Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:20])[CH2:18][CH3:19])=[N:3][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(-c2cnco2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
(194) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Propionyl chloride (2.0 equiv, 1.34 mmol, 124 mg, 0.12 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-[5-(pyridin-2-yl)oxazol-2-yl]propan-1-one (194) (89 mg, 0.44 mmol, 65% yield) as a light brown powder: mp 65-67° C.; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.86-7.75 (m, 3H), 7.31-7.26 (m, 1H), 3.18-3.08 (m, 2H), 1.29-1.21 (m, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.8, 161.9, 157.2, 150.1, 146.3, 136.9, 126.8, 124.0, 120.3, 32.5, 7.8; IR (KBr) u. 2935, 2862, 1699, 1471, 1426, 1377 cm−1; MALDI-FTMS (DHB) m/z 203.0818 (C11H10N2O2+H+ requires 203.0815).
Reaction SMILES: CC1N=C(C2C=CC(O)=CC=2)ON=1.[CH3:14][N:15]([CH3:49])[C:16]([C:18]1[CH:19]=[C:20](CCCC(O)=O)[CH:21]=[CH:22][C:23]=1[NH:24][C:25]([C:27]1[C:28]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])=[O:17].CCN=C=NCCCN(C)C.[CH3:61][C:62]1[N:66]=[C:65]([C:67]2[CH:72]=[CH:71][C:70]([O:73][C:74](=[O:108])[CH2:75][CH2:76][CH2:77]C3C=CC(NC(C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=O)=C(C(=O)N(C)C)C=3)=[CH:69][CH:68]=2)[O:64][N:63]=1>>[CH3:61][C:62]1[N:66]=[C:65]([C:67]2[CH:72]=[CH:71][C:70]([O:73][C:74](=[O:108])[CH:75]([C:20]3[CH:21]=[CH:22][C:23]([NH:24][C:25]([C:27]4[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:26])=[C:18]([C:16](=[O:17])[N:15]([CH3:14])[CH3:49])[CH:19]=3)[CH2:76][CH3:77])=[CH:69][CH:68]=2)[O:64][N:63]=1
Reactant: Cc1noc(-c2ccc(OC(=O)CCCc3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)c(C(=O)N(C)C)c3)cc2)n1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1noc(-c2ccc(O)cc2)n1
Product: CCC(C(=O)Oc1ccc(-c2nc(C)no2)cc1)c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1

Procedure:
4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenol (64 mg) and 4-{3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}butanoic acid (200 mg)(synthesized separately in a similar manner to Working Example 1-1) were treated (WSC condensation) in a similar manner to Step g) of Working Example 1-1 to give the title compound (Compound 1-2) (112 mg).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[CH2:5]([O:7][C:8](=[O:19])/[C:9](=[CH:15]\OCC)/[C:10](=O)[CH:11]([F:13])[F:12])[CH3:6]>C1(C)C(C)=CC=CC=1>[F:12][CH:11]([F:13])[C:10]1[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:19])=[CH:15][N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cn(C)nc1C(F)F
Reaction time: 0.25 h

Procedure:
A 0.25 mol solution of methylhydrazine 40% diluted in 50.0 g xylene and 4.7 g water was prepared. A solution of 0.25 mol of 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester in 100.0 g xylene was added to the methylhydrazine over 30-60 minutes at a temperature of 20-25° C. The reaction mixture was stirred for 15 min. The phases of the reaction mass were separated.
Reaction SMILES: [CH:1]1(NS(=O)(=O)O)CCCCC1.C[CH:13]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[NH:21])[CH2:14][CH3:15].[Cl:22][C:23]1[C:24]([CH3:32])=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH2:13]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[N:21][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[C:24]=1[CH3:32])=[O:31])[CH2:14][CH2:15][CH3:1]
Reactant: Cc1c(Cl)cccc1N=C=O
Reactant: CCC(C)N1CCCC1=N
Reactant: O=S(=O)(O)NC1CCCCC1
Product: CCCCN1CCCC1=NC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The cyclohexylsulfamic acid salt of 1-2-butyl-2-iminopyrrolidine (7.99 g.; 0.025 mole) is converted to free base (3.5 g.; 0.025 mole) by adding 2.5 ml. of 50% NaOH to an aqueous slurry of the salt and benzene extraction. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.19 g. (0.025 mole) of 3-chloro-2-methylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 3 hours and then taken to dryness in vacuo to give an oily residue of 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallization from methanol-ether yields the product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea HCl hydrate, m.p. = 126°-128° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,4-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0505.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:16][C:17]([OH:19])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:22](CC)CC)C.C(=O)C(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([CH2:16][C:17](=[O:19])[NH2:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: CC(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(CC(N)=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
[1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid (2) (152 g, 0.56 mol) was taken up in 1 L THF and triethylamine (66.2 g, 0.65 mol) and cooled to −10° C. Over a 1-hour period, isobutyraldehyde was added (84.7 g, 0.62 mol), and the heterogeneous mixture was stirred at 0° C. for 15 minutes. Ammonia gas was bubbled into the cold reaction mixture for 30 minutes, and the mixture was allowed to warm to room temperature. After 16 hours stirring, the reaction mixture was evaporated to dryness on a rotary evaporator, and the residue was taken up in water, extracted 3×EtOAc, washed 2×brine and dried over MgSO4. Evaporation yielded an oil which was crystallized from pentane to yield 116.5 g (77%) white crystals; mp 123–125° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([C:43](O)=O)=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CN4CCCCCC4)cc1)OCO3)C2
Yield: 27 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (14 mg) was obtained.
Reaction SMILES: Cl.C([O:4][C:5](=[O:33])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([C:18](=[O:30])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=2)[O:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=1[O:31][CH3:32])C.O.[OH-].[Na+].Cl>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:18]([CH:14]([O:15][CH2:16][CH3:17])[C:12]2[CH:11]=[CH:10][C:9]([O:31][CH3:32])=[C:8]([CH:13]=2)[O:7][CH2:6][C:5]([OH:33])=[O:4])=[O:30])=[CH:26][CH:25]=1)(=[NH:28])[NH2:29]
Reactant: CCOC(=O)COc1cc(C(OCC)C(=O)NCc2ccc(C(=N)N)cc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1ccc(OC)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a stirred suspension of (RS)-{5-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester hydrochloride (example 18.5, 0.045 g) at rt in THF (1 ml) and water (0.5 ml) was added 1.0 N NaOH (0.2 ml). The mixture was then stirred at rt under an argon atmosphere for 3 h. The mixture waa acidified to pH 5–6 by addition of 1.0 N HCl. The THF was removed (rotavapor) and the product precipitated out from the remaining water. It was collected by filtration, washed with water and cyclohexane and dried overnight under high vacuum to give (RS)-{5-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid (0.027 g) as a white powder. MS 416.3 ([M+H]+)
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCC(C(=O)O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 64.2 g of ethyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate in 200 ml of methanol and 200 ml of tetrahydrofuran was added 58 ml of 5 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized with 5 M aqueous hydrochloride solution, followed by removal of the methanol and tetrahydrofuran in vacuo, and the resulting residue was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[CH:15]1([CH:19]([C:5]2[S:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[OH:18])[CH2:16][CH2:17]1
Reactant: C1CCOC1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Product: OC(c1cc2ccccc2s1)C1CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Benzo[b]thiophene of formula II-1 (2.68 g) is added to THF (70 mL) and cooled to -78° C. n-Butyl lithium (1M in hexane, 20 mmol) is then added and the resulting solution stirred for 1.5 hours. The cooling bath is removed for 30 minutes and then cooled back to -78° C. Cyclopropylcarboxaldehyde (1.4 g) is then added in a single portion and the reaction quenched by adding a saturated NH4Cl solution. The reaction is extracted with ether, dried and solvent removed in vacuo to yield the title product as a clear oil that solidified on standing.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[CH2:8]([N:15]([CH2:17][CH2:18]Cl)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1.O.CO>[CH3:3][CH:2]([CH3:4])[CH2:1][O:5][CH2:18][CH2:17][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: CC(C)CO
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)COCCN(C)Cc1ccccc1
Yield: 71.7 %

Procedure:
A solution of 5.0 g of isobutanol in 50 ml of toluene was added at a temperature of 0° C. to a solution of 3.25 g of sodium hydride in 100 ml of toluene, and the reaction mixture was heated under reflux for 3 hours. 12.4 g of N-benzyl-N-methyl-2-chloroethylamine were then added to the reaction mixture, and the solution was heated under reflux for a further 8 hours. The reaction solution was worked up by cautiously adding 5 ml of methanol and then 100 ml of water, and the pH was then adjusted to pH 2 by adding dilute aqueous hydrochloric acid solution. After shaking, the organic phase was separated and discarded. The aqueous phase was adjusted to pH 13 by addition of aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered and concentrated. The remaining residue was purified by chromatography on silica gel using n-hexane/ethyl acetate as the eluent. 10.7 g of N-[2-(2,2-dimethylethoxy)ethyl]-N-benzyl-N-methylamine were obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]([C:12]([OH:14])=O)=[C:9]([CH3:11])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(NC1SC(C(Cl)=O)=C(C)N=1)(C)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:36][CH:37]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:38]#[N:39]>C(N(CC)CC)C>[C:38]([CH:37]([NH:36][C:12]([C:8]1[S:7][C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][C:9]=1[CH3:11])=[O:14])[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)#[N:39]
Reactant: Cc1nc(NC(C)(C)C)sc1C(=O)O
Reactant: N#CC(N)c1cccs1
Agent: Cc1nc(NC(C)(C)C)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(C)(C)C)sc1C(=O)NC(C#N)c1cccs1
Yield: 41 %

Procedure:
1.5g of 2-t-butylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-t-butylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.4g of amino-thiophen-2-yl-acetonitrile hydrochloride and 3.3ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.96g (Yield 41%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])N)[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:7]>C(O)C>[CH2:1]([NH:5][C:26]([C:23]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:10]([CH3:11])[CH2:9][N:8]([CH2:29][CH3:30])[CH2:6][CH3:7])[C:25]=2[CH:24]=1)=[S:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Reaction time: 16 h

Procedure:
n-Butylamine (2.4 cc) is added to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.86 g) in absolute ethanol (25 cc). The mixture is brought to 150° C. for 16 hours and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue obtained is purified by chromatography on a column (height: 17 cm; diameter: 2.6 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 90:10 (250 cc), 80:20 (500 cc) and 50:50 (750 cc) and then with pure ethyl acetate (750 cc), collecting 50-cc fractions. Fractions 10 to 18 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-butyl-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (0.96 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH:16]=1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 55.3 %

Procedure:
To a solution of 3.24 gm (11.3 mMol) 5-ethoxycarbonyl-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole in 100 mL ethanol was added 0.8 gm 5% palladium an carbon and the reaction mixture hydrogenated at room temperature for 18 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residual oil, which crystallized on standing at room temperature, was recrystallized from 30 mL acetonitrile to provide 1.79 gm (55%) of the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCCl>[Br:14][CH2:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2csc(Cl)n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Clc1nc(-c2cccc(CBr)c2)cs1
Reaction time: 3 h

Procedure:
600 mg of 2-chloro-4-(3-tolyl)thiazole was dissolved in a mixture of 8 ml of carbon tetrachloride and 2 ml of 1,2-dichloroethane. N-bromosuccinimide (511 mg) and 3 mg of benzoyl peroxide were added, and the mixture refluxed with stirring for 3 hours. After cooling, the precipitate was separated from the reaction mixture by filtration. It was washed with an aqueous solution of sodium hydrogen carbonate, and the solvent was evaporated under reduced pressure to give 4-(3-bromomethylphenyl)-2-chlorothiazole as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[Cl:29]C(OC(Cl)C)=O.O>ClCCCl>[ClH:29].[N:17]1([CH2:16][CH2:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(CN2CCOC(CCCN3CCCC3)C2)cc1
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C1CCN(CCCC2CNCCO2)C1
Product: Cl
Yield: 93 %

Procedure:
4-Benzyl-2-(3-pyrrolidin-1-yl-propyl)morpholine (180 mg, 0.62 mmol) prepared according to Process Step 1 was dissolved in 1,2-dichloroethane (5 mL), and the solution was mixed with triethylamine (0.086 mL, 0.62 mmol) and 1-chloroethyl chloroformate (0.20 mL, 1.87 mmol), followed by stirring under reflux for three hours. The reaction mixture was cooled and was mixed with 1,2-dichloroethane (50 mL) and water (50 mL), followed by separation. The organic layer was washed with brine (50 mL), was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (5 mL), followed by stirring under reflux for one hour. After distilling off the solvent under reduced pressure, diethyl ether (5 mL) was added for crystallization, and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure and thereby yielded 2-(3-pyrrolidin-1-ylpropyl)morpholine hydrochloride (135 mg, in a yield of 93%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([CH2:19][CH2:20][C@H:21]([O:45]C2CCCCO2)/[CH:22]=[CH:23]/[C@@H:24]2[C@@H:36]3[C@@H:27]([O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35]3)[CH2:26][C@H:25]2[O:38]C2CCCCO2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:38][C@@H:25]1[CH2:26][C@@H:27]2[O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][C@@H:36]2[C@H:24]1/[CH:23]=[CH:22]/[C@@H:21]([OH:45])[CH2:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: CO
Solvent: O
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.16 g, 0.84 mmol) was added to a stirred solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-9-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-10-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]oxecin-2(3H)-one (9.0 g, 16.7 mmol) in methanol (90 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer was separated and the water layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 9.0 g of crude product. The crude product was purified by column chromatography providing 3.5 g of the title compound (56.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[Br:21].C1(N)CCCCC1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[Br:21]
Reactant: Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Solvent: NC1CCCCC1
Product: Nc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)cc1Br
Yield: 67 %

Procedure:
Prepared analogous to Example 25 by reduction of 4-(4'-amino-3'-bromo-4-biphenyly)-4-oxo-butyric acid. Yield: 67%; m.p. 112°-113° C. (decomp.). Melting point of the cyclohexylamine salt: 183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]([N:17]1[CH2:24][CH:23]2[C:25]([CH3:27])([CH3:26])[CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[CH2:14][CH2:15][CH3:16]>ClCCl>[ClH:1].[CH2:13]([N:17]1[CH2:18][CH:19]2[C:25]([CH3:26])([CH3:27])[CH:23]([CH2:22][N:21]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:20]2)[CH2:24]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(Cl)c(Cl)c3)CC(C1)C2(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 127 %

Procedure:
A solution of 2.8 g (=0.0114 mol) 3,4-dichlorobenzene sulfonic acid chloride in 20 ml dichloromethane was added dropwise with ice cooling to a solution of 2.4 g (=0.0114 mol) 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane (=substance No. C1 in the following Table C) in 40 ml dichloromethane. Then the ice bath was removed and the reaction mixture stirred further for 3 hours at room temperature. The hydrochloride of the title compound thereby precipitated as a white precipitate. In order to complete crystallization, the reaction mixture was allowed to stand 12 more hours in a refrigerator. Then the crystals were separated by suction filtration and dried at 60° C. in a vacuum drier. 3.3 g 7-(n-butyl)-3-[(3,4-dichlorophenyl)-sulfonyl]-9,9-dimethyl-3,7-diazabicyclo [3,3,1]nonane hydrochloride with a melting point of 170-173 C were obtained.