Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])(=[O:16])=[O:15].[C:27]([N:46]1[C:50]([CH2:51][C:52](O)=[O:53])=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[C:17]([S:14]([NH:13][CH2:12][CH2:11][C:3]2[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=2[NH:1][C:52](=[O:53])[CH2:51][C:50]2[N:46]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:47]=[N:48][N:49]=2)(=[O:16])=[O:15])[CH:22]=1)#[N:24]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1N
Reactant: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1NC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
To a stirred solution of 0.30 g of N-[2-(2-amino-4-isopropylphenyl)ethyl]-5-cyano-2-methoxybezenesulfonamide, 0.298 g of (1-trityl-1H-tetrazol-5-yl)acetic acid and 0.129 g of 1-hydroxybenzotriazole monohydrate in 2.4 mL of N,N-dimethylformamide was added 0.140 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.549 g of N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-trityl-1H-tetrazol-5-yl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH3:19][O:20][C:21](OC)(OC)OC>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([O:20][CH3:21])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Reactant: COC(OC)(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2oc(OC)nc2c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and tetramethylorthocarbonate. Yield: 60%. mp 137-138° C.; MS (M+H, 291.10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH2:16])=[C:11]([NH2:17])[CH:10]=1.[O:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]([CH:28]=O)=[N:19]1.O>CN(C=O)C>[CH3:15][C:13]1[C:12]2[NH:16][C:28]([C:20]3[CH2:21][C:22]4([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[O:18][N:19]=3)=[N:17][C:11]=2[CH:10]=[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:14]=1
Reactant: O=CC1=NOC2(CCCCC2)C1
Reactant: Cc1cc(-c2c(F)cccc2F)cc(N)c1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(F)cccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 100 °C
Yield: 38 %

Procedure:
2′,6′-Difluoro-5-methyl-biphenyl-3,4-diamine (186 mg, 0.792 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a stir bar, and dry DMF (2 mL) was added. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (122 mg, 0.730 mmol, as prepared in step B of this Example) was added as a solution in DMF (2 mL). Solid Na2S2O5 (153 mg, 0.803 mmol) was added, and the mixture was heated to 100° C. for 4 h. The cooled mixture was poured into water (100 mL) and extracted three times with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by column chromatography using a 4-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:17, v/v over 30 min, yielding 105 mg (38%) of the title compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.43-7.55 (m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H), 1.63-1.83 (m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H21F2N3O: 382.2 (M+H). found: 382.2.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:45])[C:17]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][C:34]=4[CH3:44])=[O:30])=[CH:18][N:19]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[F:46])[CH2:7]1)C.O1CCOCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[F:46][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([O:22][CH3:23])[C:12]=1[N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([OH:47])=[O:3])[CH2:7]1)[N:19]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH:18]=[C:17]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:35][C:34]=1[CH3:44])=[O:30])[C:16]2=[O:45]
Reactant: CCOC(=O)C[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(N2CCC[C@H](CC(=O)O)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 91.7 %

Procedure:
83 mg (0.123 mmol) of the compound of Example 21 are stirred with 3.0 ml of dioxane and 614 μl of LiOH (1M solution in water, 5 eq.) at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 73 mg of the title compound (90% of theory) are obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(C)C.C(O)(C(F)(F)F)=[O:27]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(=[O:27])[CH3:5]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A 20 mL vial with stir bar was charged with 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (850 mg, 2.44 mmol) and TFA (9.8 mL). The solution was heated to 65° C. After 3 h, the reaction was judged complete. The mixture was concentrated under reduced pressure; the resulting residue was taken up in CH2Cl2 and loaded onto a prepacked 25g silica gel cartridge. The product was purified by chromatography on a prepacked 80g silica gel column eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. The product containing fractions were combined and concentrated to provide 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (616 mg, 86%): 400 MHz 1H NMR (CDCl3) δ 8.00-7.94 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J=6.1 Hz, 2H), 2.69-2.64 (m, 2H), 2.63 (s, 3H), 2.21-2.09 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH3:21][NH:20][C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:33]=[N:28][CH:29]=[N:30][CH:31]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-methylpiperidine-4-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 269. NMR (CDCl3): 1.71 (s, 3H, CH3), 1.77-1.90 (m, 4H, 2×CH2), 2.10-2.17 (m, 3H, CH2+CH), 2.85 (d, 3H, CH3, J=4.81 Hz), 3.02-3.05 (m, 2H, CH2), 3.78 (s, 2H, CH2), 3.90-3.94 (m, 4H, 2×CH2), 3.97-4.01 (m, 4H, 2×CH2), 5.54 (s, H, NH), 7.18 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=454.21
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[BH4-].[Li+].C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of methyl 4-bromo-3,5-dimethoxybenzoate (133.2 g) in tetrahydrofuran (500 mL) was added lithium borohydride (20.8 g) slowly at room temperature, and the mixture was further stirred for 3 hours under reflux with heating. The reaction mixture was cooled down to room temperature, and ice water (1.5 L) and ethyl acetate (1.2 L) were added, and extraction with ethyl acetate was performed. The resultant organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain 118.8 g of a title compound as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C:15]([CH:35]=[C:36]=[O:37])(OCC2C=CC=CC=2)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[OH-:39].[Na+]>CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[CH:15]([CH2:35][C:36]([OH:37])=[O:39])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(C=C=O)(NC(=O)Nc2ccc(Cl)cc2)OCc2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-benzyloxycarbonylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLE 59, 60 mg, 0.11 mmol) in MeOH (3 mL) at room temperature, 1N aq. NaOH (0.50 mL) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue (after being neutralized to acidic with TFA) was purified by HPLC to give the titled compound as a powder (26 mg). MS
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Yield: 99.8 %

Procedure:
Treatment of ((2R)-8-(2-chlorophenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.57 mmol) in ethanol (40 mL) and ethyl acetate (10 mL) with platinum (IV) oxide (84% Pt, 0.21 g) according to the procedure described for Example 69, Step 8 provided 0.7 g (100%) of ((2R)-8-(2-chlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 62.1 %

Procedure:
Dissolve 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (144 g, 0.79 mol) in dry tetrahydrofuran (5 L) and cool to −5° C. under nitrogen. Add triphenylphosphine (310 g, 1.185 mol) and 4-nitrobenzoic acid (198 g, 1.185 mol). Add diisopropyl azodicarboxylate (230 mL, 1.185 mol) drop-wise and stir at room temperature overnight. Add saturated aqueous sodium bicarbonate (1 L) and extract into dichloromethane (2×2.5 L) in a 20 L separating funnel. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify over silica gel (iso-hexane/ethyl acetate 50-100% then 10% methanol in ethyl acetate) to afford 163 g (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21].O>N1C=CC=CC=1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:17]1[CH:18]=[N:19][C:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])(=[O:14])=[O:13])=[N:16]1)=[O:24])[CH3:21]
Reactant: O=S(=O)(c1nc[nH]n1)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)n1
Reaction time: 5 h

Procedure:
3-(2-Chloro-4-trifluoromethylphenylsulfonyl)-1,2,4-triazole (3.12 g) and diethyl carbamoyl chloride (1.62 g) are dissolved in pyridine (10 ml) and reaction is performed at 50° C. for 5 h. After completion of the reaction, water (50 ml) is added to the reaction solution and the reaction product is extracted twice with ethyl acetate (100 ml). The ethyl acetate layer is washed first with 1N HCl, then with water, and subsequently dried with magnesium sulfate. The dried product is concentrated to form a crystal. Recrystallization from benzene/n-hexane produces the titled compound, 1-(diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylsulfonyl)-1,2,4-triazole, in an amount of 3.80 g; yield, 92.5%; m.p. 105.5°-107° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=[O:31])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:30][OH:31])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 79.3 %

Procedure:
To a suspension of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.13 g) in ethanol (15 ml) was added sodium borohydride (80 mg) with stirring under ice-cooling, and this mixture was further stirred for an hour at the same temperature. The reaction mixture was adjusted with dilute hydrochloric acid to pH 6 under ice-cooling and then the solvent was distilled off. To the residue was added water and the aqueous mixture was extracted with diethyl ether. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave an oil, which was crystallized by treating with n-hexane. These were crystallized from a mixture of diethyl ether and n-hexane to give pure crystals (900 mg) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 99° to 100° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[C:12]([CH3:19])=[C:13]([NH2:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][CH2:8]2)=[CH:3][CH:2]=1.C([O:29][CH2:30][CH3:31])(=O)C>>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[C:12]([CH3:19])=[C:13]([NH:18][C:30](=[O:29])[CH2:31][C:1]([CH3:20])([CH3:6])[CH3:2])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(-c3ccccc3)cc1)CO2
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(-c3ccccc3)cc1)CO2
Yield: 71 %

Procedure:
Using 3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 309, the title compound was synthesized in the same manner as in Example 1. Yield: 71%. Melting point: 218-219° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2cccnc2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 200 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg of nicotinoyl chloride*HCl. The following was obtained: 57.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]#[C:17]Br>CCOCC>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:17]#[N:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNCC(c1ccccc1)c1ccccc1

Procedure:
A cold (0° C.) solution of 2,2-diphenylethylamine (3.36 g, 17.0 mmol) in 50 ml of Et2O, was treated with a solution of cyanogen bromide (1.15 g, 10.9 mmol) in 10 ml of Et2O, under N2, resulting in the formation of a white precipitate. This precipitate was removed by filtration and the filtrate was concentrated in vacuo.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[NH:8].CS([C:19]1[N:24]=[C:23](/[CH:25]=[C:26]2/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/2)[CH:22]=[CH:21][N:20]=1)(=O)=O.C(N(C(C)C)C(C)C)C>CS(C)=O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[N:9]1[CH2:10][CH2:11][N:12]([C:19]2[N:24]=[C:23](/[CH:25]=[C:26]3/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/3)[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:14]1
Reactant: N=C(c1ccco1)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(c1ccco1)N1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
The crude material from Step 2, furan-2-yl(piperazin-1-yl)methanimine hydrochloride (16.3 mg, 0.076 mmol) was diluted in DMSO (Volume: 0.75 mL) and added to (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (19.4 mg, 0.068 mmol) in a 2-dram vial. The reaction solution was then treated with N-ethyl-N-isopropylpropan-2-amine (50 mg, 0.387 mmol) and then shaken at 100° C. for 16 h. The reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[C:17]([CH:24]=O)=[CH:16]1.[ClH:26]>C(O)C>[ClH:26].[NH:15]1[C:23]2=[N:22][CH:21]=[CH:20][CH:19]=[C:18]2[C:17]([CH:24]=[C:6]2[O:5][C:4]([NH:3][CH2:1][CH3:2])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:16]1
Reactant: CCNC1=C(C(=O)OCC)C(=O)CO1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCNC1=C(C(=O)OCC)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-(ethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.17 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.024 g, 0.17 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.026 g, y. 42%).
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].S1[C:11]2[CH:12]=[C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=5)=[N:25][NH:26][CH:27]=4)[CH:20]=[CH:19][N:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1>O.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2[C:23]([C:21]3[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]5[N:9]=[CH:8][S:3](=[O:5])[C:11]=5[CH:12]=4)[N:22]=3)=[CH:27][NH:26][N:25]=2)=[CH:29][C:30]=1[O:35][CH3:36]
Reactant: COc1cc(-c2n[nH]cc2-c2ccnc(Nc3ccc4ncsc4c3)n2)ccc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2n[nH]cc2-c2ccnc(Nc3ccc4c(c3)S(=O)C=N4)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of OXONE (=KHSO5; 141.4 mg, 0.23 mmoles) in water (2 mL) is added dropwise to a suspension of benzothiazol-6-yl-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine (Example 44) (20 mg, 0.046 mmoles) in methanol (2 mL) at rt. After stirring overnight at rt the suspension is diluted with water upon which the suspension turns to a clear yellow solution. The reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated and chromatographed on SiO2 (5% MeOH/CH2Cl2) to yield the title compound as light yellow solid: ES-MS 451.0751 [M+H]; single peak at tR=4.93 min (System 3).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH:8]3[CH2:13][CH2:14][O:15][C:6]([C:7]=23)=[CH:5][N:4]1[O:16][CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>O>[C:18]([CH:10]1[CH2:11][C:12]2[CH:3]([O:2][CH3:1])[N:4]([O:16][CH3:17])[CH:5]=[C:6]3[O:15][CH2:14][CH2:13][CH:8]([C:7]=23)[CH2:9]1)(=[O:20])[CH3:19]
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(C)=O)C2
Reaction time: 2 h

Procedure:
A mixture of 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano-[2,3,4-de]isoquinoline (10.0 g), described in Example 23, acetic anhydride (60.0 ml) and pyridine (0.5 ml) is heated on the steam bath for 4 hr. The mixture is poured into water and stirred for 2 hr. The mixture is extracted with chloroform and the extracts are washed with sodium bicarbonate solution and then with brine. The organic solution is dried and evaporated to leave the title compound. A sample, crystallized from isopropanol, had m.p. 100°-102° C.