Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([CH2:25][C:26](=O)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:33])=[N:13]2)=[CH:8][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][N:2]=[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][CH:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:33])[N:16]1[C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[N:15][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:13]=1
Reactant: NO
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(CCC(C)C)=NO)nc2n1
Yield: 22.4 %

Procedure:
Hydroxylamine hydrochloride (0.9 g) is added to a suspension, maintained at 0° C. with a bath of ice-cold water, of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (4.3 g) in a mixture (100 cc) of water and ethanol (50:50 by volume). The suspension obtained is allowed to return to a temperature in the region of 20° C. and a solution of sodium carbonate (0.7 g) in distilled water (10 cc) is added. The suspension obtained is heated to reflux for 22 hours. During this period, ethanol (80 cc) is added in two portions. Refluxing is maintained for 12 hours, adding in three portions further hydroxylamine hydrochloride (1.35 g) and sodium carbonate (1.05 g). The reaction mixture is then poured into water (1 litre). The aqueous phase is extracted with methylene chloride (3×300 cc). The organic phases are combined, washed with distilled water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness. After recrystallization in 2-propanol, 3-(2-hydroxyimino-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1 g), m.p. 200° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: Brc1n[nH]c2cccnc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(Br)c2ncccc21
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg) in DMF (10 mL) were added 2-iodopropane (0.20 mL) and K2CO3 (168 mg) at room temperature. After stirring overnight, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (147 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3](=[CH2:27])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([NH:1][CH2:2][C:3](=[CH2:27])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CN)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CNS(C)(=O)=O)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-(2-(aminomethyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (32 mg, 0.088 mmol) in DCM (438 μL) was added triethylamine (12 μL, 0.088 mmol) and methanesulfonyl chloride (7.5 μL, 0.096 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 hour and then gradually warmed up to room temperature over 1 hour. The resulting mixture was diluted with DCM (2 mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was extracted with DCM (×3) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(2-(methylsulfonamidomethyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C20H22N5O5S [M+H]+: 444, found 444. 1H NMR (600 MHz, DMSO-D6) δ 12.99 (bs, 1H), 10.11 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=8.21 Hz, 1H), 7.42 (t, J=8.21 Hz, 1H), 7.38 (t, J=6.45 Hz, 1H), 7.33 (d, J=7.63 Hz, 1H), 6.01 (s, 1H), 5.75 (s, 1H), 3.89 (d, J=6.45 Hz, 2H), 3.86 (q, J=7.04 Hz, 2H), 2.94 (s, 3H), 0.86 (t, J=7.04 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: O=CC(=O)O
Reactant: COc1cc(/C=C/C(C)=O)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(/C=C/C(=O)/C=C/C(=O)O)cc(OC)c1OC

Procedure:
A solution of 5 g (21 mmol) of (E)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one and 2 g (21.7 mmol) of glyoxylic acid monohydrate in 5.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 152°-154°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CCC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)NCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The oxime, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-ethoxyimino)-methyl]-benzamide (33.0 mg, 51.0 μmol) obtained in Step A was suspended in methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 μl) were added thereto at room temperature. The mixture was stirred at room temperature for 2 hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture, which was then extracted with methylene chloride (2×10 ml). The combined organic layers were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (methylene chloride/methanol (40:3)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-ethoxyamino)-methyl]-benzamide (Compound C-34, 21.6 mg, 71%) as a colorless syrup.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([NH2:12])=[N:10][N:11]=1.[C:13]1([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>O>[C:13]1([C:19]2[C:20]([OH:21])=[N:12][C:9]3[N:10]([N:11]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:8]=3)[C:25]=2[OH:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1nnc(-c2ccccn2)[nH]1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2nc(-c3ccccn3)nn2c(O)c1-c1ccccc1
Temperature: 180 °C
Yield: 50 %

Procedure:
20 g (124.1 mmol) 5-Pyridine-2-yl-4H-[1,2,4]triazole-3-ylamine and 52.8 g (223.4 mmol) diethyl phenylmalonate are heated in 48.8 mL (204.8 mmol) tributylamine at 180° C. over night. After addition of additional 27 mL diethyl phenylmalonate the reaction mixture is heated for another night at 180° C. The reaction mixture is diluted with water and 2N NAOH and extracted three times with methyl-tert.butylether. The organic extracts are discarded after TLC check. The aqueous phase is acidified with 2M HCl until a pH of 1. The formed precipitate is collected by filtration, washed with plenty of water and dried. 18.96 g (45%) of the desired product are obtained which are used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:17].C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:38][C:26]([F:25])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([S:33]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:3]2=[O:17])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=C1[C@@H](O)CCN1c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1[C@@H](OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
To a dichloromethane (10 mL) solution of (3S)-3-hydroxy-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one (691 mg, 2.82 mmol), triethylamine (589 μL, 4.23 mmol), and 4-(dimethylamino)pyridine (69 mg, 0.56 mmol) at 0° C. was added a dichloromethane (10 mL) solution of 4-(trifluoromethyl)benzenesulfonyl chloride (827 mg, 3.38 mmol) dropwise. After stirring for 3 hours, the mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The organic layer was washed with brine (2×100 mL), dried (magnesium sulfate) and concentrated to give the title compound, which was subjected to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=7.9 Hz, 2H), 7.85 (d, J=7.4 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 5.25 (t, J=8.0 Hz, 1H), 3.98-3.93 (m, 1H), 3.85-3.81 (m, 1H), 2.81-2.75 (m, 1H), 2.49-2.43 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20](F)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloroaniline (13.91 ml, 137.00 mmol) and 5-benzyloxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF (120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.5 mmol) dropwisely under nitrogen atmosphere. The mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 23.80 g, 89.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.80 (s, 1H), 8.66 (s, 1H), 7.64 (m, 1H), 7.34 (m, 7H), 6.92 (m, 1H), 6.78 (m, 1H), 5.26 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid ethyl ester (180 mg) and CuCN (66 mg) in NMP (2 mL) was stirred at 130° C. for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (120 mg). LC MS ESI: 387 (M+1)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C1(/C=C/CC(Cl)=O)C=CC=CC=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: O=C(Cl)C/C=C/c1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)C/C=C/c1ccccc1
Yield: 55 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (E)-4-phenylbut-3-enoyl chloride (0.198 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.19 mmol) and triethylamine (0.239 g, 2.37 mmol) in dichloromethane (5 mL) to give (E)-N-(2-azidoethyl)-4-phenylbut-3-enamide (0.168 g, 55% yield). 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J=15.6 Hz, 1H), δ 7.45 (d, J=3.3 Hz, 2H), δ 7.29 (m, 3H), δ 7.04 (t, J=4.1 Hz, 1H), δ 6.59 (d, J=15.9 Hz, 1H), δ 3.55 (q, J=6.0, 5.1 Hz, 2H), δ 3.47 (t, J=1.5 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 141.6, 134.9, 130.1, 129.1, 128.1, 120.8, 51.1, 39.4 ppm; HRMS (ESI) calcd for C11H12N4O (M+) 216.1011. found 216.1005.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:9](=[O:12])[CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C@H:9]1[CH2:10][O:12]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(F)c1)C(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(F)c1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (1S)-[3-Bromo-1-(3,4-difluoro-benzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester (0.14 g, 0.36 mmol) in ethanol:THF (2:1) (3 mL) was cooled to 0° C. and treated with sodium borohydride (0.014 g, 0.36 mmol) in one portion. After 30 minutes the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 12 hours. The solvent was removed and the residue partitioned between saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated sodium bicarbonate solution (25 mL), separated, dried (MgSO4) and the solvent removed at reduced pressure. The product was recrystallized from hexane to give the desired product as the major isomer (>9:1) by NMR (0.095 g, 90%). MS: 300 (M+H, 100%).
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34][CH2:33]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:31][CH:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34][CH2:33]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CC2COc3ccccc3C2)C1
Reaction time: 15 h
Yield: 82.4 %

Procedure:
First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 7.96 g (25 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman in 100 ml of dimethylformamide. The mixture is stirred for 15 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 5.92 g (83%) of 1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a pale yellow oil. The 1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether melts at 158°-159° after crystallisation from methanol/diethyl ether.
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([O:9]CC)=[O:8]>O.C(O)C>[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)c(I)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Reaction time: 1 h

Procedure:
A solution of 18.2 g (276 mmol) of 85 percent potassium hydroxide in 100 mL of water was added to a mixture of 67.8 g (184 mmol) of ethyl 3-iodo-2-methyl-4-methylsulfonylbenzoate in 300 mL of ethanol with stirring. After about 1 hour, all of the solids had dissolved and after 2 hours the mixture was concentrated by evaporation under reduced pressure. The residue obtained was diluted with water and the solution obtained was extracted with ether and then diluted with ethyl acetate. Aqueous hydrochloric acid (3N) was then added until the mixture was acidic. The organic phase was separated and the aqueous phase was twice extracted with ethyl acetate. The organic phase and extracts were combined and washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The 62.1 g (99 percent of theory) of colorless solid residue was the title compound. The purified compound melts at 193° C.
Reaction SMILES: O[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1.CS([O-])(=O)=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CS(C)=O.C(Cl)Cl>[CH2:30]([N:32]([CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: CCNCC
Reactant: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1
Agent: CS(=O)(=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 2 h

Procedure:
3.35 g of 1-(Hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, methanesulfonate in 15 ml dimethylsulfoxide at 0° is added dropwise with stirring to 3 ml of diethylamine in 10 ml dimethylsulfoxide. The reaction is stirred at 20° for 2 hours, diluted with methylene chloride, washed with water and then saturated aqueous sodium chloride. After drying, the solvent is evaporated to give the title compound.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C[O:24][C:25]([C@@H:27]1[CH2:29][C@H:28]1[CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[C:41]3[S:42][CH:43]=[CH:44][C:40]=3[O:39][N:38]=2)[CH2:33][CH2:32]1)=O.CN1CCOCC1.[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1)[CH3:53]>CN(C)C=O>[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH:60][C:25]([C@@H:27]2[CH2:29][C@H:28]2[CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[C:41]4[S:42][CH:43]=[CH:44][C:40]=4[O:39][N:38]=3)[CH2:33][CH2:32]2)=[O:24])[CH2:56][CH2:55]1)[CH3:53]
Reactant: CC[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCC(c2noc3ccsc23)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCC(c3noc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add TOTU (415 mg, 1.06 mmol) to a solution of trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid methyl ester (Example 22b) (300 mg, 1.0 mmol), in dimethylformamide (approximately 10 mL), and allow the reaction to stir at ambient temperature for 0.5 h. Add N-methylmorpholine (107 mg, 1.26 mmol) and trans-4-ethylcyclohexylamine (254 mg, 2.0 mmol), and stir for 6 h. Add additional equivalents of N-methylmorpholine and TOTU and continue to stir for overnight. I think again I didn't write it down Concentrate the reaction and purify the residue by column chromatography over silica gel (dichloromethane/MeOH, gradient 0→30%) to obtain 270 mg (65%), LC/MS, m/z=416 (M+H)+.
Reaction SMILES: [N+](=[C:3]([C:9]([O:11][CH:12]([C:17]([Cl:20])([Cl:19])[Cl:18])[CH:13]=[C:14]([CH3:16])[CH3:15])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-]>CCCCCCCC.[Cu]>[Cl:18][C:17]([Cl:20])([Cl:19])[CH:12]1[CH:13]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:14]2([CH3:16])[CH3:15])[C:9](=[O:10])[O:11]1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CCCCCCCC
Product: CCOC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C

Procedure:
To a refluxing suspension of copper powder (5.0 g,) 0.079 mole) in 240 ml of n-octane was added dropwise in one hour a solution of ethyl (±)-3-methyl-1-trichloromethyl-2-butenyl diazomalonate (5.0 g, 0.0146 mole) in 60 ml of n-octane. The reaction mixture was then heated under reflux for 21/2 hours and filtered. The n-octane was removed from the filtrate by evaporation under vacuum, yielding a residue which was distilled under vacuum to give ethyl (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo-[3.1.0]hexane-1-carboxylate as a highly viscous oil (2.47 g, 54% yield); bp, 123°-125°/0.3 mm.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[N:9]([CH3:13])[N:10]=[CH:11][CH:12]=2)[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4](=[O:17])[CH:3]=1.S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:5]1[C:4](=[O:17])[CH:3]=[C:2]([CH3:1])[N:7]([C:8]2[N:9]([CH3:13])[N:10]=[CH:11][CH:12]=2)[CH:6]=1)=[O:16]
Reactant: CO
Reactant: Cc1cc(=O)c(C(=O)O)cn1-c1ccnn1C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccnn2C)c(C)cc1=O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of preparation 4a (1.8 g, 90% purity, 6.95 mmol) in methanol (5 mL) is added slowly thionyl chloride (1.64 g, 13.8 mmol) at 0° C. The reaction mixture is stirred at 70° C. for 1.5 h, concentrated under reduced pressure and purified by reversed-phase HPLC (Gilson: Sunfire, 30° C., gradient of acetonitrile in water+0.1% formic acid). Yield: 199 mg (12% of theory). ESI mass spectrum: [M+H]+=248; r.t. HPLC: 0.56 min (Z018_S04).