Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23]C)[C:16]=2[O:15][CH2:14]1.C(=O)(O)[O-].[Na+]>Br.O>[NH2:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:16]=2[O:15][CH2:14]1
Reactant: COc1cccc2c1OCC(CNCCCOc1cccc(N)c1)O2
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Nc1cccc(OCCCNCC2COc3c(O)cccc3O2)c1
Yield: 52.6 %

Procedure:
N-[3-(3-Aminophenoxy)propyl]-2,3-dihydro-5-methoxy-1,4-benzodioxin-2-methanamine dihydrochloride quarter hydrate (0.79 g, 1.9 mmole), prepared in Example 2 above, was dissolved in 26.5 ml of 48% HBr and refluxed under nitrogen for 23 hours. Upon cooling, the mixture was diluted to 250 ml with water and carefully neutralized with solid sodium bicarbonate. It was then extracted with two 200 ml portions of 3:1 dichloromethane/isopropanol and the combined extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness in vacuum. The residue was column chromatographed on silica gel using 5% methanol/dichloromethane to which 1 ml/liter aqueous ammonia had been added. The product-containing fractions were combined, concentrated in vacuum, and the residue crystallized from 20 ml of isopropanol with the addition of 4 ml 4N HCl/isopropanol to give 0.33 g of the title compound (m.p. 183°-190° C.) as a beige solid, dihydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[O:6][CH2:5]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:5][CH:4]([OH:6])[CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC1CO1
Reactant: NCCCCCCN
Product: CC(C)CC(O)CNCCCCCCNCC(O)CC(C)C

Procedure:
Condensation of 4-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-4-methylpentylamine] (I: R = (CH3)2CHCH2, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:8]([CH2:22][CH2:23][CH3:24])[C:7]1=[O:25].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][C:9]2[N:8]([CH2:22][CH2:23][CH3:24])[C:7](=[O:25])[N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:2]([CH3:1])[CH:3]=3)[C:10]=2[CH3:11])=[CH:20][CH:19]=1)([CH3:38])[CH3:37])[CH3:36]
Reactant: CCCn1c(CCCc2ccc(O)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCn1c(CCCc2ccc(OC(C)(C)C(=O)OCC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 75 °C
Yield: 56.8 %

Procedure:
The crude 1-(3,4-dimethyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one (0.169 g) was combined with ethyl 2-bromoisobutyrate (0.366 g, 1.87 mmol), MgSO4 (0.043 g, 0.357 mmol) and 325 mesh K2CO3 (0.197 g, 1.43 mmol) in ethanol (8 mL) and heated a 75° C. for 16 h under N2. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with 1 N HCl (10 mL) and extracted with EtOAc and water. The organic layer was dried (MgSO4), and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 2:1 to hexanes:acetone to afford 0.124 g (69%) 2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C31H43N2O4 (M+1) 507. Found m/z 507 (100%). 1H NMR.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].[NH2:13][C@@H:14]([CH3:30])[C:15]([NH:17][C@@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:19]([NH2:21])=[O:20])=[O:16].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:21][C:19](=[O:20])[C@@H:18]([NH:17][C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH3:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1
Reactant: O=Cc1cnc(NCC(=O)O)s1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a mixture of material from Example 3 (32.2 mg, 0.107 mmol), (S)-2-amino-N-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)propanamide (42.7 mg, 0.170 mmol), EDC (31.7 mg, 0.165 mmol) and 1-hydroxy-7-azabenzotriazole (10.0 mg, 0.073 mmol) is added anhydrous DMF (1.0 mL). The reaction is flushed with N2, treated with N-methylmorpholine (59 μl, 0.537 mmol), flushed with N2 and allowed to stir at room temp for 18 h. The reaction is diluted with DMF and purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 10% Solvent B to 80% Solvent B over 12 min, ret. T=5.2 min. The product fractions are evaporated to dryness in a speed-vac for 18 h to give 26.7 mg (46.7%) of the title compound as a yellow solid as a TFA salt. LC/MS (Condition A): ret. T=1.65 min, (M+H)+ 420.09.
Reaction SMILES: [Li+].[BH4-].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:64][CH3:65])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[C:61]([O:62][CH3:63])=[CH:60][C:33]5[C:34](=[O:59])[N:35]6[CH:50]=[C:49]([C:51]7[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=7)[CH2:48][C@H:36]6[C:37](=O)[N:38](COCC[Si](C)(C)C)[C:32]=5[CH:31]=4)=[CH:24][C:15]=2[N:14](COCC[Si](C)(C)C)[C:13]3=O)=[CH:6][CH:5]=1.CCO>C1COCC1>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:64][CH3:65])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[C:61]([O:62][CH3:63])=[CH:60][C:33]5[C:34](=[O:59])[N:35]6[CH:50]=[C:49]([C:51]7[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=7)[CH2:48][C@H:36]6[CH:37]=[N:38][C:32]=5[CH:31]=4)=[CH:24][C:15]=2[N:14]=[CH:13]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
Fresh LiBH4 (183 mg, 8.42 mmol) was added to a stirred solution of the SEM-dilactam 10 (428 mg, 0.42 mmol) in THF (5 mL) and EtOH (5 mL) at room temperature. After 10 minutes, delayed vigorous effervescence was observed requiring the reaction vessel to be placed in an ice bath. After removal of the ice bath the mixture was allowed to stir at room temperature for 1 hour. LC/MS analysis at this point revealed total consumption of starting material with very little mono-reduced product. The reaction mixture was poured onto ice (100 mL) and allowed to warm to room temperature with stirring. The aqueous mixture was extracted with DCM (3×30 mL) and the combined organic layers washed with H2O (20 mL), brine (30 mL) and concentrated in vacuo. The resulting residue was treated with DCM (5 mL), EtOH (14 mL), H2O (7 mL) and silica gel (10 g). The viscous mixture was allowed to stir at room temperature for 3 days. The mixture was filtered slowly through a sinter funnel and the silica residue washed with 90% CHCl3: 10% MeOH (˜250 mL) until UV activity faded completely from the eluent. The organic phase was washed with H2O (50 mL), brine 60 mL), dried (MgSO4) filtered and evaporated in vacuo to provide the crude material. The crude product was purified by flash chromatography (97% CHCl3: 3% MeOH) to provide the pure C2/C2′ aryl PBD dimer 11 (185 mg) 61% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: Cc1cc(Cl)ccc1O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Cl)cc(Cc2ccc(C(C)(C)C)cc2)c1O

Procedure:
106.5 g (0.75 mol) 4-chloro-2-methylphenol and 45.67 g (0.25 mol) 4-tert. butylbenzylchloride are dissolved in 200 ml chloroform, and 22.5 g water-free zinc chloride are added as Friedel-Crafts catalyst. Thereafter the reaction mixture is stirred, whereby indeed at room temperature to the start of the reaction intense gas development, i.e. intense reaction, is to be noted. Subsequently the reaction mixture is stirred at 60° C. 5-6 h and washed three times each with 200 ml water for the purpose of removing the zinc chloride. The organic phase is dried across magnesium sulfate and the chloroform is driven off in a vacuum. At 182°-185° C./0.3 Torr the 4-chloro-2-methyl-6-(4'-tert. butylbenzyl)-phenol distills over as water-clear, viscous, nearly odorless liquid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][CH:10]=[CH:9][C:8]2=O)(=O)C.S(Cl)([Cl:20])=O>CN(C=O)C>[Cl:20][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Cl)c2cc1O

Procedure:
A solution of 6-acetoxy-7-methoxy-1,4-dihydroquinolin-4-one (6.2 g, 28 mmol) and thionyl chloride (75 ml) containing DMF (0.5 ml) was heated at reflux for 1 hour. The volatiles were removed by evaporation. The residue was suspended in methylene chloride (5 ml) and poured slowly into a stirred solution of methanol/ammonium hydroxide. The mixture was partitioned between water and methylene chloride and dried by passing through ,phase separating paper. Removal of the solvent by evaporation gave a solid which was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-hydroxy-7-methoxyquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:44])=[C:13]([N+:41]([O-])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:44])=[C:13]([NH2:41])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)(C)C
Yield: 101.4 %

Procedure:
(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (5.1 mmol) was hydrolyzed and coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (5.85 mmol) according to general procedures B and A to provide (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.4 g). (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g) was dissolved in MeOH, Pd/C was added and the mixture stirred under balloon pressure of hydrogen for 1 h. Mixture was filtered through celite, washed with MeOH and EtOAc and concentrated to provide (S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.06 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][N:24]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)c1cnccn1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cnccn4)nc3cc21

Procedure:
Pyrazine-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and pyrazine-2-carboxylic acid (109 mg, 0.89 mmol). The title compound was obtained as yellow powder (19 mg, 6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>C1COCC1.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:31])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(O)C1CCC(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid (0.10 g, 0.26 mmol) and 1:1 THF-N-methylpyrrolidin-2-one (1 mL) was treated with NaH (0.031 g, 0.78 mmol, 60% dispersion in mineral oil). After stirring for 10 min, the mixture was warmed to room temperature, stirred for 20 min and treated with iodomethane (0.016 mL, 0.26 mmol). After stirring fro 3 h, the mixture was treated with an additional 0.010 g of NaH and 0.015 mL of iodomethane. The resulting mixture was stirred for 24 h, acidified with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by radial chromatography (1:1 to 2:1 ethyl acetate hexane containing 1% of acetic acid, 2 mm silica gel plate) afforded 0.077 g (75%) of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: [CH:1]1([C:4](=[O:19])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[F:18])=[O:7])[CH2:3][CH2:2]1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH:1]1([C:4](=[O:19])[C:5](=[CH:20][O:21][CH2:22][CH3:23])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:9]=2[F:18])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(F)c1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Yield: 99.3 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (7.4 g), triethyl orthoformate (8.5 g) and acetic anhydride was stirred and heated at reflux for 4 hours. The mixture was evaporated to dryness. Xylene was added and the mixture was re-evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (8.8 g) as a red oil which was not further purified.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:7]=[CH:6]2.[BrH:19]>O>[BrH:19].[N:14]1([CH2:13][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2cc(CN3CCCC3)ccc2c1
Agent: Br
Solvent: O
Product: Oc1ccc2cc(CN3CCCC3)ccc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A solution of the 1-[(6-methoxy-2-naphthyl)methyl]pyrrolidine (3.63 g, 15.0 mmol) obtained in Reference Example 21 in 48% hydrobromic acid (75 ml) was stirred at 100° C. for 6 hours. The reaction solution was diluted with water, the produced crystals were collected, and washed with water, tetrahydrofuran and diisopropyl ether to obtain the titled compound (2.45 g) as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3C(OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.[ClH:22]>>[ClH:22].[CH3:21][C:14]1[CH:15]=[C:9]2[C:8]3[CH:4]([CH2:3][CH2:2][NH2:1])[CH2:5][CH2:6][C:7]=3[CH:12]=[CH:11][N:10]2[N:13]=1
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCN)CC3
Agent: Cl
Product: Cc1cc2c3c(ccn2n1)CCC3CCN
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 9-(2-aminoethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (140 mg, 0.487 mmol) in 12M hydrochloric acid (5 mL) was stirred at 100° C. for 2 days, and concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Example 18 without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][N:24]=3)=[O:33])=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:46])[CH3:47])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 227d (366 mg, 0.555 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (47 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H), 3.29 (dt, J=13.70, 6.94 Hz, 1 H), 6.86-7.00 (m, 5 H), 7.88 (d, J=8.46 Hz, 1 H), 8.11 (dd, J=8.64, 2.39 Hz, 1 H), 8.21-8.30 (m, 2 H), 8.40 (d, J=8.82 Hz, 1 H), 8.79 (s, 1 H), 8.90 (s, 1 H), 9.00 (d, J=8.46 Hz, 1 H), 11.28 (s, 1 H); MS (ESI+) m/z 560 (M+TFA+H)+; (ESI−) m/z 558 (M+TFA−H)−.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:10][C:4]1[CH:3]=[C:2]([S:12][CH3:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C[S-]
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C#N)c(C)c1

Procedure:
A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of 2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give 2-methyl-4-(methylthio)benzoic acid. 430 mg of 2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide. MS (Q1) 401.0 (M)+.
Reaction SMILES: [CH2:1]([N:16]=[C:17]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C=C(CO)CO.[C:25](=[C:28]([CH2:31]O)[CH2:29][OH:30])([CH3:27])[CH3:26]>>[CH2:1]([NH:16][C:17]([CH2:31][C:28](=[C:25]([CH3:27])[CH3:26])[CH2:29][OH:30])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)=C(CO)CO
Reactant: CCCCCCCCCCCCCCCN=C=O
Agent: C=C(CO)CO
Product: CCCCCCCCCCCCCCCNC(=O)CC(CO)=C(C)C

Procedure:
Following the procedure described in Preparation 3, but replacing octadecyl isocyanate with pentadecyl isocyanate and 2-methylenepropane-1,3-diol with 2-isopropylidenepropan-1,3-diol, the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:17](/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:25]>C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[Cl:25][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=[C:17]2[C:2]=1[NH:1][C:20](=[O:21])[CH2:19][CH2:18]2
Reactant: CCOC(=O)/C=C/c1cc2c(c(Cl)c1N)CCN(C(=O)OCC)CC2
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2cc3c(c(Cl)c2CC1)NC(=O)CC3
Reaction time: 20 h
Yield: 120.9 %

Procedure:
To a solution of 2.12 g of ethyl 7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 20 ml of chloroform and 20 ml of MeOH was added 65 mg of platinum(IV) oxide, followed by stirring for 20 hours at 1 atm under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 2.256 g of ethyl 11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a milky white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A mixture of 150 g methyl-4-hydroxybenzoate, 1.5 L 2-butanone, 272.5 g potassium carbonate and 293 ml 1-bromotetradecane is heated at reflux for 66 hours. The reaction is cooled to room temperature, filtered, the filtrate concentrated in vacuo and the residue recrystallized from methylene chloride/hexane to give 258.8 g of the desired product. MP 56°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[CH:15][C:16]([OH:18])=[O:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1>C(O)C.[Na].[Hg]>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([CH2:15][C:16]([OH:18])=[O:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C=C1c2ccccc2CCc2cc(Cl)ccc21
Agent: [Hg]
Agent: [Na]
Solvent: CCO
Product: O=C(O)CC1c2ccccc2CCc2cc(Cl)ccc21
Reaction time: 3 h

Procedure:
A solution of 2-chloro-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylideneacetic acid (23.5 g, described in Example 1) in ethanol (100 ml, hot) is added to 5% sodium amalgam (100 g). The mixture is stirred at 60°-70° C. for 3 hr and decanted. The solution is evaporated of half its original volume, acidified with conc. hydrochloric acid and extracted with chloroform. The organic extract is dried and evaporated. The residue is crystallized from diethyl ether-hexane to give the title compound as crystals, mp 142°-146° C.