Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][C:17]=2[N+:29]([O-:31])=[O:30])[CH2:11][CH2:10]1)=O)(C)(C)C.CO.C(Cl)Cl>O1CCOCC1>[C:25]([O:24][C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[C:17]([N+:29]([O-:31])=[O:30])[CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
Hydrogen chloride (1 mL, 4M in 1,4-dioxane) was added to a solution of (43) (0.1 g, 0.24 mmol) in 1,4-dioxane (5 mL) at 25° C. After 12 h, the reaction mixture was evaporated to a bright yellow solid residue which was basicified with NaOH(aq). The aqueous solution was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a yellow oily residue which was used in the next reaction without further purification (0.045 g, 59%): TLC (Rf =0.20; 15% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 8.74 (s, 1H), 8.33 (d, 1H, J=5.4), 7.94 (d, 1H, J=8.8), 6.82 (d, 1H, J=8.8), 3.60 (m, 1H), 3.12 (d, 2H, J=11.3), 2.74 (t, 2H, J=11.7), 2.21 (s, 2H), 2.05 (d, 2H, J=12.5), 1.53 (s, 9H); 13C NMR (CDCl3) δ 164.2, 146.3, 136.2, 131.1, 129.4, 118.9, 113.4, 81.2, 49.8, 44.8, 32.9, 28.2; HRMS (FAB) m/z 322.1750 (M+H)+ (C16H23N3O4 requires 322.1761); Anal. (C16H23N3O4 ·1HCl·1CH3OH) C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.0 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2S4. The solvent was evaporated to give a white solid. Recrystallization from methanol gave the product (500 mg), mp 154-155° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (81%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4.05 g (15.27 mmol) of the product prepared in step 18.1 in 25 mL of an ethyl acetate/ethanol mixture (v/v=1/1) are placed in a hydrogenation autoclave, and 0.32 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The mixture is stirred under a hydrogen pressure of 2.5 bar at room temperature for 2 hours. After filtering through thin glass fibre paper and evaporating under reduced pressure, 3.51 g of the expected product are obtained in the form of a violet solid, which is used as obtained in the following step. Yield=98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][S:6][CH2:7][C:8](O)=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:11]([C:8](=[O:9])[CH2:7][S:6][CH2:5]2)=[CH:12][CH:13]=1
Reactant: O=C(O)CSCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSCc2cc(Cl)ccc21
Yield: 51.1 %

Procedure:
3-Chlorobenzylmercaptoacetic acid from Step 2 (3.35 g) was dissolved in trifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) was added and the reaction stirred at reflux, under a nitrogen atmosphere for 16 hours. The solution was carefully poured into 10% Na2CO3 solution (500 mL) which was stirring vigorously. The organics were extracted into ether (500 mL) and washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting brown solid was purified by silica gel chromatography eluting with a 0-10% gradient of ethyl acetate in hexane to yield 7-chloroisothiochroman-4-one (1.57 g, 51%): 1H NMR (CDCl3) δ=3.49p (d, 2H, J=0.8 Hz), 3.8p (s, 2H), 7.16p (m, 1H), 7.3p (dd, 1H, J=2.0, 8.4 Hz), 7.96p (d, 1H, J=8.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([O:28][CH2:29][C@@H:30]([NH2:39])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)(=O)C>[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])([O:28][CH2:29][C@@H:30]([NH:39][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C@@H:8]3[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]3)[N:4]=2)=[CH:17][C:18]=1[F:25])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](N)c1cc(F)cc(I)c1)OC(C)(C)C
Reactant: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (215 mg, 0.509 mmol) in NMP (Volume: 4 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (260 mg, 0.509 mmol), DIEA (0.534 mL, 3.06 mmol) and then HATU (290 mg, 0.764 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by LCMS. To the crude reaction was added 150 ml of ethyl acetate washed with saturated bicarbonate (2×), water (3×), saturated salt solution, dried sodium sulfate, filtered and dried to residue. The crude product was purified by silica gel chromatograph 24 g column (DCM loading) eluting with 0-80% (EtOAc with 10% MeOH)/heptane. The desired fractions were concentrated to constant mass to give 315 mg of desired product as free base. (77% yield). LCMS (m/z): 805.3 (MH+), 1.01 min.
Reaction SMILES: [NH2:1][OH:2].C(=O)([O-])O.[Na+].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[C:8]([NH:1][OH:2])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccccc1

Procedure:
To 157 mg of said compound (19) were added 2 ml of ethyl acetate, 2 ml of aqueous saturated sodium hydrogencarbonate, and 0.012 ml of benzoyl chloride and the mixture was reacted at room temperature for 3 hours to obtain a benzoylamino-alcohol compound (compound (20), C53H65NO14Si, molecular weight of 968.18).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:3]=1[C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=O.S(Cl)(Cl)=O>ClCCl>[CH3:10][C:7]1([CH3:11])[CH2:8][O:9][C:4]([C:3]2[C:2]([F:1])=[CH:15][C:14]([F:16])=[CH:13][C:12]=2[F:17])=[N:6]1
Reactant: CC(C)(CO)NC(=O)c1c(F)cc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2c(F)cc(F)cc2F)=N1
Temperature: 25 °C

Procedure:
To a solution of 2,4,6-trifluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (43.8 g, 177.1 mmol) in dry dichloromethane (400 mL) was added thionyl chloride (58.9 ml, 415 mmol) via slow drop-wise addition over 25 minutes (reaction flask was immersed in an ice bath part way through the addition to control the temperature). After complete addition the material was stirred at ambient temperature over night. The volume was reduced to 30% by concentration under vacuum. To that was added ether (200 ml) and a solid precipitate (39.94 g off-white solid) was collected by filtration. The ether filtrate was set aside and the solid material was taken up in water (120 ml) and treated with an aqueous solution of sodium hydroxide (2N, 55 ml). Ethyl acetate (120 ml) was added and the mixture was transferred to a separatory funnel and shaken. The organic phase was collected and washed with an equal volume of water. The ethyl acetate phase was collected and the aqueous phases were back extracted with ethyl acetate (2×100 ml). The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo to provide the desired as a pure off-white solid (33.98 g). (M+H)+=230 m/e.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cu][C:17]#[N:18].[C-]#N.[K+].CN(C)[CH:24]=[O:25]>O>[C:17]([C:6]1[C:7]([O:25][CH3:24])=[CH:8][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH:5]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CCn1c2ccccc2c2cc(OC)c(C#N)cc21
Reaction time: 1 h

Procedure:
The 9-ethylcarbazole (13.0 g, 0.0428 mole) and copper(I) cyanide (4.60 g, 0.0513 mole) in 15 ml of N,N-dimethylformamide were boiled under reflux for 19 hours with powerful magnetic stirring. All dissolved within 40 min. When cooled to ≈60° the mixture was treated with a solution of 10.5 g of potassium cyanide in 35 ml of water, and stirred 1 hour. The solid was filtered, the lumps being broken up, washed on the Buchner with 250 ml of water, and dried to give 11.0 g of crude 2-cyano-9-ethyl-3-methoxy carbazole, m.p. 145°-155°. This was extracted from a Soxhlet overnight with 250 ml of heptane and the extract was cooled in ice to give 9.70 g (91%), m.p. 148°-155.5°. TLC on MK6F Silca Gel, t-butyl methyl ether, UV showed 5-10% of a non-fluorescent impurity at Rf=0.65 and 90-95% ArCN with a blue fluorescence at Rf=0.69. This was used in the next reaction.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].C1(C)C=CC=CC=1>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[N+:16]([NH:15][C:14](=[NH:19])[NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:21])[NH2:8])([O-:18])=[O:17]
Reactant: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CCN(C(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1-((S)-Nα -t-butoxycarbonyl-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine (1.2 g) in dichloromethane (25 ml) cooled to 0° to 5° C. is slowly added trifluoroacetic acid (2.8 g) and the reaction mixture is allowed to warm to room temperature and is then stirred for 6 hours. Toluene (30 ml) is then added and the mixture is concentrated by evaporation and then co-evaporated with further toluene portions (2×30 ml) and the eventual residue is triturated with ether, collected by filtration, washed with ether and dried to constant weight in vacuo to give 1-((S)-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)-piperidine trifluoroacetate as a white solid, Rf (BuOH/CH3COOH/H2O 3:2:1)=0.50.
Reaction SMILES: [C:1]([N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:34](Cl)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:43]1[CH:50]=[CH:49][C:46]([O:47][CH3:48])=[CH:45][CH:44]=1)[C:35]1[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH3:48][O:47][C:46]1[CH:45]=[CH:44][C:43]([C:34]([O:20][CH2:19][C@H:18]2[O:21][C@@H:14]([N:13]3[C:22]4[N:23]=[C:7]([N:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:8][C:9](=[O:24])[C:10]=4[N:11]=[CH:12]3)[CH2:15][C@@H:16]2[OH:17])([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:35]2[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=2)=[CH:50][CH:49]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCN(C(=O)C(C)C)c1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCN(C(=O)C(C)C)c1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c(=O)[nH]1

Procedure:
Compound 118 was prepared from compound 117 by following the procedure of example 107 utilizing compound 117 (2.2 g, 4.75 mmole), DMTCl (1.69 g, 5 mmole), dry TEA (1.01 g, 10 mmole) and dry pyridine (70 ml). The crude compound was purified using flash chromatography and methylene chloride/methanol/TEA as the eluent. 2 g (55%) of pure product was obtained as a foam.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[OH:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][C@@H:36]([OH:42])[CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])=[CH:32][CH:31]=1>CS(C)=O.O.[OH-].[Na+]>[CH3:41][CH:39]([NH:38][CH2:37][C@H:36]([OH:42])[CH2:35][O:34][C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][N:6]3[C:5]4[CH:4]=[C:3]([Cl:2])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:25][CH2:24]2)=[CH:44][CH:43]=1)[CH3:40]
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NC[C@H](O)COc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NC[C@H](O)COc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of the chloride of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (9.4 g) in 75 ml dimethylsulfoxide was added (S)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol (6.0 g) followed by 6.25 ml 4N sodium hydroxide solution. The mixture was stirred under argon at 55° for 2 hours then was cooled and diluted with 500 ml water and 35 ml 1N sodium hydroxide, and extracted with dichloromethane (3×). The extracts were backwashed with water (2×), dried over potassium carbonate and the solvent was removed in vacuo to give 12.8 g of crude (S)-1-(1-methylethylamino)-3-[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethoxy]phenoxy]-2-propanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:22]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Cl:1])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8-Chloro-3-methyl-3,7-dihydropurine-2,6-dione (868 mg) and potassium carbonate (628 mg) were suspended in N,N-dimethylformamide (10 ml), and allyl bromide was added dropwise thereto while cooling on ice. After stirring the reaction mixture at room temperature for 17 hours, the resulting white suspension was diluted with ethyl acetate (30 ml) and water (4 ml), and was filtered to give a white solid. The solid was washed with water and ethyl acetate to give 797 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[ClH:31].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=1)[CH2:11]3
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccc([N+](=O)[O-])cc3)CCN1CC2
Product: Cl
Yield: 12.6 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9, 10-dimethoxy-2H-benzo[a]quinolizine (7 g), 200 ml of toluene and 50 ml of 20% NaOH was cooled to below 10° and a solution of 4-nitrobenzoyl chloride (5 g) in toluene was added dropwise with stirring. The mixture was stirred in the cold for 1 hour and allowed to come to room temperature whereupon the solid was collected by filtration and chromatographed over silica gel using ethyl acetate-methanol (6:1) as eluant. The major fraction (5.3 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and the solvent was removed in vacuo. The salt was crystallized from methanol-ether to yield 1.5 g of the desired product, m.p. (decomposed at 269°-70°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR17##
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][C:42]=1[F:43])[C:18]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=1)(O)[C:19]([O:21][C@@:22]12[N:29]([CH3:30])[C@@H:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]=[CH:23]2)=[O:20].O.C([O-])(O)=O.[Na+]>ClCCl>[C@@:22]12([OH:21])[N:29]([CH3:30])[C@@H:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]=[CH:23]2.[F:11][C:18]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=1)([C:17]1[CH:40]=[CH:41][C:42]([F:43])=[C:15]([F:14])[CH:16]=1)[C:19]([O-:21])=[O:20]
Reactant: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1)CC2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: O=C([O-])C(F)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.66 g (0.012 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride were placed in 10 mL of dichloromethane and within 20 minutes a solution of 0.01 mol of 5b in 65 mL of dichloromethane was added dropwise at 15° C.-20° C. The mixture is stirred for 20 hours at ambient temperature, cooled to 0° C. and carefully mixed with 80 mL of water with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous NaHCO3 solution, the organic phase is separated off, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over MgSO4, and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile/diethylether. Yield: 2.60 g of white crystals (57% of theory); melting point: 233° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:16](=[O:17])[CH2:15][CH2:14][N:13]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:12](=[O:26])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([CH2:18][N:13]1[C:12](=[O:26])[CH2:11][CH2:10][N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:16](=[O:17])[CH2:15][CH2:14]1)([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CN1CCC(=O)N(CC(=O)OC(C)(C)C)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC(=O)N(CC(=O)O)CCC1=O
Reaction time: 8 h

Procedure:
1.4 g of tert-butyl (5-tert-butoxycarbonylmethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetate (starting material A3) are dissolved in 6 ml of dichloromethane, and 6 ml of trifluoroacetic acid are added. The mixture is stirred overnight and then concentrated using a rotary evaporator, and the residue is triturated with ethyl acetate/petroleum ether (1:1). The residue is filtered off with suction and dried under reduced pressure. This gives 0.89 g of the title compound which starts to melt at 250° C. (decomposition); the mass spectrum shows the molecular peaks MH+ and MNH4+ at 259 and 276 Da, respectively.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].[CH:18]1([Mg][Cl:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Cl-]>O1CCCC1>[ClH:25].[CH3:3][N:2]([CH:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([OH:11])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:1]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.5 %

Procedure:
3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 7.8 ml (15.6 mmole) of cyclohexylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammoniun chloride solution while cooling in an ice bath and extracted three times at RT, with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.03 g of crude base (98.5% of theory) were obtained, from which 2.22 g of 2-(dimethylaminophenylmethyl)bicyclohexyl-1-ol, hydrochloride (48.5% of theory) with a melting point of 220° C.-223° C. were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.