Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.COC(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13].[BH4-].[Na+].C1C[O:23][CH2:22]C1>>[NH2:14][CH:12]([CH3:13])[CH2:11][C:6]1[CH:5]=[C:10]([CH:9]=[CH:8][CH:7]=1)[CH2:22][OH:23]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccc1C=C(C)[N+](=O)[O-]
Agent: B
Agent: [BH4-]
Agent: [Na+]
Product: CC(N)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an oven-dried flask under nitrogen atmosphere was placed 12.15 mL (12.15 mmol) of 1.0 M borane in THF. This was chilled in an ice bath. A solution of 596 mg (2.7 mmol) of 3 (2 nitro 1 propenyl)benzoic acid-methyl ester in 10 mL dry THF was added to the stirred solution via syringe. Solid sodium borohydride (51.3 mg, 1.35 mmol) was then added to the mixture quickly. The mixture was stirred in the ice bath an additional 5 minutes, then at room temperature for 15 minutes The yellow color faded to colorless after about 5 minutes at room temperature. The solution was then heated at a gentle reflux under nitrogen overnight. The reaction mixture was cooled to room temperature and quenched by dropwise addition of 500 mL of water, then reheated at a gentle reflux for 2 hours. The reaction mixture was again cooled to room temperature and filtered and the residue was washed with water. The combined filtrate and washings were then basified to pH 14 with KOH pellets. Methylene chloride was used to extract the product, with the extraction being repeated 3 times (3x5ml). The solution was dried with sodium sulfate, and volatile materials were removed with a rotary evaporator. The crude amine weighed 273 mg (57%). It was carried on without purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:35])(C)(C)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:10]1[CH:11]=[C:12]([O:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])[CH:13]=[CH:14][C:9]=1[S:8][CH2:7][C:6]([OH:36])=[O:5]
Reactant: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)O
Reaction time: 5 h

Procedure:
0.143 g (0.28 mmol) of the above prepared [rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenylsulfanyl)-acetic acid tert-butyl ester was dissolved in 2.75 ml of THF/EtOH=1/1, treated with 1.38 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, since recrystallisation from AcOEt/hexane failed, 0.095 g of the title compound as colorless foam.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[NH:3]1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (Rowe F. M., et al., J. Chem. Soc., 1098, 1936) (20 g, 104.6 mmol) in 100 mL of DMF is added to a suspension of NaH (2.5 g, 104.6 mmol) in 200 mL of DMF at room temperature under argon. Some cooling is required during the addition to keep the mixture at room temperature. The mixture is stirred at room temperature for 30 minutes. Methyl iodide (14.8 g, 104.6 mmol) is added, and the mixture is stirred at room temperature overnight. The reaction is quenched by addition of 5 mL of acetic acid, and the DMF is evaporated. Residual DMF is removed by heating the wet solid in a steam bath under high vacuum. The dried solid is stirred into 300 mL of CH2Cl2 for 1 hour. The solid is removed by filtration, and the filtrate is evaporated to give 12 g (56% yield) of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.C([O:14][C:15]([C:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])C(OCC=C)=O)=[O:16])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH:17]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=1)[C:15]([OH:16])=[O:14])[CH3:32]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)CCCCC(Cc1ccc(C#N)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 24.21 ml (173.69 mmol) of triethylamine and 4.96 ml (131.58 mmol) of formic acid in 500 ml of dioxane is added to a solution of 22.5 g (52.63 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonyl-2-(4-cyanobenzyl)-heptanedioate, 970 mg (3.68 mmol) of triphenylphosphine and 240 mg (1.05 mmol) of palladium acetate in 500 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 2 hours. After conversion is complete, the reaction solution is cooled, and the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 17.5 g (87% of theory, 80% purity) of a colorless solid are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1cccs1
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(NC(=O)c3cccs3)nc2n1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is similar to that described in Example 1, starting with 2-thiophenecarboxylic acid (14 g) N,N'-carbonyldiimidazole (17.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (12.3 g). The product produced by precipitation in water (19.5 g; m.p. 216° C.) is dissolved in boiling ethanol (750 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (15.6 g) is produced, m.p. 220° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.O>CN1CCCC1>[CH2:18]([N:15]1[C:4]2=[N:5][C:6]([CH2:13][CH3:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[C:3]2[CH:17]=[N:16]1)[CH3:19]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Agent: CN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Yield: 111.3 %

Procedure:
To a solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (380 g) in 1-methylpyrrolidine (3166 mL) was added diisopropylethylamine (469.8 mL) and tetrahydro-2H-pyran-4-ylamine (163 g) and the mixture was heated at reflux for 16 h. The cooled mixture was treated with water (12 liters) and extracted with ethyl acetate (6×1250 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to afford 520 g of a dark brown oil. The product was purified by flash chomatography on silica using ethyl acetate/cyclohexane @1:4-1:2 as eluant to afford 336 g of the title compound. LC-MS m/z 347 (M+H)+, 3.02 min (ret time).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22]([OH:24])=[O:23])=[CH:14]1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1COCC1.CCCCCC>[CH3:25][Si:26]([C:14]1[O:13][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]=1[C:22]([OH:24])=[O:23])([CH3:28])[CH3:27]
Reactant: O=C(O)c1coc2ccccc12
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1oc2ccccc2c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (4 mL) in 20 mL THF at -60° C. was added 2.5 M of n-BuLi in hexane (17 mL), and the solution was stirred at between -20 and -60° C. for 1 h. To this, a solution of 3-benzofurancarboxylic acid (2.6 g) in 30 mL THF was added at <-70° C. After 1 h, TMSCl (7 mL) was added at <-70° C., and stirring was continued for an additional 1 h. The solution was allowed to warm to 0° C., quenched with 2 N HCl and extracted with methylene chloride. The organic solution was washed with brine, dried and concentrated to give 3.6 g of 2-(trimethylsilyl-3-benzofurancarboxylic acid.
Reaction SMILES: [N:1]([C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[O:3].C[N:25]([CH3:27])[NH2:26].[Cl:28][C:29](Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.C(Cl)Cl>[Cl:28][C:29]1[N:1]([C:4]2[C:5]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)[C:2](=[O:3])[N:25]([CH3:27])[N:26]=1
Reactant: CN(C)N
Reactant: O=C=Nc1cccnc1Oc1cccc(Oc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nc(Cl)n(-c2cccnc2Oc2cccc(Oc3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solids from Step B were dissolved in 100 mL of dry tetrahydrofuran. 1,1-Dimethylhydrazine (3 g, 50.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted twice with diethyl ether. The combined organic layers were then washed once with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give an oil. This oil was then dissolved in 200 mL methylene chloride and cooled to 0° C. at which temperature triphosgene (4.08 g, 13.7 mmol) was added. The reaction mixture was refluxed for 16 h, cooled to room temperature and washed once with water. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure to yield a crude oil which was purified by silica gel chromatography using 3:2/hexanes:ethyl acetate as the eluent to yield 2 g of the title compound of Step C, a compound of the invention, as a solid. 1H NMR (CDCl3 ; 300 MHz): δ 3.53 (s,3H), 6.8-6.9 (m,3H), 7.0-7.2 (m,4H), 7.3-7.4 (m,3H), 7.71 (dd,1H, J=1.9, 7.7 Hz), 8.27 (dd,1H, J=1.8, 4.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]2([C:26]([O:28]C)=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]2([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A heterogeneous mixture of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]- 1-[benzyl]-4-[carbomethoxy]-piperidine (1.2 g, 2.26 mmol) in 50% aqueous sodium hydroxide (10 mL) and methanol (50 mL) is heated to reflux for 16 hours. The methanol is evaporated and the residue is neutralized with 4 N hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The combined organic extracts are dried (NaSO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carboxy]-piperidine.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[OH:9][C:10]([CH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[CH:45][N:46]=[C:20]23)[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>CS(C)=O.C(OCC)(=O)C>[OH:9][C:10]([CH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:3][C:4](=[O:7])[O:5][N:40]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[CH:45][N:46]=[C:20]23)[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(C(C)(C)O)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(C(C)(C)O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (208 mg), sodium hydrogen carbonate (336 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, a solution of 4′-({4-[4-(1-hydroxy-1-methylethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (100 mg) in dimethyl sulfoxide (1 mL) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (39 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (37 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([CH3:35])[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:33])[C:31]([F:36])([F:30])[CH3:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)N)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)NC(=O)C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,28)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (126a) (256 mg, 0.63 mmol) dissolved in NMP (3.5 mL) was added to a solution of 2,2-difluoropropanoic acid (111 mg, 1.00 mmol), HATU (382 mg, 1.00 mmol) and DIPEA (0.438 mL, 2.51 mmol) in NMP (1.5 mL). The reaction mixture was stirred at r.t. for 2 h. Additional 2,2-difluoropropanoic acid (80 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (0.25 mL, 1.4 mmol) in NMP (1.5 mL) was added. The reaction mixture was stirrred at r.t. for another h. Water (50 mL) was added, the mixture was extracted with EtOAc (2×50 mL), the organic phase was washed with 10% NaHSO4 (aq), brine, dried over MgSO4, filtered and evaporated to give a crude product that was purified by HPLC. The fractions containing the product was combined and freeze dried. Yield 197 mg (62%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(COC)OC>[Br-:12].[NH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[CH2:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnc2ccccc2n1
Solvent: COCCOC
Product: CCOC(=O)C(=O)C[n+]1c(N)cnc2ccccc21
Product: [Br-]
Yield: 74.9 %

Procedure:
A solution of 0.9 g of 2-amino-quinoxaline, 1.25 g of ethyl bromopyruvate and 25 ml of dimethoxyethane was stirred overnight at room temperature and was filtered to obtain 1.58 g of 2-amino-carbethoxycarbonylmethyl-quinoxalinium bromide in the form of a pale yellow crystalline solid.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>C(O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][S:27][C:26]([N:2]2[C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:28])=[CH:32][CH:31]=1
Reactant: S=C=S
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 60 %

Procedure:
In the same manner as described in Example 53, ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.00 g), triethylamine (1.07 g), carbon disulfide (0.65 ml), ethanol (60 ml) and 4-chlorobenzyl chloride (1.72 g) are reacted and treated. The product is recrystallized from ethyl acetate-n-hexane to give the title compound (2.59 g, 60%) as pale yellow needles, m.p. 195°-197° C.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C[O-].[Na+].[C:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([OH:12])=[O:11].CS(O)(=O)=O>CO>[CH3:3][O:2][P:1]([CH:15]1[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:12])[O:11]1)(=[O:6])[O:4][CH3:5]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COP([O-])OC
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 20 °C
Yield: 95 %

Procedure:
Dimethyl phosphite was added drop-wise to a solution of sodium methoxide in methanol at 0° C. 2-Carboxybenzaldehyde (H) was then added portion-wise to the reaction mixture as a slurry in methanol, with the temperature kept below 5° C. The resulting pale yellow solution was warmed to 20° C. over 1 hour. Methanesulphonic acid was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform. The combined organic extracts were washed with water, dried over MgSO4, and evaporated in vacuo to yield (3-oxo-1,3-dihydro-isobenzofuran-1-yl) phosphonic acid dimethyl ester (G) as a white solid (yield: 95%). This was then used without further purification in the next stage.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C>[OH:25][N:24]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NO
Reactant: N#Cc1ccc(C=O)c(Oc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-formyl-3-phenoxy-benzonitrile (2.21 g) in dry ethanol (45 ml) was added sodium acetate (0.894 g) and hydroxylamine hydrochloride (0.757 g). The mixture was stirred at rt for 4.5 h. The solvent was evaporated and the product was purified by flash chromatography (cyclohexane/EtOAc 8:2=>3:7) to give 4-(hydroxyimino-methyl)-3-phenoxy-benzonitrile (1.42 g). Light yellow solid. MS 238.1 ([M]+)
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](Br)[CH:11]=1.CN(C=O)C>O>[CH2:2]([O:4][C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[N:8][CH:9]=1)[CH3:3]
Reactant: CCO
Reactant: Brc1cncc(Br)c1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, sodium (4.60 g, 200.0 mmol) was added to absolute ethanol (100 mL) at 0–5° C., and the stirring mixture was allowed to warm to ambient temperature over 18 h. To the resulting solution was added 3,5-dibromopyridine (31.50 g, 133.0 mmol), followed by DMF (100 mL). The mixture was heated at 70° C. for 48 h. The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3×500 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation, producing 46.70 g of an oil. Purification by vacuum distillation afforded 22.85 g (85.0%) of an oil, bp 89–90° C. at 2.8 mm Hg, (lit. bp 111° C. at 5 mm Hg, see K. Clarke et al., J. Chem. Soc. 1885 (1960)).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3][NH2:4].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=O)[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16].[BH4-].[Na+]>C1C=CC=CC=1.CO>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CCC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
A solution of 2-hydroxy-2-(3-trifluoromethylphenyl) ethanamine (3 g) and 4-(4-carbomethoxyphenyl)butan-2-one (3 g) in benzene was boiled for 21/2 hours with azeotropic removal of water and then evaporated to give an oil which was dissolved in methanol and this solution was treated with sodium borohydride (2 g) at 0° C. After 2 hours the solution was evaporated, diluted with water and extracted with dichloromethane and the product from the dried (MgSO4) organic extracts was chromatographed on silica gel eluting with 5% methanol in chloroform to yield the title compound as an oil; 1H n.m.r. τ(CDCl3) 2.00-2.90 (m, 8H); 5.33 (m,1H); 6.12 (s,3H); 6.92-7.57 (m,7H; 2H exchangeable on D2O wash); 8.16-8.50 (m,2H); 8.91 (d,3H). The product was isolated as the hydrochloride salt m.p. 147.5°-150.5° C., as a 55:45 mixture of diastereoisomers.