Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31].C(=O)([O-])O.[Na+].[ClH:40]>C(#N)C.C(O)C>[ClH:40].[CH2:30]([NH:32][C:33](=[O:34])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1)[CH3:31]
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reaction time: 20 h
Yield: 51 %

Procedure:
A suspension of 2.00 g (0.0067 mol) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 100 ml of acetonitrile was treated with 1.9 ml (0.013 mol) of triethylamine and 2.1 ml (0.027 mol) of ethyl isocyanate. The mixture was boiled under reflex for 20 hours and then poured into aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. After drying the organic phase with sodium sulphate and distillation of the solvent the residue was chromatographed over silica gel with methylene chloride/methanol 20:1. The oil obtained was dissolved in ethanol and treated with an equimolar amount of ethanolic HCl. After concentration the residue was dissolved in methylene chloride, treated with active charcoal and sodium sulphate, filtered and the solvent was distilled off in a vacuum. The residue was suspended in ethyl acetate, filtered off and dried in a vacuum. There were obtained 1.39 g (51%) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl ethylcarbamate hydro-chloride with m.p. 133°-136°.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Na].[NH:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1C=CC=CC=1.[OH-].[Na+].C(O)C>[C:1]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:19]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: C/C=C/C(=O)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
4-Anilinophenyl crotonate was prepared by adding a solution of 11.5 grams of crotonyl chloride in 50 milliliters of benzene to a solution of the sodium salt of 4-anilinophenol which was prepared by dissolving 18.5 grams of 4-anilinophenol in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol. The addition was accomplished in 30 minutes and the reaction mixture was stirred for one hour. The mixture was then poured into 150 milliliters of water. The organic layer was separated, washed three times with 10 percent sodium hydroxide solution and once with water, dried over anhydrous sodium sulfate, then allowed to evaporate. The residue was recrystallized from hexane yielding 13.3 grams of product which melted at 73°-76° C.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:11][N:10]=1)=O)(C)(C)C.[ClH:32].O1CCOCC1>>[ClH:32].[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccccc2S(C)(=O)=O)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1-c1cnc(N)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
2-[Bis(tert-butoxycarbonyl)amino)-5-(2′-methylsulfonylphenyl)pyrimidine (1.28 g, 2.8 mmol) was suspended in HCl/dioxane (10 mL, 4.0 M) and stirred 20 hours at room temp. The resulting mixture was triturated with Et2O and filtered to yield a white solid (772 mg, 95%). 1H NMR (CDCl3+few drops MeOD): δ8.53 (s, 2H), 8.22 (dd, 1H, J=7.7, J′=1.8), 7.77 (m, 2H), 7.40 (dd, 1H, J=7.4, J′=1.5), 2.94 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A mixture of ethyl 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.20 g, 0.48 mmol) and 1 N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) in ethanol (2 mL) was stirred at reflux for 1 h, cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH˜2. The mixture was diluted with water (25 mL), and the aqueous layer was extracted with dichloromethane (2×50 mL). The aqueous layer was concentrated to dryness in vacuo to afford the crude title compound as an off-white foamy solid (0.18 g): MS (ES+) m/z 393.2 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 55 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=4[N:11]3[CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:75]([NH2:78])(=[O:77])[CH3:76]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[Cl:26][C:4]1[CH:3]=[C:2]([NH:78][C:75](=[O:77])[CH3:76])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12]2=[N:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=3[N:11]2[CH2:10][CH2:9]1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Br)cc1Cl
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(NC(C)=O)cc1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(4-bromo-2-chlorophenyl)-8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (56.5 mg, 0.125 mmol), xantphos (10.8 mg, 0.0188 mmol), tris(dibenzylideneacetone)dipalladium (5.7 mg, 0.00625 mmol), cesium carbonate (61.1 mg, 0.188 mmol), acetamide (14.8 mg, 0.250 mmol) and tetrahydrofuran (0.5 mL) was stirred at 70° C. for 5 hrs. After cooling, the mixture was diluted with ethyl acetate and the precipitate was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as an amorphous (3.8 mg, 0.0088 mmol, 7%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([OH:17])=O.C[N:19](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:19])=[O:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid (20.0 g), N,N-dimethylformamide (0.5 mL) and tetrahydrofuran; (300 mL) was dropwise added oxalyl chloride (13.18 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated, and the obtained residue was dissolved in tetrahydrofuran (100 mL). This solution was dropwise added to a mixture of 25% aqueous ammonia (200 mL) and tetrahydrofuran (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hrs and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (15.4 g, 77%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide. Recrystallization from chloroform-ethanol gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=1.O>C1COCC1>[F:19][C:20]1[N:21]=[C:22]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13])[CH:23]=[CH:24][CH:25]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1cccc(F)n1
Reaction time: 3.25 h
Yield: 78.1 %

Procedure:
NaH (7.0 g, 60% oil dispersion, 0.176 mol) was added portionwise over five minutes to a stirred slurry of 2-(hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (35.8 g, 0.161 mol) in 700 mL THF. After the resulting mixture was stirred for 3.25 hours, 2,6-difluoropyridine (15.4 g, 0.134 mol) was added neat over a 20 minute period, and the mixture was stirred overnight at room temperature. Water (250 mL) was added, THF was removed in vacuo, and the aqueous residue was extracted three times with 250 mL CH2Cl2. The combined extracts were washed with brine (250 mL), filtered through Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (5% CH3CN in CH2Cl2) to yield 2-[[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide (33.2 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(=O)[nH]c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)[nH]c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:24][C:25]#[C:26][CH3:27])[C:17](=[O:23])[NH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH2:24]([N:16]1[C:15]2[C:19](=[N:20][CH:21]=[N:22][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[NH:18][C:17]1=[O:23])[C:25]#[C:26][CH3:27]
Reactant: CC#CCn1c(=O)[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)[nH]c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[7-(2-Butynyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (compound 61e) (12 mg) was dissolved in trifluoroacetic acid. This reaction solution was stirred at room temperature for five minutes, and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (8.86 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([OH:19])=O)=[O:6].Cl.[CH3:29][O:30][CH:31]1[CH2:34][NH:33][CH2:32]1>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([N:33]1[CH2:34][CH:31]([O:30][CH3:29])[CH2:32]1)=[O:19])=[O:6]
Reactant: COC1CNC1
Reactant: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)O)c21
Agent: Cl
Product: COC1CN(C(=O)c2c(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)sc3c2C(C)OC3)C1

Procedure:
The title compound was prepared from the product of Example 50A and commercially available 3-methoxyazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.29 (d, J=6.4 Hz, 3H), 3.19 (s, 3H), 3.71-3.77 (m, 1H), 3.80-3.87 (m, 1H), 4.02-4.09 (m, 1H), 4.14-4.22 (m, 2H), 4.88-5.01 (m, 2H). 5.14-5.22 (m, 1H), 7.78 (d, J=9.1 Hz, 1H), 8.02 (dd, J=8.0, 8.0 Hz, 1H), 11.82 (br s, 1H). MS (ESI+) m/z 493 (M+H)+. Anal. calcd. for C20H17ClF4N2O4S: C, 48.74; H, 3.48; N, 5.68.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=4[F:36])=[CH:22][C:21]3=[O:37])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=3[F:36])=[CH:22][C:21]2=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared in Example 116, 1.140 g, 2.08 mmol) in tetrahydrofuran (100 mL) was treated with 2N aqueous hydrochloric acid (150 mL). The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 30% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.780 g, 74%) as a white solid: HR-ES-MS m/z calculated for C24H30F2N4O6, [M+H]+ 509.2206 observed 509.2206; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.35 (t, J=6.8 Hz, 3H), 1.38-1.50 (m, 1H), 1.50-1.67 (m, 1H), 1.68-1.85 (m, 1H), 3.20-3.33 (m, 2H), 3.71-3.94 (m, 2H), 4.04-4.20 (m, 3H), 4.26 (d, J=18.7 Hz, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.71 (t, J=5.3 Hz, 1H), 4.87 (dd, J=10.3, 4.5 Hz, 1H), 4.94 (d, J=4.8 Hz, 1H), 5.05 (s, 1H), 6.41 (s, 1H), 7.09-7.35 (m, 2H), 7.53 (s, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:15].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)COc2c(C(=O)O)cccc21
Agent: O=S(=O)(O)O
Product: CN1C(=O)COc2c(C(=O)O)cc([N+](=O)[O-])cc21

Procedure:
To a solution of 85.5 g of 3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 222 ml of concentrated sulfuric acid with cooling to -8° C. is added dropwise with stirring a mixture of 20.7 ml of fuming nitric acid (d 1.50) and 20.7 ml of concentrated sulfuric acid at a temperature below 2° C. over about 30 minutes, and the solution further stirred under cooling. The resultant solution is poured into ice-cold water with stirring. The precipitated crystals are collected by filtration, washed with water and dried to give 99 g of 3,4-dihydro-4-methyl-6-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting at 256°-259° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].N1CCCC1.[CH3:18][O:19][CH2:20][C:21](=O)[CH2:22][O:23][CH3:24]>C1(C)C=CC=CC=1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:12][C:21]([CH2:22][O:23][CH3:24])([CH2:20][O:19][CH3:18])[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1)#[N:11]
Reactant: COCC(=O)COC
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COCC1(COC)CC(=O)c2cc(C#N)ccc2O1

Procedure:
5-Cyano-2-hydroxyacetophenone (13.57 g) was dissolved in toluene (120 ml), and pyrrolidine (6 ml) and 1,3-dimethoxy-2-propanone (15 ml) were added. The mixture was refluxed under heating for 1 hour while removing the generated water. After cooling, the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (ethyl acetate:hexane=2:8) to give 13.0 g of 6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[NH:4][CH:3]=1.C(OCC)(=O)C>C1COCC1.[Li+].[OH-]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: COC(=O)c1ccc2[nH]cc(Cl)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2[nH]cc(Cl)c2c1
Yield: 79.9 %

Procedure:
A solution of Example 62A (361 mg, 1.62 mmol) in THF (7 mL) and 1M LiOH (3.3 mL) was heated at 50° C. for 5 hours, treated with ethyl acetate and extracted with 10% NaHCO3 (3×). The extract was treated with 6M HCl and extracted with ethyl acetate (2×40 mL). The organic layer was dried (MgSO4), filtered, and concentrated to provide 253.2 mg of the desired compound.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61][N:39]3[C:38](=[O:42])[CH:37]=[C:36]([O:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][N:32]=4)[CH:41]=[N:40]3)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccc(Cl)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 15b from 1.20 g (5.05 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 18b) and 2.62 g (6.06 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.S(Cl)([Cl:16])=O>CCOCC.CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[N:3]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1nc(C(=O)Cl)c2ccccc21
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A stirred suspension of 1-methyl-indazole-3-carboxylic acid (0.68 g, 3.86 mol) in anhydrous ether (50 ml) was treated with thionyl chloride (0.28 ml, 3.84 mol) and a few drops of dimethylformamide. After stirring for one hour the solid dissolved. The solvent was evaporated to give 1-methyl-indazole-3-carbonyl chloride as a yellow solid (0.75 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]1([O:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: COC1=CCCCC1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1nc(COC2=CCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.7 %

Procedure:
The compound 14 (166 mg, 0.5 mmol), 1-methoxycyclohexene (280 mg, 2.50 mmol) and p-toluenesulfonic acid pyridinium (132 mg, 0.505 mmol) was dissolved in toluene (4 mL). The reaction mixture was stirred at room temperature for 20 hours. Benzene (60 mL) was added thereto, the reaction mixture was heated under reflux over 45 minutes and concentrated to a small amount. A drop of triethylamine was added to the reaction mixture, and the mixture was filtered to remove the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was extracted with hexane, and filtered off the insoluble matter. The filtrate was purified by chromatography on an alumina column (eluate: toluene) to give the compound 17 (61 mg, 30%) as crystals. Mp 69-71° C. Rf 0.57 (Al2O3 60, Type E, toluene).