Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[C:9]([Cu])#[N:10].CCOCC>CN(C=O)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([C:9]#[N:10])[S:3][CH:4]=1
Reactant: Cc1c(Br)csc1Br
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(Br)csc1C#N

Procedure:
A mixture of 2,4-dibromo-3-methylthiophene (20.0 g, 78.1 mmol) and CuCN (6.30 g, 70.3 mmol) in 150 mL of DMF was stirred at reflux for 4 hours before cooling down. The reaction mixture was poured into 1 L of ether with stirring and the precipitate was removed by filtration. The filtrate was washed with water (3×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (petrol ether: EtOAc=50:1) to afford 4-bromo-3-methylthiophene-2-carbonitrile.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[N:42]=[CH:41][N:40]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:39]=3)=[CH:35][CH:36]=2)[C:31]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[N:30]1>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([NH:68][C:64]1[CH:65]=[CH:66][CH:67]=[C:62]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[C:34]([C:38]4[N:42]=[CH:41][N:40]([C:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[N:39]=4)[CH:33]=3)[N:29]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:30]=2)[CH:63]=1)=[O:9]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(O)C(=O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-furyl)-2-oxoacetic acid (0.070 g, 0.496 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.098 g, 0.510 mmol). The solution was stirred at room temperature for 15 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 725 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[OH:30][CH2:29][CH2:31][NH:32][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:21]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: NCCO
Agent: Cl
Product: O=C(NCCO)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to ethanolamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 6.3 mg of 266. MS (Q1) 424.8 (M)+.
Reaction SMILES: [CH2:1]1[O:4][C@@H:2]1[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>>[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:1][C@H:2]([OH:4])[CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: C[C@@H]1CO1
Product: COC(=O)c1ccc(SC[C@@H](C)O)cc1Cl

Procedure:
140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.1 (M)+.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([O-:10])=[O:9])[CH:3]=1.N1C=CC=CC=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[C:18]([CH3:25])([S:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9])[CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=S([O-])c1cccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 3-pyridylsulfinic acid sodium salt (4.4 mmol, synthesised by variation A) was suspended in DMF (20 mL). Pyridine (0.8 mL) and ethyl α-bromoisobutyrate (1 mL) were added. The reaction was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with DCM (200 mL), washed with water (2×100 mL), brine (1×50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography (silica, eluent DCM, 0-10% ethyl acetate) afforded 0.24 g of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[O:9][CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(Cl)Cl>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[CH2:10][OH:12]
Reactant: COc1cccc2c1C(=O)OC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(CO)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 7-methoxy-3H-isobenzofuran-1-one (16.65 g, 101.4 mmol) in anhydrous THF (200 ml) was added at room temperature under an atmosphere of argon to a freshly prepared solution of LiAlH4 (7.70 g, 202.8 mmol, 2.0 equiv) in THF (100 ml). After 30 minutes at room temperature, TLC analysis indicated complete conversion. The reaction mixture was cooled to 0° C. and water was added dropwise until gas evolution ceased. Water (500 ml) and CH2Cl2 (500 ml) was added to form a white suspension. After filtration, the filtrate was extracted with CH2Cl2 (4 liters in total). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (15.34 g, 90%) in adequate purity for direct use in the next transformation. 1H NMR (400 MHz, CDCl3): δ=7.27 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 4.83 (s, 2H); 4.72 (s, 2H), 3.85 (s, 3H), 2.8-2.6 (br s, 2H). MS (ES+): 169 (M+H)+.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22])=[NH:6]>[Ni].O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=NN1CCN=C1N
Agent: [Ni]
Agent: Cl
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=NN1CCN=C1N

Procedure:
Analogously to Example 2, approximately 2.0 g of Raney nickel are added to a solution of 4.75 g (0.0138 mol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4,5-dihydro-imidazole dihydrochloride in 240 ml of water, and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and concentrated to dryness by evaporation. The residue is recrystallized from water, yielding the title compound in the form of the monohydrate, m.p. 280° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.17 (d, 1H); 7.66 (d, 1H); 7.54 (t, 1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:10]=1[C:11](O)=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:11](=[O:12])[C:10]=2[CH:14]=1
Reactant: Nc1ccccc1Sc1ccc(F)cc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2Sc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(2-aminophenylthio)-5-fluorobenzoic acid (64.57 mmol, 17.51 g) in 500 mL xylenes was treated with p-toluenesulfonic acid monohydrate (64.57 mmol, 12.2 g) and heated. Additional 200 mL xylene was added and heating was continued with azeotropic removal of water for 16 h. The resulting pink reaction mixture was cooled to the room temperature and added to 300 mL water. After stirring for 15 min the solid removed by filtration, washed with 3×100 mL water and dried in air for 4 h, and then under high vacuum for 20 h to obtain 2-fluorodibenzo[b,f][1,4]thiazepin-11(10H)-one as a off white solid (11.6 g, 73%); MS (M+1) 246; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.16 (t, 1H) 7.24 (d, J=7.2 Hz, 1H) 7.29-7.42 (m, 2H) 7.47 (dd, J=9.3, 2.9 Hz, 1H) 7.52-7.71 (m, 2H) 10.47-11.20 (m, 1H), MS 081119 M+1 246 (0.72).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]([CH:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:47]>CN(C=O)C>[C:49]1([CH:48]([NH:55][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:46][CH3:47])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CCC(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)c1ccc2[nH]cnc2c1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 5-benzimidazole-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt. for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 280 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)n(C#N)c3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Temperature: -50 °C
Reaction time: 4.5 h

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was dissolved in 3 ml DCM and the mixture was cooled to −50° C. BBr3 (5 eq) was added and the reaction was stirred at −50° C. for 4.5 h and then at −20° C. for 16 h. The mixture was cooled to −78° C. and MeOH (90 μl) was added followed by water. The aqueous layer was extracted with DCM 3× and the combined organic layers were concentrated. The crude product was purified on silica (EtOAc/n-Heptane 2:8-3:7). 4.9 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile was obtained as a white solid. ES/MS m/z: 330.2 (M+H), 328.3 (M−H); 1H NMR (CDCl3, 500 MHz): 7.75 (m, 1H), 7.67 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.20 (m, 2H), 6.88 (m, 2H), 2.28 (s, 3H) and 2.05 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1ccncc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Acetylpyridine (3.62 g, 29.9 mmol) was added with acetic acid (30 ml) and 47% hydrobromic acid (5.3 ml) at room temperature, subsequently added dropwise with bromine (1.6 ml in total) four times at an interval of 5 minutes, stirred at room temperature for 2 hours and 30 minutes. The mixture was further added with bromine (1.6 ml), and stirred at room temperature for 20 hours. The reaction solution was filtered, and the resulting crystals were washed with diethyl ether and dried to obtain 12.43 g of the title compound as a salt of hydrogen bromide in the form of orange crystals without purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:34][S:35]([CH:38]=[CH2:39])(=[O:37])=[O:36]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and methylvinylsulfone were reacted to give 544. LCMS m/z: 553.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[N:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1I.[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[C:47]([F:50])([F:49])[F:48].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[N:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[C:41]1[CH:42]=[CH:43][C:38]([F:37])=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:40]=1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(I)c(Cl)c2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(F)c(C(F)(F)F)c3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(((3-chloro-4-iodophenyl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (300 mg, 0.48 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (138 mg, 0.67 mmol), Pd(dppf)Cl2 (39 mg, 0.05 mmol), and K2CO3 (131 mg, 0.95 mmol) were dissolved in 1,4-dioxane (1.6 mL) and water (0.4 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)SC)#[N:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>CO>[C:1]([NH:3][C:4]([NH:24][CH2:21][C:22]#[CH:23])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=1)#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1csc(NC(=N)N)n1)NC#N
Solvent: CO
Product: C#CCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(2-guanidinothiazol-4-yl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in South Africa Pat. No. 78/2129] (3.0 g; 9.11 mmoles) and propargylamine (6.0 ml) in methanol (15 ml) was stirred and heated at reflux temperature under a positive pressure of nitrogen for 20 hours. The reaction mixture was evaporated under reduced pressure and the residue triturated with isopropanol and filtered to give product (1.5 g). Recrystallization from nitromethane gave the title compound, mp 146°-148°.
Reaction SMILES: [Na+].[I-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH:17](Cl)[C:18]2[O:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:26]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>N1C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]2[O:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:26]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(Cl)c2nc3cnccc3o2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C=Cc2nc3cnccc3o2)CC1
Temperature: 150 °C

Procedure:
NaI (2 mg) was added to a solution of 4-(2-chloro-2-oxazolo[4,5-c]pyridin-2-ylethyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 22, 18 mg, 49 μmol) in anhydrous pyridine (1 mL). The mixture was heated under microwave irradiation for 10 min at 150° C., before being concentrated in vacuo. The residue was taken up in EtOAc (20 mL), then the EtOAc solution was washed with a mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (1:1, 2×8 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (EtOAc-IH, 17:3) yielded 4-(2-oxazolo[4,5-c]pyridin-2-ylvinyl)-piperidine-1-carboxylic acid tert-butyl ester as a 1:1 mixture of (E)- and (Z)-isomers: m/z (ES+)=330.1 [M+H]+. A solution of this compound (10 mg, 30 μmol) in EtOH (1 mL) was stirred with Pd (10% on C, 1 mg) under a H2 atmosphere for 4 h. The mixture was filtered through celite, washing with MeOH. The combined filtrates were concentrated under reduced pressure to afford the title compound: RT=2.89 min; m/z (ES+)=332.2 [M+H]+.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[Cl:15][C:16]1[CH:17]=[C:18]([NH:33][C:34]2[C:35]3[N:42]([CH2:43][C:44]#[C:45][CH2:46][OH:47])[CH:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:33][C:34]2[C:35]3[N:42]([CH2:43]/[CH:44]=[CH:45]/[CH2:46][OH:47])[CH:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: OCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC/C=C/Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
70% Sodium bis(2-methoxyethoxy)aluminum hydride in toluene solution (0.8 mL) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to 0° C. A solution of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-ol (262.4 mg) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 0° C. for 2 hrs. To the reaction mixture was added 10% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100) and crystallized from hexane/ethyl acetate to give the title compound (195.9 mg) as white crystals.
Reaction SMILES: [Cl-].[Na+].[CH3:3][CH:4]([OH:117])[CH:5]1[NH:53][C:51](=[O:52])[CH:50]([CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[NH:49][C:47](=[O:48])[CH:46]([CH2:59][C:60]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[NH:62][CH:61]=2)[NH:45][C:43](=[O:44])[CH:42]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[NH:41][C:39](=[O:40])[CH:38]([CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[NH:37][C:35](=[O:36])[CH:34]([CH2:83][C:84]([NH2:86])=[O:85])[NH:33][C:31](=[O:32])[CH:30]([CH2:87][CH2:88][CH2:89][CH2:90][NH2:91])[NH:29][C:27](=[O:28])[CH:26]([NH:92][C:93]([CH2:95][NH:96][C:97]([CH:99]([NH2:101])[CH3:100])=[O:98])=[O:94])[CH2:25][S:24][S:23][CH2:22][CH:21]([C:102]([OH:104])=[O:103])[NH:20][C:18](=[O:19])[CH:17]([CH2:105][OH:106])[NH:16][C:14](=[O:15])[CH:13]([CH:107]([OH:109])[CH3:108])[NH:12][C:10](=[O:11])[CH:9]([CH2:110][C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[NH:8][C:6]1=[O:7]>>[CH3:3][C@@H:4]([OH:117])[C@@H:5]1[NH:53][C:51](=[O:52])[C@H:50]([CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[NH:49][C:47](=[O:48])[C@H:46]([CH2:59][C:60]2[C:68]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[NH:62][CH:61]=2)[NH:45][C:43](=[O:44])[C@H:42]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[NH:41][C:39](=[O:40])[C@H:38]([CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[NH:37][C:35](=[O:36])[C@H:34]([CH2:83][C:84]([NH2:86])=[O:85])[NH:33][C:31](=[O:32])[C@H:30]([CH2:87][CH2:88][CH2:89][CH2:90][NH2:91])[NH:29][C:27](=[O:28])[C@@H:26]([NH:92][C:93]([CH2:95][NH:96][C:97]([C@@H:99]([NH2:101])[CH3:100])=[O:98])=[O:94])[CH2:25][S:24][S:23][CH2:22][C@@H:21]([C:102]([OH:104])=[O:103])[NH:20][C:18](=[O:19])[C@H:17]([CH2:105][OH:106])[NH:16][C:14](=[O:15])[C@H:13]([C@H:107]([OH:109])[CH3:108])[NH:12][C:10](=[O:11])[C@H:9]([CH2:110][C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[NH:8][C:6]1=[O:7]
Reactant: CC(N)C(=O)NCC(=O)NC1CSSCC(C(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc2ccccc2)NC(=O)C(C(C)O)NC(=O)C(CCCCN)NC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(Cc2ccccc2)NC(=O)C(Cc2ccccc2)NC(=O)C(CC(N)=O)NC(=O)C(CCCCN)NC1=O
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H](N)C(=O)NCC(=O)N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC1=O

Procedure:
A pharmaceutical composition of somatostatin was prepared in the form of eye drops by adding 125 μL of 0.9% sodium chloride to 5 mg of somatostatin-14.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([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.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:33][CH2:32][C:28]1[N:27]([C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:21]=2[Cl:34])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-cyanopyrrole (820 mg) in anhydrous tetrahydrofuran (16 ml) was added lithium aluminum hydride (74 mg) and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched by adding water (2 ml) dropwise under ice-water cooling. Ethyl acetate (50 ml) and water (50 ml) were added thereto and the precipitate was filtered off. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with chloroform-methanol to give 2-aminomethyl-1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (414 mg) as a pale yellow oil.