Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.C(#N)C.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:24]
Reactant: O=c1cc[nH]c2cc(Br)cnc12
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1ccnc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 350 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (21.6 g, 150.0 mmol) and triethyl orthoformate (150 mL, 150.0 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 55-bromopyridin-3-amine (25.95 g, 150.0 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (41.5 g, 85% yield) as a yellow solid. MS [M+H]=327.0. Calc'd for C12H11BrN2O4=327.1. 2) 7-bromo-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for 1 hour. Reaction mixture was cooled to room temperature and diluted with 300 mL of Hexanes. This was heated to 60° C. and triturated in this system for 3 hrs to afford 7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brown solid. This was used without further purification. MS[M+H]=227.0. Calc'd for C8H5BrN2O=225.0. 3) 3-bromo-8-chloro-1,5-naphthyridine. 7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitrile (192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid. MS[M+H]=245.0@. Calc'd for C8H4BrClN2=243.5.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B].[OH-].[Na+]>C1COCC1>[OH:11][CH2:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: [B]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@H]1c1ccccc1
Yield: 91 %

Procedure:
1st stage: add a solution of 25.0 g (154 mmol) of trans-2-phenylcyclopropanecarboxylic acid in 100 ml of THF to a boron complex borane-THF solution drop by drop under a nitrogen atmosphere. Place the solution in the reflux for 3 hours and gently add 130 ml of NaOH 2N solution and stir the mixture for 30 minutes. Concentrate the etherised extracts in a vacuum to obtain 20.78 g of coarse trans-1-hydroxymethyl-2-phenylcyclopropane which is purified by distillation.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:8]([CH2:9][OH:10])[CH:7]2[CH2:11][CH:4]1[CH2:5][CH2:6]2.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([OH:1])(=[O:26])=[O:25].[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([OH:1])(=[O:26])=[O:25].[OH:1][CH2:2][C@@H:3]1[C@@H:8]([CH2:9][OH:10])[CH:7]2[CH2:11][CH:4]1[CH2:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OC[C@H]1C2CCC(C2)[C@@H]1CO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 3 h

Procedure:
In a 200 ml round bottom flask capped with a CaCl2 drying tube was placed 7.2 g (0.0461 moles) of (2S,3S)-2,3-bis(hydroxymethyl)bicyclo[2.2.1]heptane (m.p. 58° C.) together with 45 ml of pyridine and 18.4 g (0.096 moles) of p-toluenesulfonyl chloride. The mixture was cooled in an ice bath and stirred for 3 hours and then diluted with 10 ml of H2O. The precipitate which formed was filtered and washed to remove pyridine. The solid was recrystallized from ethanol to give 17.2 g (92%) of fine white needles, m.p. 100°-101° C., αD =+32.2° C.
Reaction SMILES: CC(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18](OC)=[O:19])[CH2:13][N+:14]([O-])=O)=[CH:8][CH:7]=1>[Fe].[Ni].O1CCCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:13][NH:14][C:18](=[O:19])[C@H:17]2[C:22]([O:24][CH3:25])=[O:23])=[CH:8][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Temperature: 8 °C
Yield: 78.5 %

Procedure:
To 2-propanol (250 ml) was added dimethyl (R)-2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (50.0 g, 158 mmol) and iron-containing developed nickel (5.0 g, containing iron 16.6%, aluminum 6.1%, manufactured by Kawaken Fine Chemical K.K.), and the mixture was reacted at 65° C. for 3 hours under a hydrogen pressure of 0.5 MPa (gauge pressure). After completion of the reaction, tetrahydrofuran (175 ml) was added, and the nickel catalyst was filtrated off. The nickel catalyst was washed with tetrahydrofuran (75 ml), and filtrate and washing liquid were combined, and acidic active alumina (5.0 g) was added to this and the mixture was thermally insulated at 50 to 60° C. The active alumina was filtrated off, then, the filtrate was concentrate under reduced pressure. The concentrated filtrate was cooled to 8° C., then, the resultant crystal was filtrated, and dried under reduced pressure, to obtain a title compound (31.4 g, 124 mmol) (yield: 78%). The spectrum data corresponded to the value in Example 2. The optical purity of the resultant compound was measured by HPLC to find a value of 99.73% ee. The content of a by-product obtained by releasing a chlorine atom was 0.06% (conditions are shown below).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:23]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[N:7][CH:6]=[CH:5]2.C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23]
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Temperature: 90 °C
Reaction time: 5 h
Yield: 30.9 %

Procedure:
6-Methyl-5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinoline-1-amine (1.49 g, 4.29 mmol) obtained in Step (1) above was stirred in a solvent of ethanol (10 mL). The reaction solution was added with tin chloride (II) dihydrate (4.06 g, 21.46 mmol), and stirred for about 5 hours at 90° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.42 g, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[CH2:6]2
Reactant: CC1Cc2c(Br)ccc(Br)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2c(Br)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 54.1 g (0.178 mol) of 4,7-dibromo-2-methyl-1-indanone in 240 ml of THF-methanol (2:1, vol.), 9.40 g (0.248 mmol) of NaBH4 was added in small portions for 2 hours at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred overnight at ambient temperature. The resulting mixture was acidified with 10% HCl to pH=4. The organic layer was separated; the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and evaporated to dryness. To the residue 500 ml of toluene were added. This toluene solution was treated with 50.0 g pTolSO3H for 5 hours at reflux. The resulting mixture was cooled to room temperature and passed through a short Silica Gel 60 column (40-63 μm, d 60 mm, l 40 mm). This column was additionally eluted with 700 cm3 of toluene. The combined extract was evaporated to dryness to give a white solid of the title product. Yield 47.2 g (92%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([CH2:24][CH2:25][C:26]([OH:28])=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29]1([N:35]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C@@H:37]3[CH2:44][NH:45][CH2:46][CH2:47][C@@H:36]23)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:16]([CH2:24][CH2:25][C:26]([N:45]1[CH2:46][CH2:47][C@H:36]2[N:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C@@H:37]2[CH2:44]1)=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To the suspension arising from the admixture of 865 mg. (4.20 mmole) of dicyclohexylcarbodiimide and 748 mg. (4.20 mmole) of 3-benzoylpropionic acid in 30 ml. of dichloromethane at 0° C. was added 1.0 g. (4.0 mmole) of dl-trans-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 10 ml. of the same solvent. The resulting mixture was stirred and allowed to warm to room temperature over 2 hours. After cooling again to 0° C. the reaction mixture was filtered, washed with dichloromethane and the filtrates evaporated to obtain a residue of dl-trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole which was used without purification in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:36]([NH:43][C:44](=[O:52])[NH:45][CH:46]([CH3:51])[CH2:47][C:48]([NH:1][CH:2]([C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCl (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated zin vacuo. The crude compound was used next step without further purification. MS ESI 701 (M+H), 723 (M+Na).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[Cl:7][C:8]1[C:13](O)=[C:12]([Cl:15])[C:11]([Cl:16])=[C:10]([Cl:17])[C:9]=1[Cl:18].O=P(Cl)(Cl)Cl.Cl>>[Cl:7][C:8]1[C:13]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:10]([Cl:17])[C:9]=1[Cl:18]
Reactant: N#CCC(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
17 g. (0.2 moles) of cyanoacetic acid are mixed thorougly with 53.2 g. (0.2 moles) of pentachlorophenol, and 19.0 ml. (0.2 moles) of phosphoroxychloride are added dropwise. The obtained mixture is heated slowly on an oil-bath, until the inner temperature rises to 85° to 90° C. and the solid melts under intensive evolution of HCl. The homogeneous melt is heated until the hydrochloric acid evolution ceases. In the meantime the first cyanoacetic acid pentachlorophenyl ester precipitate is obtained. When the hydrochloric acid evolution ceases, the system is cooled and dissolved in 500 ml. of dichloromethane, washed 3 times with 100 ml. of water, treated with decolorizing charcoal, dried and evaporated. Diisopropyl ether is added. Cyanoacetic acid pentachlorophenyl ester precipitates in the form of crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:7]1[CH:6]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a mixture of 8ml of nitric acid and 15ml of acetic acid 1g of 2-(4-hydroxyphenyl)propionic acid was added and stirred at -10° to -20° C for 4 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with a sodium hydrogen carbonate solution and water and then dried over magnesium sulfate. The chloroform solution was concentrated to give crystals, which were recrystallized from water. Yield, 700 mg (58%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].N([O-])=O.[Na+].[ClH:25]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: Cl
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrite (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound No. 19 of Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)c1cc(I)ccc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)ccc1Br
Temperature: 55 °C

Procedure:
To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:47][C:48](=[O:51])[CH2:49]Br)(C)(C)C.COC(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:49][C:48]([OH:51])=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.70 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of toluene is cooled to 0° C. At 0° C. 29.3 g (150 mmol) of bromoacetic acid tert-butyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (36 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described according to Example 69 to give the free base of the product, which was crystallized from dichloromethane/ethyl acetate to give 45 mg (50%) as a colorless solid.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO.OO>C1COCC1>[F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Temperature: 0 °C

Procedure:
A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 2.3 (80 g, 0.368 mol) in THF (800 mL) was treated with L-Selectride (405 mL, 0.405 mol, drop wise) at −78° C. under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 mL, 1.105 mol) 1M NaOH (1104 mL, 1.105 mol) were added and the reaction was allowed to warm to 0° C. The reaction was quenched by drop wise addition of H2O2 (125.1 mL, 1.843 mol). The volatiles were removed under vacuume and diluted with water (500 mL) and methylene chloride (500 mL). After separation, the organic layer was washed brine, dried over Na2SO4 and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 78%). 1HNMR (CDCl3, 400 MHz): δ 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1H), 3.55-3.27 (m, 1H), 3.18 (brs, 1H), 2.06 (brs, 1H), 1.89-1.70 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.C1(C)C(C)=CC=CC=1.[OH-].[Cs+]>O>[CH:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 5 °C

Procedure:
Into the reactor previously described are charged 49.7 grams (0.315 moles) of p-nitrochlorobenzene together with 98.7 grams of a 66.4% solution of formanilide recovered from a previous run (0.54 molecular proportions). The solution also contained 0.07 moles of p-nitrochlorobenzene, bringing the total to 0.385 mole. About 50 milliliters of xylene are added, and the mixture heated to refluxing temperature which is about 195°-198° C. To the hot mixture is added at the rate of about 0.4 ml. per minute 82.5 grams (0.55 mole) of cesium hydroxide as a 50% solution in water (165 grams) during which addition the water is continuously removed. The heating is continued for a total time of about five hours, then 250 ml. of xylene is added and the xylene solution washed twice with 200 ml. portions of 90° C. water. The xylene solution is cooled to 5° C., filtered and the cake washed with 60 ml. of 5° C. xylene. There is obtained 40.7 grams of 4-nitrodiphenylamine. The total yield determined as described in Example 1 is 72%. The conversion of p-nitrodiphenylamine is 99.1%.