Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)[CH3:3].Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20]N)[CH:17]=[CH:18][CH:19]=1.Cl>C(O)C>[CH3:1][N:2]([CH3:3])[CH:4]1[CH2:9][C:8]2[C:17]3[C:16](=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=3)[NH:20][C:7]=2[CH2:6][CH2:5]1
Reactant: COc1cccc(NN)c1
Reactant: CN(C)C1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2c3c([nH]c2c1)CCC(N(C)C)C3

Procedure:
A solution of 7 g. of dimethylaminocyclohexanone and 8.4 g. of 3-methoxyphenylhydrazine hydrochloride in 40 ml. of absolute ethyl alcohol and 12 ml. of 4-N hydrogen chloride in ethyl alcohol was heated under reflux for two hours. The reaction mixture was allowed to stand for sixteen hours, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in water, made alkaline with dilute sodium hydroxide and extracted with ether. The ether extract was washed with water, dried, ethereal hydrogen chloride was added, and the resulting oily precipitate was collected by decantation, recrystallized twice from isopropyl alcohol, suspended in chloroform and treated with dilute sodium hydroxide. The chloroform extract was evaporated to dryness under reduced pressure to give 3-(dimethylamino)-7-methoxy-1,2,3,4-tetrahydrocarbazole, m.p. 100°-105° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH2:13][C:14](OCC)=[O:15])=[C:7]([F:20])[CH:6]=1.O>C(O)COCCO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:3][N:2]([CH3:1])[C:14](=[O:15])[CH:13]=2)=[C:7]([F:20])[CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1F
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Reaction time: 6 h

Procedure:
34.7 g (0.75 mol) of methylhydrazine were added to a solution of 177 g (0.68 mol) of ethyl 3-(4-chloro-2-fluoro-5-methylphenyl)-3-oxopropionate in 500 ml of diethylene glycol. After 6 hours at 100° C., the mixture was poured into 4 l of water. The solids were subsequently removed and dried. Yield: 133 g; m.p.: 155-156° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[NH:22]1[CH:26]=[C:25]([CH2:27][CH2:28][C:29](O)=[O:30])[N:24]=[N:23]1>>[NH:24]1[C:25]([CH2:27][CH2:28][C:29]([NH:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)=[O:11])[CH2:6][CH2:5]2)=[O:30])=[CH:26][N:22]=[N:23]1
Reactant: O=C(O)CCc1c[nH]nn1
Reactant: NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Product: O=C(CCc1cnn[nH]1)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,5-dichlorobenzyl 4-(aminomethyl)piperidine-1-carboxylate hydrochloride (Example 41, step 2) and 3-(1H-1,2,3-triazol-4-yl)propanoic acid (step 1) analogously to Example 41 step 3;
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[C:11]([CH3:14])[CH:12]=O.C(O)C>C(O)(=O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:12]=[C:11]([CH3:14])[CH:10]=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CC(C=O)=CN(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cnc2c(Br)cnn2c1
Yield: 71.6 %

Procedure:
3-Amino-4-bromopyrazole (0.331 g, 2.04 mmol) and 3-(dimethylamino)-2-methyl-2-propenal (0.220 g, 1.94 mmol) were dissolved in acetic acid (6.48 mL) and ethanol (9.72 mL) and the reaction stirred at room temperature for 16 h. Solvents were removed under reduced pressure. The remaining residue was taken up in dichloromethane and purified by column chromatography (20-80% EtOAc/Hex) to give the title compound (0.294 g, 1.39 mmol). LRMS (APCI) calc'd for (C7H6BrN3) [M+H]+, 212.0; found 211.9. 1H NMR (500 MHz, cdcl3) δ 8.44 (s, 2H), 8.04 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14][C:13]=2[CH:23](O)[CH3:24])[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:2][CH:23]([C:13]1[O:14][C:15](=[O:22])[C:16]2[C:21]([C:12]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:24]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 M PBr3 in DCM (2.3 ml, 2.332 mmol) was added to a solution of 4-(3-fluorophenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B7, 390 mg, 1.372 mmol) in DCM (7.8 ml) and the mixture stirred at RT for 2 hrs. The reaction mixture was then evaporated under reduced pressure and purified on a silica Biotage SNAP 100 g, eluting with a gradient of hexane and EtOAc to give the title (227 mg, 47.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.N1C=CC=CC=1.[Cl:28][CH2:29][C:30]1[S:31][CH:32]=[C:33]([C:35](Cl)=[O:36])[N:34]=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]([NH:21][C:35]([C:33]2[N:34]=[C:30]([CH2:29][Cl:28])[S:31][CH:32]=2)=[O:36])[CH:3]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(N)cc(Br)cc32)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CCl)n4)cc(Br)cc32)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
A three necked rounded bottomed flask was charged with 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-amine (12.7 g), anhydrous DCM (100 ml) and pyridine (7.5 ml) then placed under a nitrogen atmosphere and cooled to −10° C. A suspension of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (9.39 g) in anhydrous DCM (75 ml) was added in one portion. The reaction mixture was stirred at room temperature for ˜4 hrs. Additional 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.36 g) in anhydrous DCM was added in one portion and the reaction was stirred overnight. The suspension was filtered, washing sparingly with DCM, then dried on the vacuum pump to give title compound (15.8 g).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[N:23][O:24][C:25]=3[CH3:26])=[N:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of cyclopropylmethylamine (85 mg, 103 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (78 mg, 68%) which was obtained as an off white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].C(C1NC=CN=1)(C1[NH:25]C=CN=1)=O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:25])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylic acid (example 7) (1.8 g, 5.1 mmol) in tetrahydrofuran (40 ml) treated with carbonyl diimidazole (1.8 g, 11 mmol) and heated at gentle reflux for 4 hours. The mixture was cooled and added to 0.88 aqueous ammonia solution (60 ml), stirred for 1 hour at ambient temperature and then evaporated to low bulk. The resultant white solid was diluted with ice/water, filtered, washed with cold water and air dried to give the title compound as a white solid (1.93 g, 100%).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(#N)C>CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of acetonitrile followed by agitation at room temperature for 5 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 2.2 g of 1-(2-cyanophenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[CH3:13].[CH3:14][NH2:15].CO>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:15][CH3:14])=[C:3]1[CH3:13]
Reactant: Cc1c(C=O)c2ccccc2n1C
Reactant: CN
Solvent: CO
Product: CNCc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1,2-dimethylindole-3-carboxaldehyde (11.50 g, 66.4 mmole) was added a solution of 2 M methylamine in methanol (100 mL, 200 mmole). The reaction was stirred for 4 h at RT then was concentrated to dryness to afford the crude title compound: 1H NMR (400 Hz, CDCl3) δ 8.55 (d, J=1.4 Hz, 1 H), 8.16 (d, J=7.5 Hz, 1 H), 7.42 (d, J=7.8 Hz, 1 H), 7.15 (t, 1 H), 7.07 (t, 1 H), 3.68 (s, 3 H), 3.41 (s, 3 H), 2.55 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C1[C:40]2(C[NH:42][CH2:41]2)CO1.C(N(CC)CC)C>C1COCC1>[CH2:41]([NH:42][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)[CH3:40]
Reactant: C1NCC12COC2
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1nc(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)cc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and 2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.) in THF (0.20M) was added triethylamine (3.5 equiv.) and the allowed to stir at 75° C. for 48 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(3-(2-(ethylamino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 21% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 1.28 (t, J=7.24 Hz, 3H) 2.38 (s, 3H) 3.52 (q, J=6.65 Hz, 2H) 3.80 (br. s., 6H) 4.05 (br. s., 2H) 6.50 (s, 1H) 7.41 (d, J=8.61 Hz, 1H) 7.66 (dd, J=8.22, 2.35 Hz, 1H) 7.72-7.78 (m, 1H) 7.91 (d, J=7.83 Hz, 1H) 7.96 (d, J=2.35 Hz, 1H) 8.21 (d, J=7.83 Hz, 1H) 8.26 (s, 1H). LCMS (m/z) (M+H)=486.3, Rt=0.86 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.Br[CH:11]=[C:12]([CH3:14])[CH3:13]>>[CH3:13][C:12]([CH3:14])=[CH:11][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: CC(C)=CBr
Product: COC(=O)c1ccn(C=C(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 17(a) starting from methyl 1H-pyrazole-3-carboxylate (8 g, 63.4 mmol) and 1-bromo-2-methyl propene (12.7 g, 95.2 mmol). The product was purified with flash chromatography. Yield 2.4 g. 1H-NMR (400 MHz; CDCl3): δ 1.81 (d, 3H), 1.87 (d, 3H), 3.93 (s, 3H), 6.70 (d, 1H), 6.87 (d, 1H), 7.47 (d, 1H).
Reaction SMILES: NC(C([C:12]1S[C:14]2C=CC=[CH:17][C:15]=2[N:16]=1)=O)CCCNC(N)=N.C([N:24]1CC(O)[CH2:26][CH:25]1[C:30](O)=O)(=O)C>C1COCC1.O>[CH:25]([N:24]=[C:12]=[N:16][CH:15]([CH3:14])[CH3:17])([CH3:30])[CH3:26]
Reactant: N=C(N)NCCCC(N)C(=O)c1nc2ccccc2s1
Reactant: CC(=O)N1CC(O)CC1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N=C=NC(C)C

Procedure:
A solid mixture of N-(4-amino-5-benzothiazol-2-yl-5-oxo-pentyl)-guanidine (0.24 g, 0.83 mmol) and 1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.14 g, 0.83 mmol) was dissolved in THF (10 mL) and water (2 mL). To the reaction mixture was then added N,N′-diisopropyl carbodiimide to yield a reaction mixture of pH 1.8 at 0° C. The pH of the reaction mixture was adjusted to about 5.5 with 8% NaHCO3. The reaction mixture was stirred at ambient temperature for 4 hours. The title compound was detected by HPLC (180 mg) and assayed by weight analysis.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:45])[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:5]1)[CH:2]=C.[OH2:46].CC#N.C(Cl)(Cl)(Cl)Cl.[OH2:55]>>[NH:38]([C:36]([C@H:6]1[N:7]2[C:12](=[O:13])[C:11]([N:14]([C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[CH:10][N:9]=[C:8]2[C@@:4]([CH2:1][C:2]([OH:55])=[O:46])([CH3:45])[CH2:5]1)=[O:37])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O
Reactant: C=CC[C@]1(C)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@]1(CC(=O)O)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Reaction time: 16 h

Procedure:
To a solution of 117a (1.073 g, 1.740 mmol) in 15.4 mL CH3CN/CCl4/H2O (2:2:3), were added NaIO4 (1.56 g, 7.31 mmol) and a solution of RuCl3.H2O (18 mg, 0.087 mmol) in 2.25 mL of CH3CN/CCl4/H2O (2:2:3). The mixture was stirred vigorously for 16 h, then was poured into H2O and extracted with CH2Cl2 (2×). The combined organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to afford 1.17 g of 117b as a brown foam, which was used in the following step without further purification. MS (ESI) 657.3 (M+Na+); 633.4 (M−H+).
Reaction SMILES: C(OC(N1CCC([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)CC1)=O)(C)(C)C.Br[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>C(OCC)C>[N:18]1([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:17]1
Reactant: BrCc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: CCOCC
Product: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.39 g (100% of yield) of the expected product were isolated.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[Na].O>C(O)C>[CH:5]1([NH:4][CH2:3][CH2:1][OH:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCCC1
Reactant: NCCO
Agent: [Na]
Solvent: CCO
Solvent: O
Product: OCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35181.5 %

Procedure:
A mixture of ethanolamine (4 ml, 0.066 mmol) and cyclopentanone (6.85 ml, 0.08 mmol) in ethanol (60 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled in ice and then sodium borohydide (3.04 g, 0.08 mmol) was added slowly over 20 minutes. The mixture was stirred for 15 minutes before water (10 ml) was added. The mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane and dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by vacuum distillation to give 2-(cyclopentylamino)ethanol (3 g, 35% yield) as a clear oil:
Reaction SMILES: CCN[C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].[OH:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C(N=C=NC(C)C)(C)C.OS([O-])(=O)=O.[Na+]>C1COCC1.COC(C)(C)C>[O:37]=[C:36]1[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33](=[O:42])[N:32]1[O:31][C:4](=[O:5])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]1[CH:13]([OH:30])[CH2:14][CH:15]([OH:29])[CH:16]1[CH:17]=[CH:18][CH:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(CCCC=CCC1C(O)CC(O)C1C=CC(O)CCc1ccccc1)ON1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 58.4 %

Procedure:
2 g of bimatoprost acid is dissolved in 20 ml of THF and to this solution are added at room temperature 1 g of N-hydroxy-phtalimide and 1 ml of N,N′-diisopropylcarbodiimide. The reaction mixture is stirred for 2 hours and then poured onto they mixture of 1N NaHSO4 solution and tert-butyl methyl ether (TBME). The phases are separated, the organic phase is washed with 1N NaHCO3 solution and the aqueous-alkaline phase is extracted with TBME. The united organic phase is dried over Na2SO4, filtered and evaporated. The residue is crystallized from hexane:acetone mixture to obtain 1.5 g white crystalline material.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]=[CH2:27])=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:28])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]=[CH2:27])=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:28])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoate (2.4 g, 6.2 mmol) in dichloromethane (10 mL), was added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 16 h and then concentrated in vacuo. The residue was triturated in hexanes (50 mL), the solid was filtered and dried to give the title compound as a light yellow solid (1.5 g, 73% in 2 steps): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 7.92 (d, J=8.6 Hz, 1H), 6.96-6.81 (m, 2H), 5.84-5.78 (m, 1H), 5.32-5.28 (m, 1H), 3.62 (s, 2H), 3.34 (s, 3H), 1.95 (s, 3H), 1.70-1.60 (m, 12H); MS (ES+) m/z 331.2 (M+1); MS (ES−) m/z 329.4 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]4([CH3:20])[O:19][CH2:18]4)=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C4(C)CO4)ccc3oc2nc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(=O)c3cc(C(C)CO)ccc3oc2nc1N
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of ethyl 2-amino-7-(1,2-epoxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (800 mg), 5% palladium-carbon (700 mg), ethanol (50 ml) and tetrahydrofuran (150 ml) was subjected to catalytic reduction for two hours at room temperature under ordinary pressure. Then, the catalyst was filtered off, and the filtrate was concentrated to dryness. The concentrate was purified by means of a silica-gel (80 g) column chromatography using chloroform-acetone-formic acid (9:1:0.1). The solvent was evaporated off, and the residue was recrystallized from chloroform to yield colorless prisms (499 mg) of ethyl 2-amino-7-(2hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine-3-carboxylate, m.p. 255°-256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14](OC)[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[CH:14]=1)[CH2:23][CH:24]([CH3:25])[CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Solvent: c1ccncc1
Product: CC(=O)OC(CC(C)C)c1ccc2c(c1)C(=O)OCc1cccc(C)c1O2

Procedure:
100 mg (0.27 mmol) of penicillide (Ib) are stirred in 2 ml of pyridine and 1 ml of acetic anhydride for 14 h at 25° C. with the exclusion of moisture. The reaction mixture is evaporated in vacuo, the residue is taken up in methylene chloride and the solution is washed with water. The evaporation residue of the dried organic phase is chromatographed on silica gel using hexane/diethyl ether.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COc1ccc(C(=O)/C=C/N(C)C)cc1
Agent: Cl
Product: COc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.84 (3H, s), 6.46 (1H, d, J=5.6 Hz), 6.88 (2H, dd, J=6.8, 2.0 Hz), 7.20 (2H, dd, J=6.4, 2.0 Hz), 7.37 (1H, dd, J=5.2, 1.6 Hz), 7.75 (1H, d, J=1.6 Hz), 7.91 (1H, s), 8.44 (1H, dd, J=4.8, 0.8 Hz).