Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[NH:5])#[N:2].[ClH:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)(C)C>[ClH:10].[NH:5]=[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)[NH:3][C:1]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[NH:2]
Reactant: C1COCCN1
Reactant: N#CNC(=N)NC1CC1
Agent: Cl
Solvent: CC(C)O
Product: N=C(NC(=N)N1CCOCC1)NC1CC1
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14](=[O:23])[C:15]2[C:16]([C:20](=[O:22])[CH:21]=1)=[N:17][S:18][N:19]=2>C(O)C>[Cl:12][C:13]1[C:14](=[O:23])[C:15]2=[N:19][S:18][N:17]=[C:16]2[C:20](=[O:22])[C:21]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1C=C(Cl)C(=O)c2nsnc21
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(Cl)C(=O)c3nsnc3C2=O)CC1
Yield: 14 %

Procedure:
A solution of 332 mg of 1-piperazinecarboxylic acid, ethyl ester and 200.6 mg of 5-chloro-2,1,3-benzothiadiazole-4,7-dione in absolute ethanol was heated at reflux, with stirring. The mixture was then stirred for 2 hours at room temperature, evaporated, chromatographed on silica gel, eluting with chloroform and concentrated to a red oil. This oil was crystallized from dichloromethanehexane, giving 50 mg of the desired product, mp 152°-154° C.
Reaction SMILES: [CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28]C)[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C@H:14]([CH2:15]5)[C@@:5]4(CC2)[CH2:4]1.C(Cl)(Cl)(Cl)Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:46]1COC[CH2:47]1>>[CH:25]1([CH2:24][N:13]2[CH2:12][CH2:11][C@@:10]34[C:17]5[C:16]6[CH2:15][C@@H:14]2[C@H:5]3[CH2:4][C@H:3]([C@:2]([OH:34])([C:30]([CH3:32])([CH3:33])[CH3:31])[CH3:1])[C@H:8]([OH:28])[C@@H:9]4[O:23][C:18]=5[C:19]([OH:22])=[C:20]2[CH2:47][CH2:46][C:21]2=6)[CH2:27][CH2:26]1
Reactant: C1CCOC1
Reactant: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of buprenorphine (1) (10.0 g, 21.58 mMol) in CCl4 (21.7 ml, 224.5 mMol) and THF (200 ml) was added at 0° C. LiAlH4 (320 ml, 1.0 M, 320 mMol) in THF. The reaction mixture was heated to 55° C. for 24 h. The resulting reaction mixture was cooled to 0° C. and the reaction was quenched by slow, portion-wise addition of Na2SO4·10H2O (103 g), followed by addition of EtOAc (400 ml). After 20 minutes agitation, the resulting slurry was filtered through the pre-packed Solka Floc-40 (18 g). The resulting wet cake was washed thoroughly with EtOAc (2×100 ml). The combined filtrate was concentrated to dryness, affording 13.5 g of crude compound 2 which was subsequently purified by column chromatography on silica gel to afford 6.03 g of compound 2 (62.2% yield) as a white solid with a purity of >99%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:26])[C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].[CH:27]([C:30]1[CH:31]=[C:32]([C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([O:47][CH2:48][C:49](=O)[CH3:50])=[C:42]([CH3:52])[CH:41]=2)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])([CH3:29])[CH3:28].C(O)(=O)C>O1CCCC1>[OH:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C@@H:16]([NH:15][CH:49]([CH3:50])[CH2:48][O:47][C:43]1[C:42]([CH3:52])=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:30]([CH:27]([CH3:28])[CH3:29])[CH:31]=2)=[CH:45][C:44]=1[CH3:46])[CH3:26]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(-c2cc(C)c(OCC(C)=O)c(C)c2)cc1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc(C)c(OCC(C)N[C@@H](C)[C@H](O)c3ccc(O)cc3)c(C)c2)cc1C(C)C
Temperature: 25 °C
Yield: 30.5 %

Procedure:
Sodium triacetoxyborohydride (0.23 g) was added to a mixture of 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.082 g), methyl 3-isopropyl-3′,5′-dimethyl-4′-(2-oxo-propoxy)biphenyl-4-carboxylate (0.17 g) and acetic acid (0.03 mL) in tetra hydrofuran (2.5 mL) at room temperature with stirring, and the mixture was stirred at 50° C. for 4 hrs. After being cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=9/1) followed by aminopropyl silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to afford methyl 4′-{(2RS)-2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)1-methylethylamino]propoxy}-3-isopropyl-3′,5′-dimethylbiphenyl-4-carboxylate (0.074 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:20]([CH:24]=1)[C:21](O)=[O:22])(=[O:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:21]([C:20]1[CH:24]=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][C:19]=1[O:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[CH2:6][CH2:5]2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Clc1ccc2c(c1)CCNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): MS (m/e): 462.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][C:9](=[O:11])[CH3:10].C(O)(=O)C.[N:29]([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:12][C:5]1[N:4]=[C:3]2[N:13]([CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[N:29]=[N:1][C:2]2=[C:7]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=1
Reactant: O=N[O-]
Reactant: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)nc2c1nnn2Cc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(3-amino-6-chloro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide was added to a solution of acetic acid (2 mL) and water (2 mL) at 0° C., followed by the addition of NaNO2 (180 mg, 2.6 mmol) in H2O (0.2 mL). The reaction was stirred at 0° C. for 1 h, and then basified with 30% NaOH to pH=7. The resulting precipitate was collected by filtration to afford the title compound (80 mg), which was used for the next step without further purification. MS (m/z): 353 (M+1)+.
Reaction SMILES: [CH2:1]([P:3](=[O:9])([O-:8])[S:4][CH2:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.O[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]>C(Cl)Cl>[CH2:1]([P:3](=[O:8])([O:9][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[S:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=Cc1ccccc1O
Reactant: CCCSP(=O)([O-])CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSP(=O)(CC)Oc1ccccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-propyl ethylthiophosphonate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 2-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-propyl O-(2-formylphenyl) ethylthiophosphate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([O:29][Si](C(C)(C)C)(C)C)[CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:37]>CO>[ClH:37].[ClH:37].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc3)cc3ccccc23)CC1
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To the resulting 1-(4-ethylpiperazin-1-yl)-3-[4-[2-(R)-(tert-butyldimethylsilyloxy)propoxy]phenyl)isoquinoline (0.43 g) were added methanol (10 ml) and 2N hydrochloric acid (50 ml) and dissolved, and the resulting mixture was stirred at room temperature for 4.5 hr. The solvent was evaporated, and the resulting residue was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.22 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:39])([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>ClCCl.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:38])([CH3:39])[CH2:31][C:32]2[CH:33]=[CH:34][N+:35]([O-:6])=[CH:36][CH:37]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccncc2)ccc1-c1cnco1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2cc[n+]([O-])cc2)ccc1-c1cnco1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
30 mg (0.1 mmol) of 60% 3-chloroperoxybenzoic acid were added to a stirred solution of 20 mg (0.051 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(4-pyridyl)ethyl]oxalamide in 1 ml of dichloromethane. The mixture was stirred for 1 hour then diluted with ethyl acetate, washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether to give 13 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-oxido-4-pyridyl)ethyl]oxalamide as an off-white solid. MS: m/e 411 [M+]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH:13]C(=O)C)[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])C.[ClH:18]>>[ClH:18].[NH2:13][C@@H:6]([C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C[C@@H](NC(C)=O)[C@H](C)[C@H](C)CC
Agent: Cl
Product: CC[C@@H](C)[C@@H](C)[C@H](N)CC(=O)O
Yield: 89 %

Procedure:
(3R,4R,5R)-3-Acetylamino-4,5-dimethyl-heptanoic acid ethyl ester (13.63 g, 56.0 mmol) was heated under reflux with 200 mL of 1M hydrochloric acid for 72 hours. The solution was cooled and extracted 2× with 50 mL aliquots of MTBE. The aqueous phase was evaporated to a semisolid. Acetonitrile (4×100 mL) was added and evaporated to give 10.75 g (89% yield) of the titled compound as a white crystalline solid: 1H NMR (CD3OD, 399.77 MHz) 0.87 (t, J=7.3 Hz, 3H), 0.94 (t, J=6.6 Hz, 6H), 1.02-1.15 (m, 1H), 1.37-1.53 (m, 2H), 1.58-1.68 (m, 1H), 2.64 (dd, J=17.5, 7.4 Hz, 1H), 2.73 (dd, J+17.5, 4.8 Hz, 1H), 3.54-3.61 (m, 1H). Low resolution mass spec: nominal m/e calc'd for C9H20ClNO2 (M+H)+: 174. Found: m/e 174.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:11][C@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH3:10])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(C(F)(F)F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[N:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.03 g (3.90 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Step A) in 12 ml. of DMF was treated with 0.788 g (7.79 mmole) of triethylamine at 25° C. With stirring 0.901 g (3.89 mmole) of diphenylcarbamoyl chloride was added in portions over 2 hours. After 16 hours the mixture was concentrated in vacuo to an orange oil which was chromatographed over an 88×2.5 cm LH 20 column with 11 ml. fractions of methanol. Fractions 35-43 were combined and concentrated to 1.136 g (64%) of pale yellow oil which contained a major spot by TLC (80:18:2 chloroform-methanolammonia water, Rf =0.45).
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:37])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([OH:36])=[O:35].[C:38]([C@@H:40](O)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:42]=1)#[N:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:37][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([O:36][C@H:40]([C:38]#[N:39])[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:42]=1)=[O:35]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Yield: 72.3 %

Procedure:
1.9 ml of pyridine and 4.8 g of dicyclohexylcarbodiimide were added to a solution of 4.9 g of (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylic acid in 39 ml of methylene chloride and a solution of 5.3 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 9.8 ml of methylene chloride was added with stirring to the mixture. After stirring the mixture for 2 hours, 30 mg of 4-dimethylamino-pyridine were added thereto and the mixture was stirred for 2 hours. The mixture was cooled to 0° C. and was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was successively eluted with a 9-1 cyclohexane-ethyl acetate mixture and with a 6-4 methylene chloride-petroleum ether (b.p.=35°-70° C.) mixture to obtain 6.73 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate with the same characteristics of the compound of Example 2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[N:6]#[C:7][NH2:8].[ClH:9]>C(COC)OC>[ClH:9].[N:1]1([C:7]([NH2:8])=[NH:6])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#CN
Reactant: c1cn[nH]c1
Agent: Cl
Solvent: COCCOC
Product: N=C(N)n1cccn1

Procedure:
In a 500 ml four-necked flask fitted with gas inlet tube and gas outlet tube, internal thermometer and reflux condenser with in each case two safety wash bottles connected upstream and downstream, 34.1 g (0.5 mol.) of pyrazole and 21.0 g (0.5 mol.) of cyanamide are dissolved in 330 ml of dimethoxyethane. At 80° C., dry hydrogen chloride gas is introduced into the reaction solution at a rate of about 15 l/h for about 50 minutes. The solution is then allowed to cool and the precipitated solid is removed by filtration. The product obtained is dried under reduced pressure (100 mbar, 80° C.) to give 1H-pyrazole-1-carboxamidine hydrochloride in the form of a colorless, finely crystalline solid. Yield: 70.6 g (96%), melting point: 160 to 168° C. (literature: 165 to 166° C.) 13C-NMR (DMSO-d6) δ 152.3, 146.0, 131.5, 111.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cccc(F)c1[N+](=O)[O-]

Procedure:
Reaction of 2.0 g (2.6 mmol) 2,6-difluoro-nitrobenzene with a 2 molar solution of methylamine in THF analogously to the process for preparing Intermediate 10a. Red solid. Yield: 1.8 g (86%); mass spectroscopy: [M+H]+=171.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]=[C:7](Cl)[C:8]([F:11])([F:10])[F:9].Cl[C:18](=[CH2:21])[C:19]#[N:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[CH:21][C:18]=2[C:19]#[N:20])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: FC(F)(F)C(Cl)=NCc1ccc(Cl)c(Cl)c1
Reactant: C=C(Cl)C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)-2,2,2-trifluoroacetimidoyl chloride (20.0 g, 0.069 mol) and 2-chloroacrylonitrile (7.2 g, 0.082 mol) in N,N-dimethylformamide is cooled to 5° C. and treated with a solution of triethylamine (22 mL, 0.16 mol) in N,N-dimethylformamide (38 mL). When the addition is half complete, the cooling bath is removed and the reaction mixture is treated with the remaining triethylamine solution, stirred for two hours and diluted with water. The aqueous mixture is filtered to obtain the title product as a tan solid (18.38 g, mp 230°-232° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]2[CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)#[N:2].[NH:21]1[C:29]2[C:24](=[C:25]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:14]2[CH2:19][CH2:18][CH:17]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]5[CH:23]=[CH:22][NH:21][C:29]=5[CH:28]=[CH:27][CH:26]=4)[CH2:31][CH2:32]3)[CH2:16][CH2:15]2)=[CH:7]1
Reactant: CCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A solution of 4-(5-cyano-1-ethyl-indol-3-yl)-cyclohexanone (1.5 g, 5.6 mmol), 1-(indol-4-yl)piperazine (1.19 g, 5.9 mmol), sodium triacetoxyborohydride (1.73 g, 8.2 mmol) and acetic acid (0.9 ml, 15 mmol) in 1,2-dichloroethane (30 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×80 ml), and washed with brine (3×80 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 0.98 g (39%) of product as a white solid: mp 226° C. (dec.).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(CCC)=CC=2)[CH2:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH:25]=2)=[CH:20][CH:19]=1>>[O:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:4]3[CH2:5][CH2:6][NH:7][C@H:2]([CH3:1])[CH2:3]3)=[CH:19][CH:20]=2)=[CH:25]1
Reactant: Brc1ccc(-c2coc3ccccc23)cc1
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Product: C[C@@H]1CN(c2ccc(-c3coc4ccccc34)cc2)CCN1
Yield: 21 %

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 3-(4-bromophenyl)-1-benzofuran (obtained as described in Malamas et al., 2000, J. Med. Chem., 43, 1293-1310). Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as beige solid (21%). HPLC (Condition A), Rt: 3.0 min (HPLC purity: 93.4%). M+(ESI): 293.2
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:13](=[O:25])[NH:14][CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:23]3)[CH:15]1[NH:14][C:13]([C:8]1([NH2:7])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:25])[CH2:24]2
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2C3CC4CC(C3)CC2C4)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(=O)NC2C3CC4CC(C3)CC2C4)CCCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a solution of [1-(adamantan-2-ylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester (710 mg) in DCM (10 mL) was added TFA (1.5 mL) at 0° C. The mixture was stirred and allowed to warm to RT over night. The reaction mixture was evaporated and the residue was re-dissolved in DCM and washed with saturated NaHCO3 and brine. The organic layer was dried with Na2CO2 and evaporated to give a residue that was purified by flash chromatography using ethyl acetate as an eluent to give the desired material as a colorless glass (377 mg). MS (ESI): 263.4 (MH+).