Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]([NH2:35])=[C:18]2[CH2:36][C:37]2[O:41][C:40]([C:42]([O:44]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:43])=[CH:39][CH:38]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:42]([C:40]1[O:41][C:37]([CH2:36][C:18]2[CH:17]([C:15]([OH:16])=[O:14])[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]=2[NH2:35])=[CH:38][CH:39]=1)([OH:44])=[O:43]
Reactant: NC1=C(Cc2ccc(C(=O)OC(c3ccccc3)c3ccccc3)o2)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC1=C(Cc2ccc(C(=O)O)o2)C(C(=O)O)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 0.17 h

Procedure:
A mixture of 0.550 g of 3-(5-diphenylmethoxycarbonyl-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester and 0.380 g of anisol is treated with 10 ml of trifluoroacetic acid and left to stand for 10 minutes at room temperature. The mixture is diluted with an equal volume of toluene and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and a 10% aqueous dipotassium hydrogen phosphate solution (pH 7.8). The layers are separated, the aqueous phase is washed several times with ethyl acetate and the pH adjusted to 2.5 by addition of 20% aqueous phosphoric acid. After extraction with ethyl acetate, the resulting organic extracts are washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is recrystallised from ethyl acetate and yields the 3-(5-carboxy-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid, which melts at 194°-195°; [α]D20 = + 315° ± 1° (c = 1.010 in dioxan): thin-layer chromatogram (silica gel): Rf = 0.65 (system n-butanol/acetic acid/water 67:10:23) and Rf = 0.38 (system n-butanol/ethanol/water 40:10:50); infrared absorption spectrum (in mineral oil): characteristic bands at 2,99μ, 5,67μ, 5,76μ, 5,90μ, 6,04μ, 6,26μ, 6,51μ and 6,53μ (shoulder).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[OH:15].O.[NH2:17][NH2:18]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][C:3]=1[OH:15]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(O)c1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(Cl)c(O)c2)=NN1

Procedure:
3-(4-chloro-3-hydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(4-chloro-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
13 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is heated to reflux with 9 g of propargyl alcohol and 0.1 g of p-toluenesulphonic acid. The excess propargyl alcohol is thereupon slowly (5hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether phase is dried with sodium sulfate and evaporated. There is obtained dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester which is purified on Kieselgel.
Reaction SMILES: [NH2:1][S:2]([C:5]1[S:9][C:8]([NH:10]C(=O)C)=[N:7][C:6]=1[CH3:14])(=[O:4])=[O:3].FC1C(F)=CC=CC=1CSC1N=C(NS(C2SC(NC(=O)C)=NC=2C)(=O)=O)C=C(OC)N=1>O.NN.O>[NH2:10][C:8]1[S:9][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[C:6]([CH3:14])[N:7]=1
Reactant: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Agent: COc1cc(NS(=O)(=O)c2sc(NC(C)=O)nc2C)nc(SCc2cccc(F)c2F)n1
Agent: NN
Solvent: O
Product: Cc1nc(N)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]acetamide (the product from Example 53, step (0.44 g) in hydrazine hydrate (1.5 ml) was stirred at room temperature for 4 h. The mixture was diluted with H2O and extracted with EtOAc (×4). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as an off-white solid. Yield 0.23 g.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:12])[CH3:11])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[C:16]([CH3:29])[C:15]=1[OH:30].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:30][C:15]1[C:16]([CH3:29])=[CH:17][C:18]([C:2]2[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:12])[CH3:11])[CH:3]=2)=[CH:19][C:14]=1[CH3:13]
Reactant: COc1nnc(Cl)cc1C(C)=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
250 mg of 1-(6-Chloro-3-methoxy-pyridazin-4-yl)-ethanone and 232 mg of tetrakis(triphenylphosphine) palladium (0) are dissolved in 5 ml DME and the solution is stirred for 5 min at RT under argon. 400 mg of 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol and 1.4 ml of a 2M aqueous solution of sodium carbonate are added and the reaction solution is stirred at 95° C. for 4 h. The reaction solution is filtered through a silica gel cartridge, eluting with dichloromethane. The solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 334 mg. LC-MS (ES+) 273 (M+H)+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N:31]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[CH:27][C:26]=5[F:46])=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 20.1 %

Procedure:
To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg, 0.877 mmol, from example 6) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.584 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, the reaction mixture was warmed up to 40° C. and continued to stir for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (1:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (65 mg, 18%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH:22]([F:24])[F:23]>[OH-].[Na+].O1CCOCC1.O>[F:23][CH:22]([F:24])[S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(S)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(SC(F)F)cc2c1-c1ccccc1

Procedure:
6-Mercapto-3-nitro-4-phenylquinoline (1.00 g) was dissolved in a mixture of 2N-sodium hydroxide (20 ml) and dioxane (20 ml), and into the solution was introduced chlorodifluoromethane gas for 2 hrs. at 75°-80° C. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with aqueous 2N-sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was recrystallized from isopropyl ether to give 6-difluoromethylthio-3-nitro-4-phenylquinoline as yellow prisms. Yield 948 mg (80.5%). m.p. 101°-103° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16].O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)COc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid methyl ester (0.21 g, 0.46 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.039 g, 0.93 mmol). The resulting mixture was stirred at ambient temperature for three hours. The reaction was acidifed to pH 4 with 0.2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.16 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:7]=2[O:6]1)#[N:2].S([O-])([O-])(=O)=O.[Ba+2]>O1CCCC1.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH:5]([CH2:4][CH2:3][C:1]#[N:2])[CH2:9][C:8]=2[CH:10]=1
Reactant: N#CCCC1Cc2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: N#CCCC1Cc2cc(N)ccc2O1
Yield: 95.6 %

Procedure:
Starting from 3.2 g (15 mmol) of 2-cyanoethyl-5-nitro-2,3-dihydrobenzofuran in 80 ml of tetrahydrofuran, hydrogenated in the presence of 0.32 g of palladium on 5% barium sulfate under the conditions described in step 7 of Example 7, 2.7 g of product were obtained.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([CH2:25][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)([NH2:28])[CH3:27])[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:28][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:14])([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)[CH3:27])[CH2:24][CH2:23]1
Reactant: Cc1nnc(C(C)(N)CC2CC2)o1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: Cc1nnc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 1-cyclopropyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-amine (example 173b) as starting materials and isolated (70 mg, 46%); MS (ESI, m/z): 473.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8])[CH3:2].C(O)(=O)C(O)=O.[CH2:16]([NH:18][NH2:19])[CH3:17].Cl>C(O)C>[CH2:16]([N:18]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:19]1)[CH3:17]
Reactant: CCOCC(=O)CC#N
Reactant: CCNN
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOCc1cc(N)n(CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a 25 mL round bottom was added 4-(ethyloxy)-3-oxobutanenitrile (550 mg, 4.33 mmol), ethyl hydrazine oxalate (641 mg, 4.33 mmol), and HCl (2.163 mL, 4.33 mmol) in ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated, and partitioned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated. 1-Ethyl-3-[(ethyloxy)methyl]-1H-pyrazol-5-amine (420 mg, 2.234 mmol, 51.6% yield) was isolated as yellow oil. The product was used in the next step without further purification. LCMS (M+H)+=170.1 (M+H); 1H NMR (400 MHz, DMSO-d6) ppm 1.08 (t, J=6.95 Hz, 3 H) 1.19 (t, J=7.07 Hz, 3 H) 3.37-3.43 (m, 2 H) 3.81 (q, J=7.24 Hz, 2 H) 4.15 (s, 2 H) 5.09 (s, 2 H) 5.22 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:34].[Li+].[OH-]>CO.O>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[CH2:6][CH2:5]2)[C:3]1=[O:34]
Reactant: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.5 %

Procedure:
To a solution of (E)-methyl 1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (75 mg, 0.16 mmol) in methanol (4 mL) was added a solution of LiOH in H2O (2 M, 4 mL) at rt and the mixture was stirred for 8 h at rt. The reaction mixture was concentrated to remove methanol and extracted with CH2Cl2 twice. The combined organic phases were dried, filtered and concentrated to give (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (106 mg, 65%). 1H NMR (CD3OD): 1.94 (m, 4H), 3.26 (s, 3H), 4.15 (m, 3H), 4.22 (m, 1H), 7.01 (d, 1H), 7.28 (d, 1H), 7.53 (m, 1H), 7.66 (m, 1H), 7.76 (m, 1H), 8.01 (m, 3H), 8.08 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(C(C)=O)CCC2
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of 1-acetyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (350 mg, 1.40 mmol) in ethyl acetate (20 mL) was taken in a Fischer Porter apparatus and treated with 10% palladium on carbon (100 mg, Aldrich). After rinsing the sides of the flask with ethyl acetate, methanol (30 mL) was added and the mixture was stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (270 mg, 1.23 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.86 (m, 2 H), 2.06-2.13 (m, 3 H), 2.53-2.61 (m, 2 H), 3.56-3.61 (m, 2 H), 3.73 (s, 3 H), 4.55 (bs, 2 H), 6.46-6.91 (m, broadened signals caused by amide rotomers, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10]3=[C:11]([CH2:13][CH2:14][N:9]3[C:8]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:7]2=3)[CH:12]=1)([O-])=O>[Pd]>[CH:5]1[C:4]([NH2:1])=[CH:12][C:11]2[CH2:13][CH2:14][N:9]3[C:10]=2[C:6]=1[C:7]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:8]=13
Reactant: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCC1
Agent: [Pd]
Product: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1

Procedure:
Following the procedure of Example 1, step 3, 2-nitro-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole was hydrogenated over 5% palladium on carbon to provide 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine which was used for the coupling reactions.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]([CH2:25][C:26]#[N:27])(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:25]=[C:26]([NH2:27])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried ill vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR (DMSO-d6): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][CH:5]2[O:9][CH2:8][CH2:7][O:6]2)[CH2:20][CH2:19]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCCCC1OCCO1
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC2OCCO2)CC1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of 5.4 g of 2-(3-chloropropyl)-dioxolan and 15.9 g of 1-(2-methoxyphenyl)-piperazine in 60 ml of dimethylformamide was stirred at 80° C. for 4 hours. After cooling to 20°-25° C., the reaction mixture was poured into 500 ml of ice cold 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane:ethanol 95:5. 9.8 g of 2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-dioxolan was obtained as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[C:10]1=[O:24].[CH2:25](NC1C=CC=CC=1C)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])[C:10]1=[O:24]
Reactant: C=CCNc1ccccc1C
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CCCC[C@H](N)C1=O

Procedure:
(S)-3-Amino-1-o-tolylazepan-2-one trifluoroacetate (17 mg, 0.051 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allyl-2-methylaniline in step A. Anal. Calcd. for C13H18N2O m/z 218.2. found: 219.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2(O)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A solution of 128 mg (0.392 mmol) of tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-3,4-dihydroxy-piperidine-1-carboxylate in 1.5 ml of dimethyl sulphoxide was added dropwise to a suspension of 16 mg (0.4 mmol) of sodium hydride (60% dispersion in refined oil) in 3 ml of dimethyl sulphoxide. After 15 minutes a solution of 61 mg (0.39 mmol) of p-methoxybenzyl chloride in 1 ml of dimethyl sulphoxide was added dropwise at room temperature within 10 minutes and the mixture was stirred for 18 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (200 mg) was purified by chromatography on silica gel with a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained (in addition to starting material and bisalkylated product) 63 mg (38% of theory) of tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-4-hydroxy-3-(4-methoxy-benzyloxy)-piperidine-1-carboxylate as a colourless oil; MS: 448, 450 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH2:46].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH:46][C:5](=[O:7])[C@H:4]1[CH2:8][CH2:9][C:10](=[O:11])[N:3]1[CH2:1][CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)CC[C@@H]1C(=O)NCc1ccc(F)cc1Cl
Reaction time: 0.17 h

Procedure:
1-ethyl-5-oxoproline (0.100 g, 0.64 mmol) was dissolved in a mixture of dichloromethane (3 ml) and dimethylformamide (0.5 ml) and to this was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.147 g, 0.77 mmol), 1-hydroxybenzotriazole (0.104 g, 0.77 mmol), and N-ethyl morpholine (0.244 ml, 1.92 mmol). The mixture was stirred for 10 minutes and then 2-chloro-4-fluorobenzylamine was added to the mixture and stirring continued overnight (˜16 hrs) at room temperature. The mixture was then treated with saturated aqueous sodium hydrogen carbonate (˜2 ml) and stirred vigorously for ˜10 minutes. The aqueous layer was removed using a phase separator and extracted with more dichloromethane (2×1 ml). The combined organic layers were concentrated to give a yellow oil and this was subsequently purified by mass-directed automated HPLC to give N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-D-prolinamide (0.065 g) as a white solid. LC/MS [M+H]+=299, retention time=2.16 minutes.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1C(C1NC2C(C=1)=CC(O)=CC=2)=O.OC1C=C2C(=CC=1)NC(C(O)=O)=C2>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCc2ccccc2C1
Agent: O=C(O)c1cc2cc(O)ccc2[nH]1
Product: c1ccc2c(c1)CCNC2

Procedure:
According to the procedure described for the synthesis of Example 1/step 1 (3,4-dihydro-1H-isoquinolin-2-yl)-(5-hydroxy-1H-indol-2-yl)-methanone was synthesized from 5-hydroxy-indole-2-carboxylic acid and 1,2,3,4-tetrahydro-isoquinoline which was yielded in 72% as white solid. MS (m/e): 293.0 (MH+, 100%).