Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=O)[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].Cl.[OH:53][NH2:54]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31](/[C:44](=[N:54]/[OH:53])/[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13]
Reactant: NO
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(/C(C)=N/O)c2)C(=O)OC(C)(C)C)c1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (10 mg, 0.0147 mmol) and hydroxyamine hydrochloride (2.0 mg, 0.0294 mmol) in ethanol (0.1 mL) was heated at 80° C. for 2 h. The reaction mixture was purified by reverse phase prep HPLC to give the title compound: HPLC retention time: 2.16 min (method A). MS (ESI) (M+H)+ 697.90
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:27]([C:30]1[N:34]2[CH2:35][C@H:36]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=3[F:55])[CH2:37][CH2:38][C@@H:39]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:33]2=[N:32][CH:31]=1)(=[O:29])[CH3:28]>O1CCCC1>[F:55][C:49]1[C:50]([F:54])=[CH:51][CH:52]=[CH:53][C:48]=1[C@H:36]1[CH2:35][N:34]2[C:30]([C:27]([OH:29])([CH3:28])[C:2]([F:4])([F:3])[F:1])=[CH:31][N:32]=[C:33]2[C@H:39]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][CH2:37]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(O)C(F)(F)F)cnc21
Reaction time: 0.08 h
Yield: 31.3 %

Procedure:
(Trifluoromethyl)trimethylsilane (0.273 mL, 1.85 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 74 μL, 0.074 mmol) were sequentially added to a solution of tert-butyl (6S,9R)-3-acetyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (150 mg, 0.37 mmol) in tetrahydrofuran (1 mL). After 5 min, additional (trifluoromethyl)trimethylsilane (100 μL, 0.678 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 25 μL, 0.025 mmol) were added. After 30 min, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (55 mg). MS 476.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:12]=1)[C:5](OCC)=[O:6])[CH3:2].[BH4-].[Na+]>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=2)[CH:12]=1)[CH2:5][OH:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(CO)Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1
Yield: 99 %

Procedure:
The compound was synthesised in an analogous method to Example 1 using ethyl 2-ethoxy-3-{3-[3-(4-methylsulfonyloxyphenyl)propoxy]phenyl}propanoate (0.642 g, 1.42 mmol) and sodium borohydride (93.26 mg, 2.47 mmol). The reaction was quenched after 28 hours to give 0.574 g (yield 99%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[N:8]=[C:7]([S:16][CH3:17])[N:6]=[C:5]2SC.[NH3:20]>O1CCCC1>[CH3:17][S:16][C:7]1[N:6]=[C:5]([NH2:20])[C:4]2[C:9](=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: N
Reactant: COc1c(Cl)cc2c(SC)nc(SC)nc2c1OC
Solvent: C1CCOC1
Product: COc1c(Cl)cc2c(N)nc(SC)nc2c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 0.1 mole of 6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline in 200 ml. of tetrahydrofuran is added a solution of 0.1 mole of anhydrous ammonia in tetrahydrofuran. The mixture is stirred at room temperature for 18 hours and the precipitate which forms is collected and recrystallized from dimethylformamide/water to yield 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccccc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
To a stirred suspension of (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (116 mg, 0.32 mmol) in toluene (0.65 ml) was added iodobenzene (129 mg, 0.63 mmol), copper (I) iodide (6 mg, 0.032 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (15 mg, 0.063 mmol), and Cs2CO3 (206 mg, 0.63 mmol). The resulting suspension was heated at 100° C. in a capped scintillation vial with stirring for 2 days. The reaction mixture was filtered through diatomaceous earth, washing with CH2Cl2. The filtrate was dried and concentrated. Purification of the residue by FCC provided the desired product (97.7 mg, 70%). MS (ESI): mass calcd. for C25H37N3O4, 443.3; m/z found, 444.3 [M+H]+. 1H NMR (CDCl3): 7.30-7.25 (m, 2H), 6.96 (dd, J=14.5, 7.2 Hz, 1H), 6.85 (dd, J=7.7, 5.5 Hz, 1H), 5.04-4.91 (m, 1H), 4.88-4.71 (m, 1H), 3.89-3.43 (m, 6H), 2.92-2.79 (m, 1H), 2.70-2.20 (m, 6H), 2.07-1.74 (m, 7H), 1.71-1.52 (m, 2H), 1.43-1.41 (m, 9H).
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]C2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CC1
Yield: 63 %

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.20 mmol) was dissolved in CH2Cl2 (1 ml). Triethylamine (0.30 ml, 2.2 mmol), followed by 2-chlorobenzenesulfonyl chloride (64 mg, 0.30 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 18 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 25% EtOAc/hexanes) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclopropanecarboxylate (47 mg, 63% 2 steps) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.85 (m, 2 H), 1.23 (t, J=7.5 Hz, 3 H), 1.23 (m, 2 H), 2.98 (bs, 4 H), 3.14 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H), 7.37 (t, J=7.3 Hz, 1 H), 7.42-7.53 (m, 2 H), 8.00 (d, J=7.8 Hz, 1 H), 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.1, 45.7, 46.7, 48.8, 60.5, 126.9, 132.1, 132.2, 132.3, 133.6, 136.0, 173.8; ESI-MS: m/z 373.3 (M+H)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[CH:12][N:11](C)[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)#[CH:18]>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[N:3]=[C:4]([CH3:16])[N:5]([C:8]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[CH:9]=3)[C:6]=2[CH3:7])[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: Cc1nc(I)c(C)n1-c1ccn(C)c(=O)c1
Product: COc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1

Procedure:
The title compound, light brown solid, MS: m/e=320.1 (M+H+), was prepared in accordance with the general method of example 1c from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1-methyl-1H-pyridin-2-one and 1-Ethynyl-3-methoxy-benzene.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:47])=[C:9]([CH2:11][O:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:45][CH3:46])[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:47])=[C:9]([CH2:11][O:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:45][CH3:46])[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
After a mixture of ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (1500 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1330 mg, yield: 93%). This was recrystallized from acetone-hexane. Melting point: 153–154° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: OCc1cccnn1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnn2)n1

Procedure:
Prepared by the method of Example 20 using pyridazine-3-methanol (0.1 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.15 g). Yield 0.038 g.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25]Br)[CH2:7][CH3:8].[NH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>C(OCC)(=O)C>[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])[CH2:7][CH3:8]
Reactant: O=C1NCCN1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2CCNC2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (5 mL) of 7-propyl-3-(trifluoromethyl)-6-(3-bromopropyloxy)-1,2-benzisoxazole as prepared in Example 7 (322 mg, 0.88 mmol), was added 2-imidazolidinone (320 mg, 3.52 mmol) and CsCO3 (320 mg, 0.97 mmol) then stirred at room temperature overnight. After aqueous work-up and silica gel chromatography (hexanes: 70% ethyl acetate), the title compound was obtained.
Reaction SMILES: O.[Br-].[CH3:3][C:4]1[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:6][C:7]([CH:10]=[C:11]2C=CC=CC2[PH+](C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:9]=1.C=O.ClCCl.[OH-].[Na+]>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>[CH3:3][C:4]1[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:6][C:7]([CH:10]=[CH2:11])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=C2C=CC=CC2[PH+](c2ccccc2)c2ccccc2)nc1-c1ccccn1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(O)c(C(C)(C)C)c1C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: C=Cc1ccc(C)c(-c2ccccn2)n1
Temperature: 23 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
0.9 g (1.7 mmols) of [3-methyl-2,2'-bipyridin-6-yl-(methylene)]-triphenylphosphonium bromide monohydrate is dissolved in a well stirred emulsion consisting of 15 ml of 35% formaldehyde solution, 20 ml of dichloromethane, 5 mg of di-tert.-butyl-p-cresol and 22 mg of tetrabutylammonium cyanide. A solution of 0.5 g of sodium hydroxide in 2.5 ml of water is added dropwise at 25° C. After stirring for 1 hour at 23° C., the dichloromethane phase is separated off and washed with 20 ml of water. After the addition of 5 mg of di-tert.-butyl-p-cresol, the mixture is concentrated in vacuo and 20 ml of dilute hydrochloric acid are added to the residue. The precipitating crystalline triphenylphosphine oxide is washed with three times 20 ml of ethyl acetate. The aqueous phase is covered with a layer of 20 ml of ethyl acetate and rendered alkaline with potassium carbonate. The organic phase is dried over sodium sulfate and freed from solvent in vacuo. After renewed addition of 5 mg of di-tert.-butyl-p-cresol, the residue is distilled in a bulb tube oven at a maximum of 150° C./0.93 Pa. 0.24 g (71% of theory) of 3-methyl-6-vinyl-2,2'-bipyridine are obtained as a colourless liquid. UV absorption (in chloroform): λ=250 nm (ε=15,450); λ=293 nm (ε=7,700).
Reaction SMILES: [CH2:1]([C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
The process is performed as in Example 3, starting with 2.66 g of tert-butyl (1S)-1-benzyl-2-oxopropylcarbamate in 25 cm3 of ethanol, with 0.58 g of sodium borohydride. After 4 h 30 min at a temperature in the region of 20° C., the reaction mixture is worked up in an identical manner. 2.7 g of tert-butyl (1S)-1-benzyl-2-hydroxypropylcarbamate are obtained in the form of a white solid melting at 125° C., as a mixture of the two diastereoisomers (70/30).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].ClCCl>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (160.0 mg, 0.0004927 mol) and ethanol (7 mL, 0.1 mol) and the reaction heated at 85° C. Ammonium chloride (264 mg, 0.00493 mol) in water (7 mL, 0.4 mol) was then added followed by the addition of iron (110 mg, 0.0020 mol) in two portions. The reaction was heated at that temperature for another hour. The reaction mixture was poured into dichloromethane (60 mL) and extracted. The extracts were washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure to obtain the product as a colorless solid. MS m/z=295.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([C:25]([N:3]2[CH2:4][CH2:5][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[NH:13][C:14]=3[C:2]2([CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:26])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1(c2ccccc2)NCCc2c1[nH]c1ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC1(c2ccccc2)c2[nH]c3ccccc3c2CCN1C(=O)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 21.7 %

Procedure:
The title compound was prepared by the addition of 1-methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline (105 mg, 400 μmol), CHCl3 (9 mL), 3,4-difluorobenzoyl chloride (85 mg, 480 μmol), and DIEA (140 μL, 800 μmol) to a 25 mL flask. The solution was allowed to stir at 60° C. under N2 for 17 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 20% EtOAc) to yield 35 mg of title compound; 1H NMR (CDCl3) δ 7.54 (1H, d), 7.48 (2H, d), 7.12-7.32 (9H, m), 4.05 (1H, m), 3.64-3.70 (1H, m), 3.19 (1H, m), 2.96 (1H, m), 2.29 (3H, s); MS (ESI): 403 (MH+).
Reaction SMILES: C1COCC1.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14][C:15](=[O:16])[C:7]=12)=[O:13].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.[NH4+].[Cl-]>Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:15]([C:7]2[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=[CH:11][N:6]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ncccc2C(=O)O)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a THF (15 ml) solution of pyridine-2,3-dicarboxylic acid anhydride (1.0 g, 6.7 mmol) was added dropwise a THF solution of 4-methoxyphenylmagnesium bromide (0.89M, 8.0 ml, 7.1 mmol) at -78° C. The reaction mixture was stirred at the same temperature for 1 h and then a saturated aqueous solution of NH4Cl (20 ml) was added to quench the reaction. The reaction mixture was diluted with 1N HCl and extracted with AcOEt. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (E. Merck, Kieselgel 60/chloroform:methanol=10:1) to give 2-(4-methoxyphenylcarbonyl)-3-pyridine carboxylic acid (479 mg) as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[CH3:40][C:41]([CH3:49])([C:43]1[N:47]=[C:46]([CH3:48])[O:45][N:44]=1)[NH2:42]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:42][C:41]([C:43]3[N:47]=[C:46]([CH3:48])[O:45][N:44]=3)([CH3:49])[CH3:40])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=401.2 [M+H]+.
Reaction SMILES: CO.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=O)=[CH:7][CH:6]=1)[CH3:4].[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>[Zn].C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(OC(C)=O)CCC.C(O)(=O)C.O>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[CH:22][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: CCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Zn]
Solvent: CCCCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc([N+]([O-])=Cc2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
In a 5-L 4-necked round bottom flask equipped with a stirrer, thermometer, dropping funnel and ice-acetone bath was placed 2800 mL of methanol, 300 mL of distilled water, 400 g (2.64 moles, 1.0 equiv.) of 4-ethyl-1-nitrobenzene (11), 349.7 g (2.9 moles, 1.1 equiv.) of p-tolualdehyde, and 367.5 g (5.62 moles, 2.13 equiv.) of zinc powder. The reaction mixture was cooled to 0° C., then with vigorous stirring the dropwise addition of 792.0 g (13.2 moles, 5.0 equiv.) of acetic acid was started. There was a 3-5 minute induction period before the exotherm began. When the acetic acid addition was complete, the reaction mixture was stirred for 1 hour at 10° C. The reaction mixture changes from gray opaque to greenish white, which signifies reaction completion. The reaction mixture was checked for reaction completion by TLC (1 BuOAc, 2 PhCH3, 4 CHCl3) eluted on silica-gel and viewed under short-wave UV light. After the 1 hour reaction period, 500 mL of dichloromethane was added to solubilize any undissolved product. The zinc acetate salts were filtered off (≃1 kg) and washed with 200-300 mL of dichloromethane. (Salts may also be slurried in dichloromethane to remove any remaining product.) The filtrates were stripped to a mush under aspirator vacuum to a pot temperature of 57° C. The green mush was cooled to 25° C. and 1000 ml of dichloromethane and 1000 mL of distilled water were added to the flask. The mixture was stirred vigorously to dissolve all product and salts, then poured into a separatory funnel. The product layer was removed and washed a second time with 1000 mL of fresh distilled water. The product layer was stripped under aspirator vacuum on a steam pot until most of the dichloromethane had been removed. While still hot, with vigorous stirring 2500-3000 mL of heptane was added, then cooled to 20°-25° C. and stirred 1-2 hours. The greenish white product was collected, washed with heptane and dried in a warm air oven overnight. The yield of green-white crystals was 467.9 g (74%): MP 97°-99° C.; IR (KBr) (>C=N) 6.33μ, (N→O) 8.65μ; NMR (CCl4, Me4Si) δ1.3 (T, 3H), 2.4 (S, 3H), 2.7 (Q, 2H), 7.2 (D, 4H), 7.7 (Q, 2H), 7.8 (S, 1H), 8.2 (D, 2H); TLC (1 BuOAc, 2 PhCH3, 4 CHCl3, 4 CHCl3), silica-gel coated plates, viewed under short-wave UV light, major spot for the desired nitrone, Rf=0.50.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH3:26])[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 6 g of ethyl 2-aminothiazole-4-ylglyoxylate, 6 g of p-toluenesulfonyl isocyanate and 40 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.