Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: Nc1scc(Cl)c1-c1nnc[nH]1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The titled compound was synthesized from 4-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid via protocol A. LCMS method [4], retention time=1.035; MS(ESI) 389.1 (MH+, 35Cl).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([OH:18])[CH2:13]2.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21].C(OC(C)C)(C)C>C(Cl)Cl.O>[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([O:18][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH2:13]2
Reactant: C[Si](C)(C)Cl
Reactant: OC1Cc2cccc(Br)c2C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OC1Cc2cccc(Br)c2C1
Reaction time: 0.08 h

Procedure:
5.2 ml of anhydrous triethylamine is added drop by drop to 5.3 g of product obtained in Stage B in 50 ml of methylene chloride. After cooling to 0°, +5° C., 3.5 ml of trimethylsilyl chloride in 15 ml of methylene chloride is introduced drop by drop, with agitation for 5 minutes at 0° C. and for 15 minutes at ambient temperature. The reaction mixture is poured into 200 ml of a water and ice mixture and 100 ml of isopropyl ether. After decanting, the organic phase is washed with water to obtain a pH of 7.5-8, and the aqueous phases with water are extracted by isopropyl ether. The organic phases are reunited, dried, concentrated to dryness and 6.81 g of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@@H:11]([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:23])[N:4]=[C:3]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C@H:11]([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:32])([CH3:1])[C:3]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[N:4][C@:5]3([CH3:23])[C:14]=2[CH:15]=1
Reactant: C[C@@H]1C[C@@H]2[C@](C)(N=C(NC(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H]2[C@](C)(N=C(NC(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(N)ccc2O1
Yield: 98.1 %

Procedure:
A solution of tert-butyl ((4aR,6R,11bR)-3,3,6,11b-tetramethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (50 mg, 0.107 mmol) in THF (1 ml) was hydrogenated under hydrogen balloon in the presence of palladium 10 wt. % on activated carbon (34.1 mg, 0.032 mmol) for 1.5 h. The mixture was filtered through the plug of Celite, filter cake was washed with ethyl acetate. The combined filtrate was concentrated to afford crude tert-butyl ((4aR,6R,11bR)-10-amino-3,3,6,11b-tetramethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (46 mg, 0.105 mmol, 98% yield) which was used without further purification. MS m/z=438.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=Cc2cc(C(C)(C)C)c(OCC(C)C)c(-c3ccccc3)c2C1
Temperature: 5 °C
Reaction time: 7 h
Yield: 99.9 %

Procedure:
To a solution of 34.0 g (97.0 mmol) of 6-tert-butyl-5-isobutoxy-2-methyl-4-phenylindan-1-one in 300 ml of THF cooled to 5° C. 5.00 g (132 mmol) of NaBH4 was added. Further on, 150 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was evaporated to dryness, and the residue was partitioned between 500 ml of dichloromethane and 500 ml of 1 M HCl. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness to give a colorless oil. To a solution of this oil in 500 ml of toluene 1 g of TsOH was added, and this mixture was refluxed with Dean-Stark head for 15 min and then cooled to room temperature using a water bath. The resulting solution was washed by 10% aqueous Na2CO3. The organic layer was separated, the aqueous layer was extracted with 2×100 ml of dichloromethane. The combined organic solution was dried over K2CO3 and then passed through a short pad of silica gel 60 (40-63 um). The silica gel pad was additionally washed by 100 ml of dichloromethane. The combined organic elute was evaporated to dryness. This procedure gave 32.4 g (99%) of 5-tert-butyl-6-isobutoxy-2-methyl-7-phenyl-1H-indene which was further used without an additional purification.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[N+:6](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:8])=[O:7].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH2:3]([C@@H:2]([C@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][N+:6]([O-:8])=[O:7])[CH:1]=[O:5])[CH3:4]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCCC=O
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from butyraldehyde and (E)-(2-nitrovinyl)-benzene according to the general procedure. The enantiomeric ratio was determined by HPLC with an OD-H column at 220 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=40.61 min, minor enantiomer tminor=51.74 min. The diastereomeric excess was determined by 1H NMR. [α]D20=−99.5 (c=1.1, CHCl3).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH2:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22](Br)[C:23]#[CH:24]>CC(C)=O>[CH2:24]([NH:21][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: CCCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCNCCCCCCCCCCCCCC

Procedure:
5 g (47 mmol) of anhydrous sodium carbonate are added to a solution of 10.0 g (47 mmol) of n-tetradecylamine in 100 ml of absolute acetone, and the suspension is heated to reflux. At that temperature 5.9 g (50 mmol) of propargyl bromide in 50 ml of acetone are then added dropwise and the mixture is subsequently heated at reflux for 2 hours. After aqueous working-up, the product is obtained in the form of a brown oil having a purity of >90%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[C:15]1=O)[CH2:21]2.C(OC)(=O)C1C=CC=CC=1>C1COCC1.C(OCC)C.O>[CH2:15]1[CH:16]2[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:22]2)[CH2:21][CH:14]1[CH2:23]3
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1C2CC3CC1CC(C2)C3
Reaction time: 0.17 h
Yield: 106.8 %

Procedure:
LiAlH4 (800 mg) was slowly added to a suspension of TiCl3 (THF)3 (16.5 g, 44.6 mmol) in anhydrous THF (15 ml) at 0° C. After 10 minutes at 0° C., triethylamine (3.5 ml) was added and the mixture was refluxed for one hour. A solution of 2-adamantanone 5 (822 mg, 5.47 mmol) and of the methyl benzoate ester 4b prepared previously (1.2 g, 444.50 mmol) in anhydrous THF (10 ml) was added dropwise to the mixture. The reaction mixture was refluxed for 3 hours. Water was added carefully to the mixture at 0° C., which was then diluted with diethyl ether. The organic phase was washed with a saturated solution of NaCl, then dried over MgSO4 and concentrated under reduced pressure. Chromatography on silica gel using cyclohexane/EtOAc (v/v:99/1) as eluent mixture made it possible to obtain 2-[1-(3-tert-butyldimethylsilyloxy)phenyl)-1-methoxy-methylene]tricyclo[3.3.1.1]decane 3b (796 mg, 66%) in the form of a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.09 (t, 1H), 6.81 (d, 1H), 6.70 (m, 2H), 3.20 (s, 3H), 3.14 (br s, 1H), 2.54 (br s, 1H), 1.87-1.67 (m, 12H), 0.91 (s, 9H), 0.14 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ 155.5, 143.6, 136.9, 131.2, 129.0, 122.6, 121.2, 119.5, 57.6, 39.3, 39.2, 38.9, 37.4, 32.9, 30.5, 25.8, 18.3, −4.70.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[NH:9][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH:15]2
Reactant: Cc1ccc(NN)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccn1
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Yield: 16.1 %

Procedure:
(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and 2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (2 g, Yield 16%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:7]2=[CH:8][C:9]3[N-:13][C:12]4[C:14]([C@@H:56]([C:59]([O:61][CH3:62])=[O:60])[C:57](=[O:58])[C:11]=4[C:10]=3[CH3:63])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[N-:26][C:24](=[CH:25][C:5](=[N:6]2)[C:4]=1[CH3:64])[C:23]([CH:27]=[CH2:28])=[C:22]4[CH3:29])[C@@H:17]([CH3:30])[C@@H:16]3[CH2:31][CH2:32][C:33]([O:35][CH2:36]/[CH:37]=[C:38](/[CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH3:49])[CH3:44])\[CH3:39])=[O:34].[Mg+2:65].CC(C)=[O:68]>>[CH3:1][CH2:2][C:3]1[C:7]2=[CH:8][C:9]3[N-:13][C:12]4[C:14]([C@@H:56]([C:59]([O:61][CH3:62])=[O:60])[C:57](=[O:58])[C:11]=4[C:10]=3[CH3:63])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[N-:26][C:24](=[CH:25][C:5](=[N:6]2)[C:4]=1[CH:64]=[O:68])[C:23]([CH:27]=[CH2:28])=[C:22]4[CH3:29])[C@@H:17]([CH3:30])[C@@H:16]3[CH2:31][CH2:32][C:33]([O:35][CH2:36]/[CH:37]=[C:38](/[CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][C@@H:48]([CH2:50][CH2:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH3:49])[CH3:44])\[CH3:39])=[O:34].[Mg+2:65]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Reactant: CC(C)=O
Agent: [Mg+2]
Product: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C=O)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C

Procedure:
To 100 g of dried chlorell were added 800 ml of acetone. The mixture was treated in the same manner as described in Example 1 whereby 0.190 g in total of chlorophyll A and chlorophyll B was obtained.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc[cH-]c1
Reactant: C[Si](C)(C)OCCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1=CC=CC1
Reaction time: 12 h
Yield: 64 %

Procedure:
150 ml of a 2.3 M sodium cyclopentadienylide solution in tetrahydrofurane (346 mmol) is slowly added to a solution of 68.2 g (346 mmol) 2-trimethylsiloxy-1-bromo-ethane in tetrahydrofurane. The immediate formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours. Then, an ammonium chloride aqueous solution is added. The organic phase is extracted, dried with magnesium sulphate and the volatile part is distilled under vacuum, obtaining an orange oil. This oil is distilled in order to obtain a colorless oil. (Tb.: 63-65° C., 0.02 bar (15 mmHg.)). (40.3 g, 221 mmol. Yield:64%). 1H-NMR (CDCl3): 6.50-6.00 (m,3H), 3.75 (m,2H), 2.95 (m,2H), 2.65 (m,2H), 0.15 (s,9H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:20])C=O>O>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:6]=2[N:15]=[C:11]1[C:8]1[CH:9]=[CH:20][N:17]=[CH:16][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)Nc1ccc(C(F)(F)F)cc1N
Solvent: O
Product: CC(C)n1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 0.44 g of N1-isopropyl-4-trifluoromethylbenzene-1,2-diamine, 0.51 g of isonicotinealdehyde-bisulfite adduct and 4 ml of N,N-dimethylformamide was stirred for 1 hour at 150° C. The reaction mixture was allowed to cool to room temperature, and water was poured into this, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a solid residue. The residue was washed with hexane, to obtain 0.50 g of 1-isopropyl-2-(pyridin-4-yl-)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 219).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C#N)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: Cl.Cl.[CH:3]([NH:6][NH2:7])([CH3:5])[CH3:4].[C:8]([O:18]CC)(=O)[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[Na]>O.C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:10]1[CH:9]=[C:8]([OH:18])[N:6]([CH:3]([CH3:5])[CH3:4])[N:7]=1)=[O:13])[CH3:16]
Reactant: CC(C)NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(C(C)C)n1
Temperature: 140 °C
Yield: 28.4 %

Procedure:
A solution containing 29 g of isopropylhydrazine dihydrochloride in 150 ml of water was added dropwise to a stirred solution of 41.7 g of diethyl oxalacetate, sodium salt in 300 ml of acetic acid and 150 ml of toluene. The mixture was heated at 140° C. for 5 h. The mixture was left to cool to room temperature and then the solvent was evaporated under reduced pressure and the residue azeotroped with toluene. The residue was partitioned between dichloromethane and water. The dichloromethane extract was washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was triturated with diethyl ether to give a white solid which was filtered then washed three times with cold diethyl ether and dried to give 11.1 g of 5-hydroxy-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:22]=[CH:23][C:24]([O:26]C)=[O:25])=[CH:16]2)=[O:11].C(O)C.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:16]2)=[O:11]
Reactant: COC(=O)C=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)C=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
22 (60 mg, 0.167 mmol) was dissolved in DMF (1.5 mL) and ethanol (3 mL) was added. 3N NaOH solution (1.5 mL) was added and the reaction mixture was stirred overnight. The solvent was removed and water (10 mL) was added. The solution was neutralized using 20% HCl. The resulting precipitate was filtered and washed with water. 53 mg (92% yield) of yellow solid 23 was obtained. mp: 268° C. (dec). 1H NMR (DMSO-d6, ppm): 12.27 (brs, 1 H, COOH), 11.53 (s, 1 H, NH), 10.38 (s, 1 H, NH), 8.07-7.35 (m, 9 H, Ar--H, CH=CH), 6.88 (s, 1 H, Ar--H), 6.48-6.44 (d, 1 H, J=16.2 Hz, CH=CH). Anal. (C20H14N2O4 0.4H2O), C, H, N.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH2:15][CH2:14]1.C([O-])(=O)C.[Na+].C(O)C>O>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:2]2[CH:3]=[C:4]([F:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: CNC1CCN(C)CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CCC(NCc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 1.4 %

Procedure:
Combine 1,3-difluoro-5-nitro-benzene (1.78 mL, 15.7 mmol), 1-methyl-4-(methylamino)piperidine (2.74 mL, 18.85 mmol), sodium acetate (2.45 g, 29.8 mmol) and absolute ethanol (10 mL) in a sealed tube. Heat and stir at 100° C. for 16 hr. Cool the reaction mixture to ambient temperature and pour into water (100 mL). Extract with ethyl acetate (2×100 mL). Wash combined organic layers with saturated aqueous NaCl solution (100 mL), dry over sodium sulfate, filter, and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to obtain 0.06 g (1.4%)of the title intermediate: 1H NMR (CDCl3): 7.3 (m, 1H), 7.2 (m, 1H), 6.7 (m, 1H), 3.6 (m, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])=[CH2:2].[CH2:15]1[O:18][CH:16]1[CH3:17].[Cl-].[Li+]>CN(C)C=O>[OH:18][CH:16]([CH3:17])[CH2:15][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[C:7]1=[O:14]
Reactant: C=COCCN1C(=O)NC(C)(C)C1=O
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)N(CC(C)O)C(C)(C)C1=O

Procedure:
297 g (1.5 mols) of 3-(2-vinyloxyethyl)-5,5-dimethylhydantoin, prepared as described in Example 1, 87 g (1.5 mols) of propylene oxide, 7.5 g of lithium chloride and 750 ml of dimethylformamide are allowed to react for 4 hours and 30 minutes at 90°-112° C. A further 83.5 g (1.44 mols) of propylene oxide are then added dropwise in the course of 3 hours and 30 minutes at 112°-113° C. and the mixture is left to react for a further 15 minutes. It is then concentrated on a rotary evaporator at 80° C. under vacuum from a waterpump and dried to constant weight at 80° C. and 13.3 Pa. 382 g (99.6% of theory) of a brown, clear, viscous crude product are obtained and are purified by distillation. 347.7 g (90.4 g) of a clear, colourless distillate boiling at 149°-152° C./13.3 Pa are obtained.
Reaction SMILES: N[C:2]([CH3:6])=[CH:3][C:4]#[N:5].[C:7]([NH:11][NH2:12])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C(O)C>[C:7]([N:11]1[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(N)=CC#N
Reactant: CC(C)(C)NN
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)n(C(C)(C)C)n1

Procedure:
To a mixture of 3-aminobut-2-enenitrile (60 g, 731 mmol) and tert-butylhydrazine (96 g, 731.1 mmol) in ethanol (35 ml), triethylamine (220 ml, 2195 mmol) was added. The mixture was refluxed for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The concentrate was extracted with water (100 ml) and ethylacetate (700 ml). The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to obtain the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]N1C(=O)CCC1=O>>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Product: O=[N+]([O-])c1ccccc1CBr

Procedure:
1-Methyl-2-nitro-benzene was reacted with N-bromosuccinimide as described in the synthesis of Example 1e to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]([CH2:24]O)[CH2:22][OH:23])[CH2:17][CH2:16]1)[CH2:13][CH3:14]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:23][CH2:22][CH:21]([C@H:18]3[CH2:17][CH2:16][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:20][CH2:19]3)[CH2:24][O:8]2)=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: CCC[C@H]1CC[C@H](C(CO)CO)CC1
Reactant: N#Cc1ccc(C=O)cc1F
Product: CCC[C@H]1CC[C@H](C2COC(c3ccc(C#N)c(F)c3)OC2)CC1

Procedure:
A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde and 4.0 g of 2-(trans-4-n-propylcyclohexyl)-propane-1,3-diol is reacted analogously to Example 5. 2-(4-Cyano-3-fluorophenyl)-5-(trans-4-n-propylcyclohexyl)-1,3-dioxane is obtained. The following compounds are prepared analogously:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[C:18]([Cl:26])[CH:17]=4)[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Cl:26])[CH:17]=4)[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)OC)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)O)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-methoxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.6 g, 33 mmol) prepared in example 92c in the mixture of tetrahydrofuran (60 mL) and methanol (30 mL) was added the solution of sodium hydroxide (1N, 30 mL). After the reaction mixture was stirred at room temperature for 2 h, the crude was concentrated. The residue was neutralized to “pH”-4 with the dilute hydrochloride solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 1.5 g, 99%).