Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>C1COCC1>[C:5]1([C:14]2([OH:22])[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF (270 mL) was stirred at room temperature for 2 hours under nitrogen. Phenylmagnesium bromide (46.5 mL of 3.0M solution in diethyl ether, 139.5 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 hours, the mixture was allowed to warm to room temperature and kept at ambient temperature for 12 h. It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Kugelrohr distillation (150° C./0.25 mm Hg yielded 18.58 g (82%) of 2-phenyl-2-indanol in solid form (mp 54°C.). 1H-N.M.R. (CDCl3) d 2.24 (br s, 1H), d 3.20 (d, J=16.2 Hz, 2H), d 3.43 (d, J=16.2 Hz, 2H), d 7.18-7.40 (m, 7H), d 7.51(br d, J=7.1 Hz, 2H)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[BH4-].[Na+]>>[CH3:3][CH:4]([CH3:8])[CH2:5][CH2:6][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 64.3 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0252 g, 0.0847 mmol), isovaleraldeldyde (0.0165 mL, 0.154 mmol), and sodium borohydride (0.0082 g, 0.217 mmol) provide 0.0100 g (32%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C22H30N3O2 368.2338, found 368.2355; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.36 (m, 2H), 7.17-7.12 (m, 2H), 7.03 (d, 1H, J=8.8 Hz), 3.28-3.19 (m, 2H), 2.96 (tt, 1H, J=3.4, 11.7 Hz), 2.71-2.63 (m, 2H), 2.43-2.28 (m, 2H), 2.06-1.92 (m, 2H), 1.84 (qt, 1H, J=3.9, 13.2 Hz), 1.71-1.51 (m, 4H), 0.99 (d, 6H, J=6.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:38][CH3:39]>>[CH2:38]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:39]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)c2)o1
Reactant: CCI
Product: CCN(Cc1ccc(Oc2ccccc2)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 776,(1H, s), 7.55-7.48,(5H, m), 7.40-7.36,(3H, m), 7.24,(1H, b), 7.13,(1H, t), 7.00,(4H, m), 4.694.51,(2H, m), 3.39-3.22,(2H, m), 2.55,(3H, s), 2.31,(3H, s), 1.08,(3H, b). LCMS; retention time 3.93 min, MH+ 504.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:34]([C:27]1[N:26]=[C:25]([CH2:24][CH2:23][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12)=[O:35]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1nc(CCN2CCOCC2)n2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of n-methylaniline (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (105 mg, 64%). 1H NMR (DMSO-d6) δ 8.23 (1H), 8.00 (1H), 7.30 (2H), 7.19 (3H), 7.05 (1H), 6.81 (1H), 3.52 (4H), 3.48 (3H), 2.95 (2H), 2.45 (2H), 2.33 (4H); m/z (M+H)=365.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]3[CH2:24][CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]3=[O:21])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-((4-chlorophenyl)(phenyl)methyl)piperazine (0.29 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.21-7.47 (m, 19H), 4.37 (s, 1H), 4.14-4.15 (br s, 2H), 3.40-3.48 (m, 4H), 3.35 (t, J=6.7 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.22-2.28 (m, 4H); MS (DCI+) m/z 564 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O:26][CH2:27][CH3:28])(=[O:25])[C:22]([CH3:24])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:21]([O:26][CH2:27][CH3:28])=[O:25])[CH3:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(=O)C(C)=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: CCOC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the same manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and ethyl pyruvate gives 7-chloro-2-[[1-(ethoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oily product. NMR (CDCl3) δ1.20 (t, 3, CH2CH3), 2.25 (2, 3, CH3), 4.23 (q. 2, CH2CH3), 4.50 (broad s, 2, 3-CH2), between 6.95 and 7.6 (m, 9, NH and arom H's).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:27]1([CH2:33][C:34](OC)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH2:15][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
4-Acetyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) was dissolved in anhydrous THF (6 mL) and cooled to 0° C. To this was added a solution of lithium hexamethyldisilazane (1.0M in hexanes; 4.84 mL). This was left to stir at 0° C. for 10 minutes before addition of a THF solution (2 mL) of methyl phenylacetate (0.661 g). The reaction mixture was left to stir for a total of 4 hours before being quenched by the addition of 1M aqueous HCl (50 mL). The reaction mixture was extracted with Et2O (3×75 mL) then the combined organic extracts were dried over magnesium sulfate and filtered. Evaporation of solvents under reduced pressure gave a thick yellow oil which was purified by column chromatography on silica gel, using an increasingly polar gradient of Et2O in DCM as eluent. Evaporation of solvents under reduced pressure gave the desired 4-(3-oxo-4-phenyl-butyryl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.225 g); NMR (CDCl3): 1.45 (s, 9H), 1.54 (m, 2H), 1.76 (d, 2H), 2.28 (tt, 1H), 2.71 (br t, 2H), 3.61 (s, 2H), 4.12 (br d, 2H), 5.44 (s, 1H), 7.12-7.36 (m, 5H), 15.30 (s, 1H); MS: 344 (M−1−).
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(2-tolyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave the crude product which was purified by column chromatography giving the pure product (gum). This gum was dissolved in 5 ml of NH4OH, concentrated and dried under high vacuum to get the ammonium salt of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide in 67% yield, m.p. 180-184° C. (NH3+ salt).
Reaction SMILES: C([N:3]1[N:14]=[CH:13][C:12]2[C:11]3[N:10](CCCCO)[N:9]=[C:8]4[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:6]([C:7]=34)=[N:5][C:4]1=2)C.ClC1C2C=NN(CC)C=2N=C2CCC3C=CC=CC=3C(=O)C=12.NN.CNN>>[N:9]1[NH:10][C:11]2[C:12]3[CH:13]=[N:14][NH:3][C:4]=3[N:5]=[C:6]3[CH2:23][CH2:22][C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[C:8]=1[C:7]=23
Reactant: CCn1ncc2c1nc1c3c(nn(CCCCO)c32)-c2ccccc2CC1
Agent: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Agent: CNN
Agent: NN
Product: c1ccc2c(c1)CCc1nc3[nH]ncc3c3[nH]nc-2c13

Procedure:
By substituting the 4-chloro-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one (obtained in Example 6) for the 4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one in the procedure of Example 2 and also substituting hydrazine for the methylhydrazine, 2,5,7,8-tetrahydro-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indaceneis obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH:5]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:23]/[CH:24]=[O:25])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(-n2cncn2)c(F)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2cncn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (prepared as described in Reference Example 7) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 218 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[N+:25]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[NH2:25]
Reactant: CCC(Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1N)C1CC1
Yield: 94 %

Procedure:
[4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.55 g, 1.38 mmol) and Na2S2O4 (1.93 g, 11.1 mmol) were treated substantially as in Part E of Example 9 to yield 94% of 4-(2-chloro-4-trifluoromethyl-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 369.8 [(M+H)+, 100].
Reaction SMILES: [H-].[Na+].CS([O-])(=O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]3[CH2:26][O:25]3)[C:18](=[O:27])[CH:17]2[CH3:28])[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:36]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][C@H:39]2[OH:44])[CH2:37]1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.CCOC(C)=O.CO>[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]([OH:25])[CH2:26][N:41]3[CH2:42][CH2:43][C:38]4([CH2:36][CH2:37]4)[C@H:39]([OH:44])[CH2:40]3)[C:18](=[O:27])[CH:17]2[CH3:28])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC1C(=O)N(CC[C@@H]2CO2)CCN1c1ccc(Cl)c(Cl)c1
Reactant: O[C@@H]1CNCCC12CC2
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=O)N(CC[C@@H](O)CN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
A solution of methanesulfonyl chloride (53 mg, 0.46 mmol) in DMA (0.5 mL) was added at 0° C. to a solution of 4-(3,4-dichloro-phenyl)-1-((R)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one (160 mg, 0.46 mmol) and 2,4,6-trimethylpyridine (279 mg, 2.30 mmol) in DMA (2 mL), then after 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford crude methanesulfonic acid (R)-4-[4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-2-hydroxy-butyl ester (254 mg) as a light yellow gum. This was dissolved in DMA (2 mL), cooled to 0° C., and treated with NaH (55% dispersion in mineral oil, 41 mg, 0.94 mmol). After 15 min, as the methanesulfonate intermediate had disappeared, with mass spectrometry confirming the formation of the epoxide intermediate, 4-(3,4-dichloro-phenyl)-3-methyl-1-((R)-2-oxiranyl-ethyl)-piperazin-2-one [m/e=329, (M+H)+)], cesium carbonate (184 mg, 0.56 mmol) and a solution of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 77 mg, 0.47 mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol) in DMA (1 mL) were added. The reaction mixture was heated at 80° C. for 20 h, then diluted with EtOAc/MeOH 4:1 and filtered through diatomaceous earth. The filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient) to produce the title compound (101 mg, 47%). Light yellow foam, MS: 456.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1)=[O:4].O[Li].O>CCO.CO.O.CCOC(C)=O>[O:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1COc2ncccc21
Agent: [Li]O
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)C1COc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dihydrofuro[2,3-b]pyridine-3-carboxylic acid methyl ester (21.2 mmol) in 20 mL EtOH and 15 mL MeOH was added a solution of LiOH.H2O (23.3 mmol) in 6 mL H2O. After stirring at RT for 1 h, the reaction mixture was diluted with 20 mL EtOAc and extracted twice with water. The water phase was acidified to pH 3 and extracted 5 times with EtOAc and 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as beige solid.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:9].C(O)(=[O:12])C>>[CH:4]12[CH2:7][CH2:8][CH:1]([CH2:6][CH2:5]1)[C:2](=[O:9])[C:3]2=[O:12]
Reactant: CC(=O)O
Reactant: O=C1CC2CCC1CC2
Product: O=C1C(=O)C2CCC1CC2

Procedure:
In analogy to Example 1 Step B]: from bicyclo[2.2.2]octan-2-one, 1.416 g, (synthesis: JOC., 1993, 58, 7622), SeO2 (2.218 g) in acetic acid (8 ml) on heating at 130° C. for 12 h, purification of the crude product by flash chromatography (heptane/AcOEt 100-75%), there was obtained bicyclo[2.2.2]octane-2,3-dione (0.396 g) as yellow solid. MS (ESI): 156 (M+NH4)+.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[C:8]1([S:14]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CO/C=C/C(C)=O
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)/C=C/Sc1ccccc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-4-methoxy-3-buten-2-one (purity 90%, 5.66 ml, 49.9 mmol) and thiophenol (5.13 ml, 49.9 mmol) in benzene (60 ml) was added p-toluene 25 sulfonic acid-monohydrate (30 mg, 0.16 mmol), followed by heating while stirring on an oil bath at 55° C. for 30 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with cyclohexane 3 times. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution twice and with saturated brine, followed by drying with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (190 g, n-hexane:ethyl acetate=10:1). After evaporated under a reduced pressure, the titled compound was recrystallized from n-hexane-n-nonane to obtain as a colorless crystalline.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])/[C:4]([O:6]CC)=[O:5])[CH3:2].[Li+].[OH-].Cl>C(O)C.O>[CH2:1](/[C:3](=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])/[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\CC)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.1 %

Procedure:
Ethyl-(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-hexaneoate (17) (0.040 g, 0.112 mmol) was dissolved in ethanol (4 mL) and added a solution of LiOH×H2O (0.038 g, 0.898 mmol) in water (1 mL). The mixture was stirred at ambient temperature for 15 hours, followed by five hours at 70° C. The mixture was cooled, added 1M HCl until pH=1 and diluted with water (2 mL). The mixture was extracted twice with heptane (10 mL) and the combined organic extracts were dried (Na2SO4). Purification by flash chromatography (heptane:EtOAc 95:5 then 4:1) afforded 0.028 g (76%) of the title compound as a pale yellow oil. 1H-NMR (200 MHz, CDCl3): δ 0.90-1.07 (2×t, 6H), 2.00-2.10 (m, 2H), 2.20-2.30 (m, 4H), 2.35-2.50 (q, 2H), 2.75-2.90 (m, 6H), 5.27-5.44 (m, 8H), 6.05-6.20 (m, 1H), 6.30-6.43 (m, 1H), 7.50-7.70 (m, 1H); MS (electrospray): 327.2 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[CH3:27]>CN(C)C=O>[CH2:26]([N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH3:27]
Reactant: COC(=O)C(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(C(C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Methyl 2-(2-nitrobenzenesulfonylamino)propionate (17 g; 59 mmol) is dissolved in 600 ml of dimethylformamide, and caesium carbonate (1.5 eq.; 88 mmol; 28.6 g) is then added. The reaction medium is stirred for 30 minutes at room temperature, followed by dropwise addition of ethyl bromide (4 eq.; 236 mmol; 17.6 ml) and the resulting mixture is stirred overnight at room temperature. The reaction medium is evaporated to dryness, taken up in dichloromethane, filtered and evaporated to dryness. The crude product is chromatographed on silica (eluting with dichloromethane) to give 17.1 g of the expected product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[CH:6]([C:17]([OH:19])=[O:18])[CH2:5]2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][CH:28]1[C:32]2([CH2:34][CH2:33]2)[CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[C:20]([O:24][C:25]([NH:27][CH:28]1[C:32]2([CH2:33][CH2:34]2)[CH2:31][N:30]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:15])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CNCC12CC2
Reactant: O=C(O)C1CN(C2CC2)c2cc(F)c(F)cc2C1=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CC2
Temperature: 120 °C

Procedure:
250 mg of 1-cyclopropyl-6,7-difluoro-2,3-dihydro-4-oxoquinoline-3-carboxylic acid and 250 mg of compound 11 were added to 4 ml of dimethyl sulfoxide and the mixture was heated at 120° C. for 2 hours. After cooling, the solvent was removed under reduced pressure and the residue was crystallized by the addition of ethanol. The crystals were collected by filtration. The procedure gave 7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2.[OH-].[K+].Cl.[CH:16]([N:19]([CH:23]([CH3:25])[CH3:24])[CH2:20][CH2:21]Cl)([CH3:18])[CH3:17].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:21][CH2:20][N:19]([CH:23]([CH3:25])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(CCn1ncc2cc(Br)ccc2c1=O)C(C)C
Reaction time: 18 h

Procedure:
6-Bromophthalazinone (11.2 gm, 0.05 mole) was slurried in 80 ml dimethylsulfoxide. To this was added 22 ml 45% KOH (0.25 mole). After stirring 10 minutes 16 gm 2-(diisopropylamino)ethyl chloride hydrochloride was added and the mixture stirred for 18 hours. A water bath was used to moderate the slightly exothermic reaction (temperature <=25°). Water (100 ml) was added to the reaction mixture, which was then stirred another hour.