Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].N1CCCCC1.CC(O)=O>C(O)(C)C>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A mixture of pentane-2,4-dione (20.0 g, 200 mmol), 4-nitrobenzaldehyde (30.2 g, 200 mmol), piperidine (1.70 g, 20.0 mmol), and HOAc (1.20 g, 20.0 mmol) in 500 mL of isopropanol were heated with a heat gun until a homogeneous solution resulted. The reaction mixture was then stirred at room temperature for 18 hours. The precipitated solids were filtered, sequentially washed with isopropanol and ether, and air dried to give 28.3 g of the title compound. The filtrate also yielded 5.10 g of 3-(4-nitrophenyl)methylenopentane-2,4-dione for a combined yield of 72%: mp 90-91° C. The product was used in the next step after spectral characterization.
Reaction SMILES: [OH-].[K+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.O>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([S:20][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:17]=[CH:18][CH:19]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CSc1cccc(Br)c1)c1ccccc1
Reaction time: 16 h
Yield: 101 %

Procedure:
Add potassium hydroxide (4.89 g, 87.3 mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) to a solution of 3-bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% in water) at 0° C. After stirring 16 h, add water to precipitate a yellow solid. Filter to obtain the desired intermediate (24.6 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14])#[N:18]
Reactant: COC(=O)C1CCOc2cc(F)c(Br)cc21
Reactant: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Temperature: 160 °C
Yield: 77 %

Procedure:
Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg, 1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by the addition of Cu(I)CN (643 mg, 7.18 mmol). The reaction was bubbled with argon for 20 minutes, then heated at 160° C. under a slight argon bubble for 6 hours. The reaction was cooled to ambient temperature and loaded directly onto a Biotage 25 column (silica gel), eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([C:35]([CH3:38])([CH3:37])[CH3:36])[O:3][C@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C@@H:7]([O:31]C(=O)C)[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:5]1.[CH3:40][Si:41]([CH3:78])([C:74]([CH3:77])([CH3:76])[CH3:75])[O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[CH:45]([C@@H:46]([O:70]C(=O)C)[CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[O:62][Si:63]([CH3:69])([CH3:68])[C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:44]1.C([O-])([O-])=O.[K+].[K+]>CO.O1CCOCC1>[CH3:39][Si:2]([CH3:1])([C:35]([CH3:38])([CH3:37])[CH3:36])[O:3][C@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C@@H:7]([OH:31])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:23][Si:24]([CH3:29])([CH3:30])[C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:5]1.[CH3:78][Si:41]([CH3:40])([C:74]([CH3:77])([CH3:76])[CH3:75])[O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[CH:45]([C@@H:46]([OH:70])[CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[O:62][Si:63]([CH3:68])([CH3:69])[C:64]([CH3:65])([CH3:66])[CH3:67])[CH2:44]1
Reactant: CC(=O)O[C@H]1C[C@H]2[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O[Si](C)(C)C(C)(C)C)CC12
Reactant: CC(=O)O[C@H]1C[C@H]2[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@@H](O[Si](C)(C)C(C)(C)C)CC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Temperature: 40 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a stirred solution of 3β,17β-di(dimethyltert-butylsilyloxy)-6α-acetoxyandrostane and 3α,17β-di(dimethyltert-butylsilyloxy)-6α-acetoxyandrostane (90/10 mixture, 7.58 g) in MeOH/dioxane 1/4 (100 mL), K2CO3 (896 mg) was added. After stirring for 72 h at 40° C., the mixture was quenched by addition of H2O. The organic solvents were evaporated and the concentrated solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness to give 3β,17β-di(dimethyltert-butylsilyloxy)androstane-6α-ol and 3α,17β-di(dimethyltert-butylsilyloxy)androstane-6α-ol (90/10 mixture, 6.30 g, 85%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.30 (bb, 1H), 3.55 (bb, 1H), 3.47 (m, 1H), 2.05 (bb, 1H), 1.92-1.73 (m, 2H), 1.68-0.87 (m, 17H), 0.84 (s, 18H), 0.72 (s, 3H), 0.62 (s, 3H), 0.56 (m, 1H), 0.02 (s, 3H), 0.01 (s, 6H), 0.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH2:5]Br.NC(N)=[S:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][SH:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: FC(F)(F)Oc1ccc(CS)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzylbromide (5 g) in ethanol (100 ml) was added thiourea (5 g) and the mixture heated under reflux for 2 hours. The mixture was evaporated to dryness and the residue taken up into water (100 ml). To this solution was added sodium hydroxide pellets (3 g) and the mixture heated under reflux for 1 hour. The mixture was allowed to cool to room temperature and acidified with concentrated hydrochloric acid, the mixture was extracted with ether, dried and evaporated to give the subtitle compound as a colourless waxy solid (3.5 g).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1)=O>O1CCCC1>[C:12]([CH2:13][C:17]([C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:23][CH:24]=1)=[O:16])#[N:14]
Reactant: CC#N
Reactant: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)CC#N)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium 1.6 M in hexane (1.63 ml, 2.61 mmol) was diluted with tetrahydrofuran (2 ml) and cooled to −78° C. Acetonitrile (107 mg, 0.137 ml, 2.61 mmol) was added dropwise and stirring was continuing for 1 hour. (S)-tert-butyl 2-(4-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (420 mg, 1.31 mmol) dissolved in tetrahydrofuran was slowly added to the white slurry over a 10 min period. After 3 hours, the reaction was quenched by addition of saturated ammonium chloride solution (5 ml) and extracted with diethyl ether (10 ml). The organic layer was dried over MgSO4 and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.O>[CH2:12]([N:1]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 5-amino-pyridine-2-carbonitrile (37) (800 mg, 6.72 mmol) in DMF (8 mL) was added NaH (60%) (806 mg, 20.2 mmol) portion wise at 0° C. Benzyl bromide (2.3 mL, 20.2 mmol) was subsequently added and the mixture allowed to stir at rt for 3 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (2×50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluted with 30% EtOAc/pet-ether) to obtain compound 38 (1.3 g, 65%) as a pale yellow solid. Rf: 0.7 (10% MeOH/CHCl3); (m/z): 300 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 8.14 (1H, d, J=2.8 Hz), 7.65 (1H, d, J=9.2 Hz), 7.37-7.25 (10H, m), 7.08 (1H, dd, J=3.6, 9.6 Hz), δ 4.88 (4H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCNc1ccccn1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCCNc1ccccn1)c1ccccc1

Procedure:
A mixture of 2-(3-aminopropylamino)pyridine (6 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for 1 hour and concentrated to give N-benzoyl-N'-[3-(2-pyridylamino)propyl]thiourea. The benzoyl thiourea is added to a solution of potassium carbonate (1.4 g.) in water (80 ml.) at 60°. The solution is maintained at this temperature for 1 hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid is removed by filtration and the filtrate is basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the title product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].[CH3:24][NH2:25]>>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:25][CH3:24])=[O:14]
Reactant: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reactant: CN
Product: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C

Procedure:
WO 95/27693 discloses that a 2-substituted phenyl-N-alkylacetamide compound having an alkoxy group at the 2-position typified by 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide is useful as an agricultural fungicide, and also discloses, as a method for producing the compound; a method in which methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate is reacted with methyl iodide to obtain methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate, and then the methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate is reacted with methylamine to obtain 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([C:7](=[O:17])[CH:8]([Br:18])[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(CC(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2)cc1
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of the product of step 1 (60 g, 246 mmol) in CCl4 (900 mL) and CHCl3 (900 mL) was added dropwise a solution of Br2 (43.2 g, 270 mmol) in CCl4 (50 mL). After addition was completed, the mixture was concentrated to about 1/3 of its original volume. The mixture was washed with saturated NaHCO3 (500 mL) and Na2S2O8 (2×250 mL). The pale yellow solution was dried over Na2SO4 and concentrated to dryness. The residue was stirred in 10 % EtO2 /hexane for 20 h and filtered to give 59 g of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:35](=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH3:35])[C:21](=[O:25])[CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (404, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)[C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1.O.C(OC(C)C)(C)C>CC1C=CC(C)=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([OH:6])[CH2:7][OH:8])[C:9]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OC[C@H](CO)O1
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: OC[C@@H](O)COCc1ccccc1

Procedure:
To this end, 1,2-isopropylidene-sn-glycerol is dissolved in p-xylene and stirred with the addition of potassium-tert.-butylate and benzyl chloride. Upon completion of the reaction, water and diisopropyl ether are added in equal parts; and a phase separation is carried out. The 3-benzyl-sn-glycerol in the upper phase is obtained by evaporation and subjected to additional cleaning steps.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g 4-(oxirane-2-ylmethoxy)-9H-carbazole (II), 80.0 g of 2-(2-methoxyphenoxy)ethylamine hydrogenchloride monohydrate (IV) and 52.4 g of anhydrous calcium carbonate in 330 ml isopropanol is, with intensive stirring, heated at 80° C. for 4 hours. When the epoxide has reacted, the mixed salts are filtered off from the reaction mixture and isopropanol is distilled off from the filtrate. The obtained honey-like concentrate is dissolved, when hot, in 210 ml of ethylacetate, the solution is cooled to the temperature of 40° C., inoculated and stirred at the temperature of 40° C. for 30 minutes. After the crystal precipitates, the mixture is cooled to 0° C., and is kept like that with stirring for a minimum of four hours. After filtration and washing with cooled ethylacetate, 65 to 70 g of wet crude Carvedilol is obtained (HPLC contents>98 area %, HPLC contents of the bis-derivative 1.2-1.5 area %).
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>ClCCl.CO>[C:1]1([N:7]([CH2:31][CH2:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:27][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Reactant: CCCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCc4nnn[nH]4)c4ccccc4)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide and n-hexyl chloroformate. Yield: % of theory, C34H39N9O3 (621.7) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: CC1O[N:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH:10]=[CH:11][CH:12]=2)[N:3]=1.[CH2:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23]>>[CH2:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:18]2[CH2:17][CH2:16][N:15]([C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:4]([NH2:3])=[NH:5])=[O:14])[CH2:20][CH2:19]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23].[C:13]([O-:14])(=[O:31])[CH3:9]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(-c2cccc(C(=O)N3CCNCC3)c2)no1
Product: CC(=O)[O-]
Product: CCCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccc(C(=N)N)c3)CC2)cc1

Procedure:
Similarly, reaction of [3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]piperazin-1-ylmethanone with 4-propyl-phenylsulphonyl chloride and subsequent hydrogenation gives the compound 3-[4-(4-propylphenylsulphonyl)piperazine-1-carbonyl]benzamidine, acetate, FAB 415.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2.[H-].[Na+].[CH3:30]N(C)C=O.CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:30])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of ethyl 5-fluoro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.45 g), 60% sodium hydride (52 mg) and N,N-dimethylformamide (10 mL) was stirred at 4° C. for 30 min. Methyl iodide (0.095 mL) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8) to give the title compound (0.20 g, yield 43%) as colorless prism crystals.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][CH:20]2[CH:12]([NH:13][C:14]3[CH:15]=[C:16]([Cl:24])[C:17]([Cl:23])=[CH:18][C:19]=32)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[Cl:24][C:16]1[C:17]([Cl:23])=[CH:18][C:19]2[C@@H:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C@H:12]3[NH:13][C:14]=2[CH:15]=1
Reactant: O=C(c1ccccc1)N1CCC2Nc3cc(Cl)c(Cl)cc3C2CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@H]1N2
Temperature: 170 °C
Yield: 21.8 %

Procedure:
A mixture of 3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (0.20 g, 0.55), potassium hydroxide (1.0 g, 17.8 mmol), and ethylene glycol (5 mL) was heated to 170° C. Upon the disappearance of starting material, the reaction was cooled to room temperature, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give the title compound (31 mg, 22%) as a tan solid. 1H NMR (d-MeOH) δ 8.54, 7.02, 6.63, 3.73, 3.08-2.88, 2.40, 2.17, 1.81, 1.65: IR (drift) 2934, 2916, 2866, 2850, 2831, 1627, 1608, 1569, 1481, 1466, 1372, 1365, 953, 775, 662 cm−1; HRMS (FAB) calcd for C12H14C12N2+H 257.0612, found 257.0619.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6].[BH4-].[Na+]>CO.ClCCl>[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([CH3:1])[CH2:29][CH2:30]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6]
Reactant: C=O
Reactant: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCNCC4)ncc3C)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C)CC4)ncc3C)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.711 mL, 9.60 mmol) is added to a stirred solution of 2-[5-methyl-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid methylamide (346 mg, 0.845 mmol) in CH3OH (10 mL) and dichloromethane (10 mL) at room temperature. The resultant mixture is stirred for 90 minutes. After being cooled to 0° C., the mixture is treated with powdered sodium borohydride (211 mg, 8.00 mmol) and stirred for 60 minutes. The mixture is allowed to stir at room temperature for 3 hours, concentrated and subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-8%, to give the title compound as a yellowish foam (280 mg, 78% yield). ES+(m/z) 424 [M+H].
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.C(N(CC)CC)C.Cl.[CH:18]1([NH:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[NH2:9][C:8]1[N:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:25]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNC1CCCCC1
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cnn(C2CCCCC2)c1N

Procedure:
Firstly ethoxymethylenemalononitrile (2.43 g, 19.9 mmol) and then 8 ml of triethylamine are added to a solution of cyclohexylhydrazine hydrochloride (3 g, 19.9 mmol) in 36 ml of ethanol at room temperature. The mixture is refluxed for 20 min and then cooled. The solvent is stripped off in a rotary evaporator, and the residue is taken up in DCM, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel (mobile phase: dichloromethane/methanol 0-10%).