Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>ClCCl>[C:5]1([S:11]([NH:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of BBr3 in dichloromethane (1 M) was added at −78° C. to a solution of 2.0 g of (8c) in 50 ml of dichloromethane. After stirring at room temperature for 3 hours, the solution was cooled to −78° C. and 100 ml of methanol were then added. The mixture was stirred at room temperature overnight and then concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Temperature: 25 °C

Procedure:
2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1.4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHCO3/H2O. The mixture was adsorbed onto silica gel and then chromatographed. eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z=249.8, 251.8, 253.8.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>C(O)C(F)(F)F>[CH3:14][C:12]1[C:11](=[O:15])[O:10][CH2:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Solvent: OCC(F)(F)F
Product: CC1=N[C@@H](c2ccccc2)COC1=O
Yield: 44.2 %

Procedure:
(S)-2-phenylglycinol (3.00 g, 21.9 mmol, 1.0 equiv.) (34) and ethyl pyruvate (2.67 mL, 24.1 mmol, 1 equiv.) were refluxed in trifluoroethanol (50 mL) over activated 4 molecular sieves (8.00 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo delivered the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (7:3) to furnish the title compound as a white solid (1.83 g, 44%); m.p. 70.0-71.0° C. (lit 71.0-72.0° C.); v(max)(KBr) 3007 (C—H), 1735 (C═O), 1640 (C═N) cm−1; δH (250 MHz, CDCl3) 7.45-7.32 (5H, m. Ph), 4.88-4.81 (1H, m, PhCH), 4.56 (1H, dd, J 4.49 Hz, T 9.48 Hz, 6β-H), 4.25 (1H, dd J 13.01 Hz, T 14.99 Hz, 6α-H), 2.41 (3H, s, CH3); δc (62.5 MHz, CDCl3) 160.7, 155.9, 137.2, 129.4, 128.7, 127.5, 71.9, 60.1, 22.2; m/z (CL, NH3), 189 (M+, 25%), 159 (12%), 130 (24%), 104 (100%), 90 (21%), and 78 (6%); HRMS for C11H11NO2 requires 189.0787 found 189.0782. [α]D20 +253.0 (c 0.98 CHCl3) (the enantiomer lit. [α]D20 −237.1 (c 1.11 CHCl3)).
Reaction SMILES: [NH2:1][OH:2].[OH2:3].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O)[CH2:15][CH2:14][N:13]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:8][CH:7]=1)=O>C(O)C>[OH:2]/[N:1]=[CH:4]/[C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:3])[CH2:15][CH2:14][N:13]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:10][CH:11]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(C=O)cc2)C1
Reactant: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C=N/O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydroxylamine 50% solution in water (236.5 μL of 50% w/v, 3.580 mmol) was added to a stirred solution of di tert-butyl 2-(4-formylphenyl)piperazine-1,4-dicarboxylate (699 mg, 1.790 mmol) in ethanol (20 mL) at ambient temperature. Stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a white foam. Taken onto the next step as is (725.8 mg, assume 100% yield).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH2:28])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH:28][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:14])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1N
Reactant: O=C(O)c1c[nH]c2cnccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2cnccc2c1=O
Temperature: 80 °C

Procedure:
To 4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (48 mg, 0.25 mmol), 5-tert-butyl-1H-indol-6-amine (48 mg, 0.25 mmol) in DMF (1 mL) was added HATU (106 mg, 0.28 mmol), followed by triethylamine (1064, 0.76 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was then purified by reverse phase HPLC 10-99% ACN in water to give N-(5-tert-butyl-1H-indol-6-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide. MS m/z: 361.5 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@@H:11]([CH3:29])[CH2:10]2)=[C:4]([F:30])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:40](=[O:42])[CH3:41])=[C:4]([F:30])[CH:3]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc(Cl)cc3F)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3F)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of (2S,4R)-N-(4-chloro-2-fluorophenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (60 mg, 0.14 mmol, 1 equ.) in acetyl chloride (0.5 mL) was added diisopropylethylamine (25 uL, 0.14 mmol, 1 equ.). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 99.5/0.5) to afford pure N-(4-chloro-2-fluorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (140 mg, 92%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[BH4-].[Na+].O.C(O)(=O)C>C(O)C>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: OCc1ccnc2ccccc12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 10 g of 4-quinolinecarboxaldehyde in 400 ml of absolute ethanol at room temperature is added 2.4 g of sodium borohydride. After 45 minutes, 20 ml of water is added and the reaction mixture is stirred for an additional 20 minutes. Acetic acid (20 ml) is added slowly. The reaction mixture is evaporated to a small volume and partitioned between water and methylene chloride. The organic layer is washed with saturated potassium carbonate, saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (1:10) as eluent to yield 4-hydroxymethylquinoline; Rf =0.59.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCc2sc3ncnc(Cl)c3c2CC1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNCC4)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 12A from tert-butyl 4-chloro-5,6,8,9-tetrahydro-7H-pyrimido[5′,4′:4,5]thieno[2,3-d]azepine-7-carboxylate from Example 84A (680 mg, 2.00 mmol) and 3-chloro-4-fluoroaniline (306 mg, 2.10 mmol) to yield 419 mg (60%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.ClCCl>C1COCC1>[CH2:50]([NH:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4nnc(N)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C)c3cc(-c4nnc(NCc5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-amino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 111 (0.04 g, 0.0755 mmol) in anhydrous THF (2 mL), cooled at −78° C., was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (0.083 mL) and benzyl bromide (0.001 mL dissolved in 0.1 mL THF). The reaction mixture was allowed to warm to room temperature. The reaction mixture was heated at 70° C. for 3 hours. Dichloromethane (50 mL) was added. The organic layer was washed with 1% citric acid, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 6-benzylamino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 114 (0.027 g, 0.0435 mmol).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1C=CC=CC=1.Cl>O.N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:27])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOP(=O)(Cc1ccc(C(=O)N(C)c2ccccc2)cc1)OCC
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=S)N(C)c2ccccc2)cc1)OCC
Temperature: 25 °C

Procedure:
A suspension of 0.40 g of 4-diethoxyphosphinylmethyl-N-methyl-N-phenylbenzamide and 0.56 g of phosphorus pentasulfide in a mixed solvent of 20 ml of dry benzene and 5 ml of dry pyridine was refluxed for 7 hours. After being allowed to cool to room temperature, the reaction mixture was poured into 50 ml of ice water. The water layer was made acidic with 4N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; benzene:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-methyl-N-phenylthiobenzamide. Recrystallization from benzene-n-hexane gave 0.23 g of yellow needles.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(O)CC(O)C.[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24]1(C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1]([O:10][CH2:28][CH2:29][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7]
Reactant: Cc1ccccc1
Reactant: CCCCCCO
Reactant: O=C(O)CCCCC(=O)O
Agent: [Ti+4]
Agent: CC(O)CCO
Agent: CCCC[O-]
Product: CCCCCCOC(=O)CCCCC(=O)OCCCCCC
Yield: 96.3 %

Procedure:
To a mixture of 2.1 mol (306.6 g) of adipic acid, 0.7 mol (63 g) of 1,3-butanediol and 2.1 mol (214.2 g) of n-hexanol, were added 0.8 g of titanium tetrabutoxide, 0.2 g of stannic octylate and 80 g of toluene, and dehydrating esterification was carried out. When 37.8 ml of water was distilled out, 143 g of n-hexanol was added. An ester mixture was prepared such that the theoretical amount is 1.4 mol of diester to 0.7 mol of the ester alcohol. After acid value became 0.28, was added 0.5 g of butyl titanate, and at a reaction temperature of 180° C. under atmospheric or subatmospheric pressure, ester-interchange reaction was carried out and 71.4 g (93%) of n-hexanol was recovered. After treatment for removing catalyst, alkali washing and water washing were carried out and distillation was carried out under reduced pressure to provide 263 g (119%) of dihexyl adipate, 19.8 g of intermediate fraction and 252 g of residual portion. The viscosity of a higher boiling portion was 99 c.p.s. at 21° C. The plasticizing efficiency to polyvinyl chloride was 48 and heat loss of 50 phr sheet after heating at 160° C. for 2 hours was 0.6% by weight. A 150 g of remaining liquid was subjected to fractional distillation (240°-265° C./0.5 mm) and 138 g (92%) of 1,3-butanediol bis-n-hexyl adipate was obtained. It was revealed that the major part of the product is the bis-compound. The viscosity of bis compound at 21° C. was 90 c.p.s. and plasticizing efficiency was 47.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>O.CC(C)=O>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1CCCC2
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2c(c1O)CCCC2
Temperature: 145 °C
Yield: 90 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-1-naphthol (7.42 g, 50 mmol) and potassium carbonate (25.5 g, 185 mmol) were placed in a glass tube inside a stainless steel pressure reactor. The reactor was charged with CO2 at 40 bar and then heated to 145° C. The pressure rose to 60 bar and then slowly dropped to 20 bar over the 3 day reaction period. The bomb was cooled and the solid product was taken up in water (˜500 ml) and acetone (˜500 ml). The mixture was evaporated in vacuo to remove the acetone and then washed with DCM (3×150 ml). The aqueous was acidified with 2M hydrochloric acid to give a white suspension. This was extracted with DCM (4×250 ml), which was then dried over sodium sulphate and evaporated in vacuo to give the crude product. This was recrystallised from aqueous ethanol and dried under high vacuum to provide 8.64 g (45 mmol, 90% yield) of the title compound as a pale brown powder. 1H NMR (200 MHz., d6-DMSO) δ 1.81 (4H, m); 2.67 (2H, m); 2.81 (2H, m); 6.73 (1H, d); 7.61 (1H, d); 11.78 (1H, bs). EIMS m/z=192 (M+); 174; 146
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2N=CC=[C:9]([C@H:13](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)[C:7]=2[CH:8]=1.[O:25]=[C:26]1[O:33][C:32](=[O:34])[CH:31]2[CH2:35][CH:27]1[CH2:28][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30]2.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O1CCCC1>[C:7]1([C@H:9]([NH2:29])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:8]=1.[C:39]([O:38][C:36]([N:29]1[CH2:30][C@H:31]([C:32]([O:2][CH3:1])=[O:34])[CH2:35][C@H:27]([C:26]([OH:33])=[O:25])[CH2:28]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Product: C[C@@H](N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 139.1 %

Procedure:
Under a nitrogen stream, quinidine (69.9 g, 0.215 mol) and tetrahydrofuran (200 mL) were charged and the mixture was cooled to −5 to 5° C. tert-Butyl 2,4-dioxo-3-oxa-7-azabicyclo[3,3,1]nonane-7-carboxylate (50.0 g, 0.196 mol) was added at the same temperature, and the used container was washed with tetrahydrofuran (50.0 mL). Methanol (9.41 g, 0.29 4 mol) was added dropwise at −5 to 5° C., and the mixture was stirred at −5 to 5° C. for 2 hr. To the reaction mixture were added ethyl acetate (350 mL) and 20 w/v % aqueous citric acid solution (250 mL), and the mixture was partitioned. The aqueous layer was extracted again with ethyl acetate (125 mL×2). The organic layers were combined and washed successively with 20 w/v % aqueous citric acid solution (250 mL) and water (250 mL×2). The organic layer was concentrated under reduced pressure. To the residue were added ethanol (100 mL) and ethyl acetate (450 mL), the mixture was heated to 60-70° C., and (R)-phenethylamine (23.7 g, 0.196 mol) was added. The mixture was stirred at 50-60° C. for 1 hr, at 20-30° C. for 1 hr and at −5 to 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate (2:9, 100 mL), and dried under reduced pressure at 50° C. to give (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (1R)-1-phenylethylamine salt as a white crystalline powder (55.7 g, yield 69.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][C:25]([C:10]2[C:9](=[O:8])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)=[O:26])[CH:6]=1
Reactant: Cc1cc(N)no1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
A solution of 6.0 g of 3-amino-5-methylisoxazole and 10 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 150 ml of toluene was refluxed for 16 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. The solution was cooled to room temperature, treated with 30 g of activated manganese dioxide, stirred for three hours at 30° C., and filtered. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1% methanol-dichloromethane as the eluent) to yield 5.8 g (49%) of 1,4-dihydro-N-(5-methyl-3-isoxazolyl)-4-oxo-1-phenyl-3-quinolinecarboxamide m.p. 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]([CH:26]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-:28].C[NH3+].[C:31]([BH3-])#[N:32].[Na+]>>[ClH:28].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]([CH2:26][NH:32][CH3:31])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: [BH3-]C#N
Reactant: [Cl-]
Agent: C[NH3+]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2ccc(F)cc2)c1
Product: Cl
Yield: 53.1 %

Procedure:
Using 1-[(4-fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (0.55 g), methylammonium chloride (1.17 g) and sodium cyanoborohydride (0.27 g), a procedure as in Example 4 was performed to give the title compound as a colorless crystal (yield 0.33 g, 53%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCCCCCCNCC
Reactant: O=C1CCC(=O)O1
Product: CCCCCCCN(CC)C(=O)CCC(=O)O

Procedure:
In a manner similar to Preparation 4, react ethyl(heptyl)amine with succinic anhydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([Cl:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22]CC)=[O:21])[CH:6]([C:16]([F:19])([F:18])[F:17])[O:7]2.O.[OH-].[Li+].Cl>C1COCC1.C(O)C.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([Cl:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[CH:6]([C:16]([F:18])([F:19])[F:17])[O:7]2
Reactant: CCOC(=O)C1=Cc2c(cc(Cl)c(OCC)c2Cl)OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(Cl)cc2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 70 %

Procedure:
The product of step 1 was dissolved in 5 mL THF and 1 mL ethanol. A solution of 61 mg of lithium hydroxide monohydrate in 6 mL of water was added to the organic solution. The vessel was capped and heated to 80° C. for 1 hour. After cooling to room temperature, the sample was concd using a nitrogen stream. The basic solution was then acidified with 3N HCl until the pH=2 and extracted 4 times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and solvent removed. The sample was purified by reverse phase chromatography to afford 72.6 mg (70%) of a brown solid: 1H NMR (CDCl3, CD3OD/300 MHz) 1.46 (t, 3H, J=6.6 Hz), 4.08 (q, 2H, J=7.2 Hz), 5.71 (q, 2H, J=6.9 Hz), 7.01 (s, 1H), 8.08 (s, 1H); MS (ES+) 357 (M+1, 100), 359 (M+3, 68); LC-MS purity 100% at 3.166 min. (UV and ELSD); HRMS (ES−) m/z calcd for (M−1; C13H8O4Cl2F3) 354.9746, found 354.9744.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[OH-:10].[Na+].CC(O)=[O:14]>>[CH3:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:14].[CH3:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:14])=[O:10]
Reactant: CSc1ccc(C)cn1
Reactant: CC(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccc(S(C)(=O)=O)nc1
Product: Cc1ccc(S(C)=O)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.69 g 5-methyl-2-methylsulfanyl-pyridine in 15 mL HOAc was added NaBO3.4H2O (1.92 g). This mixture was stirred at room temperature for 5 hours. The reaction mixture was then poured into ice. NaOH (10 M) was used to adjust the pH to 7. The mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/ethyl acetate) to yield 0.51 g of 2-methanesulfinyl-5-methyl-pyridine and 0.27 g of 2-methanesulfonyl-5-methyl-pyridine.