Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[CH3:2].[N:22]1([CH2:28][CH2:29][CH2:30][Cl:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[ClH:31].[ClH:31].[N:22]1([CH2:28][CH2:29][CH2:30][O:20][C:19]([C:7]2[CH:6]=[CH:5][C:4]3[N:3]([CH2:1][CH3:2])[C:15]4[C:10]([C:9]=3[CH:8]=2)=[CH:11][C:12]([C:16]([O:18][CH2:30][CH2:29][CH2:28][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:17])=[CH:13][CH:14]=4)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCCC1
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(C)O
Product: CCn1c2ccc(C(=O)OCCCN3CCCCC3)cc2c2cc(C(=O)OCCCN3CCCCC3)ccc21
Product: Cl

Procedure:
To 250 ml of isopropyl alcohol is added one equivalent of 9-ethylcarbazole-3,6-dicarboxylic acid, 2 equivalents of 3-piperidinopropylchloride, and a catalytic amount of benzyltrimethylammonium chloride. The mixture is heated to reflux for 2 hours. Upon cooling a solid forms which is collected, washed with ether, dried and dissolved in water. The aqueous solution is made basic with saturated sodium bicarbonate, and the product is extracted with ether. The ether solution is washed with water, dried, and acidified with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give bis(3-piperidinopropyl)-9-ethylcarbazole-3,6-dicarboxylate dihydrochloride.
Reaction SMILES: NC([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1)=O.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[OH-].[Na+].C[N:60](C)C=O>N1C=CC=CC=1>[NH2:60][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:21][CH2:22]3)=[O:19])=[C:13]([F:33])[C:12]=2[F:34])[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Reactant: CN(C)C=O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2F)ccn1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,3-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (295 mg) was dissolved in N,N-dimethylformamide (4 ml). Water (0.0563 ml), [bis(trifluoroacetoxy)iodo]benzene (536 mg) and pyridine (0.303 ml) were added thereto at room temperature in this order, followed by stirring for 25 hr and 10 min. The reaction was stopped by adding a 1N aqueous solution of sodium hydroxide (9 ml), and the reaction mixture was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was washed with water (30 ml) in twice, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:3), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a pale yellow solid (168.4 mg, 61%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:11]1Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Hg](C#N)[C:36]#[N:37]>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[C:36]#[N:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Hg]C#N
Reactant: O=C(OC[C@H]1OC(Br)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#C[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 524.3 %

Procedure:
A suspension of 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (I) (1.98 mol) and dry Hg(CN)2 (750 g; 2.97 mol) (mercury (II) cyanide was dried in vacuo at 140° for 12 hours) in dry CH2Cl2 (10.0 L), was stirred for 16 h at room temperature protected from moisture. The insolubles were collected and discarded. The filtrate was washed in succession with 5% aqueous KI (2×6.0 L) and water (2×6.0 L), dried over Na2SO4 (1.0 kg) and charcoal (35 g), then concentrated in vacuo to an oil. This material was diluted with EtOH (2.0 L) then concentrated in vacuo to an oil. The oil was slowly added to petroleum ether (bp, 63°-75°)-EtOH (21.0 L; 7.0 L) with vigorous stirring. The oil slowly solidified, and after 3 h of stirring, the resulting solid was collected and washed with petroleum ether (bp, 63°-75°) (1.0 L). This material was washed by resuspension (17 h) in EtOH (1.50 L). The off-white colored solid was collected, washed with petroleum ether (bp, 63°-75°) (2×500 ml) then dried to constant weight in vacuo to give 598 g (64°) of product; mp, 77.5°-79°. Additional reactions were carried out to give a total of 4894 g of product suitable for further transformation.
Reaction SMILES: Br[CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH2:30])([CH3:20])([CH3:19])[CH3:18].C(OCC)C>C1(C)C=CC=CC=1>[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH:30][CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@H](NC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Di-t-butyl bromomalonate (15.9 g.) was added to a stirred solution of L-alanyl-L-proline t-butyl ester (26 g.) in toluene (30 ml.) which was cooled to 0° C., and the mixture was allowed to warm up to laboratory temperature during 2 hours and was stirred at that temperature for 14 hours. Diethyl ether (300 ml.) was added, the mixture was filtered to remove unreacted L-alanyl-L-proline t-butyl ester as the hydrobromide salt thereof, andthe filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (400 ml.) and the mixture was washed successively twice with aqueous 0.5N-citric acid solution (100 ml. each time), once with water (100 ml.) and once with saturated aqueous sodium chloride solution (100 ml.), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of dichloromethane and ethyl acetate as eluant, and there was thus obtained as an oil N-[di-t-butoxycarbonylmethyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a colorless gum. Recrystallization from methanol gave the product (300 mg), mp 158-159° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 78.4 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.73 g) in anhydrous acetonitrile (7 ml), N,N-diisopropylethylamine (0.22 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.57 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=7/3), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.78 g) was obtained.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[CH3:36][S:33]([CH2:32][C:31]1[N:37]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 50 mg (48% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH2:12]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1cccc(Nc2ccc3c(c2)CC(=O)N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 5-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (20 mg, 0.083 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (31 mg, 0.1 mmol), N,N-diisopropylethylamine (54 mg, 0.42 mmol), EDCI (32 mg, 0.17 mmol) and HOBt (11 mg, 0.083 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][OH:15])[C:9]=1[CH3:16].Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)[N:23]=1.O>O1CCCC1>[CH3:16][C:9]1[C:10]([CH2:14][OH:15])=[N:11][CH:12]=[CH:13][C:8]=1[S:7][CH2:6][CH2:5][CH2:4][S:3][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)[N:23]=1
Reactant: Cc1c(SCCCS)ccnc1CO
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.9 g of sodium hydride (80% strength suspension) are suspended in 350 ml of tetrahydrofuran under a nitrogen atmosphere. A solution of 73 g (0.31 mol) of [4-(3-mercaptopropylsulfanyl)-3-methylpyridin-2-yl]methanol in tetrahydrofuran (350 ml) is then added dropwise with vigorous stirring at room temperature during the course of 2 h. The suspension is then stirred at room temperature for a further 2.5 h. A solution of 51.6 g (0.26 mol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine in tetrahydrofuran (1000 ml) is then added dropwise during the course of 3.5 h and the mixture is stirred at room temperature for a further 18 h. The mixture is then cooled to 0° C. and cautiously treated with water (500 ml) with vigorous stirring. The organic solvent is then distilled off. The aqueous residue is diluted with a further 500 ml of water and cooled to 0° C. The beige precipitate is filtered off, washed with water and dried in a high vacuum at 40° C. The crude product is then dissolved in hot toluene (1.2 l) and clarified with activated carbon (25 g) and kieselguhr (15 g). After filtration at boiling heat, the solution is concentrated to 750 ml and treated with diisopropyl ether (1.2 l). For complete precipitation, the suspension is cooled to 0° C. with stirring. The precipitate is filtered off and then dried in vacuo at 40° C. For further purification, the product is suspended in hot methanol (1.2 l) and treated again with diisopropyl ether (500 ml) after cooling to room temperature. After filtration and drying in vacuo, 82 g (80%) of the title compound of m.p. 127-129° C. are isolated.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
0.574 g (0.003 mol) of 1-benzyl-4-hydroxypiperidine dissolved in 5 ml of dimethylformamide was added dropwise at 0° to a suspension of 0.14 g (0.0035 mol) of sodium hydride in 5 ml of dimethylformamide. The mixture was left to warm to room temperature and was stirred for 1.5 hrs. Then, 0.39 ml (0.0033 mol) of benzyl bromide was added dropwise. The mixture was stirred at 40° for 18 hrs. The solvent was removed, the residue was taken up in water, adjusted to pH 11 with 2N aqueous NaOH and extracted with ether. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.333 g (40%) of 1-benzyl-4-benzyloxypiperidine was obtained as a yellow oil. MS: me/e=282 (C9H24NO+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
2-Fluorophenylacetic acid (2.0 g, 13.14 mmoles) was dissolved in 20 ml dichloromethane. To this mixture, oxalylchloride (1.66 g, 13.14 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 20 ml dichloromethane. To this mixture, 4-fluoroanisole (1.10 g, 8.76 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.75 g, 13.14 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (1.17 g, 54% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.25 (s, 1H), 7.73 (dd, J=9.5, 3.2 Hz, 1H), 7.43 (dt, J=8.8, 3.1 Hz, 1H), 7.35 (d, J=6.2 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (dd, J=9.1, 4.6 Hz, 1H), 4.50 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1>>[ClH:1].[CH3:25][C:24]1[CH:23]=[C:22]([OH:26])[C:21]([CH3:27])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c(C)cc1O
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-amino-2,5-dimethylphenol (40 mg, 0.290 mmol) similar to Example 117 and isolated as an orange solid (35 mg, 47%). 1H NMR (CDCl3): 8.79–8.77 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.14 (bs, 1H), 7.91–7.86 (m, 1H), 7.46–7.42 (m, 1H), 7.09 (bs, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: FC1CCCNC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)C1
Yield: 97 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3-fluoropiperidine hydrochloride gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (0.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 4.88-4.71 (m, 1H), 3.79 (s, 3H), 3.47 (ddd, J=29.8, 12.8, 2.1 Hz, 1H), 3.32-3.15 (m, 2H), 3.07-2.99 (m, 1H), 2.11-1.99 (m, 2H), 1.95-1.76 (m, 1H), 1.74-1.62 (m, 1H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][C:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C(O)=O)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][CH:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Solvent: CS(C)=O
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cc(C(C)(C)C)c1
Yield: 93.6 %

Procedure:
A solution of 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenylmethyl)thio]propyl]-malonic acid XI (6.71 g, 11 mmol) in DMSO (10 ml) was stirred at 130° C. for 1.5 hours. The solvent was removed under reduced pressure and water was added to the residual oil. The precipitate was filtered off, washed with water, and dried under vacuum to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-5-[(triphenylmethyl)thio]-pentanoic acid XII (5.86 g, 10.3 mmol, 94%) as a white solid: 1H NMR (CD3OD) δ1.3 (s, 9H), 1.3-1.5 (m, 4H), 2.1 (m, 2H), 2.4 (m, 1H), 2.7 (m, 1H), 2.8 (m, 1H), 7.1-7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) δ27.4, 31.7 (3C), 32.3, 32.7, 35.6, 39.2, 48.4, 67.7, 125.7, 127.7, 128.6, 128.9, 130.8, 131.6, 132.0, 140.8, 146.3, 152.7, 170.3, 178.8.
Reaction SMILES: [ClH:1].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>N1C=CC=CC=1>[CH2:2]([Cl:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Cl
Reactant: CCCCCCCCO
Solvent: c1ccncc1
Product: CCCCCCCCCl

Procedure:
In JP 74/034 646, for example, n-octyl alcohol is reacted with HCl gas at 130° C., with pyridine as a catalyst, to form n-octyl chloride. The product is distilled off at reduced pressure. The yield here is only 93.6%, based on the alcohol used.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-:11].[Na+]>CCOC(C)=O>[C:5]([OH:7])(=[O:6])[C@@H:4]([C:3]1[CH:10]=[CH:5][CH:4]=[CH:3][CH:10]=1)[OH:11].[NH2:2][C@H:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](C)N
Product: O=C(O)[C@H](O)c1ccccc1
Yield: 51 %

Procedure:
A solution of ethyl 3-aminobutyrate hydrochloride (4.5 g, 26.8 mmol) in 27 mL of 1N NaOH was extracted 2X with EtOAc. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure. Recrystallization of the residue 3X from EtOAc afforded 1.93 g (51%) of product as a single chiral diastereomer as determined by NMR spectroscopy (m.p. 125°-125° C.). 1H-NMR (300 MHz, CDCl3) δ 1.00 (d, J=7Hz, 3H), 1.27 (t, J=7Hz, 3H), 2.23-2.45 (m, 2H), 3.13 (m, 1H), 4.13 (q, J=7Hz, 2H), 4.85 (s, 1H), 7.17-7.33 (m, 3H), 7.41 (d, J=8Hz, 2H).