Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:17])[C:15]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([Cl:9])[C:15]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: CCN1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCN1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 66.9 %

Procedure:
General procedure C was followed using N-ethylpiperazine (31 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (47 mg, 66%), umax (CHCl3)/cm−1 2975, 2820, 1559, 1448, 1245, 1151, 957; m/z (ESI) C11H16Cl2N3 requires 260.0716, found [M+H]+ 260.0719.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N)C>CN(C=O)C.C(Cl)Cl>[NH2:25][C:26]1[C:34]([Br:35])=[C:33]([F:36])[CH:32]=[CH:31][C:27]=1[C:28]([NH:9][CH2:10][CH3:11])=[O:30]
Reactant: Nc1c(C(=O)O)ccc(F)c1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(F)c(Br)c1N
Temperature: 23 °C
Reaction time: 17 h
Yield: 77.4 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU; Aldrich; 5.36 g, 14.10 mmol) was added to a mixture of 2-amino-3-bromo-4-fluorobenzoic acid (Example 719; 3.00 g, 12.82 mmol), ethylamine (2.0 M in MeOH; Aldrich; 7.05 mL, 14.10 mmol), and TEA (2.68 mL, 19.23 mmol) in a mixture of DMF (10 mL) and DCM (10.00 mL), and the resulting solution was stirred at 23° C. for 17 h. The reaction mixture was then diluted with DCM (100 mL), and the resulting solution was sequentially washed with water (2×80 mL), 0.5 N aqueous NaOH (50 mL), and brine (50 mL), then concentrated in vacuo. The residue was chromatographically purified (silica gel, 0-60% EtOAc/hexanes) to yield 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (2.59 g, 9.92 mmol, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, t, J=4.5 Hz), 7.59 (1H, dd, J=8.8, 6.3 Hz), 6.86 (2H, br. s.), 6.57 (1H, t, J=8.5 Hz), 3.20-3.29 (2H, m), 1.11 (3H, t, J=7.2 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −101.26 (1F, s). m/z (ESI, +ve) 260.9/262.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]([CH3:15])[CH3:14].O.N.[CH3:18][N:19]1CCCC1=O>>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([C:18]#[N:19])=[CH:5][C:4]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CN1CCCC1=O
Reactant: CSc1cc(C(C)C)c(Br)cc1C(C)C
Agent: N
Solvent: O
Product: CSc1cc(C(C)C)c(C#N)cc1C(C)C
Temperature: 25 °C

Procedure:
4-Cyano-2,5-diisopropylphenyl methyl sulfide was prepared as follows: A mixture of 20.4 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide prepared as in Example 1C and 8.9 g of cuprous cyanide was heated at reflux in 100 ml of N-methylpyrrolidone under nitrogen for 2 hours. After cooling to ambient temperature, the reaction mixture was poured into a mixture of 200 ml of water and 100 ml of concentrated aqueous ammonia. The product was filtered and extracted into ether. The extract was washed with 5% HCl followed by a saturated solution of sodium chloride. The organic layer was dried over sodium sulfate and the solvent removed to give 15.5 g of 4-cyano-2,5-diisopropyl methyl sulfide which was recrystallized from n-hexane giving pure product having a melting point of 72°-75°C.
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:11]([CH2:32][OH:33])[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:11]([CH2:32][O:33][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](COCc3ccc(Cl)cc3)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A suspension of sodium hydride (71 mg, 1.8 mmol) in dry DMF (5 mL) was cooled to 0° C., and a solution of methyl 2-azido-4-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (33) (680 mg, 1.5 mmol) in dry DMF (5 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and 4-chlorobenzyl chloride (295 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4.5 hours, cooled at 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (10 mL) was co-evaporated from the residue. The residue was treated with hexane (10 mL) and filtered to give methyl 2-azido-4-O-benzyl-6-O-(4-chlorobenzyl)-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (34) (620 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[CH2:14][O:15][C:5]2([CH2:4][CH2:3][C:2]([CH3:1])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6]2)[O:8]1
Reactant: OCCO
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1(C)CCC2(CC1)OCCO2
Yield: 100 %

Procedure:
Methyl 1-methyl-4-oxocyclohexanecarboxylate (30 g) was dissolved in benzene (300 ml). Ethylene glycol (30 ml) and p-toluenesulfonic acid monohydrate (1 g) were added, and the mixture was refluxed for 4 hours. The water which formed during the heating was removed by using a water trap. After cooling, the mixture was washed with water and dryed (MgSO4). The solvent was distilled off to give methyl 4,4-ethylenedioxy-1-methylcyclohexanecarboxylate as an oil (37.8 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[C:9]1([C:15](=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccnc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1cccnc1)c1ccccc1
Yield: 30.2 %

Procedure:
To a mixture of 4.3 g of 3-pyridinecarbaldehyde, 5.4 g of phenylacetic acid, and 11.4 ml of acetic anhydride, 5.6 g of triethylamine is added with stirring, and the mixture is stirred at 100° C. for 4 hours. The reaction mixture is alkalified with 10% aqueous sodium bicarbonate solution. The aqueous solution is warmed and filtered. The filtrate is adjusted to pH 4.5 with 10% hydrochloric acid, and the resulting precipitate is collected and recrystallized from ethanol to give 2.7 g of the title compound, m.p. 190°-192° C.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.C(Cl)Cl>[CH2:2]([N:9]1[CH2:10][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=3)[O:13]2)[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
1 M HCl in Et2O (5.0 ml) was added dropwise to a solution of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 g, 0.80 mmol) in DCM (4 ml). The mixture was stirred at RT overnight. The formed precipitate was filtered off, washed with DCM, dried under vacuum and purified by preparative HPLC to give (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (290 mg, trifluoroacetate salt) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[C:21](O)=[O:22])[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=1.S(Cl)([Cl:29])=O>>[ClH:29].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[C:21]([Cl:29])=[O:22])[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)[nH]c1=O
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1ccc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.5 g (20 mmol) of the above pyridone acid and 25 ml of thionyl chloride is stirred overnight at room temperature. The solid is filtered, washed with ether and dried under high vacuum over phosphorus pentoxide to give 8.62 g of 6-[3-(3-pyridinylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid chloride hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:15](=[O:17])[CH3:16])[O:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(CNC(C)=O)=CO2
Temperature: 0 °C

Procedure:
The crude amine obtained in Step C is dissolved in 10 ml of anhydrous pyridine; the mixture is then cooled to 0° C. 0.41 g (4 mmol) of acetic anhydride is added to that solution; stirring is then maintained for 30 minutes. The solvent is then evaporated in vacuo; the residue is then taken up in dichloromethane. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. After during over magnesium sulphate and evaporation of the solvent in vacuo, the title amide is obtained pure in the form of a white solid after passage over a silica column (eluant: MeOH/CH2Cl2: 10/90).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:17]2[C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cccc(-c5ccccc5)c4c3CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Yield: 121.7 %

Procedure:
A mixture of 3-benzyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g, 0.62 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.11 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.198 g (90%) of a brown foam. Crystallization from ethyl acetate gave 0.030 g of the title compound as a beige solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ 7.97, 7.48-7.36, 7.16, 6.94, 3.12-3.08, 3.02-2.98, 2.87-2.83, 2.47-2.43; IR (drift) 3053, 3025, 2927, 2895, 2833, 1458, 1428, 1415, 1335, 1292, 1262, 790, 760, 751, 703 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found 263.1550.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:19]([O:23][C:24]([NH:26][NH:27][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Reaction time: 72 h
Yield: 72.4 %

Procedure:
To a solution of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid (1.13 g, 4.50 mmol) in DCM (6.5 ml) was successively added Hydrazinecarboxylic acid tert-butyl ester (0.59 g, 4.50 mmol), HOBT (0.69 g, 4.50 g) and EDCI.HCl (1.29 g, 6.758 mmol). The mixture was stirred at R.T for 72 h. The solvent was removed under reduced pressure and the residue was diluted with DCM was added. The organic layer was washed twice with water, twice with HCl 1N and twice with water. The organic layer was dried over Na2SO4, filtered and evaporated to afford 1.19 g (73%) of N′-[1-(4-Fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazinecarboxylic acid tert-butyl ester as a colorless semi-solid.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:25]=O)=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:25][NH:6][CH3:5])=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2ccc(Cl)cc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cc(Cl)ccc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 6-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and CuI (0.03 g) in DMF/Piperidine (20 ml) was heated at 60° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157-159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82-7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=0.9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>C1COCC1>[NH2:5][CH2:4][C:3]1[C:2]([NH2:1])=[N:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cc(-c2ccccc2)nc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1c(-c2ccc(Cl)cc2Cl)cc(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, a solution of 2-amino-4-(2,4-dichloro-phenyl)-6-phenyl-nicotinonitrile (580 mg, 1.71 mmol) in THF (2 ml) is added slowly to a suspension of LiAlH4 (324 mg, 8.52 mmol) in THF (2 ml). After stirring for 2 h at room temperature, the reaction mixture is cooled to −20° C. and water (0.4 ml) is added. After 15 min, ethyl acetate is added and the mixture is filtered through Decalite. The organic phase is then separated, washed with water, and dried over sodium sulfate. Purification by flash chromatography (silica gel, methanol, dichloromethane) affords the title compound, MS: m/e=343.8 (M+H+), as a light yellow solid (36 mg, 6%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C[Li].Cl[C:16]([N:18]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17].C1C[O:34]CC1>>[C:16]([N:18]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)([OH:34])=[O:17]
Reactant: CCCCN1CCC(CO)CC1
Reactant: C1CCOC1
Reactant: O=C(Cl)N1c2ccccc2C2CCCCC21
Agent: [Li]C
Product: CCCCN1CCC(CC2CCCC3c4ccccc4N(C(=O)O)C23)CC1
Reaction time: 0.17 h

Procedure:
1-Butyl-4-piperidinylmethanol (0.500 g 2.12 mmol) was dissolved in dry THF (3 ml) and treated with methyllithium (1.5M solution in diethyl ether) 2.16 ml, 2.33 mmol) with stirring under nitrogen. After 10 minutes, N-chlorocarbonyl-1,2,3,4,4a,9a-hexahydrocarbazole (0.630 g, 2.68 mmol) (Ref: WO 89/09217) in dry THF (5 ml) was added dropwise with stirring. After 48 hours, the reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica-gel chromatography, eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3 to give the title compound as a clear, colourless oil, which was converted to the oxalate salt, nap 187°-189° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O-])([O-])=O.[Na+].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added Na2CO3 (12.1 ml, 2M in water) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture was stirred at room temperature for 4 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ7.34 (m, 5H), 5.27 (d, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:2][CH3:3]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(C(C)=O)cc1C(=O)OC
Yield: 43.5 %

Procedure:
Iodoethane (16.4 g, 0.105 mol) was added to a stirred mixture of 5-acetyl-2-hydroxybenzoic acid methyl ester (10 g, 51.5 mol) and anhydrous potassium carbonate (14.4 g, 0.104 mol) in 2-butanone (200 ml) and the resulting mixture heated under reflux for 3 days. The solvent was removed by evaporation under vacuum and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was removed and extracted with further ethyl acetate (4×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (130 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give the title compound as colourless crystals (10.15 g, 89%), m.p. 50-55° C. Found: C,64.88; H,6.38. C12H14O4 requires C,64.85; H,6.35%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.83 h
Yield: 169.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.84 g) and commercially available 4-nitrophenol (3.42 g) was mixed and stirred at 170° C. for 50 minutes. After cooling to room temperature in air, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the admixture was extracted 3 times with ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol to obtain 4.54 g of the title compound (yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C[N:22]1CCOCC1.N.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:22])=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 84a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutylchloroforamte (0.148 mL, 1.14 mmol). The resulting mixture was allowed warm to room temperature with stirring for thirty minutes. Subsequent cooling in an ice bath was followed by addition of ammonia gas and warming to room temperature. The title compound was isolated by the addition of water and collection of the solid by vacuum filtration was used without further purification (0.289 g, 96%).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:3]([C:9](=[O:10])[NH2:11])([CH3:2])[CH2:4]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C(N)=O)CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C(N)=O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 409.7 %

Procedure:
To a solution of 3-Methyl-piperidine-3-carboxylic acid amide hydrochloride (740 mg, 4.1 mmol) in a cosolvent of 1,4-dioxane and water (12 mL, v:v=5:1) was added sodium carbonate (1.6 g, 15 mmol). The mixture was cooled to 0° C., benzyl chloroformate (900 mg, 0.53 mmol) was added, and the mixture was allowed to stir at room temperature for 3 h. LCMS showed starting material was consumed. The volatile components were removed, and the residue was extracted with ethyl acetate, purified by column chromatography (eluting with 10% methanol in dichloromethane) to give 600 mg (53%) of 3-Carbamoyl-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method K, ESI): RT=1.18 min, m+Na=298.8; 1H NMR (400 MHz, CDCl3) δ: 7.32-7.23 (m, 5H), 5.07-5.03 (m, 2H), 4.30-4.10 (m, 1H), 4.10-3.90 (m, 1H), 3.10-2.40 (m, 2H), 1.65-1.75 (m, 2H), 1.60-1.30 (m, 2H), 1.25-1.15 (m, 1H), 1.09 (s, 3H).