Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2[C:37]3[C:32](=[C:33]([F:39])[CH:34]=[CH:35][C:36]=3[F:38])[O:31][CH2:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:6]([O:5][CH2:4][CH2:3][CH2:2][N:13]([CH:29]1[CH:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[C:37]2[C:32](=[C:33]([F:39])[CH:34]=[CH:35][C:36]=2[F:38])[O:31][CH2:30]1)[CH2:14][CH2:15][CH2:16][OH:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Reactant: NCCCO
Reactant: BrCCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1N(CCCO)CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl 3-bromopropyl ether (7.8475 g, 34.27 mmol) was dissolved in 50 ml of THF then 3-aminopropanol (2.56 g, 34.13 mmol) was added the reaction was stirred at room temperature for three days. The reaction was quenched with 100 ml of Sat. potassium carbonate solution and the solution washed with ethyl acetate. The organic layer washed with Sat. potassium carbonate solution (2×100 mL) then dried over sodium sulfate and concentrated. This amine solution was used without any further purification. The amine solution (3.91 g, 17.5 mmol) was dissolved in 100 ml of THF. 4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (2.0486 g, 5.97 mmol) was added and the reaction was stirred at room temperature overnight. Triethylamine (3 ml) was added and the reaction was stirred at room temperature for 2 h. Then additional amine solution (2.85 g, 12.8 mmol) was added and the reaction was stirred overnight at room temperature then warmed to reflux and stirred overnight. The reaction was quenched with water (100 ml) and washed with ethyl acetate (100 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified by column using EtOAc/Hex. as the eluent (gradient from 0/100 to 100/0 in 45 minutes). Yield: 570 mg, 17%. 1H NMR (CDCl3 400 MHz) δ7.64-7.59 (m, 2H), 7.45-7.40 (m, 2H), 7.36-7.25 (m, 5H), 7.00 (td, J=9.5, 5.1 Hz, 1H), 6.42 (td, J=8.8, 3.7 Hz, 1H), 4.74 (dd, J=12.4, 5.1 Hz, 1H), 4.65 (s, 1H), 4.42 (s, 2H), 4.32-4.26 (m, 1H), 4.06-4.01 (m, 1H), 3.59 (t, J=5.4 Hz, 2H), 3.41 (t, J=5.9 Hz, 2H), 2.87 (bs, 1H), 2.71-2.53 (m, 3H), 2.50-2.42 (m, 1H), 1.74-1.62 (m, 3H), 1.60-1.50 (m, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][O:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]([OH:14])[CH2:15][NH:4][CH2:3][CH2:1][OH:2])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: NCCO
Reactant: Clc1ccc([C@@H]2CO2)cc1Cl
Solvent: CC(C)O
Product: OCCNC[C@H](O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
In a 3 neck flask equipped with a mechanical stirrer, thermocouple and addition funnel in an ambient temperature water bath was added ethanolamine (330 mL, 5.47 mol). (R)-2-(3,4-dichlorophenyl)oxirane (184 g, 976 mmol) in isopropanol (75 mL) was added dropwise over 1 h. Reaction temperature stayed <30° C. during addition. The reaction mixture was stirred at ambient temperature for 14 h, diluted with 2000 mL of ice water and extracted three times with 1000 mL of ethyl acetate. The combined organic phases were dried over MgSO4, filtered over Celite and concentrated in vacuo affording (1R)-1-(3,4-dichlorophenyl)-2-(2-hydroxyethylamino)-ethanol (244 g, 100%) as a white semi-solid. 1H-NMR (400 MHz, CDCl3) δ 7.58-7.54 (m, 2H), 7.35-7.32 (m, 1H), 5.51 (s, 1H), 4.64 (dd, J=5.0, 7.2 Hz, 1H), 4.49 (s, 1H), 3.43 (dd, J=5.0, 10.4 Hz, 2H), 2.69-2.50 (m, 4H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=250.3; tR=0.84 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:10][CH2:11][S:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1.[OH:21][CH:22]([C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][CH:36]=1)[CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[C:31]([O:33][CH3:34])=[O:32]>C(#N)C.CO>[F:20][C:15]1[CH:14]=[C:13]([S:12][CH2:11][CH2:10][N:28]2[CH2:29][CH2:30][C@@H:25]([CH2:24][CH2:23][CH:22]([OH:21])[C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=4)[N:38]=[CH:37][CH:36]=3)[C@@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27]2)[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Fc1cc(F)cc(SCCBr)c1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Yield: 44.3 %

Procedure:
0.332 g of potassium carbonate, then 0.4 g of potassium iodide and, finally, 0.675 g of 1-[(2-bromoethyl)thio]-3,5-difluorobenzene, dissolved beforehand in 5 cm3 of acetonitrile, were added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 1 cm3 of methanol. The mixture was heated for 3 hours at a temperature in the region of 80° C. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and the cake was washed with 2 times 5 cm3 of acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 18 to 21 were combined and then evaporated as above. 0.47 g of methyl (3R,4R)-1-[2-(3,5-difluorophenylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate was obtained in the form of a viscous oil with an orange-yellow color.
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].[OH:26]O>N>[C@@H:8]1([N:5]2[CH:6]=[N:7][C:3]([C:1]([NH2:2])=[O:26])=[N:4]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OO
Agent: N
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 6 h
Yield: 51.2 %

Procedure:
A mixture of 3-cyano-1-(2,3,5 -tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazole (705 mg., 2.0 mmole), 28% aqueous ammonia (20 ml.) and 30% hydrogen peroxide (3.0 ml.) was stirred at 25° for 6 hrs. An additional 3.0 ml. portion of 30% hydrogen peroxide was then added and stirring at 25° was continued for 12 hrs. The excess hydrogen peroxide was destroyed by addition of platinum black, the solution was filtered, the filtrate was evaporated to dryness. The residue was dissolved in methanol and silic gel (5.0 g.) was added to the solution. The solvent was removed and the silica gel mixture was applied to a silica gel column. Elution with ethyl acetate-methanol (1:1) provided 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (250 mg., 51.2%).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][C:9]([C@H:11]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[C:13](=[O:26])[C@H:12]1[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])=[O:10].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH3:7][O:8][C:9]([C@@H:11]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[C:13](=[O:26])[C@H:12]1[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])=[O:10]
Reactant: COC(=O)[C@@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
To 200 ml of benzene are added 8.5 g of cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester and 3.1 g of 1,8-diazabicyclo[5,4,0]-7-undecene, and the mixture is heated under reflux for 72 hours. To the reaction mixture, after cooling, is added 100 ml of ethyl acetate, followed by washing with 100 ml and 50 ml of 1N--HCl, and 100 ml of water in this order. To the resulting mixture is added 100 ml of chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the residue is added 50 ml of ethyl acetate. The resulting insolubles are collected by filtration, and washed with 30 ml of ethyl acetate to yield 6.4 g of crude product, which is recrystallized from 220 ml of ethyl acetate to yield trans-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[NH2:6].[CH3:14][C:15]1([CH3:26])[O:20][C:19](=[O:21])[C:18](=[CH:22]OC)[C:17](=[O:25])[O:16]1>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[NH:6][CH:22]=[C:18]1[C:17](=[O:25])[O:16][C:15]([CH3:14])([CH3:26])[O:20][C:19]1=[O:21]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 50 °C
Yield: 96.4 %

Procedure:
3-Methoxy-4-methoxycarbonylaniline (14.15 g, 78 mmol) was suspended in isopropanol and heated at 50° C. 2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (14.8 g, 80 mmol), (Montatsh. Chem. 1967, 98, 564), was then added in portions over 10 minutes and the mixture was heated at reflux for 30 minutes. The mixture was left to cool to ambient temperature overnight. The precipitate formed was collected by filtration, washed with isopropanol and dried under vacuum to give 5-((3-methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.2 g, 96%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH:6][C:19](=[O:20])[C@@H:18]([CH2:21][OH:22])[NH:17][C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16]
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CS)NC(=O)[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
L-Cysteine methyl ester hydrochloride was acylated with N-(tert-butoxycarbonyl)-D-serine by using in an analogous manner the procedure described in Example 1(e) to yield N-[N-(tert-butoxycarbonyl)-D-seryl]-L-cysteine methyl ester as white crystals of m.p. 105°-106° C.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:21]3)[CH:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)cc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 0.223 g (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-2-pyrimidinyl]-1H-benzimidazole (WO 2008/032064) and 0.345 g (2.5 mmol) of powdered K2CO3 in 20 mL CH2Cl2 was cooled to 0° C., and 0.086 g (0.75 mmol) of methanesulfonyl chloride was added. The reaction mixture was allowed to warm to room temperature, and after stirring overnight water was added. The organic layer was separated, washed successively with aqueous acetic acid and aq. ammonia, and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (4:1) gave 0.176 g (67% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole: mp (MeOH) 273-274° C.; 1H NMR (CDCl3) δ7.74 (dd, J=8.4, 0.6 Hz, 1H), 7.38 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.79 (t, J=7.6 Hz, 1H), 5.54 (s, 1H), 4.05 (s, 3H), 3.83-3.79 (m, 8H), 3.64 (m, 4H), 3.35 (m, 4H), 2.82 (s, 3H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.7; H, 5.3; N, 18.75%.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH2:11]([N:13]1[C:25]2[C:24]([CH2:26][OH:27])=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:13]1[C:25]2[C:24]([CH:26]=[O:27])=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]
Reactant: CCn1c2ccccc2c2cccc(CO)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c2ccccc2c2cccc(C=O)c21
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A 50-mL round-bottom flask was placed a solution of methyl 9-ethyl-9H-carbazole-1-carboxylate (1.3 g, 5.14 mmol, 1.00 equiv) in THF (50 mL). To the mixture was added LiAlH4 (840 mg, 22.11 mmol, 4.00 equiv) in several batches at 0° C. and allowed to stir at this temperature 30 minutes. Then, the reaction was quenched with aqueous NaOH (2M, 12 mL). The mixture was then extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording (9-ethyl-9H-carbazol-1-yl)methanol as white solid (1 g, (86%). Meanwhile, a 250-mL 3-necked round-bottom was charged with a solution of (COCl)2 (840 mg, 6.67 mmol, 1.50 equiv) in DCM (40 mL). To this was added DMSO (1 g, 12.80 mmol, 3.00 equiv)-78° C. and allowed to stir for 30 min at this temperature. To this solution was added a solution of (9-ethyl-9H-carbazol-1-yl)methanol (1 g, 4.44 mmol, 1.00 equiv) in DCM (5 mL) at −78° C. The resulting solution was stirred at −78° C. for 5 hours. Then, triethylamine (TEA) (10 mL) was added and allowed to stir an additional hour at −78° C. Upon completion, the reaction was quenched with water and extracted with DCM (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording 9-ethyl-9H-carbazole-1-carbaldehyde as light yellow solid (0.9 g, 90.8%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: Nc1cc(F)ccc1N1CCCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(F)ccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.6 %

Procedure:
Isonicotinoyl chloride hydrochloride (454 mg, 2.55 mmol, commercially available product) and triethylamine (385 μl, 3.83 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 5-fluoro-2-(1-piperidinyl)aniline (248 mg, 1.27 mmol), obtained as described in Referential Example 17-2. The resulting mixture was warmed to room temperature and stirred for 17 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane/ethyl acetate=1.5/1). Thus, N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0348) (257 mg, 67.6%) was yielded as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1cc(F)ccc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A suspension of 2,5-difluorobenzaldehyde (291.5 mg, 2.05 mmol), 2-methyl-2-nitropropane (427.3 mg, 4.14 mmol) and zinc (407.3 mg, 6.23 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature, stirred for 2 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (393 mg; 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15](C4C=CC=C(Cl)C=4)[CH2:14][C:13](=[O:23])[N:12](CC(F)=O)[CH:11]3C3C=C(F)C=CC=3C)[C:5]2=[CH:4][CH:3]=1.CN1CCC(N)CC1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[NH:12]1[C:13](=[O:23])[CH2:14][CH2:15][C:10]2([C:5]3[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:36])[CH2:11]1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Agent: CN1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CCC2(CN1)C(=O)Nc1ccccc12
Yield: 105.3 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 1-methyl-piperidin-4-ylamine (0.1 g, 0.88 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.041 g, 36.7%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:3]=1[N+:21]([O-])=O.C(N(CC)CC)C.C(O)=O>C(#N)C.[Pd]>[NH2:21][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a stirred solution of 2-{4-[(4-methyl-3,5-dinitro-2-pyridinyl)amino}phenyl]ethanol (step 1, 4.2 g, 13.1 mmol), triethylamine (9.6 mL, 68.9 mmol), 10% Pd—C (624 mg, 0.59 mmol) in acetonitrile (14 mL) was added dropwise a solution of formic acid (2.3 mL, 61.0 mmol) in acetonitrile (6.2 ml,) at 0° C. over a period of 30 min. After stirring at room temperature for 5 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL). The solution was washed with 1N aqueous NaOH (50 mL), brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) afforded 2.2 g (60%) of the title compound as red crystals: 1H-NMR (CDCl3) δ 8.42 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 6.7 (1H, br s), 3.85 (2H, t, J=6.6 Hz), 2.47 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH:25]([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([CH:25]([F:26])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CN2CCCNCC2)cc1
Product: FC(F)c1nnc2ccc(N3CCCN(Cc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzyl-1,4-diazepane and 6-chloro-3-difluoromethyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 1 to give 6-(4-benzyl-1,4-diazepan-1-yl)-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O.O.Cl>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CCC/C=C/C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of t-BuOK (1 g, 8.9 mmol) in DMSO (15 mL) at rt, was added compound cyanoacetamide (0.824 g, 9.8 mmol) and (E)-hept-3-en-2-one (1 g, 8.91 mmol). Reaction mixture was stirred for 30 min at rt. Additional t-BuOK (3 g, 26.7 mmol) was added and reaction was stirred at rt in presence of air. On completion, it was diluted with H2O and slowly by 4N HCl. Precipitated solid was filtered, washed with water and dried. Crude product was triturated with ether to afford the title compound (0.5 g, 33%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=O)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:7]([C:6]3[CH:5]=[C:4]([CH:23]=[CH:22][CH:21]=3)[C:3]([OH:2])=[O:24])=[N:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A solution of 1.7 g (5.5 mmol) N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester from Preparation 3 in a 3:1:1 mixture of THF/methanol/water was added 10 mL (10 mmol) 1N NaOH. The mixture was stirred 4 hours at room temperature before concentrating on a rotary evaporator. The residue was treated with 6M HCl then filtered, washed with water (1×) and dried in a vacuum oven overnight at 70° C. to provide 1.5 g (91%) desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1[CH2:20][CH:19]([CH2:21]Br)[O:18][CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][N:10]([CH2:21][CH:19]3[CH2:20][CH2:15][CH2:16][CH2:17][O:18]3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Reactant: BrCC1CCCCO1
Product: O=c1c2cc([N+](=O)[O-])ccc2cnn1CC1CCCCO1

Procedure:
Step (b) of Example 125 was repeated, except that the compound prepared in step (b) of Example 137 and tetrahydro-2H-pyran-2-methyl bromide were used as the starting compounds. Thus, 7-nitro-2-(tetrahydropyran-2-yl)methyl-2H-phthalazin-1-one was obtained.