Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[NH:16][C:15]2[CH:25]=[CH:26][CH:27]=[N:28][C:14]1=2)=[O:12])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[NH:16][C:15]2[CH:25]=[CH:26][CH:27]=[N:28][C:14]1=2)=[O:12]
Reactant: O=C1Nc2cccnc2N(C(=O)CCNCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: NCCC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
16.4 gm of 11-[3-(benzylamino)propionyl]-5,11-dihydro-6H-pyrido-[2.3-b][1,4]benzodiazepin-6-one (prepared according to Example 6), together with 3 g of palladium-on-charcoal, were hydrogenated in 300 ml of absolute ethanol for 7 hours at 70° C. and 5 atm. Then the catalyst was filtered off, the alcohol was distilled off, and the residue was purified on a column. After evaporation of the eluate, the residue was recrystallized from ethanol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[CH3:30]O>>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH3:30])=[O:19])(=[O:16])=[O:15]
Reactant: CO
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 1, piretanide can be reacted with thionyl chloride and methanol to yield methyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.[ClH:27]>C(OCC)C.O1CCOCC1>[ClH:27].[NH2:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Benzyl (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate (12.8 g, 36 mmol) was stirred in HCl, 2 M in diethyl ether (90 mL) and HCl, 4 M in dioxane (18 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with hexanes (100 mL) and filtered to collect the title compound (7.98 g, 76%) as a fine white powder. 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.40-7.15 (m, 10H), 5.23 (s, 2H), 4.36-4.31 (m, 1H), 3.26-3.12 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.Cl.[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][N:15]([CH3:14])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: CN(C)c1ccc(O)c(C=O)c1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc(N(C)C)ccc1O
Temperature: 0 °C
Yield: 34 %

Procedure:
0.5 g (3 mmol) of 5-(dimethylamino)-2-hydroxybenzaldehyde (Bull. Chem. Soc. Jpn. (1978), 51 (8), 2433–2434) and 0.72 g (3.33 mmol) of N-methyl2-(4-nitrophenyl)ethylamine hydrochloride are placed in solution in 30 ml of anhydrous methanol under an inert atmosphere in the presence of 0.65 ml of triethylamine (4.5 mmol). The reaction mixture is stirred vigorously for 18 hours before the addition, by portions, of 126 mg (3.33 mmol) of NaBH4. Stirring is maintained for a further 4 hours before adding 10 ml of ice-cold water. The reaction mixture is extracted twice with 50 ml of CH2Cl2. The organic phase is washed with 10 ml of water, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: CH2Cl2/MeOH: 97/3). The expected product is obtained in the form of a brown oil with a yield of 34% (0.34 g).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)=[CH:9][N:8]2[C:30]=1[CH3:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:31][C:30]1[N:8]2[CH:9]=[C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:4][CH2:3][CH2:2][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Reactant: C1COCCN1
Product: Cc1c(CCCN2CCOCC2)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12

Procedure:
The compound (20.0 mg) obtained in Example 14 and morpholine (1 mL) were processed in the same manner as in Production Example 46-3 to obtain the entitled compound (13.0 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C@@H:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C@@H:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CC[C@H]1CC[C@@H](c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCO)CC[C@@H]2c2ccc(F)cc2)cc1

Procedure:
white solid, m.p. 96° C., [α]D20=+97.5° (c=1.1287 in chloroform) and MS: m/e=378.2 (M+H+); [(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester: colorless oil, [α]D20=+94.0° (c=1.0868 in chloroform) and MS: m/e=406.1 (M+H+)].
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 274.9 %

Procedure:
To a solution of 45 (1.1 g, 0.717 mmol) in MeOH (30 mL) and water (10 mL) was added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g, 17.76 mmol) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to RT then concentrated to dryness. The residue was partitioned between DCM and water and the organic phase was collected, dried over Na2SO4, filtered and concentrated to afford the title compound 46 (1.04 g, 100% yield), which was used crude in the next step with no additional purification. MS (m/z): 528.1 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(CNC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Benzyl chloroformate (231.3 g, 1.3 mol) was added gradually to a mixture of aminoacetaldehyde dimethyl acetal (152.0 g, 1.3 mol) in toluene (750 mL) and aqueous NaOH (72.8 g, 1.82 mol; in 375 mL of water) at 10-20° C. After the addition was completed, the mixture was stirred at ambient temperature over 4 hours. The organic layer was separated, washed with brine (2×100 mL) and concentrated to provide the title compound as an oil (281.5 g, 90% yield). 1H NMR (CDCl4, 300 MHz) δ 3.33 (t, J=6.0 Hz, 2H), 3.39 (s, 6H), 4.37 (t, J=6.0 Hz, 1H), 5.11 (s, 2H), 7.30 (m, 5H); MS (DCI/NH3) m/z 257 (M+NH4)+, 340 (M+H)+.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][NH:20][C:19](=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8]
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCCNC(=O)CCCCCCCCCCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of 4.0 M hydrochloric acid in dioxane (1 mL) was added dropwise to a solution of amide 4 (154 mg, 0.40 mmol) in dichloromethane (3 mL) which was pre-cooled to 0° C. After this time, the reaction was then allowed to warm to ambient temperature and stirred for an additional 2 hours. After this time, the solvent was removed under vacuum to give salt 5 (124 mg, 86%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 1.34 (s, 12H), 1.53-1.66 (m, 6H), 1.87-1.98 (m, 2H), 2.19-2.37 (m, 3H), 2.88-2.97 (m, 8H), 3.20-3.28 (m, 2H), 3.28-3.33 (m, 2H); m/z (ESI) 286 [C16H35N3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([NH2:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:12][N:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nsc(-c2ccc(Cl)cc2)n1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nsc(-c3ccc(Cl)cc3)n2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1,2,4-thiadiazol-3-amine (423 mg, 2.0 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. EtOH was used in the second extraction to assist solublizing the sulfonamide. After drying over Na2SO4, solvent was removed in vacuo. The crude crystalline product weighed 0.45 g. The crude product was taken up in 13 mL of hot HOAc, diluted with 7 mL of H2O and seeded to give white needles (384 mg) after collection by filtration, washing with H2O, and drying in vacuo. The product had mp 220-221° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:21]([C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc2ccccc2c2[nH]cnc12
Product: c1ccc(Oc2nc3ccccc3c3[nH]cnc23)cc1

Procedure:
In step (4) of Reaction Scheme IV a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula XX is reacted with phenol to provide a 4-phenoxy-1H-imidazo[4,5-c]quinoline of Formula XXI. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form a phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XX.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]2[C:11]=1[C:19](=[O:21])[N:23]([C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:13]2=[O:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Yield: 51.2 %

Procedure:
A mixture of 3-(t-butoxycarbonylamino-methyl)-phthalic acid (3.3 g, 11.2 mmol) and 3-amino-3-methyl-piperidine-2,6-dione hydrochloride (2.0 g, 11.2 mmol) in pyridine (40 mL) was refluxed for 17 hours. The mixture was cooled and concentrated. The residue was dissolved in EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (40 mL), Sat. NaHCO3 (40 mL), water (40 mL), and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (Silica gel) to give [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamic acid t-butyl ester (2.3 g, 51%): 1H NMR (CDCl3) δ 1.43 (s, 9H, 3(CH3)), 2.08 (s, 3H, CH3), 2.10-2.15 (m, 1H), 2.69-2.84 (m, 3H), 4.62 (d, J=6.5 Hz, 2H, CH2), 5.46 (m, 1H, NH), 7.64-7.76 (m, 3H, Ar), 8.15 (s, 1H, NH).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][C@@H:9]([NH:15]C=O)[C:10]([O:12]CC)=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][C@H:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH2:5][OH:4])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
12.7 g (30.2 mmol) of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 100 ml of abs. CH2Cl2 and 15.6 ml (120.8 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 100 ml of abs. ethanol the reaction mixture is again allowed to stand for 24 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethanol and then a mixture of 100 ml of propylene oxide and 100 ml of ethanol is added dropwise. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is stirred overnight in ether and again filtered with suction. The filter product is dried, giving white crystals of 2(R)-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid. Melting point: 170° C. (decomp.). ee=92%; αD =-45.6°± 1° (c=1.0 H2O).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]1([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[SH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:26][C:22]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=[CH:24][N:23]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nccn1-c1ccccc1
Product: O=C(CSc1nccn1-c1ccccc1)N1CCCc2ccccc21
Yield: 69 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1-phenyl-1H-imidazole-2-thiol as the nucleophile to yield 27 as a yellow gum (69%): MS m/z: 350 (M+H)+. Anal. Calcd. For, C20H19N3OS: C, 68.74; H, 5.48; N, 12.02; S, 9.18. Found: C, 68.47; H, 5.71; N, 11.75; S, 8.96.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH:18]([CH3:20])[C:17](=[O:21])[CH:16]([CH3:22])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH:18]([CH3:20])[C:17](=[O:21])[CH:16]([CH3:22])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=O
Solvent: c1ccccc1
Product: CCOC(=O)N1CC(C)C(=O)C(C)C1
Reaction time: 6 h

Procedure:
Ethyl chloroformate (10.0 g, 90 mmol) was added to a stirred solution of 1-benzyl-3,5-dimethyl-4-piperidinone (5.0 g, 24 mmol) in benzene (20 ml), refluxed with stirring for 6 hr and concentrated to dryness to give 1-carbethoxy-3,5-dimethyl-4-piperidinone as oil. Yield 4.51 g (90%), C10H17NO3, m/z 200 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[CH:15]1([NH:21][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 97.9 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (5.00 g, 23.2 mmol), cylohexylamine (3.98 mL, 34.8 mmol), and triethylamine (4.8 ML, 35 mmol) in acetonitrile (75 mL) was reluxed for 22 h under an argon atmosphere. The reaction mixture was concentrated to a volume of ˜20 mL and the precipitated solid was filtered. The filtrate was diluted with ethyl acetate and was washed with 1M citric acid (1×) followed by saturated NaHCO3 (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 50-70% dichloromethane/hexanes (v/v)) to give compound 45 as a yellow solid (6.32 g, 98%). ESI-MS m/e 279.2 (M+1).
Reaction SMILES: S.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.C(N)(=[S:22])C>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([NH2:12])=[S:22])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(N)=S
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: S
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=S)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Hydrogen sulfide (gas) was bubbled into a solution of (3,4-dichloro-phenyl)-acetonitrile (1.86 g, 10 mmol, 1.0 eq)) and triethyl amine (10 mmol, 1 eq) in ethanol (10 ml) for about 1 hour. After 1 hour the reaction mixture capped and stirred at room temperature overnight. TLC showed that most of nitrile was converted to thioacteamide. Excess of H2S was removed by bubbling nitrogen into the reaction mixture for 30 min. The reaction mixture was then concentrated and purified by silica gel chromatography (ISCO system, 30–60% ethylacetate/hexane) to give the title compound (1213) (55% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][N:13]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CN(CC(=O)Nc1ccccc1[N+](=O)[O-])Cc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CN(CC(=O)Nc1ccccc1N)Cc1ccccc1
Yield: 46.3 %

Procedure:
A suspension of N-(2-nitrophenyl)-2-(N-benzyl-N-methylamino)acetamide (30 g) and platinum oxide (0.3 g) in methanol (500 ml) was shaken in an atmosphere of hydrogen at laboratory temperature and atmospheric pressure until the uptake of hydrogen was complete. 6.6 Litres of hydrogen were absorbed. The mixture was filtered, and evaporated to dryness to give an oil which was extracted with boiling cyclohexane (1litre). On cooling, N-(2-aminophenyl)-2-(N-benzyl-N-methylamino)acetamide (12.5 g) was obtained as off-white crystals, m.p. 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1.ClCl>C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:28][CH:27]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.4 %

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2 Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[Mn]([O-])(=O)(=O)=O.[K+].Cl.C[C:23](C)=[O:24]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:24][CH3:23])=[O:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: CC(C)=O
Reactant: OCc1ccc(OCC2CC2)c(Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(OCC2CC2)c(Cl)n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of (6-chloro-5-(cyclopropylmethoxy)pyridin-2-yl)methanol (14.0 g) in acetone (100 mL) was added dropwise a solution of potassium permanganate (14.5 g) in water (100 mL) over 40 min at 0° C., and the mixture was stirred at the same temperature for 20 min. The reaction mixture was acidified with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (100 mL), potassium carbonate (9.06 g) and methyl iodide (4.10 mL) were added thereto, and the mixture was stirred with heating at 70° C. for 20 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.27 g).