Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([N:14]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)nc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Yield: 47 %

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine with itaconic acid yields the crude (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid as a green solid (yield 47% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:23][CH:24]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(CC(=O)O)Cc2ccccn2)cc1
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoyl-phenethyl)amino)acetate (150 mg, 0.37 mmol) in DCM (3.0 mL) and TFA (3.0 mL) was stirred at room temperature for overnight. Solvent was removed under reduced pressure to give 2-((pyridin-2-ylmethyl)(4-sulfamoylphenethyl)amino)acetic acid (129 mg, 100%). 1H NMR (400 MHz, CD3OD) 8.73 (d, J=5.6 Hz, 0.46H), 8.58 (d, J=4.4 Hz, 1H), 8.57 (t, J=8.0 Hz, 0.46H), 8.16 (t, J=7.6 Hz, 1H), 8.01 (d, J=8.4 Hz, 0.54H), 7.96 (t, J=6.8 Hz, 0.54H), 7.79 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.2 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.51 (s, 2H), 4.06 (s, 2H), 3.36 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H); MS (ESI), 355 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:22])=[C:16]3[C:15](I)=[N:14]2)[CH2:9][CH2:8]1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:22][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:2]4[NH:3][CH:4]=[CH:5][N:1]=4)[CH2:8][CH2:9]3)[N:14]=[C:15]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[C:26]([O:25][CH3:24])[CH:31]=3)[C:16]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCN(Cc2ncc[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 41.2 %

Procedure:
1-[1-(1H-2-Imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (127 mg, 0.299 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (115 mg, 0.329 mmol), palladium tetrakistriphenyphosphine (21 mg, 0.018 mmol) and sodium carbonate (76 mg, 0.718 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give tert-butyl N-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (64 mg, 41%). 1H NMR (DMSO-d6) δ 1.48 (m, 9H), 1.87 (m, 2H), 2.23 (m, 4H), 2.94 (m, 2H), 3.56 (s, 2H), 3.88 (s, 3H), 4.66 (m, 1H), 6.92(s, 2H), 7.21 (m, 2H), 7.90 (d, J=8.14, 1H), 8.04 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[N:15]([CH2:28][CH2:29][O:30][CH3:31])[N:16]=[C:17]2[C:26]=1[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:19]=[C:18]2[NH2:27]>>[NH2:27][C:18]1[C:17]2=[N:16][N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]([CH2:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)([CH3:33])[CH3:32])=[C:26]2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccncc1
Yield: 82.3 %

Procedure:
Using the method of Example 68, isonicotinoyl chloride hydrochloride (710 mg, 4.00 mmol) was reacted with 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.60 mmol, prepared as described in Example 590). The crude product was purified as described in Example 68 to provide 551 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}isonicotinamide as a white solid, mp 166-168° C. MS (ESI) m/z 419 (M+H)+; Anal. Calcd for C23H26N6O2: C, 66.01; H, 6.26; N, 20.08. Found: C, 65.93; H, 6.41; N, 20.44.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[C:9]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH2:55].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH:55][C:12]([C:10]1[S:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(-c3ccccc3)sc2C(=O)O)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)CNC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a mixture of 5-phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carboxylic acid (prepared according to example 2) (50 mg, 0.134 mmol) in anhydrous dimethylformamide (1.4 ml) were added HATU 152 mg, 0.402 mmol), glycine methyl ester hydrochloride (20 mg, 0.161 mmol) followed by collidine (124 μl, 0.938 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and pre-absorbed on SiO2. Purification chromatography (hexane to hexane:ethyl acetate; 6:4 to dichloromethane:methanol; 95:5) gave 47 mg of a mixture of {[5-Phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carbonyl]-amino}-acetic acid methyl ester and collidine. 1H NMR (CDCl3, 400 MHz) 7.76-7.73 (m, 2H), 7.61 (s, 1H), 7.57-7.54 (m, 2H), 7.42-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.19-6.17 (m, 1H), 4.14-4.12 (m, 2H), 3.79 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH:11]=1>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]1
Reactant: CCCC1CC=C(c2ccc(F)c(F)c2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10 mmol of 1-(2,3,4-trifluorophenyl)-4-propylcyclohex-1-ene (prepared from 2,3,4-trifluophenyllithium and 4-propylcyclohexanone and subsequent dehydration with p-toluenesulfonic acid), 0.1 g of palladium-on-active charcoal (1%) and 15 ml of toluene is hydrogenated to saturation at room temperature. After filtration and removal of the solvent, the residue is dissolved in 15 ml of dimethyl sulfoxide, 1.2 g of potassium tert.-butanolate are added and the mixture is stirred at room temperature for 2 hours. Acidification and customary working up give trans-1-(2,3,4-trifluorophenyl)-4-propylcyclohexane.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(C(=O)CCC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 24 h
Yield: 70.3 %

Procedure:
The intermediate (S)-ethyl 4-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-4-oxobutanoate (124 mg, 0.25 mmol) was dissolved in THF (4 mL) and treated with LiOH (12 mg, 0.5 mmol) in water (1 mL) and stirred for 24 h. The reaction mixture was evaporated to half-volume, diluted with water (5 mL) and the pH adjusted to pH ˜7 with a 1 N solution of hydrochloric acid. The resulting precipitate was filtered with the aid of water and air dried to afford the title compound as a solid (82 mg, 70%). LC/MS (Method A) 6.72 min, [M+1]+ 467.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O:8][C:9]([N:11]1[CH2:17][C:16](=O)[C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(N(CC)CC)C>[C:4]([O:8][C:9]([N:11]1[CH2:17][C:16](=[N:2][OH:3])[C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C2(CC2)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=NO)C2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
1.25 g of hydroxylamine hydrochloride and 1.8 g of triethylamine were added to a solution of 1.9 g of compound 66. The mixture was stirred at room temperature for 1 day. The solvent was removed under reduced pressure and 10% citric acid aqueous solution was added to the residue. The mixture was extracted with chloroform and the extract was washed with water. The extract was dried and the solvent was removed under reduced pressure to yield 1.86 g of title compound 67.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 22.8 g (0.111 mol) of N-3-hydroxypropyl phthalimide and 14.46 g (0.111 mol) of ethyl acetoacetate was heated at 145°-150° C. for 12 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was cooled to room temperature, dissolved in dichloromethane, and washed with brine. The separated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 211°-219° C. (0.125 mm Hg) to yield 17.3 g (54%) of a white solid; m.p. 67°-71° C. NMR: (CDCl3) δ2.0 (2H,m), 2.2 (3H,s), 3.3 (2H,s), 3.7 (2H,t), 4.05 (2M,t), 7.62 (4H,d).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c1) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20]>C1CCCCC1>[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[O-:34])([CH3:22])([CH3:21])[CH3:20].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCCCC1
Product: Cc1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 1 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum was purged with nitrogen. Operating in an atmosphere of nitrogen, the vessel was charged with a cyclohexane solution (500 ml) which contained 50 grams poly(isobutylene-co-para-bromomethylstyrene) (Mv=10k, 4.6% para-bromomethylstyrene). A cyclohexane solution of tetrabutylammonium 2,6-di(t-butyl)-4-methylphenoxide was prepared in a second flask under nitrogen by placing 100 ml cyclohexane, 30 ml tetrabutylammonium hydroxide (1M in methanol) and 6.6 g 2,6-di(t-butyl)-4-methylphenol into the flask and concentrating this solution down to half its volume. This solution was then added to the flask containing the poly(isobutylene-co-para-bromomethylstyrene). Then 2.5 ml methacrylic acid was added to the polymer solution and the temperature of the solution was raised to 50° C. The reaction was complete in one hour and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg and 40° C. GPC of the recovered polymer (50 g, 100% yield) was identical to that of the starting poly(isobutylene-co-para-bromomethylstyrene). The analysis for the methacrylate content (FTIR and NMR) indicate that the modified polymer had 0.58 meq/gram which is consistent with the complete conversion of methacrylic acid to methacrylic ester.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=NC)[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C([O-])([O-])=O.[K+].[K+].[C:18]([NH:26][NH2:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:2][N:3]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][N:27]=[C:4]1[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCC(=NC)NC
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCCCc1nnc(-c2ccccc2)n1C
Yield: 0 %

Procedure:
To a solution of N,N′-dimethyl-5-hexenimidamide hydrochloride (3.1Mmol) in MeOH (20 ml) were added K2CO3 (3.1Mmol) and benzhydrazide (3.1Mmol). The solution was heated to reflux for 24 h. Volatiles were evaporated in vacuo, the crude dissolved in DCM, washed with water and dried over Na2SO4. After filtration and concentration to dryness in vacuo, the crude was purified by column chromatography (DCM:MeOH=98 to 2) to give 196 mg of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])#[N:12]>CC(N(C)C)=O>[CH3:1][C:2](=[CH2:6])[C:3]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([C:11]#[N:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:4]
Reactant: C=C(C)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated with thionyl chloride (714 mg, 6 mmol) at 0° C. The mixture was stirred for 30 min then 4-cyano-3-trifluoromethyl-aniline (1.0 g, 6.0 mmol) was added. The resulting suspension was stirred overnight and then quenched with NaHCO3. The reaction mixture was extracted with ethyl acetate, washed with brine and dried with Na2SO4. The resulting concentrated crude product was purified on column (Ethyl acetate:Hexane, 1:2) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#C[Si](C)(C)C)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (500 mg, 1.27 mmol), ethynyl(trimethyl)silane (137 mg, 1.4 mmol), copper(I) iodide (23 mg, 0.12 mmol), Dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) and DIPEA (700 μl, 4.12 mmol) is stirred under argon atmosphere in NMP (4 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 319 mg (61%). HPLC-MS: M+H=412; tR=2.11 min (*Method—4).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.Cl.O1CCOCC1.[I-:28].[Na+]>O1CCCC1>[I:28][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate (10 g; 32.3 mmol) in tetrahydrofurane (100 ml) at room temperature was slowly added a 4N solution of hydrochloric acid in dioxane (56.5 mL; 226 mmol). The mixture was stirred at 60° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (75 mL), sodium iodide (38.7 g; 258 mmol) was added and the mixture was heated at reflux for 48 h. The volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate and was successively washed with water, a solution of sodium thiosulphate, water and brine. The organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford 10.83 g (71%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][C@H:5]1[CH3:18])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:6][C@H:5]1[CH3:18]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N
Yield: 93.2 %

Procedure:
tert-Butyl [(1R*,3R*,4R*)-4-azido-3-methylcyclohexyl]carbamate (example 010; 1.2 g; 4.7 mmol) is dissolved in MeOH (20.0 mL) and pressure hydrogenated over Pd (10% on charcoal; 0.1 g) at 20 bar and ambient temperature over night. After filtration through a pad of celite the solvent is removed under reduced pressure to yield 1.0 g of the title compound as off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[NH:3]1
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of (S)-tert-butyl 6-methyl-8-oxo-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.4 g, 1.2 mmol) in DCM (12 mL) was added trifluoroacetic acid (2.5 mL, 31.7 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated and EtOAc (10 mL) was added. The resulting precipitate was collected via filtration and dried to provide the desired compound (267 mg, 64%). MS (ESI): mass calcd. for C10H10N6O, 230.2; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.44 (d, J=1.4 Hz, 1H), 8.85-8.81 (m, 2H), 8.69 (s, 1H), 4.92 (m, 1H), 4.31-4.23 (m, 1H), 4.10-3.96 (m, 1H), 1.24 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:9]([O:11]N1C(=O)CCC1=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:9]([NH:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(N[C@H](C(=O)ON1C(=O)CCC1=O)c1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Z-Phg-OSu (640 mg) in DMF (10 ml), 463 mg (1.84 mmol) of Tyr(3-tBu)-OMe and 408 mg (3.34 mmol) of DMAP were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give Z-Phg-Tyr(3-tBu)-OMe in the amount of 905 mg (quantitative).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([N:24]2[CH2:25][CH2:26][N:21]([C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH2:22][CH2:23]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 49 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 49%). MS (m/e): 475.4 (M+H+, 100%).