Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[NH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2CC2C=CC=CC=2)=[CH:5][C:4]=1[C:21]([O:23]CC)=O.[CH3:26][N:27](C=O)C.C(O)=O>C(N)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:3]2[N:2]=[CH:26][N:27]=[C:21]([OH:23])[C:4]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2cccc[n+]2Cc2ccccc2)[nH]c1N
Agent: [Br-]
Solvent: O=CO
Solvent: NC=O
Product: Oc1ncnc2[nH]c(-c3ccccn3)cc12

Procedure:
Under a protective gas, 27.07 g of 2-(5-amino-4-ethoxycarbonyl-1H-pyrrol-2-yl)-N-benzyl-pyridinium bromide in 195 ml of formamide are heated for 16 hours at 150° C. with 97.6 ml of DMF (dried over 4A molecular sieve) and 48.8 ml of formic acid. When the dark-brown reaction mixture is cooled in an ice-bath, the title compound crystallizes and can be filtered off and washed with isopropanol and diethyl ether; 1H-NMR (300 MHz, DMSO-d6): 12.5 and 11.9 (2s, 2H), 8.60 (d, J=7, 1H), 8.05-7.8 (m, 3H), 7.28 (dd, J1 =7, J2 =9, 1H), 7.20 (s, 1H); FAB-MS: (M+H)+ =213.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:25])[NH:15][C:16]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[CH:13][C:9]=2[C:8]([NH:26][C:27](=[O:37])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-])=O)=[N:7]1)=[O:5])[CH3:2]>C(OC(=O)C)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:25])[NH:15][C:16]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[CH:13][C:9]=2[C:8]([NH:26][C:27](=[O:37])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2N)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Yield: 84.9 %

Procedure:
The suspension of 1.8 g (3.451 mmol) of 5-(1-Methyl-1-phenyl-ethylcarbamoyl)-3-(2-nitro-benzoylamino)-thieno[2,3-c]pyrazole-1-carboxylic acid ethyl ester and 500 mg of Pd/C (10%) in 45 mL of ethylacetate was shaken under hydrogen pressure (40 psi). The catalyst was renewed (500 mg) after 8 hours and the mixture treated for further 8 hours. The catalyst was then filtered over a celite pad and the solvent removed under vacuum. The crude was purified on silica gel (eluant dichloromethane-methanol 98:2) yielding 1.44 g (85%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)[CH2:41][C:37]1[NH:36][CH:40]=[CH:39][N:38]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCOCc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCOCc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
The compound (81.2 mg) obtained in Example 60-4 was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 4 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The aqueous layer was washed with chloroform and then evaporated to dryness. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (63.0 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([S:9][C:10]2[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=2[Cl:18])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1)([OH:3])=O.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[Cl:18][C:11]1[CH:12]=[N+:13]([O-:17])[CH:14]=[C:15]([Cl:16])[C:10]=1[S:9][C:7]1[S:8][C:4]([C:1](=[O:3])[NH:29][CH:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:5][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c[n+]([O-])cc2Cl)s1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)c[n+]([O-])cc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 4-((5-carboxy-3-nitrothiophen-2-yl)thio)-3,5-dichloropyridine N-oxide (200 mg, 0.54 mmol) from above and 1-methylpiperidin-4-amine (64.0 mg, 0.65 mmol). The title compound was obtained as a solid (70.0 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.67 (1H, m), 8.51 (1H, s), 3.65 (1H, m), 2.85 (2H, m), 2.50 (3H, s), 2.24 (2H, m), 1.77 (2H, m), 1.57 (2H, m). MS m/z: 463.08, 465.08 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:16](OC)=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11](OC)=[O:12])[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:15]=[C:10]([CH2:11][OH:12])[CH:9]=[C:8]([CH2:16][OH:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)cc(CO)c1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of dimethyl 5-butoxyisophthalate (0.51 g, 1.90 mmol) in THF (16 mL) was slowly added LiAlH4 (0.40 g, 10.5 mmol). The reaction mixture was stirred for 8 h. The reaction was quenched by the addition of 2N aq. HCl (5 mL). The mixture was extracted with Et2O (2×25 mL) and EtOAc (2×25 mL), the organics layers combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (0.24 g) as an oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:32]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:31])[CH3:30])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8].[C:34]1([O-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:4][CH:5]=[C:6]([CH:32]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:30])[CH3:31])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8]
Reactant: [O-]c1ccccc1
Reactant: CC(C)[C@@H](NC(=O)c1cnc(Cl)c(Cl)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)c1cnc(Oc2ccccc2)c(Cl)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 35.2 %

Procedure:
5,6-Dichloro-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)nicotinamide (35 mg, 0.068 mmol), 0.5 mL DMF, and sodium phenolate (9.51 mg, 0.08 mmol) was heated for 1 hr at 120° C. Example 624 was isolated as a white solid by preparative reverse phase HPLC (13.7 mg, 35.2% yield), M+H=570.07.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1)=[O:4].[N:30]1([CH2:35][CH2:36][NH2:37])[CH:34]=[CH:33][N:32]=[N:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>CO>[N:30]1([CH2:35][CH2:36][NH:37][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH2:18][C:16]3[N:17]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[CH:10][C:5]([S:3]([C:2]([F:29])([F:1])[F:28])=[O:4])=[CH:6][CH:7]=4)[O:14][CH:15]=3)=[CH:21][CH:22]=2)[CH:34]=[CH:33][N:32]=[N:31]1
Reactant: NCCn1ccnn1
Reactant: O=Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CNCCn4ccnn4)cc3)co2)cc1)C(F)(F)F

Procedure:
A solution of 120 mg (0.28 mmol) 4-{2-[(E)-2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzaldehyde, 31 mg (0.28 mmol) (2-[1,2,3]triazol-1-yl-ethyl)-amine and 5 mg toluene-4-sulfonic acid in 10 ml methanol was stirred at room temperature for 1 hour, then 18 mg (0.28 mmol) sodium cyanoborohydride was added and the mixture stirred over night. After evaporation and chromatography on silica with ethyl acetate/methanolic ammonia 85:15, the title compound was isolated as light yellow solid melting at 111-113° C.; yield 89 mg (60%).
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[N:26][C:25]=3Cl)=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>CO.[Pd]>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[N:26][CH:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)Nc2cccc(CN3CCC(C(=O)NC(C)(C)C)CC3)c2)c(Cl)nn1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(CN3CCC(C(=O)NC(C)(C)C)CC3)c2)cnn1
Reaction time: 4 h

Procedure:
A solution of 3-chloro-6-methyl-pyridazine-4-carboxylic acid [3-(4-tert-butylcarbamoyl-piperidin-1-ylmethyl)-phenyl]-amide (53 mg, 0.119 mmol) in methanol (5 mL) is treated with palladium 10 wt % on activated carbon wet (50% water) (5.1 mg, 0.048 mmol, 0.4 eq) and AcOH (0.00683 ml, 0.119 mmol). The mixture is stirred under hydrogen atmosphere for 4 h. The suspension is filtered over celite and the solvent is evaporated. The residue is purified by prep HPLC E delivering the title compound (7 mg, 14%) as a light yellowish powder, LC-MS A: tR=0.58 min; [M+H]+=410.4.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][N:14]([C:17]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21]1)=[O:18])[CH2:13][CH2:12]2)(=O)=O.[CH2:38]([Sn](CCCC)(CCCC)C=C)[CH2:39]CC.[Cl-].[Li+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:38]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][N:14]([C:17]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@H:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21]1)=[O:18])[CH2:13][CH2:12]2)=[CH2:39]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3C2)CN1C(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 159.1 %

Procedure:
A solution of 1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate (1.74 g, 3.15 mmol), tri-n-butyl vinyl tin (1.10 g, 1.46 mmol) and lithium chloride (0.40 g, 9.45 mmol) in 25 mL DMF was purged with nitrogen for 10 min. Then bis(triphenylphosphine)palladium (II) chloride (0.22 g, 0.32 mmol) was added, and the mixture stirred at 25° C. under nitrogen for 18 h. The mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer separated and washed with water then brine, dried over anhydrous sodium sulfate and concentrated to an oil. The oil was purified by column chromatography on silica gel (gradient elution, 10 to 65% EtOAc in hexanes) to give a colorless oil, 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.00 g, 74% yield). LRMS (ESI) m/z 453.2 [(M+Na)+; calcd for C23H30N2O6Na: 453.5].
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])=[CH:10][CH:9]=1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:18]([O:17][CH:15]([O:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]\[CH2:5][OH:4])=[CH:13][CH:12]=1)[CH3:16])[CH3:19]
Reactant: CCOC(C)Oc1ccc(/C=C\COC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(C)Oc1ccc(/C=C\CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.8 Grams of 4[Z)-(1-ethoxyethoxy)cinnamyl acetate and 50 ml of methanol solution containing 5 g of potassium carbonate were stirred at a room temperature for 2 hours. The solvent was removed by evaporation, and to the residue thus obtained was added water and extracted with ether. The ether extract was washed with water, dried and the solvent remove by evaporation to yield 4(Z)-(1-ethoxyethoxy)cinnamyl alcohol.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[CH:48]1([CH:51]=O)[CH2:50][CH2:49]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:51]([CH:48]5[CH2:50][CH2:49]5)=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Reactant: O=CC1CC1
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2nc(C3CC3)[nH]c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF was combined with 20 μL (0.27 mmol) cyclopropanecarbaldehyde and stirred for 2 days at RT. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([NH2:26])[S:18][C:19]=1[CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24]>>[CH3:14][C:15]1[N:16]=[C:17]([NH:26][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[O:9])[S:18][C:19]=1[CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: CC(=O)Oc1ccccc1C(=O)Nc1nc(C)c(CCO[N+](=O)[O-])s1
Yield: 25 %

Procedure:
Pet-159 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 2-acetoxy-benzoic acid (Aspirin) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 25%.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)Cl.O>C(O)C.O1CCOCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Oc2cc(O)cc(O)c21
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC(=O)c1c(O)cc(O)cc1O2
Yield: 51 %

Procedure:
1.40 g of 2-nitro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10,11 -one (Compound 70) and 4.40 g of tin (II) chloride.2H2O were suspended in 20 ml of ethanol and 20 ml of 1,4-dioxane, followed by reflux under heating for 3 hours. Water was added to the reaction solution, which was then extracted in ethyl acetate. The extracted solution was sequentially washed in water and then an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (elution solvent; dichloromethane:methanol=95:5), to recover the entitled Compound 71 represented by the formula (0.64 g; yield of 51%). The melting point of the amorphous powder recovered by recrystallization in hexane and ethyl acetate was 227-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)=[O:30].OO>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][S:25](=[O:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=CO
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCSC2)C(=O)Nc2cnccn2)cc1Cl
Agent: OO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCS(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A slurry of 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-thiopyran-3(R)-yl)-propionamide (prepared as in Example 18, 10.0 mg, 0.0227 mmol) in formic acid (68.5 μL, 1.816 mmol) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (7.7 μL, 0.068). The resulting solution was stirred at 0° C. for 10 min. The reaction was quenched by the addition of a 10% aqueous sodium sulfite solution (1 mL) and then extracted with ethyl acetate (2×5 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 93/7 chloroform/methanol) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(1-oxo-hexahydro-1λ4-thiopyran-3(R)-yl)-N-pyrazin-2-yl-propionamide (10.0 mg, 96.5%) as a beige gum: EI-HRMS m/e calcd for C19H22ClN3O4S2 (M+Na)+ 478.0632. found 478.0632.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O1CCCC1>[NH2:1][C:2](=[S:29])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCC(N)=O)ccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CCC(N)=S)ccn1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 152.7 %

Procedure:
Under argon atmosphere, tert-butyl N-[4-(3-amino-3-oxopropyl)-2-pyridyl]-carbamate (11.79 g, 44.44 mmol) dissolved in tetrahydrofuran (100 ml) was added with Lawesson's reagent (9 g, 22.22 mmol) and stirred at 70-80° C. for 30 minutes. After the reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform chloroform:methanol=20:1) to obtain 9.544 g (76%) of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH3:18][C:19]1[C:20]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:22][N:21]=3)[CH2:30][CH2:31]2)=[O:13])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C(F)(F)F)cc2C)CC1
Yield: 47.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 87, the title compound (230 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:3][C:4](OCC)=[O:5].ClC1C(OC(C)C)=CC([N:27]=[C:28]=[O:29])=C(F)C=1>>[F:15][C:9]([F:14])([C:2]1[NH:1][C:28](=[O:29])[NH:27][C:4](=[O:5])[CH:3]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Product: O=c1cc(C(F)(F)C(F)(F)F)[nH]c(=O)[nH]1

Procedure:
using ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3- 4-chloro-2-fluoro-5-isopropoxyphenyl)-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 141°-143° C.;
Reaction SMILES: [CH2:1]([C:18]([OH:56])([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([OH:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1.[O:63]=[C:64](Cl)OC(Cl)(Cl)Cl>CCOCC>[CH2:1]([C:18]1([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:37][C:64](=[O:63])[O:56]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)OC1CCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (6Z,9Z,28Z,31Z)-19-((8Z,11Z)-heptadeca-8,11-dienyl)heptatriaconta-6,9,28,31-tetraene-18,19-diol (540 mg, 0.67 mmol) in anhydrous ether (5 mL) was added pyridine (81 μL, 1.0 mmol). To this solution was added diphosgene (132 μL, 1.1 mmol) slowly over 5 minutes. The solution was stirred for 2 hours at room temperature then concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with 5% ether in hexanes) to afford 4,5-di((8Z,11Z)-heptadeca-8,11-dienyl)-4-((9Z,12Z)-octadeca-9,12-dienyl)-1,3-dioxolan-2-one as a colorless oil (310 mg, 57%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.C(N(CC)CC)C>C(O)(C)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 82 °C

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82° C. for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35° C. to remove the tetrahydropyranyl group to yield (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.