Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:44])([CH3:43])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:42])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][C:46]([O:48][CH2:49][C@H:50]1[O:55][C@H:54](Br)[C@H:53]([O:57][C:58]([CH3:60])=[O:59])[C@@H:52]([O:61][C:62]([CH3:64])=[O:63])[C@H:51]1[O:65][C:66]([CH3:68])=[O:67])=[O:47].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:58]([O:57][C@@H:53]1[C@@H:52]([O:61][C:62](=[O:63])[CH3:64])[C@@H:51]([O:65][C:66](=[O:67])[CH3:68])[C@@H:50]([CH2:49][O:48][C:46](=[O:47])[CH3:45])[O:55][C@H:54]1[O:41][C:34]1[C:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]([C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:16][CH2:15]3)=[O:18])([CH3:44])[CH3:43])=[CH:27][C:28]=2[CH3:42])=[C:37]([CH:38]([CH3:39])[CH3:40])[NH:36][N:35]=1)(=[O:59])[CH3:60]
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13][N:12]=2)[CH:6]=1.[Li+].[OH-]>COCCOC.O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][NH:17][C:16]([C:15]1[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:6]=2)=[N:12][O:13][C:14]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: COC(=O)Cc1cccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)Cc1cccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 51 is dissolved in DME (2 mL). A solution of 1 M LiOH in H2O (0.2 mL) and is added and the mixture is stirred overnight at room temperature. The mixture is concentrated, then acidified with 1 M HCl, extracted with EtOAc (10 mL), dried over MgSO4, filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound I1 as an off-white solid: 1H-NMR (400 MHz, CD3CN) δ=7.61 (s, 1H), 7.57 (m, 1H), 7.38 (m, 5H), 7.33 (d, J=2.4 Hz, 1H), 7.28 (m, 2H), 7.20 (dd, J=9.2, 2.8 Hz, 1H), 7.16 (t, J=5.2 Hz, NH), 6.90 (d, J=8.8 Hz, 1H), 4.04 (t, J=5.2 Hz, 2H), 3.63 (q, J=5.2 Hz, 2H), 3.59 (s, 2H). MS calculated for C26H21Cl2N2O5 (M+H+) 511.0, found 511.0.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:6]=1.[H][H]>CO.[Ni]>[NH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:8]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:21])=[O:20]
Reactant: [H][H]
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reaction time: 5 h
Yield: 45.2 %

Procedure:
N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide (O6.075; 4.2 g) was dissolved in methanol (120 ml), and Raney nickel (about 700 mg) was added. With a hydrogen balloon attached, hydrogenation was effected on a magnetic stirrer. After 5 h, the catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by means of preparative chromatography. The product-containing fractions were combined, freed of the acetonitrile, basified with sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.73 g of the desired compound were obtained.
Reaction SMILES: CO[CH:3](OC)[CH:4]([CH3:8])[C:5](=O)[CH3:6].COC(OC)CC(=O)CC.[OH:21][NH:22][C:23]([NH2:25])=[O:24].[Cl-:26].[NH4+]>CO.Cl>[ClH:26].[CH3:8][C:4]1[C:5]([CH3:6])=[N+:22]([O-:21])[C:23]([OH:24])=[N:25][CH:3]=1
Reactant: [Cl-]
Reactant: COC(OC)C(C)C(C)=O
Reactant: NC(=O)NO
Agent: CCC(=O)CC(OC)OC
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(O)[n+]([O-])c1C
Temperature: -7 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
The synthesis of the precursor 4,4-dimethoxy-3-methylbutan-2-one was performed in analogy to E. E. Royals and K. C. Brannock (J. Am. Chem., 1953, 75, 2050-2053) and yielded a mixture of 58% of the desired precursor, 24% of the byproduct 1,1-dimethoxy-pentan-3-one and about 18% elimination product. 102 g of this mixture (0.405 mol of 4,4-dimethoxy-3-methylbutan-2-one) were dissolved in 30 ml of methanol and added dropwise to 0.698 mol of N-hydroxyurea in 400 ml of 2M HCl, while the internal temperature was maintained at −10 to −4° C. The solution was thawed to room temperature, stirred for 1 h, and then evaporated to dryness. The residue was slurried with 200 ml of acetone, the solid filtered off and washed with little ice-cold acetone. After drying, the crude product was heated with 150 ml of ethanol to boiling, filtered hot, concentrated to 50 ml and cooled to −18° C. The precipitated solid was filtered off, washed with little ethanol and dried. 20 g of this solid was again recrystallized from 100 ml of ethanol, and finally 10 g (12% yield) of the title compound were obtained (content of 85% the title compound and 13% ammonium chloride).
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[Na+].[Na+].P([O-])([O-])([O-])=O.O.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17]>O>[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Reagent(ii) is a buffer prepared by first dissolving 144.8 grams (1.020 mol) of disodium hydrogen phosphate in 1.00 liter hot deionized water. The phosphate dissolved in the hot deionized water upon stirring. To this solution 102.95 grams (0.4902 mol) of citric acid monohydrate were added. The resulting solution was then diluted to 10.0 liters with additional deionized water, thus forming a citrate-phosphate solution, with a pH of 5.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:27]([NH:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>>[CH:27]([N:30]([CH:31]([CH3:33])[CH3:32])[C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:5]3[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:14]2)=[O:17])=[N:19][CH:20]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)NC(C)C
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cn2)CC1
Yield: 72 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using diisopropylamine. And then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:42]2[N:43]=[C:44]([NH:47]C(OC(C)(C)C)=O)[S:45][CH:46]=2)\[C:23]([NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23](=[O:24])[NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])[N:43]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Yield: 24.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (1.10 g, 1.40 mmol), DCM (7.0 mL) and TFA (5.39 mL, 70.0 mmol). Additional TFA (3.24 mL, 42.0 mmol) was added after 1 h at rt and the solution was diluted with DCM and concentrated in vacuo after an additional 30 min. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (178 mg, 23%) as a white powder. LCMS: Rt=0.30 min, m/z=518.9 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=9.0 Hz, 1H) 6.92 (s, 1H) 5.23 (dd, J=9.1, 5.7 Hz, 1H) 4.12-4.23 (m, 3H) 3.72-3.62 (m, 2H assumed; obscured by water) 3.61-3.52 (m, 1H assumed; obscured by water) 3.26 (dd, J=14.5, 5.9 Hz, 1H) 1.36 (s, 4H). 1H NMR (400 MHz, D2O) δ 7.23 (s, 1H), 5.48 (d, J=5.8 Hz, 1H), 4.71-4.65 (m, 1H), 4.44 (t, J=8.2 Hz, 2H), 3.89-3.73 (m, 3H), 3.54 (dd, J=14.9, 4.9 Hz, 1H), 1.65-1.56 (m, 2H), 1.56-1.46 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:61]2[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]2)=[O:23])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(CCO)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Piperidinethanol (33.6 mg, 260 μmol, 3 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (26 mg, 48% of theory, purity about 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Br[C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:13]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:8])=[CH:5][CH:4]=1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2ccc(C)cc2C(=O)O)cc1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 4-methoxybenzoyl chloride and 2-bromo-5-methylbenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:17]([N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)=[O:19])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:7])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cl)cc1
Product: COC(=O)CCCN(C(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)phenylalanine and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)phenylalanyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)phenylalanyl]-4-(p-anisidino)butyric acid (M.P. 163° to 165°).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][C@@H:12]2[CH2:27][N:15]3[CH2:16][CH2:17][N:18]([C:20]4[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[CH2:19][C@@H:14]3[CH2:13]2)=[CH:8][CH:7]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][CH2:5][C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][C@@H:12]2[CH2:27][N:15]3[CH2:16][CH2:17][N:18]([C:20]4[N:21]=[CH:22][C:23]([F:26])=[CH:24][N:25]=4)[CH2:19][C@@H:14]3[CH2:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)Cc1ccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 0.13 g (0.33 mmol) of (7S,8aS)-7-(4-((methoxycarbonyl)methyl)phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Example 11i) in 15 mL of anhydrous ethyl ether was added dropwise to an ice-cold suspension of 0.025 g (0.65 mmol) of lithium aluminum hydride in 15 mL of anhydrous ethyl ether and the mixture stirred for 30 min. The reaction was carefully quenched at 0° C. with 0.025 mL of water, 0.025 mL of 15% sodium hydroxide, and 0.075 mL of water. The precipiate which formed was filtered through Celite, the filtrate concentrated in vacuo, and purification of the residue by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 0.075 g (63%) of the title compound. mp (.HCl) 145°-147° C. HRMS calcd for C20H26FN4 O2 (MH+): 373.2040, found: 373.2054.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.8, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:11][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:26]
Reactant: COc1cc(O)c(C(C)=O)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above prepared 1-(5-chloro-2-hydroxy-4-methoxy-phenyl)-ethanone (4.22 g, 21.0 mmol) in 50 mL of acetonitrile were successively added Cs2CO3 (8.22 g, 1.2 eq.) and ethyl bromoacetate (2.44 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over magnesium sulfate, and evaporation of the solvents left 6.05 g of the title compound as off-white solid, used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O>[Ni].CO>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC1SC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CC1SC(=O)NN=C1c1ccc(N)c(N)c1
Yield: 86.4 %

Procedure:
13.7 g (51.4 mM) of 5-(4-amino-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one are placed under a hydrogen atmosphere at 3 bar for 4 hours in the presence of 24 g of Raney nickel in 280 ml of methanol. The reaction medium is then filtered and the filtrate is concentrated under vacuum to give 10.5 g of 5-(3,4-diaminophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of a solid, which is treated with diisopropyl ether, filtered off and stored under argon at low temperature.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:17]3[N:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=[N:20][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH3:30])[CH2:28][OH:29]>O>[OH:29][CH2:28][CH:27]([NH:26][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:17]3[N:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=[N:20][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1)[CH3:30]
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc(Br)nc1
Reactant: CC(N)CO
Solvent: O
Product: CC(CO)Nc1ccc(-n2c(=O)c3ccccc3c3nc4ccccn4c32)cn1
Temperature: 180 °C
Reaction time: 0.83 h
Yield: 67 %

Procedure:
A mixture of compound 21 (1.0 equiv., 0.583 mmol, 0.228 g) and 2-amino-1-propanol (1.5 ml) was stirred for 50 min under microwave irradiation (microwave settings: temperature=180° C., maximum pressure=17 bar, maximum power=200 W). The reaction mixture was mixed with water (10 ml) and stirred at room temperature for 5 min. The resulting precipitate was filtered off and subsequently washed with water and tetrahydrofuran to afford 6-[6-[(2-hydroxy-1-methyl-ethyl)amino]-pyridin-3-yl]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (I11) (0.150 g, yield=67%, purity (LC)=96%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[N:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[N:18]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)(C)C.O1CCCC1.O>[F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[N:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[N:18]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)O
Temperature: 25 °C
Yield: 61 %

Procedure:
Ethyl 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionate (3.23 g; 8.27 mmole) was dissolved in a warm mixture of isopropanol (150 ml) and tetrahydrofuran (30 ml). The solution was allowed to cool to a temperature of 25° C. and a solution of sodium hydroxide (0.34 g) in water (10 ml) was added slowly with stirring. The reaction mixture was stirred at room temperature for a period of 10 minutes and then aqueous 2M sodium hydroxide (0.5 ml) was added and the solution was stirred at room temperature for 5 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure and the residue was dissolved in water. The aqueous solution was treated with aqueous 2M hydrochloric acid until acidic and the precipitated product was collected by filtration and air dried. The product was recrystallised from toluene to give the title compound (1.83 g; 61%), mp 132°-138° C. The assigned structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[C:21]([CH2:24][NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:23])[NH2:22]>COCCOC.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>[F:1][C:2]1[C:3]([C:30]2[CH:31]=[C:26]([NH:25][CH2:24][C:21]([NH2:22])=[O:23])[CH:27]=[CH:28][CH:29]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: NC(=O)CNc1cccc(B(O)O)c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2ccc(F)c(-c3cccc(NCC(N)=O)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol), 2M aqueous Na2CO3 solution (0.13 mL) (Starting Material 13), (Ph3P)2PdCl2 (22 mg, 0.027 mmol) and 3-(carbamoylmethyl-amino)-phenylboronic acid (55 mg, 0.26 mmol) in 1,2-dimethoxyethane (5 mL) was heated at 103° C. for 3 days. The reaction mixture was filtered and concentrated. The crude material was purified by C18 reverse phase chromatography to give 2-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-phenylamino]-acetamide. (Yield 1 5mg, 28%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16]>CN(C=O)C.O>[CH2:3]([O:10][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1ncc(-c2ccc(C#N)cc2F)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(-c2ccc(C#N)cc2OCc2ccccc2)o1
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g) in DMF (35 mL) was added benzylalcohol (5.61 g) at 0° C., and the mixture was stirred for 30 min. 3-Fluoro-4-(2-methyl-1,3-oxazol-5-yl)benzonitrile (3.50 g) was added to this reaction mixture at 0° C., and the mixture was stirred at room temperature for 1 hr, and diluted with water. The resultant precipitate was collected by filtration and washed with water to give the title compound (5.20 g).