Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[C:16]([F:33])=[C:17]([NH:21][S:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[C:16]([F:33])=[C:17]([NH:21][S:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CCc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CCc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-ethyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.196 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as an off-white solid (52 mg, 51% yield). MS (ESI): 492 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]3[S:26][C:27]([CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:28][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(C1C=C2C(=CC=1)NC(C#N)=C2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[CH2:29][C:27]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([CH2:21][OH:22])[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[C:16]2[CH:28]=1
Reactant: CCOC(=O)c1cnc2sc(CC(F)(F)F)cc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#Cc1cc2cc(C=O)ccc2[nH]1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(CO)cnc3sc(CC(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
Ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carboxylate (45 mg, 0.1 mmol) was dissolved in CH2Cl2 (3 mL). Trifluoroacetic acid (2 mL) was added to the solution. After 2 hours, the solution was concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), and washed with a 10% solution of K2CO3 (2×1 mL), and dried over anhydrous K2CO3. The organic phase was concentrated to give tan residue, which was used in the next step without further purification. This residue was dissolved in 1,2-dichloroethane (1 mL). 5-formyl-1H-indole-2-carbonitrile (23 mg, 0.14 mmol) and sodium tri(acetoxy)borohydride (32 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solution was diluted with EtOAc (10 mL) and washed with 0.1 N NaOH (1×5 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by reversed-phase preparative HPLC (95:5-5:95 MeCN/H2O with 0.1% HCl buffer). The product containing fractions were lyophilized to afford the product as a white solid (1.4 mg, 2.5% yield), Compound 278. LC-MS: 1.45 min, 500.2 m/z [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C@@H:12]1[O:22][C:20](=[O:21])[C@@H:19]([NH:23][C:24]([C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:18][O:17][C:15](=[O:16])[C@H:14]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:13]1[O:42]C(C(C)C)=O>C1(C)C=CC=CC=1>[CH2:35]([C@@H:14]1[C@@H:13]([OH:42])[C@H:12]([CH3:11])[O:22][C:20](=[O:21])[C@@H:19]([NH:23][C:24]([C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:18][O:17][C:15]1=[O:16])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1O
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
Diisobutylaluminum hydride (1.5 M in toluene, 23.3 mmol) was added dropwise to a 15° C. solution of natural product UK-2A (5.8 mmol, 3.0 g) in toluene (60 mL). The mixture was stirred an additional 15 min and quenched with EtOAc (20 mL). Hydrochloric acid (2N, 100 mL) was added slowly and stirred vigorously for 15 min. The layers were separated and the organic layer dried (MgSO4) and concentrated in vacuo to give 1.82 g (70%) of Compound 1 as a foamy, light yellow solid. Exact Mass: m/z calcd. for C22H24N2O8 [M]+=44.1533, found 444.1513. 1H-NMR data was consistent for Compound 1.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])[NH:14][C:13](=[O:21])[N:12]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:11]3=[O:27])[CH:4]=1)=[O:2].CO>C(O)(=O)C>[OH:2][CH2:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])[NH:14][C:13](=[O:21])[N:12]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:11]3=[O:27])[CH:4]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(C=O)c3)cc2c1=O
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(CO)c3)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a solution of N-[6-(3-formyl-pyrrol-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (580 mg, 1.47 mmol, crude from previous step) in methanol (5 ml) sodium borohydride (112 mg, 2.95 mmol) is added at 0° C. and allowed to stir for 30 minutes. A small quantity of acetic acid is added to destroy excess sodium borohydride. The reaction mixture is diluted with ethyl acetate and washed two times with water and the solvent of the organic layer is removed by rotavapor evaporation to give a red-brown oil which is purified by flash chromatography with DCM/methanol from 98:2 to 95:5 to yield the title compound as an orange solid, m.p. 250-270° C. (decomp.).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1)(=O)C.Cl>C1COCC1>[OH:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1
Reactant: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(CC2=C[C@H](O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
(R)-3-(3-Methoxybenzyl)-4-oxocyclopent-2-enyl acetate (0.1 g, 0.38 mmol) was dissolved in THF (1 ml), 3N HCl (5 ml) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 to pH=6.9 and extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-4-hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone as yellow oil: 71 mg (yield: 85%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:3][CH:2]=1.[CH2:14]=[O:15]>>[OH:15][CH2:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:8]=1
Reactant: C=O
Reactant: O=c1ccc(-c2ccncc2)c[nH]1
Product: O=c1[nH]cc(-c2ccncc2)cc1CO

Procedure:
The reaction of 5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-5-(4-pyridinyl)-2(1H)-pyridinone is carried out by heating the reactants at about 75° to 125° C. It is preferably run using an acidic pH of about 2.0 to 5.0, a large molar excess of formaldehyde and a reaction temperature of about 90° to 110° C. The quantity of formaldehyde can vary widely provided it is in excess of said 5-(4-pyridinyl)-2(1H)-pyridinone. In practice, a large excess, e.g., from about 10-fold to 100-fold or greater can be used; however, as little as a 2-fold excess or less of formaldehyde can be used although the reaction time is longer. Because of its ready availability and low cost, 37% aqueous formaldehyde solution is preferred.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.Br[CH2:34][C:35]([NH2:37])=[O:36]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: NC(=O)CBr
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(CC(N)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine and 2-bromoacetamide were reacted at room temperature to give 541. LCMS m/z: 490.3 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Yield: 46 %

Procedure:
The title compound was synthesized as described for Example 12 in 46% yield starting from 1-(3-bromophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (56.2 mg, 0.12 mmol), pyrimidin-5-ylboronic acid (17.0 mg, 0.14 mmol), PdCl2(dppf)-CH2Cl2 adduct (10.2 mg, 0.01 mmol), K2CO3 (aq) (0.19 mL, 0.37 mmol).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[N:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:15].[OH-].[K+].Cl>CO>[Cl:15][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:14]=[N:13][NH:12][N:11]=2)=[CH:9][C:4]=1[C:3]([OH:16])=[O:2]
Reactant: COC(=O)c1cc(-c2cn[nH]n2)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2cn[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of 2-chloro-5-(2H-[1,2,3]triazol-4-yl)-benzoic acid methyl ester (0.095 g, 0.4 mmol) in methanol (2 mL) was added potassium hydroxide (0.25 g). The mixture was shaken at room temperature for 12 h. The mixture was diluted with methanol and acidified with HCl (2 mL, 6M). The mixture was concentrated in vacuo, diluted with water and sonicated. The solids were collected by filtration and washed with hexanes to afford the title compound (0.075 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.Cl>O1CCOCC1.O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])[CH:4]=1
Reactant: COc1cc(N2CCC[C@@H]2C)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N)cc(N2CCC[C@@H]2C)c1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a suspension of (S)-1-(3-methoxy-5-nitrophenyl)-2-methylpyrrolidine (430 mg, 1.82 mmol) and Zinc (1.18 g, 18.2 mmol) in dioxane (20 mL) and H2O (10 mL) was added dropwise conc. HCl (1.8 mL) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was filtered and the filtrate was adjusted to pH˜8 by the addition of solid NaHCO3, and then extracted with ethyl acetate (50 mL). The organic layer was dried with Na2SO4, concentrated and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford (S)-3-methoxy-5-(2-methylpyrrolidin-1-yl)benzenamine (269 mg, 72%) as yellow oil. LC-MS: 207 [M+H]+, tR=1.193 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[S:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1>C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[S:27])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1cccc(NC(=S)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 73 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-aminobenzanilide (0.213 g, 1.0 mmol) and 3,5-dichlorophenyl isothiocyanate (0.208 g, 1.0 mmol). Trituration in ethyl acetate gave the product (0.304 g); m.p. 174-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]([NH2:20])=[S:19].N.CO>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:4]1[N:17]=[C:18]([NH2:20])[S:19][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)CCc1ccccc1
Reactant: NC(N)=S
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(N)sc1CCc1ccccc1
Yield: 91 %

Procedure:
Reflux equimolar 3-chloro-2-oxo-5-phenyl-pentanoic acid methyl ester and thiourea in MeOH (1.0 M) for 4 h. Basify with ammonia-MeOH and add brine. Extract with ethyl acetate (4×). Wash combined organic layers with brine, dry (MgSO4), and concentrate under reduced pressure to give (91%) of title compound. HPLC (GRAD80-100M) t=2.193 (95%). MS (APCI): 263 (M+1).
Reaction SMILES: I[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[NH:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:12]([C:11]1[CH:10]=[N:9][C:8]2[NH:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCCN2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCCN3)C1
Temperature: 140 °C
Yield: 91.1 %

Procedure:
A mixture of 5-iodo-6-nitro-1,2,3,4-tetrahydro-1,8-naphthyridine (0.50 g, 1.6 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.39 g, 2.0 mmol), DIPEA (0.64 g, 5.0 mmol) and 1-butanol (6 mL) was heated at 140° C. for 14 h, then allowed to cool. The solvent was removed under reduced pressure, then the residue was diluted with EtOAc and washed with aq. Na2CO3 solution. The organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 10 to 90% EtOAc in hexanes, to give the sub-title compound (0.55 g, 89%). LCMS calc. for C18H28N5O4 (M+H)+: m/z=378.2. Found: 378.1.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13]>O>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O-:13].[Na+:2]
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [O-]c1ccc2ccccc2c1

Procedure:
A solution of sodium 2-naphtholate is prepared by mixing 210 ml. of water, 59.7 ml. of sodium hydroxide solution (24%), 41.0 g. (0.285 mole) of 2-naphthol. The mixture is stirred until the solid dissolves and then diluted with water to a volume of 567 ml. at 12°-15° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20]([NH2:22])[CH3:21]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:22][CH2:20][CH3:21])[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
0.50 g (0.00167 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesufonamide and 11 ml (0.167 mol) of ethylamine were dissolved in 20 ml of ethanol and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.271 g (53%) of 4-amino-N-(2-amino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p. 272-274° C.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].OO>CO.CS(C)=O>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:26])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1

Procedure:
To a solution at 65° C. of 40.0 g (112 mmol) of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 400 ml of methanol and dimethyl sulfoxide (3:2) are added 10.1 ml (118 mmol) of aqueous 35% sodium hydroxide solution and then 19.8 ml (21.8 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 15 minutes. After reaction for 30 minutes at 65° C., the mixture is cooled, partially concentrated under reduced pressure and taken up in dichloromethane. The organic phase is washed with water and is then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is crystallized from acetonitrile and then recrystallized from acetonitrile, to give 25.2 g of N2-(tert-butyl)-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
152 (380 mg, 1.2 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (57 mg, 2.4 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]3[CH2:37][CH2:38][N:33]([CH2:31][CH3:32])[CH2:34][CH2:35]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CCN1CCNCC1
Product: CCN1CCN(CCCCCCOc2c(OC)ccc3c(Nc4c(Cl)cncc4Cl)cc(=O)[nH]c23)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1-ethylpiperazine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 12.00-11.60 (br, 2H), 10.46 (s, 1H), 9.21 (s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.95 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H), 3.84-3.35 (br m, 8H), 3.35-3.10 (br m, 4H), 1.84-1.70 (m, 4H), 1.52-1.32 (m, 4H), 1.27 (t, 3H); MS (ESI): 548.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[Cl:43])[C:26]2=[O:44])=[C:20]([F:45])[CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([Cl:43])=[C:34]([N:27]2[C:26](=[O:44])[N:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][C:20]=3[F:45])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: [H][H]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 57 %

Procedure:
A mixture of 313 mg (0.475 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B), 10 mg of platinum oxide, and 4 mL of ethanol was shaken with hydrogen at approximately 3 atm for 2.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated to dryness. The residue was flash chromatographed on about 60 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) to give a 57% yield of the title compound as a cream-colored solid, mp 208°-210° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:34]1[N:43]=[CH:42][C:41]2[C:36](=[CH:37][C:38]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:39][CH:40]=2)[C:35]1=[O:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[N:43]=[CH:42][C:41]2[C:36](=[CH:37][C:38]([N:44]3[CH2:45][CH2:46][N:47]([CH2:23][CH2:22][CH2:21][C:7]4([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:26])([F:25])[F:1])[C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[O:14][C:13]5[C:8]4=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:48][CH2:49]3)=[CH:39][CH:40]=2)[C:35]1=[O:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2Oc2ccccc21
Reactant: O=c1c2cc(N3CCNCC3)ccc2cnn1Cc1ccccc1
Product: O=C(NCC(F)(F)F)C1(CCCN2CCN(c3ccc4cnn(Cc5ccccc5)c(=O)c4c3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Step (c) of Example 92 was repeated, except that the compound prepared in step (b) of Example 114 and the compound prepared in step (e) of Example 137 were used as the starting compounds. Thus, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=2[N:5]2[N:13]=[C:14]([CH3:16])[CH:15]=[C:4]2[N:3]=1.[Na].[CH2:18]([OH:20])[CH3:19]>>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[C:2]([O:20][CH2:18][CH3:19])=[N:3][C:4]3[N:5]([N:13]=[C:14]([CH3:16])[CH:15]=3)[C:6]=2[CH:11]=1
Reactant: Cc1cc2nc(Cl)c3cnc(Cl)cc3n2n1
Reactant: CCO
Agent: [Na]
Product: CCOc1nc2cc(C)nn2c2cc(Cl)ncc12
Reaction time: 1 h

Procedure:
2.5 g. of 5,8-dichloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine are added to a solution of 0.3 g. sodium in 20 ml. of ethanol. The mixture is stirred at 60° for 1 hour. After addition of 10 ml. of water, 8-chloro-5-ethoxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine precipitates and is filtered off, yield: 1.8 g. (68%); m.p. 175.6° (ethyl acetate).