Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclopropyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.23 mmol of cyclopropylamine. LC/MS [8.78 min; 398 (M+1)]
Reaction SMILES: CO[C:3]([O:6][CH3:7])([CH3:5])[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH2:31][CH2:32][OH:33])CO)=[O:26])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:24][C:25]([N:27]1[C@@H:28]([CH2:31][CH2:32][OH:33])[CH2:7][O:6][C:3]1([CH3:4])[CH3:5])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Yield: 47.8 %

Procedure:
2,2-Dimethoxypropane (87 ml, 0.707 mol) and p-toluenesulphonic acid monohydrate (1.33 g, 7 mmol) were added to a stirred solution of the diol 4 (14.39 g, 70 mmol) in dichloromethane (319 ml) at 25° C. The reaction was monitored by TLC (ethyl acetate-hexanes 2:1) until complete (36 h). The reaction mixture was then washed with aqueous NaHCO3 (5%, 2×50 ml), brine (50 ml), dried (MgSO4) and concentrated to form a colourless oil, which crystallised upon standing. The ratio of the desired five-membered ring product 5 to the undesired six-membered ring product 6 was 6.4:3.6. Recrystallisation from heptane gave 5 as colourless needles (8.2 g, 48%). Spectral data for this sample were consistent with those given in the literature3. 1 H NMR (200 MHz, CDCl3) 4.17 (m, 1H), 3.97 (m, 1H), 3.86-3.42 (m, 3H), 3.33 (br, 1H), 1.76 (m, 2H), 1.5 (s, 3H), 1.46 (s, 9H); 13C NMR (50 MHz, CDCl3) 153.9, 93.6, 80.9, 68.2, 58.6, 53.9, 37.7, 27.7, 26.3, 243.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[OH:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][C:33]([OH:32])([C:39]([OH:41])=[O:40])[CH2:34][CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1(O)CCNCC1
Product: O=C1N=C(N2CCC(O)(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Hydroxy-piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:38]3[CH2:39][CH2:40][CH:35]([C:32]4[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=4)[CH2:36][CH2:37]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Yield: 60.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (0.50 g, 1.27 mmol) in ethanol (10 ml) was treated with 4-(4-pyridinyl)piperidine (Monatsh.Chem.; 3; 1882; 867) (0.41 g, 2.54 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 72 hours. Further 4-(4-pyridinyl)piperidine (0.21 g, 1.27 mmol) was added and the mixture heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a pale yellow oil (0.39 g).
Reaction SMILES: C[O-].[Na+].CO.[C:6]12([C:16]3[CH:36]=[CH:35][C:19]([C:20]([CH2:22][O:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[I:34])[C:27]([O:29][CH3:30])=[O:28])=O)=[CH:18][C:17]=3[O:37][CH3:38])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[Br-].[CH3:40]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:34][C:33]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:23][CH:22]=[C:20]([C:19]1[CH:35]=[CH:36][C:16]([C:6]23[CH2:13][CH:12]4[CH2:14][CH:8]([CH2:9][CH:10]([CH2:11]4)[CH2:15]2)[CH2:7]3)=[C:17]([O:37][CH3:38])[CH:18]=1)[CH3:40]
Reactant: COC(=O)c1ccc(I)c(OCC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OC=C(C)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1

Procedure:
A solution of 30% sodium methoxide in methanol (0.3 ml, 1.6 mmol) is added over 8 hours to a mixture of methyl 3-[4-(1-adamantyl)-3-methoxybenzoylmethyloxy]-4-iodobenzoate (870 mg, 1.55 mmol) and methyltriphenylphosphine bromide (790 mg, 2.21 mmol) in THF (10 ml).
Reaction SMILES: [C:1]([O:14][CH:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][CH:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:16]1[CH3:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC1(C)O[O:36]1>>[C:1]([O:14][CH:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([OH:36])[CH:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:16]1[CH3:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC1(C)OO1
Reactant: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1C
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)N(O)C(c2ccccc2)C1C
Yield: 99.4 %

Procedure:
The general procedure of Example 2 is repeated using 11.5 g (25.5 mmol) of 2,6-diphenyl-3-methylpiperidin-4-yl laurate and 570 mL (25.5 mmol) of dimethyldioxirane (0.045M in acetone). 11.8 g (99% yield) of the title compound is isolated: mp 84°-91° C.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])(CC)C.C1CCCCC1.[CH:52]1([C:58]([CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:60]1([C:58]2([CH:52]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)[CH:10]3[CH2:9][N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:13][CH2:12][N:11]3[C:14](=[O:15])[O:59]2)[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(C1CCCCC1)C1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN12
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
1,1-Dimethylethyl 4-(triphenylmethyl)-1-piperazine carboxylate (1.0 g, 2.3 mmol) and tetramethylethylenediamine (1.0 g, 8.6 mmol) were dissolved in tetrahydrofuran (10 mL), which was cooled to −78° C. A 1.0 M solution of sec-butyllithium in hexane and cyclohexane (7.2 mL, 7.2 mmol) was added thereto, and the mixture was stirred for 2 hours and the temperature was elevated to −50° C. After cooling to −78° C. again, a solution of dicyclohexyl ketone (1.1 g, 5.9 mmol) in tetrahydrofuran (10 mL) was added dropwise thereto, and the mixture was stirred for 15 hours while elevating the temperature to room temperature. To the reaction solution was added an aqueous saturated ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain the title compound (0.95 g, yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([Cu])#[N:22]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:21]#[N:22])=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: N#C[Cu]
Product: N#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 46 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (2.0 g) was reacted with CuCN as in General Procedure 6 to give the title compound as an off-white solid (46% yield). M.p. 221-222° C., LCMS: m/z=320.77 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.28 (t, J=4.6 Hz, 2H), 3.45-3.54 (m, 2H), 4.48 (s, 2H), 6.69 (s, 1H), 7.29 (d, J=2.5 Hz, 1H), 7.41 (dd, J=8.6 Hz, 2.5 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.67 (bs, 1H), 7.75 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1.CC(O)=O.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>ClC(Cl)C.CO>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1
Reactant: COC(=O)c1cccc(CN)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
Suspended 3-aminomethyl-benzoic acid methyl ester hydrochloride (100 mg. 0.99 mmol) in 3 mL of dichloroethane in a microwave tube and added 100 uL of AcOH. To this was added benzaldehyde (0.10 mL, 1.00 mmol). The mixture was sealed and heated at 120° C. for 20 minutes resulting in a homogeneous solution. 2 mL of MeOH was added and the mixture was treated with NaBH4 (56.8 mg, 1.50 mmol) resulting in gas evolution. The mixture stirred for 19 h. The mixture was quenched with careful addition of 5% HCl resulting in a bi-phasic mixture. The aqueous phase was removed and treated with 50×2-200 Dowex acidic ion exchange resin. The product was liberated with 10% NH3 in MeOH and concentrated to give 197 mg of 3-(benzylamino-methyl)-benzoic acid methyl ester, partially contaminated with starting benzyl amine (15%).
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:31])[CH2:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:21](O)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:4][C:21](=[O:22])[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:19][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:31]
Reactant: O=C(CC(C(=O)O)c1ccc(Br)cc1)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)C(CC(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
Di-iso-propylethylamine (3.21 g, 4.33 mL, 24.8 mmol) was added in one portion to a stirred suspension of 4-(benzyloxy)-2-(4-bromophenyl)-4-oxobutanoic acid (2.25 g, 6.21 mmol), ammonium chloride (0.332 g, 6.21 mmol) and N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (2.36 g, 6.21 mmol) in dimethylformamide (40 mL) at room temperature under nitrogen. After stirring for 2 h the volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and aqueous hydrochloric acid solution (1.0 M; 50 mL). The phases were separated and the aqueous layer washed with dichloromethane (2×50 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5% methanol: dichloromethane) to give the title compound as a white solid (1.14 g, 51%). LC/MS: 3.20 min; z/e 362 and 364, calcd (M+1) 362 and 364. 1H NMR (400 MHz: CDCl3): 7.45 (2H), 7.30 (5H), 7.15 (2H), 5.45 (2H), 5.10 (2H), 3.95 (1H), 3.30 (1H), 2.70 (1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[O:34])[N:23]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.05 mmol) in dry DMF (1 mL) was added sodium hydride (5 mg, 0.106 mmol) at 0° C. under nitrogen. After 1 h at 0° C., a solution of 2-chloro-N,N-dimethylethanamine hydrochloride (9 mg, 0.064 mmol) and potassium carbonate (9 mg, 0.064) in 1 mL of DMF was added and the resulting mixture was stirred for one hour at 40° C. The reaction mixture was cooled to 0° C. and a saturated solution of NH4Cl was added while stirring, keeping the temperature below 10° C. The resulting mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by PREP HPLC (method G) to give the desired product as a white solid (5 mg, 17% yield). 1H NMR (500 MHz, CDCl3): 8.35 (1H, s), 7.34 (2H, d), 7.29 (2H, d), 7.23-7.25 (3H, m), 7.17-7.20 (2H, m), 5.01 (1H, s), 3.77 (4H, m), 3.28 (2H, t), 2.63 (2H, t), 2.47 (2H+1H, m), 2.35 (6H, s), 2.24-2.32 (2H, m), 1.98-2.12 (1H, m), 1.67-1.89 (9H, br s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[C:23]2[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][O:20]1)[CH3:18]>CN(C)C=O>[CH2:17]([CH:19]1[C:23]2[C:24]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][O:20]1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCC1OCc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 112.6 %

Procedure:
In a 0.5-2.0 ml micro-wave vial 3-ethyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 106, 49.7 mg) was dissolved in N,N-dimethylformamide (1.5 ml) to give a pale yellow solution. 2-chloro-5-nitropyridine (48.0 mg, 0.303 mmol) and potassium carbonate (125 mg, 0.908 mmol) were added. The reaction vessel was sealed and heated in micro-wave Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction completed. The reaction mixture was then quenched with 5 ml of water and diluted with 25 ml of Et2O. The aqueous phase was extracted with 3×10 ml of Et2O. The collected organic phases were passed through a phase separator cartridge and evaporated under vacuum to give the title compound as a pale yellow oil (97.6 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:17][CH2:18][C:19]([NH2:21])=[O:20]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: NCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=NCC(N)=O
Yield: 93.9 %

Procedure:
Fifteen grams of 2-(3-dimethylaminopropoxy)benzaldehyde and 8.1 g of glycinamide, hydrochloride are reacted in 300 ml of ethanol in the presence of 4.8 g of 85% potassium hydroxide as described in Example 1 to give 20 g of a crude semi-solid product. The crude product is triturated with 100 ml of isopropyl ether and cooled to yield 17.9 g of solid; melting point 71°-73° C. (sintering at 60° C.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:18]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[O:19][CH2:20][CH2:21][C:12]2=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:18]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[O:19][CH2:20][CH2:21][C:12]2=1
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(O)cc21

Procedure:
A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 25, in 250 ml. of anhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound, m.p. 170°- 171° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([CH2:7][O:8][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)([OH:6])=[O:5].O>C(OCC)C.CN(C)C=O>[CH3:3][O:5][C:4]([CH2:7][O:8][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CON=c1c2nccc3cccc(c32)n2cccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 0.57M solution of diazomethane in diethyl ether (108 cc.) is added to a suspension of 7-carboxymethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (15 g.) in dimethylformamide (150 cc.) cooled to 0° C. The mixture is kept at between 0° and 5° C. for 3 hours and is then allowed to return to a temperature of about 20° C. Water (450 cc.) is then added, the mixture is cooled in an ice-water bath and the yellow crystals thus obtained are filtered off. After drying, the crude methyl ester (14.17 g.) is obtained. After recrystallisation from ethyl acetate (280 cc.), the 7-methoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline obtained melts at 148 ° C. with decomposition.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH3:17].Cl>C(OCC)C.C1COCC1.O>[NH2:13][CH2:12][C:11]1[CH:10]=[C:9]([CH3:17])[C:8]([OH:7])=[C:15]([CH3:16])[CH:14]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(C)c1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 23.9 %

Procedure:
To a suspension of LiAlH4 (1.51 g, 39.8 mmol) in diethyl ether (40 mL) a solution of 4-hydroxy-3,5-dimethylbenzonitrile (4.89 g, 33.2 mmol) in diethyl ether (20 mL) and THF (10 mL) is added dropwise at rt. The mixture is stirred at rt for 22 h before it is cooled with an ice-bath and carefully treated with water (10 mL), acidified with 25% aq. HCl and diluted with water (30 mL). The mixture is extracted with diethyl ether. The etheral extract is discarded. The aqueous phase is basified to pH˜8 by adding solid NaHCO3, saturated with NaCl, and extracted with diethyl ether followed by EA. The combined organic extracts are dried over MgSO4 and evaporated to leave 4-aminomethyl-2,6-dimethyl-phenol (1.20 g) as a solid. LC-MS: tR=0.51 min, [M+1]+=152.19.
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].Br[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCCCC(CC)CNc1ccccc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)CN(CCC)c1ccccc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of N-(2-ethylhexyl)aniline (8.9 parts), 1-bromopropane (7.4 parts), anhydrous potassium carbonate (11 parts) and N,N-dimethylformamide (30 parts) was stirred at 125° C. for 24 hours. An additional quantity of 1-bromopropane (5 parts) was added and the mixture stirred for a further 18 hours at 125° C. The cooled mixture was filtered and poured into water. The product was extracted into dichloromethane and evaporated to yield N-(2-ethylhexyl)-N-propylaniline (8.9 parts, 78%) which was reacted with acetic anhydride prior to use to remove any unreacted starting materials.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C1(C(C2C=CC=CC=2)=N[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[O:36][CH3:37])C=CC=CC=1>C(O)C>[F:35][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[C:29]2[NH:28][C:16]3[CH2:15][CH2:14][NH:13][CH2:18][C:17]=3[C:34]=2[CH:33]=1
Reactant: COc1cc(F)ccc1NN=C(c1ccccc1)c1ccccc1
Reactant: O=C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1cc(F)cc2c3c([nH]c12)CCNC3
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
p-Toluenesulfonic acid (129 mg, 0.75 mmol) was added to piperidin-4-one hydrochloride (50.8 mg, 0.37 mmol) and 1-(diphenylmethylene)-2-(4-fluoro-2-methoxyphenyl)hydrazine (80.0 mg, 0.25 mmol) in ethanol (1.25 mL) at 25° C. over a period of 1 min under air. The resulting suspension was stirred at 80° C. for 16 hours. The reaction mixture was diluted with EtOH (20 mL), and EtOAC (100 mL) then washed sequentially with saturated NaHCO3 (75 mL), saturated NaHCO3 (75 mL), and saturated brine (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (containing 0.1% NH3, CH3CN/H2O) as eluents. Fractions containing the desired compound were evaporated to dryness to afford 8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (25.0 mg, 46%) as an off-white solid.