Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]=[CH2:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].O1CCCC1>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]=[CH2:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)O)c1csc(N)n1
Yield: 59.6 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.6 g.), 2 N aqueous solution of sodium hydroxide (14.1 ml.), tetrahydrofuran (14.1 ml.) and methanol (15 ml.) was stirred at 40° C. for 1.5 hours. The resultant solution was concentrated in vacuo, and the residue was dissolved in water. After the solution was adjusted to pH 2.8 with 10% hydrochloric acid under ice cooling, the precipitates were collected by filtration, washed with water and acetone in turn and dried to give 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.91 g.), mp. 187° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][C:29]4=[O:37])=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccncc2)c2ccc(C=O)cc21
Solvent: C1CCNCC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1nc(CCc2ccncc2)c2ccc(C=C3C(=O)Nc4ccccc43)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of 3-(2-(pyridin-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (54 mg, 0.142 mmol), oxindole (19 mg, 0.142 mmol) in MeOH (2.0 mL) was treated with piperidine (1.5 uL, 0.0142 mmol) and the reaction heated to 60° C. and stirred for 4 hours at which time the solvent was removed and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/MeOH) to give the title compound (57 mg, 80%) as a yellow film. MS ESI 497.2 [M+H]+, calcd for [C29H32N4O2Si+H]+ 497.24.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=O.Cl>O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[CH:18]/[CH:17]=[C:16](\[CH3:20])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:21])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
Zinc dust (654 mg, 10.0 mmol) was slurred in 20 ml dry tetrahydrofuran under an inert atmosphere (nitrogen or argon), and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml dry benzene was rapidly added. The resulting solution was refluxed overnight to form active Ti(II) reagent, and a solution of retinal (710 mg, 2.5 mmol) in 5 ml dry tetrahydrofuran was added. After refluxing for a further two hours, the solution was cooled to room temperature, poured into 50 ml 2 N aqueous hydrochloric acid, and extracted with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was purfied by chromatography on a silica gel column. Elution with hexane gave 430 mg (65% yield) of beta-carotene which crystallized in the flask. The beta-carotene was identified by tlc comparison with an authentic sample, and by melting point comparison of a recrystallized sample; mp 180°-182°.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH2:11]([S:14]([C:17]1[N:21]=[CH:20][NH:19][N:18]=1)(=[O:16])=[O:15])[CH2:12][CH3:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:19]1[CH:20]=[N:21][C:17]([S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])=[N:18]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
Dipropylcarbamoyl chloride (5.4 g.) was added to a solution of 5.25 g. 3-propylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture was refluxed under anhydrous conditions for 2.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride, the filtrate was distilled under reduced pressure to remove solvent, and the residue was dissolved in methylene dichloride. The resulting solution was washed with ice-cold 0.1N aqueous sodium hydroxide (2 × 50 ml.), then with 0.01N aqueous sulphuric acid (50 ml.) and finally with water. The resulting solution was dried over anhydrous sodium sulphate and was then distilled under reduced pressure to give a solid residue. This residue was recrystallized twice from petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 79° - 80°C. Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:32]([O:39][NH2:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][NH:40][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 85.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanoic acid (1.30 g, 3.14 mmol), N,N′-carbonyldiimidazole (533 mg, 3.28 mmol) and O-benzylhydroxylamine hydrochloride (550 mg, 3.45 mmol) in tetrahydrofuran (10 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide as a yellow solid (1.4 g, 86% yield): mp, 137.0-139.0° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.8 Hz, 3H, CH3), 3.05-3.16 (m, 2H, CH2), 3.72 (s, 3H, CH3), 4.09 (q, J=6.8 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.68 (t, J=7.8 Hz, 1H, NCR), 6.87-7.02 (m, 3H, Ar), 7.23-7.41 (m, 5H, Ar), 8.11 (d, J=8.1 Hz, 1H, Ar), 8.48 (s, 1H, Ar), 8.62 (dd, J=1.8, 8.2 Hz, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.64, 34.17, 50.76, 55.45, 63.71, 76.67, 111.68, 112.37, 118.02, 119.76, 124.70, 128.16, 128.62, 129.75, 130.42, 132.52, 135.74, 135.79, 147.73, 148.69, 151.50, 165.73, 165.99, 166.17. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.34; H, 4.71; N, 8.05.
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:13][CH3:14])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22]3)=[C:17]([CH3:30])[CH:16]=2)[CH2:31][CH3:32])=[CH:8][C:7]=1[CH3:33])[CH3:2]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Yield: 98.2 %

Procedure:
10% palladium carbon (50 mg) was added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl-2-methyl-phenyl)-1-penten-3-ol (Example 28; 150 mg, 0.306 mmol) in methanol (6 mL) and ethyl acetate (1.5 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for three hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to give the target product as a colorless oil (148 mg, 98%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-:19].[Na+].[OH-].[Na+].Cl>O1CCOCC1>[CH:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:14][C:15]=2[CH:16]=[CH:17][C:4]=1[C:1]([OH:3])=[O:19]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 5 h

Procedure:
A mixture of 2-acetylphenoxathiin (4.80 g), sodium hypochlorite solution (95 ml; 5.7% available chlorine), 4% sodium hydroxide solution (100 ml) and dioxan (100 ml) was mechanically stirred on the steam bath for 5 hrs. The solution was poured on to ice and excess hydrochloric acid with stirring. The white precipitate was filtered off and dissolved in hot 4% sodium hydroxide solution (40 ml) and filtered. The sodium salt of the required acid crystallised from the filtrate on cooling and was filtered off, dissolved in boiling water, and the acid precipitated by addition of excess hydrochloric acid. It was filtered off and recrystallised from acetic acid, m.p. 253° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67](O)=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 92%. [α]D =+4.2° (c=0.83, tetrahydrofuran).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[NH:8]2)[CH3:2].[Mg].ClCCl.[NH4+].[Cl-]>CO>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[NH:8]2)[CH3:2]
Reactant: CCOc1cccc2[nH]c(C(=O)OC)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1cccc2c1CC(C(=O)OC)N2
Temperature: 25 °C

Procedure:
Methyl 4-ethoxyindole-2-carboxylate (1.02 g, 4.568 mmol) was dissolved in methanol (20 ml) and magnesium shavings (0.55 g, 22.6 mmol) were then added, with stirring, at room temperature under nitrogen. After the reaction started, a water bath was used to maintain the reaction temperature between 15-20° C. At the end of the reaction, dichloromethane (200 ml) was added to the mixture, followed by NH4Cl solution (200 ml). The organic phase was separated out and the aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in order to give a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][C@H:27]([OH:25])[CH2:28][CH2:29][CH2:30][CH3:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: CCCC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC[C@@H](O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.056 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added (R)-(+)-1,2-epoxyhexane (5.6 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated at 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was filtered to remove excess of K2CO3. The collected solution was concentrated under reduced pressure. The crude product was purified using silica gel column chromatography using an automated system, eluting with a gradient of (0% to 60% EtOAc/hexanes for 30 min followed by 60% EtOAc/hexanes to 100% EtOAc for 10 min. The title compound, (R)-7,8-Bis(4-chlorophenyl)-2-(2-hydroxyhexyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (8.3 mg, 32% yield) was obtained as a yellow oil. MS [M+H]+: found 457; 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.28-7.19 (m, 6H), 7.06-7.02 (m, 2H), 4.13-4.08 (m, 1H), 4.00-3.90 (m, 2H), 1.49-1.24 (m, 6H), 0.83 (t, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[C@@H:15]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][O:42][CH2:43][C@H:44]([O:46][CH2:47][CH3:48])[CH3:45])=[CH:37][CH:36]=2)[C@H:14]([CH2:49][OH:50])[CH2:13]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH2:47]([O:46][C@H:44]([CH3:45])[CH2:43][O:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C@@H:15]2[C@@H:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:17][NH:12][CH2:13][C@H:14]2[CH2:49][O:50][C:1](=[O:3])[CH3:2])=[CH:36][CH:37]=1)[CH3:48]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COC(C)=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
0.89 mmol of acetyl chloride are added to a solution of 0.81 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) and 0.97 mmol of Et3N in 7 ml of CH2Cl2 under argon at 0° C. After 1 h, the reaction mixture is diluted with CH2Cl2 and washed with successively with saturated aqueous NaHCO3 solution and brine. The combined aqueous phases are extracted with CH2Cl2—the combined organic layers are dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and is identified based on the Rf value.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl.[OH:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:20][C:19](=[N:25][OH:24])[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:8][CH2:9]2)[CH:18]=1
Reactant: NO
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Yield: 63.2 %

Procedure:
1-(4,4-Dimethylpentanoyl)-4-(4-cyanopyridin-2-yl)piperazine (2.91 g) obtained in Example 53 was dissolved in ethanol (20 mL), and hydroxyamine hydrochloride (2.16 g) and potassium carbonate (5.38 g) were added thereto and heated under reflux for 2 hours. Then, the solvent was evaporated away, and the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away to obtain 2.04 g of the entitled compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: COc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-methoxy-benzyl bromide (67 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-methoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (65 mg, 42%) as a light yellow oil. APCI-MS (M+H) 327.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH-:15])[CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12.[OH-].[Na+].[CH:18](O)=[O:19]>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][CH:18]=[O:19])[CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12
Reactant: COc1cc(CC[NH-])cc2c1OCO2
Reactant: O=CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCNC=O)cc2c1OCO2
Yield: 81.8 %

Procedure:
6.95 g (30 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethylamide hydrochloride was dissolved in 30 ml of water, and the mixture was made basic with 25% sodium hydroxide aqueous solution. The mixture was extracted with 30 ml of toluene. The toluene layer was washed with 10 ml of water, added with 2.73 g (59.3 mmol) of formic acid, refluxed under heating for 2 hours at normal pressure to distill off about 15 ml of the toluene while separating the produced water by an azeotropic distillation and then cooled. The deposited crystal was filtered out, washed with 3 ml of toluene and dried to obtain 5.48 g of N-[2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl]formamide (C). Yield: 83%; melting point: 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCO
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OC)cc(OC)c1
Yield: 88 %

Procedure:
A solution of 3,5-dimethoxyphenylacetic acid (2.0 g; 10 mmol) and H2SO4 (conc.; 0.2 mL) in EtOH (50 mL) was refluxed overnight. The solution was concentrated, and the resultant material was dissolved in aqueous NaOH (1M). After extraction with ether (2×75 mL), washing of the combined organic phase with brine, drying (Na2SO4) and evaporating, 2.0 g (88%) of the sub-title compound was obtained.
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1I.[CH3:28][N:29](C)C.O1CCOCC1>O>[C:28]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:17]=1[OH:16])[C:21]([O:23][CH3:24])=[O:22])#[N:29]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CN(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 154.5 %

Procedure:
(Boc)2O (44.7 g, 0.21 mol) was added portion-wise over 10 min to a 0° C. solution of compound 2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37 mol), dioxane (140 L) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL×3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:34][CH:33]([CH3:35])[CH3:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 60 °C
Yield: 76.3 %

Procedure:
Prepared using General Procedure 2: To a solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (21 mg, 0.04 mmol) in IPA (2 mL) was added sodium isopropoxide (5 mg, 0.06 mmol). The reaction mixture was heated at 60° C. for 2 h. Upon cooling, the solvent was evaporated and the product was purified by a silica gel column chromatography (EA/hexanes) to afford (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (15 mg, 68%). LCMS-ESI (m/z) calculated for C28H34N2O2SSi: 491.7, found 492.2 [M+H]+, tR=5.17 min (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH3:13])=[O:11])=O)=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[N:12]([CH3:13])[C:10](=[O:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccc(Cl)cc2)n[nH]c1=O

Procedure:
400 mg (1.78 mmol) of 2-(4-chlorobenzoyl)-N-methylhydrazinecarboxamide from Example 34A are heated under reflux overnight in 7 ml 3 N aqueous sodium hydroxide. After cooling, it is adjusted to pH ca. 11 with aqueous citric acid solution and the resulting precipitate filtered off, washed with water and dried in vacuo. 350 mg (95% of theory) of the target compound are thus obtained.