Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:14][NH3+:15].C(OCC)(=O)C.O>N1C=CC=CC=1>[OH:14][N:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [NH3+]O
Reactant: COC(=O)C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.5 %

Procedure:
41.0 g (0.25 mol) of methyl phenylglyoxalate are dissolved in 300 ml of pyridine. 19.1 g (0.27 mol) of hydroxylammonium hydrochloride are added in portions to this solution. When the addition is complete, the reaction mixture is stirred at room temperature for 20 hours. After addition of ethyl acetate and water, the organic layer is separated, washed with diluted HCl and water and dried over magnesium sulfate. Evaporation of the solvent gives 45 g (100%) of crude methyl α-(hydroxyimino)-2-phenylacetate as a slightly brownish liquid. This compound is used without further purification in the next reaction step. 1H-NMR (CDCl3), δ [ppm]:7.55-7.30 (m, 5 aromatic H); 3.96 and 3.87 (s, 3H, CH3O of the trans and cis isomers). The trans/cis isomer ratio is approximately 3:1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(=C)C.CC(C)C.[CH2:16]=[CH:17][CH2:18][CH3:19]>[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH:17]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH2:18][CH3:19])[CH3:16]
Reactant: Oc1ccccc1
Reactant: C=CCC
Agent: C=C(C)C
Agent: CC(C)C
Agent: [Al+3]
Product: CCC(C)c1ccccc1O
Temperature: 150 °C

Procedure:
105 g of phenol and 5.3 g of aluminum oxide catalyst that was calcined in air at a temperature of 450° C. was charged in an autoclave and heated to 150° C. A raffinate stream containing 80% isobutylene, 18.7% isobutane and 1.4% 1-butene was then charged over a period of 3.5 hours. The amount of raffinate charged was 75 g with a isobutylene to phenol mole ratio of 0.95:1. The yield of OTBP at the end of 7 hours was 49%. The amount of 1-butene in the feed that reacted to form 2-sec-butylphenol was 1.3%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:2].C1(C)C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH:27]=[N:26][CH:25]=2)=[N:9][CH:10]=1)[CH3:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(OCC)c1ccc(C=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(-c2cnco2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
In methanol (5 mL) was dissolved 5-(diethoxymethyl)picolinaldehyde (148 mg, 0.707 mmol) obtained in Step 1. To the solution were added toluene-4-sulfonylmethylisocyanide (345 mg, 1.77 mmol) and potassium carbonate (244 mg, 1.77 mmol) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-(5-(diethoxymethyl)pyridin-2-yl)oxazole (161 mg, 92% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Cl[C:22]1[C:23]([F:32])=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:22]3[CH:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=3[F:32])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c([N+](=O)[O-])cc3F)CC2)CC1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
2d (0.12 g), 5-chloro-4-fluoro-2-nitro-phenylamine (0.1 g) and diisopropylethylamine (0.1 mL) were combined in 1.2 mL of DMSO and stirred at 110° C. for 3 days. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum and purified on column chromatography (eluent: 10 to 50% EtOAc in hexane+0.1% triethylamine) to yield 60a.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[C:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17])=[O:25])(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)c3ccccc3OC(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.0 g.) in dry pyridine (20 ml.) was added o-acetoxybenzoylchloride (0.8 g), and the mixture was stirred at room temperature for 16 hours. The solution was then heated to 100° C. for 1 hr., cooled to 20° C. and poured into a mixture of ice and excess N-HCl. The mixture was filtered and the solid residue crystallised from aqueous ethanol to give ethyl 6-o-acetoxybenzamido-4-hydroxycinnolin-3-yl carboxylate, m.p. 240°-2° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:21])[NH:16]2)[CH:8]([CH3:10])[CH3:9])[CH3:4].[Br:23][CH:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:22])[CH:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:21])[N:16]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH:8]([CH3:9])[CH3:10])[CH3:4]
Reactant: CCCCCCCCCCCC(Br)Br
Reactant: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2CCCCCCCCCCCCBr)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of NaH (60% in mineral oil, 0.42 g, 10 mmole) in anhydrous DMF (20 mL), 3-methyl-2-(2-methyl-1H-indol-4-yloxy)-butyric acid ethyl ester (2) (1.88 g, 7.0 mmole) and dibromododecane (2.30 g, 7.0 mmole) were added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (50 mL) and washed with water (3×30 mL). The organic layer was separated, dried over sodium sulphate and concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (3) Yield: intermediate (3) 1.32 g, 35%, by-product (4) 1.56 g, 31%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.Cl>O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([O:12][CH2:21][CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1)=[O:11]
Reactant: ClCCCC1OCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCCCC1OCCO1

Procedure:
The title compound was prepared in two steps. Boc-Phe-OH was reacted with 2-(3-chloropropyl)-1,3-dioxolane according to Example 10 Step 1, and the subsequent product reacted with hydrogen chloride in dioxan according to Example 79 Step 5.
Reaction SMILES: [CH3:1][C:2]1[C:24]([C:25]2[C:26]([CH3:52])=[CH:27][C:28]3[C:38]([CH:39]([CH3:41])[CH3:40])=[C:37]([O:42]C(C)=O)[C:36]([O:46]C(C)=O)=[C:35](C=O)[C:29]=3[C:30]=2[O:31]C(C)=O)=[C:23]([O:53]C(C)=O)[C:5]2=[C:6](C=O)[C:7]([O:17]C(C)=O)=[C:8]([O:13]C(C)=O)[C:9]([CH:10]([CH3:12])[CH3:11])=[C:4]2[CH:3]=1.OS(O)(=O)=O>[OH-].[Na+]>[CH3:52][C:26]1[C:25]([C:24]2[C:2]([CH3:1])=[CH:3][C:4]3[C:9]([CH:10]([CH3:11])[CH3:12])=[C:8]([OH:13])[C:7]([OH:17])=[CH:6][C:5]=3[C:23]=2[OH:53])=[C:30]([OH:31])[C:29]2=[CH:35][C:36]([OH:46])=[C:37]([OH:42])[C:38]([CH:39]([CH3:40])[CH3:41])=[C:28]2[CH:27]=1
Reactant: CC(=O)Oc1c(OC(C)=O)c(C=O)c2c(OC(C)=O)c(-c3c(C)cc4c(C(C)C)c(OC(C)=O)c(OC(C)=O)c(C=O)c4c3OC(C)=O)c(C)cc2c1C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(C(C)C)c(O)c(O)cc2c(O)c1-c1c(C)cc2c(C(C)C)c(O)c(O)cc2c1O
Yield: 95 %

Procedure:
More specifically, the gossypol acetic acid 1 (5 g, 8.65 mmol) in 50 ml of 40% NaOH was heated under nitrogen at 90° C. for 3.5 hours in the dark. The reaction mixture was cooled and poured slowly onto ice (300 ml) and concentrated H2SO4 (35 ml) mixture to form white precipitation. The precipitation was filtered, washed with water and dried to afford apogossypol (3.8 g, 95%) as a white solid. 1H NMR (CDCl3 δ 7.61 (s, 2H), 7.50 (s, 2H), 5.93 (s, 2H), 5.27 (s, 2H), 5.13 (s, 2H), 3.88 (m, 2H), 2.12 (s, 6H), 1.55 (d, J=5.5 Hz, 12H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[CH:22][CH:21]=2)C1C=CC=CC=1.C([O-])=O.[NH4+].C(N(CC)CC)C>C(O)C.[Pd]>[N:30]1([CH2:29][CH2:28][O:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:12]2[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][N:13]=2)=[CH:26]3)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: c1ccc(COc2ccc3[nH]nc(-c4cc5cc(OCCN6CCOCC6)ccc5[nH]4)c3c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Temperature: 67 °C
Yield: 61.7 %

Procedure:
1.12 g of 5-benzyloxy-3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yI]-1H-indazole are dissolved in 55 ml of absolute ethanol and then 424 mg of palladium-on-charcoal, 587 mg of ammonium formate and 227 μl of triethylamine are successively added. The reaction medium is stirred at 67° C. (internal temperature of the suspension). A substantial amount of gas is seen to be given off. After stirring for one hour, the medium is filtered through paper and the catalyst is rinsed with absolute ethanol. The filtrate is concentrated under vacuum to obtain 558 mg of 3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-ol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(C)=O)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: NC(N)=O.[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]=[O:38])[N:31]=[CH:30]3)=[O:16])[N:11]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[BH4-].[Na+]>CO>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH2:37][OH:38])[N:31]=[CH:30]3)=[O:16])[N:11]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CC=O)c2)cc1
Agent: NC(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
Preparation of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-241-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea 72: 1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-oxoethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea (2.179 g, 3.929 mmol) was suspended in MeOH (40 mL) and treated with sodium borohydride (0.7432 g, 19.64 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature until complete conversion of the starting material to product was observed by HPLC analysis. The reaction mixture was concentrated under reduced pressure and then diluted with saturated aqueous NH4Cl and extracted into dichloromethane. The organics were dried (MgSO4) and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 2-6% iPrOH/DCM) to provide 1.21 g (55%) of the desired compound. MS (APCI+) m/z 557 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H, J=9.1 Hz), 7.35 (s, 1H), 6.85-7.4 (m, 8H), 6.24 (s, 1H), 4.87 (t, 1H, J=5.4 Hz), 4.43 (t, 1H, J=5.6 Hz), 4.28 (d, 1H, J=5.9 Hz), 3.80 (q, 1H, J=5.5 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: O.[CH3:2][C:3]1([CH3:13])[CH2:8][CH2:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH2:4]1.[O-]Cl.[Na+]>[Na+].[Br-].CCOC(C)=O>[CH3:2][C:3]1([CH3:13])[CH2:8][CH2:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH2:4]1
Reactant: CC1(C)CC=C(CCCO)CC1
Agent: [Br-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(CCC=O)CC1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
PIPO (CAS RN: 091993-31-6; 5.04 g, 0.017 mol), NaBr (0.60 g, 0.006 mol) and KHCO3 (6.40, 0.063 mol) were charged in a 2 1 reactor together with water (60 g), EtOAc (250 g) and 3-(4,4-dimethyl-cyclohex-1-enyl)-propan-1-ol (100.0 g, 0.573 mol, purity: 96.5%). The pot temperature was set to 25° C. and 13% w/w aqueous NaOCl (426.8 g, 0.745 mol) was introduced over 2 hours. Stirring was continued for 1 hour and then the aqueous phase separated. Then 300 g of a 2% w/w aqueous ascorbic acid was added, and the reaction mixture was stirred for 1 hour. The aqueous phase was separated and the organic phase washed with NaHCO3 and then with water. The organic phase thus obtained was concentrated and the crude product purified by a flash distillation (58°–60° C., 1 hPa) to yield 68.4 g of 3-(4,4-dimethyl-1-cyclohexen-1-yl)propanal (yield: 66%; GC purity: 92.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)nc1C

Procedure:
6-Amino-2-methylnicotinic acid (1.00 g) was suspended in methanol (15 mL), concentrated sulfuric acid (0.5 mL) was added, and the mixture was stirred with heating under reflux for 18 hr. The reaction mixture was cooled, aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (0.82 g).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(O)=O)([CH3:35])[CH3:34].C1C2C(C(O)=O)C3C(=CC=CC=3)C=2C=CC=1>>[CH:4]1[C:5]2[CH:13]([C:14]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=3)=[O:15])[C:11]3[C:10](=[CH:12][CH:34]=[CH:33][CH:35]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: O=C(O)C1c2ccccc2-c2ccccc21
Product: CC(C)c1ccc(C(=O)C2c3ccccc3-c3ccccc32)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 9-fluorenecarboxylic acid, mp 146°-147° C.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@H:8]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:42])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=2)=[CH:16][CH:15]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(C)(C)C>FC(F)(F)C(O)=O>[CH3:41][O:40][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C@H:8]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:7][C:6]([OH:43])=[O:5])=[CH:15][CH:16]=2)=[O:42])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]
Reactant: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)OC(C)(C)C)NS(C)(=O)=O)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NS(C)(=O)=O)cc2)ccc1NC(=O)Nc1ccccc1C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
(R)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(methanesulphonylamino)-propanoic acid tert-butyl ester [55 mg, Reference Example 6(a)] was dissolved in anhydrous trifluoroacetic acid (2 ml) and allowed to stand at ambient temperature for 30 minutes. The reaction mixture was evaporated and the residue was triturated with diethyl ether to yield the title compound (42 mg) as an amorphous white solid. MS: MH+ 555. [Elemental analysis:—C, 55.3; H, 5.1; N, 9.2%. Calculated for C27H30N4O7S:—C, 58.5; H, 5.45; N, 10.1%].
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([O:24]CC)=O)=[N:3]1.[OH-].[NH4+:28]>CO>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([NH2:28])=[O:24])=[N:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccn3)nc1-2
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3ccccn3)ncc1CC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (220 mg, 0.63 mmol) in methanol (250 mL), 33% aqueous ammonium hydroxide (100 mL) was added and the solution was stirred at 65° C. for 8 hours.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:19](OC(=O)C)(=O)[CH3:20]>C(O)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[C:5]([CH3:17])[N:4]=[C:3]([CH3:18])[C:2]=3[N:1]=[C:19]2[CH3:20])=[CH:10][CH:11]=1)#[N:16]
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(nc(C)n2-c2ccc(C#N)cc2)c(C)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 3-amino-4-(4-cyanophenyl)amino-2,6-dimethylpyridine (4.20 g, 17.6 mmol), acetic anhydride (12.6 ml) and acetic acid (12.6 ml) was stirred at 100° C. for 16 hours. The excess of reagents was removed under reduced pressure, and the residual gum was dissolved in water and the solution was rendered basic by the addition of concentrated aqueous ammonia. The white solid which precipitated was filtered off and dried in vacuo to give the title compound (4.06 g, 88%), mp 260°-262° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.[CH3:16][C:17]([CH:19]([O:22][CH3:23])[O:20][CH3:21])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:17]1([CH3:16])[CH2:12][C:11](=[O:13])[C:6]2[CH:5]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(OC(F)(F)F)ccc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(OC)C1(C)CC(=O)c2cc(OC(F)(F)F)ccc2O1
Yield: 64.6 %

Procedure:
To a solution of 0.5 g (2.27 mmole) of the compound obtained in step 2 dissolved in 10 ml of toluene were added 0.55 ml (4.54 mmole) of pyruvic aldehyde dimethyl acetal and 80 mg (1.14 mmole) of pyrrolidine. The reactants were heated to reflux for about 12 hours using Dean-Stark apparatus. After completion of the reaction, toluene solvent was removed therefrom under reduced pressure. The residue so obtained was extracted with ethyl acetate and concentrated to give residue, which was purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate of 10:1 to obtain 0.470 g (yield 65%) of the title compound.
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.5 g (0.01 mole) of 3-trifluoromethylbenzenesulfonylchloride was added gradually over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.) to complete the reaction. After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 1. m.p. 126°-127° C., yield 1.9 g (50%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:32]2O[CH:34]=[CH:35][CH:36]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[S:37]1C=CC=C1B(O)O>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:32]2[S:37][CH:34]=[CH:35][CH:36]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: OB(O)c1cccs1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 63, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H) 7.86 (d, J=7.72 Hz, 2H) 7.55-7.78 (m, 5H) 7.50 (t, J=6.25 Hz, 1H) 7.38 (d, J=2.57 Hz, 1H) 7.16-7.21 (m, 1H) 6.58 (s, 1H) 5.69 (d, J=7.72 Hz, 1H) 4.19 (d, J=4.78 Hz, 2H) 3.48 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).