyclooctyl hydroxylamine (Compound 36 Part B, 1.0 g, 7.0 mmol) was reacted with 4-nitrophenyl isocyanate (1.2 g, 7.3 mmol) to provide 1.1 g of the desired product as a pale yellow solid, m.p. 143°-144° C. Analysis: Calculated for C15H21N3O4 : %C, 58.62; %H, 6.89: %N, 13.67; Found: %C, 58.5; %H, 7.56; %N, 13.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]4[CH:19]=[N:18][CH:17]=[CH:16][C:7]4=[N:8][C:9]=3[O:10][C:11]=2[C:12]([NH2:15])=[CH:13][CH:14]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]4[CH:19]=[N:18][CH:17]=[CH:16][C:7]4=[N:8][C:9]=3[O:10][C:11]=2[C:12]([NH:15][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)c2c1oc1nc3ccncc3cc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c2c1oc1nc3ccncc3cc12)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-chloro-11-oxa-7,10-diaza-benzo[b]fluoren-1-ylamine (35 mg, 0.13 mmol) in the dichloromethane (2.0 mL) is added 3-(trifluoromethyl)benzoyl chloride (54.2 mg, 0.26 mmol). After the mixture is stirred for 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (98/2) to give the product as a solid: 1H NMR 400 MHz (DMSO) δ 10.85 (s, 1H), 9.53 (s, 1H), 9.37 (s, 1H), 8.63 (d, 1H), 8.24 (s, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.67 (t, 1H), 7.48 (d, 1H); MS m/z 442.85 (M+1).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]([O:5][CH3:6])=[O:4])=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(OC)cc1)N1CCCCC1
Yield: 71.2 %

Procedure:
To a solution of methyl 2-bromo-2-(4-methoxyphenyl)acetate (2.5 g, 9.65 mmol) in THF (50 ml), was added piperidine (1.64 g, 19.3 mmol) and the mixture reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was portioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain (methyl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (1.81 g, 71.4% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:25]2=[S:26])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(Cl)c1NCCCNC1CCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Cl)c1N1CCCN(C2CCC2)C1=S
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of the diamine of Step A (3.28 g) in dry chloroform (48 mL) was added dropwise under nitrogen at 0° C. triethylamine (3.62 mL). Thiophosgene (1.49 mL) was then added dropwise via syringe and the mixture was stirred in the cold for another 15 minutes. Stirring was continued at room temperature for 1.5 hours, water was added and the the pH was adjusted to 8 with triethylamine. The aqueous layer was further extracted with dichloromethane and the combined extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potasium carbonate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with hexane-ethyl acetate 9:1 provided the title compound (3.1 g, 81%) which was further triturated and sonicated with hexane and hexane-ether. The off-white solid was collected, washed with hexane and dried (2.69 g, 75.3%), m.p. 89-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccccc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and benzoic acid to yield (3aR,4S,7aR)-methyl 4-(benzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=6.370 min; LC-MS Method II
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:12]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[CH2:13]3)[N:9]=[C:10]([I:11])[C:5]2=[C:4](OC(C)C)[N:3]=1.[NH3:24]>>[C@@H:12]1([N:8]2[C:6]3=[N:7][C:2]([NH2:1])=[N:3][C:4]([NH2:24])=[C:5]3[C:10]([I:11])=[N:9]2)[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[CH2:13]1
Reactant: N
Reactant: CC(C)Oc1nc(N)nc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](CO)O1
Product: Nc1nc(N)c2c(I)nn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 70 °C

Procedure:
A soln. of compd. 6-amino-1-[2-deoxy-β-D-erythro-pentofuranosyl]-3-iodo-4-isopropoxy-1H-pyrazolo[3,4-d]pyrimidine 12 (F. Seela, G. Becher, Synthesis 1998, 2, 207.) (1 g, 2.3 mmol) in a aq. 25% NH3 soln. (80 ml) was heated at 70° C. for 4 d. The solvent was evaporated to dryness, the residue dissolved in hot water and crystallized. Colorless needles (640 mg, 71%). M.p. 154°. TLC (A): Rf0.2. UV (MeOH): 223 (31800), 260 (8700), 278 (9100). 1H-NMR ((D6)DMSO): 2.12 (m, Hα—C(2′)); 2.67 (m, Hβ—C(2′)); 3.38, 3.44 (m , H2—C(5′)); 3.73 (m , H—C(4′)); 4.33 (m, H—C(3′)); 4.73 (t, J=5.7, OH—C(5′)); 5.17 (d, J=4.3, OH—C(3′)); 6.27 (‘t’, J=6.5, H—C(1′)); 6.34 (br, NH2); 6.62 (br, NH2). Anal. calc. for C10H13IN6O3 (392.2): C, 30.63; H, 3.34; N, 21.43; Found: C, 30.91; H 3.61; N, 21.27.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O>CC(C)=O.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Yield: 94.9 %

Procedure:
A solution of 8-(1,3-benzodioxol-5yl)-1,4-dioxaspiro[4.5]decan-8-ol (IIIb; 5 g, 18 mmole) in 75 ml acetone, 1 ml 12 N HCl, and 50 ml water, was stirred for 2 hr. After dilution with an additional 50 ml water the solid was collected to give the product (4.0 g, 95%, mp: 166°-168° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]([F:28])=[CH:18][C:16]=3[N:17]=2)=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30].C(N(CC)C(C)C)(C)C.O>O1CCCC1>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][NH:22][C:20]1[C:19]([F:28])=[CH:18][C:16]2[N:17]=[C:13]([C:3]3[C:2]([NH:1][C:32](=[O:33])[N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[CH:6][N:5]([CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][O:8]4)[N:4]=3)[NH:14][C:15]=2[CH:21]=1
Reactant: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3N)nc2cc1F
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1

Procedure:
A solution of 132 mg of N1-{2-[4-amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine in 8 mL of tetrahydrofuran with 428 μL of diethylcarbamoyl chloride and 560 μL of N,N-diisopropylethylamine is heated at 55° C. for 48 hours. 15 mL of water are added and then the aqueous phase is extracted with 3×15 mL of ethyl acetate. The organic phases are washed with 2×15 mL of distilled water, dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge, with a 95/5 dichloromethane/-methanol eluent. 18 mg of 3-[3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea are isolated in the form of a yellow resin. 1H NMR (400 MHz, DMSO-d6, δ in ppm), after addition of a drop of TFA-d1 (trifluoroacetic acid CF3COOD-d1) and of a drop of acetic acid-d4-(CD3OD-d4): 1.16 (t, J=7.5 Hz, 6H); 1.56 (m, 2H); 1.70 (m, 1H); 1.97 (m, 2H); 2.14 (m, 1H); 2.86 (s, 6H); 3.37 (m, 6H); 3.50 (t, J=6.5 Hz, 2H); 3.68 (m, 1H); 3.96 (m, 1H); 5.48 (broad d, J=10.0 Hz, 1H); 6.88 (d, J=7.5 Hz, 1H); 7.42 (d, J=11.0 Hz, 1H); 8.11 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[C:15]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=1[NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:1]1([CH2:6][C:7]2[N:23]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12]3[CH:13]=[CH:14][C:15]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:16][C:11]=3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1CCCC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from cyclopentylacetyl chloride (Step B) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:14]([C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(=O)[nH]c2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(=O)[nH]c2)n1
Yield: 12.1 %

Procedure:
Following the procedure in Example 118A, 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (46 mg, 0.19 mmol) was treated with phenyl chloroformate (0.10 mL, 0.79 mmol) to afford phenyl 3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (8 mg, 0.023 mmol, 12%). 1H NMR (300 MHz, MeOD) δ 7.68 (d, 2H), 7.38 (t, 2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.63 (d, 1H), 6.34 (s, 1H), 1.30 (s, 9H); LC-MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ON1C(=O)CCC1=O.[NH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][OH:39].C(N(CC)CC)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O.O>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([NH:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][OH:39])=[O:17])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of Z-Glu(OBzl)OH (5.62 g, 15 m mole) (Hayakawa et al. Bull. Chem. Soc. Japan, 39: 391 (1966)) in tetrahydrofuran (20 ml), N-methylmorpholin (1.53 ml) and isobutyl chloroformate (1.98 ml) were added with stirring at -15° C. To this mixture a solution of HOSu (N-hydroxy-succinimide) (3.45 g) in tetrahydrofuran (10 ml) was added with stirring at -15° C. The mixture was stirred at -15° C. for 30 min., and at 0° C. for 30 min. To this mixture a solution of H-Ser-OH (3.15 g, 30 mmole) in H2O (15 ml) containing triethylamine (4.2 ml) was added with stirring at 0° C. The mixture was stirred at 0° C. for 2 hr. and at room temperature for 15 hr. After removal of the organic solvent, the residue was extracted with three portions of ethyl acetate, which were washed successively with 1N citric acid and sat. NaCl solution, and dried over Na2SO4. After evaporating the residue was solidified by addition of ether. Reprecipitation from methanol-ether to yield (I) (5.29 g, 76.9%), RfI 0.74 RfII 0.70, mp 104°-105° C. [α]D27 +5.7 (C=1.12 in methanol).
Reaction SMILES: FC1C=C2C(=CC=1)N(C[C:12]1[O:13]C(C(F)(F)F)=CC=1)C(=O)C2C1C(O)=CC2OCOC=2C=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([OH:49])=[C:37]([CH:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH:38]=1>>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([OH:49])=[C:37]([C:39]2([CH2:12][OH:13])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH:38]=1
Reactant: O=C1Nc2ccccc2C1c1cc(Br)ccc1O
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1
Product: O=C1Nc2ccccc2C1(CO)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 35D, and making non-critical variations to replace 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 334.2 (M+1), 336.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([N:8]1[CH:12]=[C:11](I)[CH:10]=[N:9]1)([CH3:7])[CH3:6])C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][C:45]([S:49][C:50]1[N:54]3[N:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]3=[N:52][N:51]=1)=[CH:44][CH:43]=2.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.CC(N(C)C)=O>[CH3:7][C:5]([N:8]1[CH:12]=[C:11]([C:39]2[CH:40]=[N:41][C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([S:49][C:50]2[N:54]4[N:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]4=[N:52][N:51]=2)=[CH:44][CH:43]=3)[CH:10]=[N:9]1)([CH3:6])[C:4]([OH:3])=[O:14]
Reactant: CCOC(=O)C(C)(C)n1cc(I)cn1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C(C)(C)C(=O)O)c5)cc4c3)n2n1
Yield: 19 %

Procedure:
A microwave vessel was charged with 2-(4-iodo-pyrazol-1-yl)-2-methyl-propionic acid ethyl ester (50 mg, 0.162 mmol), bis(pinacolato)diboron (50 mg, 0.195 mmol), potassium acetate (48 mg, 0.486 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (6.6 mg, 0.008 mmol), and DMA (0.6 mL). The vessel was flushed with nitrogen and capped. The reaction mixture was microwaved at 130° C. for 30 min. 3-Bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (48 mg, 0.13 mmol) and dichlorobis(triphenylphosphine) palladium(0) (5.7 mg, 0.008 mmol) were added, followed by DMA (0.4 mL) and a 2 M aqueous solution of potassium carbonate (0.5 mL). The reaction mixture was microwaved at 130° C. for 1 h. Solid sodium sulfate was added to soak up the water, and the liquid layer was filtered through a 0.45 um filter. The crude mixture was diluted to 2 mL with DMSO and purified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 11 mg of 2-methyl-2-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-propionic acid as a cream-colored solid (19% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH:34]([CH3:37])[CH2:35][OH:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 44 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and 2-amino-1-propanol (0.05 mL), was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8.8 mg, 44% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.06 (d, J=7.6 Hz, 1 H), 8.53 (s, 1 H), 7.31-7.27 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.93 (m, 4 H), 6.71 (s, 1 H), 4.29 (m, 1 H), 3.95 (s, 2 H), 3.73 (dd, J=10.8, 4 Hz, 1 H), 3.62 (dd, J=10.8, 6.4 Hz, 1 H), 1.26 (d, J=6.8 Hz, 3 H); MS m/z 466 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[CH:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[CH:31][C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1947) in 2 mL of CDCl3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1948.