Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].[CH2:28]([N:30]1[CH:34]=[C:33](I)[CH:32]=[N:31]1)[CH3:29]>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:32]=[N:31][N:30]([CH2:28][CH3:29])[CH:34]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: CCn1cc(I)cn1
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cnn(CC)c3)nc21

Procedure:
The title compound (a foam, mp 60°-62° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and N-ethyl-4-iodopyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:41]1[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:28])[F:29])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: 25 °C

Procedure:
The product from step 2 (150 mg, 0.19 mmol) and triphenylphosphine (74 mg, 0.28 mmol) were dissolved in THF (4 mL) and to the solution was added water (1 mL). The mixture was heated to reflux under a nitrogen atmosphere for 12 h. The mixture was cooled to ambient temperature and the solvents were removed in vacuo. The residue was purified on a 12 g silica gel column eluting with a gradient of 0-10% methanol:chloroform. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=774.7.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=O)[CH2:15]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:13][C:14]1([CH3:23])[C:15]2[C:4](=[O:6])[C:3]3[C:2](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:1][C:16]=2[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CCOC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)Cc2[nH]c3ccccc3c(=O)c2C(C)(C)C1
Reaction time: 9 h
Yield: 18 %

Procedure:
1.49 ml (10 mmol) of ethyl 2-aminobenzoate and 1.73 ml (10 mmol) of 3,3,5,5-tetramethyl-cyclohexanone were mixed with 20 ml of toluene. 20 mg (0.1 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 9 h, toluene was removed under vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to obtain 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)-acridone (18%). Following the procedure of Step 3 in Example 1, but substituting 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)acridone for 9-(10H)acridone, gave 9-chloro-1,1,3,3-tetramethyl-1,2,3,4-tetrahydroacridine (21%), which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound (3%, overall yield 0,1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol ((ix), 329 g, 1.0 mmol) was dissolved in acetone (40 mL) and 2-iodoxybenzoic acid (45%, 1.245 g, 2.0 mmol) was added. The RM was heated to reflux for 3 h (suspension). The acetone was then removed under reduced pressure and the residue was taken up with water and 2 M NaOH. The beige suspension was filtered, washed with water and dried overnight under vacuum to afford the title compound as a beige powder (tR 4.31 min (conditions 5), MH+=327, 1H-NMR in DMSO-d6: 9.03 (d, 1H); 8.53 (d, 1H); 8.49-8.41 (m, 2H); 8.39 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.62 (dd, 1H)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[C:21]2[C:20]([OH:22])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:13]([CH3:12])=[N:14][NH:15]2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1n[nH]c2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.63 mmol) of 3,4-difluoronitrobenzene, 93.1 mg (0.63 mmol) of 3-methyl-1H-indazol-4-ol (from example I) and 95.6 mg (0.69 mmol) of potassium carbonate are suspended in 5 ml of anhydrous dimethylformamide and stirred at 50° C. for five hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography. The mobile phase used is a mixture of cyclohexane and ethyl acetate (1:1).
Reaction SMILES: C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CC(C(O)=O)C2)C=C3C(F)(F)F)CC1)(C)(C)C.C[O:35][C:36]([CH:38]1[CH2:41][N:40]([CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([O:53][C@H:54]2[CH2:59][CH2:58][C@H:57]([C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:56][CH2:55]2)[CH:47]=[CH:46]3)[CH2:39]1)=[O:37]>>[C:60]([C@H:57]1[CH2:56][CH2:55][C@H:54]([O:53][C:48]2[CH:47]=[CH:46][C:45]3[C:50](=[CH:51][CH:52]=[C:43]([CH2:42][N:40]4[CH2:41][CH:38]([C:36]([OH:37])=[O:35])[CH2:39]4)[CH:44]=3)[N:49]=2)[CH2:59][CH2:58]1)([CH3:63])([CH3:61])[CH3:62]
Reactant: COC(=O)C1CN(Cc2ccc3nc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3n2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS(M+H+): 397.39; 1H NMR (400 MHz, METHANOL-d4) Shift 8.15 (d, J=8.78 Hz, 1H), 7.89-7.94 (m, 1H), 7.86 (d, J=8.78 Hz, 1H), 7.67 (dd, J=1.88, 8.66 Hz, 1H), 6.96 (d, J=8.78 Hz, 1H), 5.10-5.22 (m, 1H), 4.55 (s, 2H), 4.20-4.47 (m, 4H), 3.71 (quin, J=8.28 Hz, 1H), 2.28 (d, J=9.54 Hz, 2H), 1.92 (d, J=14.31 Hz, 2H), 1.36-1.52 (m, 2H), 1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[N:3]=1.P(Cl)(Cl)([Cl:31])=O>C(Cl)(Cl)Cl>[Cl:31][C:2]1[C:11]2[CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[N:3]=1
Reactant: CC1(C)CCc2nc([C@H]3CCCN3C(=O)OCc3ccccc3)nc(O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2nc([C@H]3CCCN3C(=O)OCc3ccccc3)nc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture phenylmethyl(2R)-2-(4-hydroxy-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.39 mmol) and phosphorous oxychloride (1 mL) in chloroform (3 mL) was stirred at 80° C. for one hour. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The mixture was stirred for 15 minutes and pH was maintained above 7 by the addition of solid sodium bicarbonate. The organic layer was separated and washed with water (10 mL) and brine, dried over sodium sulfate, filtered and concentrated to give phenylmethyl(2R)-2-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-1-carboxylate (117 mg, 74%). MS (EI) for C22H26ClN3O2: 400 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[C:6]=3[CH:17]=2)=[O:26])=[N:23][CH:24]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: COC(=O)C1=C(C)c2cc(N)ccc2CCC1
Product: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(F)cn3)ccc2CCC1

Procedure:
In a manner similar to the procedure of step 3A, methyl 2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from preparation J, step J1, was coupled with 5-fluoropicolinic acid to afford the titled compound of Step 43A. 1H NMR (500 HMz, chloroform-d) δ 9.82 (br. s., 1H), 8.48 (d, J=2.7 Hz, 1H), 8.36 (dd, J=8.7, 4.6 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.66-7.59 (m, 2H), 7.22 (d, J=8.1 Hz, 1H), 3.83 (s, 3H), 2.57 (t, J=6.6 Hz, 2H), 2.45 (s, 3H), 2.17-2.10 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[Cl:9])[NH:6][C:14](=[O:15])[CH:13]=[C:12]2[C:11]([F:21])([F:20])[F:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)c2cc(Br)c(Cl)cc2[nH]1
Yield: 63.7 %

Procedure:
This compound was prepared according to General Method 11 (EXAMPLE 22) from 4-bromo-3-chloroaniline (2.06 g, 10.0 mmol), ethyl 4,4,4-trifluoroacetoacetate (2.30 g, 12.5 mmol) in 50 mL toluene followed by heating in 33 mL conc. H2SO4 to afford 2.08 g (64%) of 6-bromo-7-chloro-4-(trifluoromethyl)-quinolin-2(1H)-one, an off-white solid. This material was converted to the corresponding imino ether according to General Method 12 (EXAMPLE 22) with isopropyl iodide (4.32 g, 25.4 mmol) and CsF (3.85 g, 25.4 mmol) in 32 mL DMF to afford 1.34 g (57%) of 6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline, a white solid, after flash chromatography (hexanes). Data for 6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline: 1H NMR (400 MHz, CDCl3) δ 8.22 (broad s, 1H), 8.00 (s, 1H), 7.17 (s, 1H), 5.51 (hept, 1H, J=6.2), 1.40 (d, 6H, J=6.2).
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[Cl-].[CH3:13][O:14][C:15](=[O:19])[C:16](O)=[O:17]>>[CH3:13][O:14][C:15](=[O:19])[C:16]([NH:11][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:17]
Reactant: COC(=O)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CN
Agent: [Cl-]
Product: COC(=O)C(=O)NC/C=C(\C)CCC=C(C)C

Procedure:
Said substance is manufactured according to AAV 1, by converting geranylamine and oxalic acid monomethylester chloride with each other and the product is purified by column chromatography (pentane/diethyl ether=1/1).
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH:13]=[CH:12][N:11]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[N:8]([C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)(=O)C.[Mn]([O-])(=O)(=O)=[O:30].[K+].S([O-])(O)=O.[Na+]>CC(C)=O.O>[C:20]([N:8]1[C:9]2[C:10]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:11]3[CH:12]=[CH:13][C:14]=2[C:5](=[O:4])[C@H:6]([OH:30])[C@H:7]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)OC1=C[C@@H](c2ccccc2)N(C(C)=O)c2c1ccn1c(C)c(C)nc21
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](O)[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
2.0 g (5.4 mmol) of (9S)-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2h][1,7]-naphthyridine are dissolved in 30 ml of acetone and 6 ml of water. 1.0 g (6.4 mmol) of potassium permanganate is then introduced in portions at 0° C. After 30 min, the brown suspension is admixed with 1 ml of saturated sodium hydrogensulphite solution, filtered through Celite and washed with methanol and dichloromethane. The filtrate is concentrated and the residue crystallized using ethanol. 0.3 g (16%) of the title compound is isolated as a yellow solid (m.p. 192° C.).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:33](=[O:35])[CH3:34])=[CH:25][CH:24]=1
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (109 mg, 0.27 mmol) and Et3N (150 μL, 1.1 mmol) in CH2Cl2 (4 mL) was added acetic anhydride (40 μL, 0.4 mmol), and the resulting solution was then stirred at rt for 18 h. The resulting white suspension was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (93 mg, 92%). MS (ESI): mass calcd. for C21H21N3O2S, 379.14; m/z found, 380.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.33-7.24 (m, 3H), 4.78 (br m, 0.5H), 4.23 (m, 0.5H), 3.78-3.73 (br m, 2.5H), 3.56 (m, 1.5H), 3.32 (dd, J=9.3, 2.2 Hz, 0.5H), 3.27 (dd, J=11.4, 2.3 Hz, 0.5H), 3.01 (dd, J=9.1, 2.2 Hz, 0.5H), 2.84 (dd, J=9.7, 2.1 Hz, 0.5H), 2.77 (br d, J=9.9 Hz, 0.5H), 2.56 (dd, J=9.9, 1.2 Hz, 0.5H), 2.08 (s, 1.5H), 2.00 (s, 1.5H), 1.98 (br m, 0.5H), 1.91 (br m, 0.5H), 1.80 (br m, 0.5H), 1.66 (br m, 0.5H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CC(N=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)C1C=CC(CCC2C=CC=CC=2)=CC=1>>[ClH:1].[CH3:2][CH:3]([N:19]=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(N)c1ccccc1OCCc1ccccc1
Reactant: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccccc1OCCc1ccccc1

Procedure:
Substituting this amine for the α-methyl-ρ-phenethylbenzylamine of Example IV results in the formation of hexahydro-2-[α-methyl-o-(2-phenylethoxy)benzylimino]azepine hydrochloride, having a M.P. of 189°-90° C. (dec.)
Reaction SMILES: [I-:1].[Na+].[C:3]1([C:9]2([CH:14](C)S([O-])(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(C(C)=O)C(C)C>[C:3]1([C:9]2([CH2:14][I:1])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C1(c2ccccc2)CCCC1)S(=O)(=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: ICC1(c2ccccc2)CCCC1
Yield: 44.8 %

Procedure:
5.00 g (33.3 mmol) of sodium iodide were added to a solution of 1.00 g (3.93 mmol) of (1-phenylcyclopentyl)-methylmethanesulfonate [prepared as described in step (ii) above] in 10 ml of methyl isobutyl ketone, and the resulting mixture was heated under reflux for 18 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between diethyl ether and water. The organic phase was washed with water, with a saturated aqueous solution of sodium hydorgencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 1: 1 by volume mixture of methylene chloride and hexane as the eluent, to give 504 mg (yield 45%) of the title compound as an oil.
Reaction SMILES: C(O[C:4]([O:13]CC)([CH3:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[CH:16](OCC)=[O:17].[Na].O>C1C=CC=CC=1>[CH:16]([CH:6]([CH2:5][C:4]([CH3:12])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCC(C)(OCC)OCC
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C=O)CC(C)=O
Reaction time: 3 h

Procedure:
A mixture of 106.3 g (0.489 mol) of ethyl 4,4-diethoxypentanoate and 80 ml (73.6 g, 0.99 mol) of ethyl formate was added dropwise to a vigorously stirred suspension of 12.7 g (0.55 gram atom) of sodium (shavings) in 300 ml of anhydrous benzene at 10-15° C. over 3 h. Stirring was continued for a further 3 h, and the reaction mixture was left to stand overnight. 250 ml of water were added with vigorous stirring, and this was continued for a further 15 min. The water layer was separated off, and the benzene layer was extracted with 70 ml of water. The combined aqueous extracts were acidified to pH 2 and extracted with ethyl acetate (5×50 ml), and the organic extracts were dried over calcium chloride.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C@@H:11]3[N:12]4[CH2:1][CH2:2][S:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]([C:13]4=5)[C@@H:10]3[CH2:17]2)=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Product: O=[N+]([O-])c1cc(F)ccc1OCCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3

Procedure:
The title compound of EXAMPLE 6 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and and 1-(3-chloropropoxy)-4-fluoro-2-nitrobenzene following the procedure described in EXAMPLE 4. 1H NMR(CDCl3, 300 MHz): δ 7.6 (m, 1H), 7.25 (m, 1H), 7.04 (m, 1H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J=6.6 Hz), 6.75 (m, 1H), 4.25 (m, 2H),3.82 (m, 2H), 3.59-3.00 (m, 8H), 2.80 (m, 2H), 2.48 (m, 2H), 2.22 (m, 2H), 1.20 (m, 2H) ppm. LRMS (ES)+: 444 (M+H)+.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[OH-].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[CH2:19]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: OCCOCCOCCOCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To Compound 1 (5.2 g, 21.8 mmol), potassium hydroxide (1.2 g, 21.4 mmol) was added; this was followed by stirring on an oil bath at 130° C. for 15 minutes, after which the oil bath was removed and benzyl chloride (2.7 g, 21.3 mmol) was gradually added. This was again heated to 130° C. and stirred for 2 hours. After the solution was allowed to cool to room temperature, water was poured to stop the reaction, and extraction from methylene chloride was conducted. The combined organic phases were dried with sodium sulfate, filtered, and concentrated under reduced pressure, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate—5% methanol-ethyl acetate solution) to yield Compound 19 (light-yellow oil 2.3 g, 32%).
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21].IC>O1CCCC1>[Cl:16][C:17]1[C:18]([CH3:2])=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc(F)c1Cl
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
BuLi (68.8 mL, 110 mmol) was diluted with tetrahydrofuran (THF) (80 mL) and cooled to −20° C. 2,2,6,6-tetramethylpiperidine (18.56 mL, 110 mmol) was added dropwise and the mixture stirred at −20° C. for 15 minutes. The solution was cooled to −50° C. whereupon 3-chloro-4-fluorobenzoic acid (8.73 g, 50 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at −50° C. for 4 hours before iodomethane (12.51 mL, 200 mmol) was added dropwise. The mixture was allowed to reach room temperature overnight and quenched with water (100 mL). The mixture was acidified with 5N HCl (200 mL) and extracted with tert-butyl methyl ether (3×300 mL). The combined extracts were washed with water (100 mL), brine (100 mL) dried over anhydrous magnesium sulfate and concentrated to a crude product. The solid was recrystalised from cyclohexane (note: some insolubles not satisfactorarily removed) to afford product in 5.73 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(C#N)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a stirred and cooled (ice-bath) solution of 27 parts of 4-fluorobenzeneacetonitrile in 180 parts of N,N-dimethylformamide are added 6.2 parts of sodium hydride dispersion 78% and the whole is stirred for 1 hour while cooling. Then there are added dropwise 31 parts of 1-bromopentane. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding 21 parts of 4-fluoro-α-pentylbenzeneacetonitrile; bp. 85°-93° C at 0.1 mm. pressure.