Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C.O>ClCCl>[N+:22]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCOc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCOc1ccccc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Under a nitrogen atmosphere, 2-phenoxyethylamine (1 7.6 ml, 0.13 mol) was added dropwise to a chilled (ice bath) solution of 4-chloro-3-nitroquinoline (21.5 g, 0.1 mol), triethylamine (21.5 ml, 0.16 mol) in dichloromethane (500 ml). The reaction was maintained at ambient temperature overnight. Water was added and the phases were separated. The organic phase was dried (MgSO4), filtered, and the bulk of the solvent was removed under vacuum. Hexane was added and the solution was chilled in a refrigerator. The resulting precipitate was recovered by vacuum filtration to provide 19.1 g of 3-nitro-N-(2-phenoxyethyl)quinolin-4-amine as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5].Cl[CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.[CH2:30]([SH:34])[CH2:31][CH2:32][CH3:33]>C1COCC1.O>[CH2:30]([S:34][CH2:17][CH2:18][S:19]([OH:21])(=[O:5])=[O:20])[CH2:31][CH2:32][CH3:33].[F:1][C:2]([F:14])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCCCS
Agent: COc1ccc(C(=NO)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCSCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 40 mL of THF are dissolved 4.38 g (20.0 mmol) of 2,2,2-Trifluoro-1-(4-methoxyphenyl)-ethanone oxime and the solution is cooled in an ice-bath. To the solution are added successively 2-chloroethanesulfonyl chloride (2.3 mL, 22.0 mmol) and triethylamine (6.4 mL, 46.0 mmol), and the reaction solution is stirred at 0° C. for 1 h. Then, 1-butanethiol (2.4 mL, 22.0 mmol) and triethylamine (4.2 mL, 30.0 mmol) are added successively, and the reaction solution is stirred at room temperature for 0.5 h. After the reaction mixture is poured into water, the crude product is extracted with ethyl acetate twice, washed with water, dried over MgSO4 and concentrated. The residue is purified by column chromatography on silica gel with hexane—ethyl acetate (10:1 to 5:1) as an eluent to afford the product as yellow oil. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 0.92 (t, 3H), 1.41 (m, 2H), 1.57 (m, 2H), 2.56 (t, 2H), 2.93 (t, 2H), 3.66 (t, 2H), 3.87 (s, 3H), 7.00 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1.[C@H:19]1([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:39])[CH:35]=3)[N:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[C@H:19]1([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:39][C:1]([N:13]4[CH2:18][CH2:17][S:16][CH2:15][CH2:14]4)=[O:12])[CH:35]=3)[N:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CSCCN1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCSCC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, thiomorpholine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=405.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 36.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,6-dichlorobenzenesulfonylchloride (0.0479 g, 0.195 mmol) to obtain 4-(2,6-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ˜0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); tR=1.56 min [10-99% CH3CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)+m/z for C9H17NO3=188.1; Found 188.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at 25° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled down to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried in vacuo to afford the crude, desired (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1019: 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz); C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(F)c(CO)cc1F
Reaction time: 0.75 h

Procedure:
2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase was washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 46 mg (37% yield, 76% purity) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH3:21])=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:32][NH:33][OH:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:33]([OH:34])[CH3:32])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH3:21])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12
Temperature: 4 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(methoxymethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 332 mg 0.9467 mmol) in anhydrous DMF (8.0 mL) was added CDMT (200 mg 1.136 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.13 mL 1.136 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2.0 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (395 mg 4.734 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by recrystallisation in hot IPA (20 ml) with cooling at 4° C. overnight to give 194 mg (60%) of 1-(4-fluorobenzyl)-N-hydroxy-3-(methoxymethyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a white solid. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, APCI, +mode): RT—1.028 min, m/e=344.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ =3.26 (s, 3H), 3.34 (s, 3H), 4.57 (s, 2H), 5.54 (s, 2H), 7.14 (t, 2H), 7.36 (m, 2H), 7.87 (s, 1H), 8.02 (s, 1H), 8.92 (s, 1H). Found: C, 62.72; H, 5.20; N, 12.17%. C18H18FN3O3, requires C, 62.97; H, 5.28; N, 12.24%.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11](=O)([O-])[O-].[Na+].[Na+].[N+:17]([C:20]1[CH:21]=[C:22]2[C:27](=[O:28])OC(=O)[C:23]2=[CH:29][CH:30]=1)([O-:19])=[O:18]>O>[N+:17]([C:20]1[CH:30]=[CH:29][CH:23]=[C:22]2[C:21]=1[CH2:11][N:1]([CH:2]([CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:8]([OH:10])=[O:9])[C:27]2=[O:28])([O-:19])=[O:18]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Reaction time: 3 h

Procedure:
To a stirred solution of glutamic acid (10 mmol) and sodium carbonate (10.5 mmol) in water (50 mL) is added 4-nitrophthalic anhydride (10 mmol). The resulting mixture is stirred for 3 hours. The mixture is filtered. The filtrate is then acidified to pH 1 with 4 N hydrochloric acid to afford 2-(4-nitro-1-oxoisoindolin-2-yl)glutaric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[N:21]1)[CH3:19]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:22]3[N:23]=[N:24][N:20]([CH2:18][CH3:19])[N:21]=3)=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: CCn1nnc(-c2ccc(C(=O)Cl)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nnc(-c2ccc(C(=O)N[C@@H]3CCCC[C@@H]3c3ccc(OC)c(OC)c3)cc2)n1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound C2) are dissolved in 100 ml of methylene chloride and 3.0 ml of triethylamine. A solution of 3.0 g of 4-(2-ethyl-2-H-tetrazol-5-yl)benzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted, after stirring for 2 h, with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulphate and concentrated. The residue is taken up in petroleum ether (low)/ethyl acetate in the ratio 2/1, filtered off with suction and dried. 5.2 g of the title compound of m.p. 188-192° C. are obtained.
Reaction SMILES: [C:1]([N:6]=[C:7](OCC)[CH2:8][CH2:9][CH2:10][CH3:11])(OCC)=[O:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>>[CH2:8]([C:7]1[NH:6][C:1](=[O:2])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:25])([F:26])[F:15])[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=NC(=O)OCC)OCC
Reactant: NNc1ccccc1C(F)(F)F
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Yield: 66 %

Procedure:
Ethyl-N-carbethoxyvalerimidate (from Example 3, Step B) was reacted with 2-(trifluoromethyl)phenylhydrazine according to the procedure of Example 3, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) gave a 66% yield of the title compound as white crystals, mp 124°-126° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 286 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 37 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess N-methylpiperazine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.085 g, 37%) as a white solid. MS (ISP) 552 8 [(M+H)+]; mp 180° C. (dec.).
Reaction SMILES: [N+](C1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:12]3)([O-])=O.C=O.Cl.[CH3:19][N:20]([CH3:22])[CH3:21]>[Ni].C(O)C>[CH3:19][N:20]([CH3:22])[C:21]1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:12][CH2:13]3
Reactant: O=C1c2cccc([N+](=O)[O-])c2OC12CC2
Reactant: CN(C)C
Agent: [Ni]
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)c1cccc2c1OC1(CC1)C2=O
Reaction time: 3 h
Yield: 138 %

Procedure:
A mixture of 7-nitrospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (10 g.), formalin (37% formaldehyde, 10 ml.), trimethylamine hydrochloride (2 g.) and Raney nickel (10 g.) in ethanol (500 ml.) was subjected to reduction at 49°-56° C. for 3 hours under hydrogen pressure of 50 kg/cm2. After removing the catalyst by filtration, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and the solution was washed with 5% aqueous solution of sodium hydrogen carbonate then with water, followed by drying. The solvent was evaporated off and the residue was subjected to column-chromatography on silica-gel. The first fraction eluted with hexane-ethyl acetate (9:1) was recrystallized from ethanol to give 7-dimethylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (5.87 g.) as yellow needles melting at 68.3° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5](=[O:6])[CH2:7][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([OH:29])[CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([Cl:17])[CH:19]=1
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Reactant: COC(=O)C(Cl)C(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC)c(Cl)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0° C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil) in THF (30 ml). After 15 min the solution was cooled to −40° C. and n-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.5 g, 5.6 mmol, prepared from Heck route) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Cl)[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].[Cl:30]C1C=CC=CC=1C=O.C(OC(=O)CC(C(OCC)=O)=O)C.C(OC(=O)/C=C(\N)/C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:30])[CH:13]=2)[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)C1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OCC)=C(C)N1
Agent: CCOC(=O)/C=C(/C)N
Agent: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(Cl)c2)C(C(=O)OCC)=C(C)N1

Procedure:
In the same way, 2-methyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5,6-tricarboxylic acid triethyl ester is prepared from 14 g of 2-chlorobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 60 ccs of ethanol.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=1.C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)c(O)cc1OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(C)=O)c(O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 13.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19 mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g, 19 mmol), NaHCO3 (1.8 g, 20 mmol) and acetronitrile (120 mL) was stirred and refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to a dark oil. The oil was taken up in anhydrous ether and ethereal HCl was added to precipitate 8.7 g of an off-white hydrochloride salt. A 2.0 g sample of the salt was converted to its free base and chromatographed by preparative HPLC (silica gel with 5% MeOH/CH2Cl2 as eluent). Concentration of the desired fractions gave 1.1 g of a white solid, which was recrystallized from EtOH to yield 0.85 g of the product, m.p. 122°-124° C.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([CH3:35])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]([CH3:35])[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(CCN1CCC(O)CC1)Oc1ccccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)Oc1ccccc1[N+](=O)[O-]

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine.