Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (81) (1.35 g; 2.29 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.09 g) as an oil.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH3:29])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([C:7]2[O:8][C:9]3[C:17]([O:18][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=4[CH3:29])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=c1cc(N2CCOCC2)oc2c(O)cccc12
Reactant: Cc1cc(F)ccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1Oc1cccc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
To a mixture of 2-(4-morpholinyl)-8-hydroxy-4H-1-benzopyran-4-one (77 mg, 0.31 mmol), 4-fluoro-2-methylphenylboronic acid (48 mg, 0.31 mmol) and copper acetate (57 mg, 0.31 mmol) suspended in dichloromethane (3.1 ml) was added triethylamine (216 uL, 1.56 mmol) and the mixture was stirred at room temperature for 24 h. The solvent was removed and the product chromatographed through a silica column with 0-10% methanol in dichloromethane to yield an off white solid (37 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[N:5]2.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][B-](F)(F)F)[CH2:30][CH2:29]1)=[O:27])[CH3:24].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:6]=[N:5]3)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CC(C)(C)C1CCC(Oc2cnc3cc(Br)ccc3n2)CC1
Reactant: CCOC(=O)C1CCN(C[B-](F)(F)F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(Cc2ccc3nc(OC4CCC(C(C)(C)C)CC4)cnc3c2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
6-Bromo-2-(4-tert-butyl-cyclohexyloxy)-quinoxaline (0.2879 g, 0.0007925 mol), potassium ((4-(ethoxycarbonyl)piperidin-1-yl)methyl)trifluoroborate (0.4392 g, 0.001585 mol), palladium acetate (0.01068 g, 4.755E-5 mol) 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.06800 g, 0.0001426 mol) and cesium carbonate (0.7746 g, 0.002377 mol) were added to a capped 40 mL vial equipped with a magnetic stir bar. The vial was degassed and purged with argon. Tetrahydrofuran (7.713 mL, 0.09510 mol) and water (1.142 mL, 0.06340 mol) were added and the reaction mixture was degassed, purged with argon then stirred at 60° C. for 24 hours. An additional 1 eq. of potassium ((4-(ethoxycarbonyl)piperidin-1-yl)methyl)trifluoroborate; 0.03 eq. of palladium acetate; 0.09 eq. of 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl and 1.5 eq. of cesium carbonate were added. The mixture was degassed, flushed with argon and heated at 60° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water, then brine. The layers were separated and the organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography (24 g SiO2 column; 0-10% MeOH in methylene chloride) to give the title compound. ESI-MS (M+H+): 454.1
Reaction SMILES: C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:37]([C:40]3([C:43]([F:46])([F:45])[F:44])[CH2:42][CH2:41]3)=[CH:38][N:39]=[C:34]2[C@H:33]([NH2:47])[CH2:32][CH2:31]1.[O:48]=[C:49]1[NH:57][C:52]2=[N:53][CH:54]=[CH:55][CH:56]=[C:51]2[C:50]21[CH2:65][C:64]1[C:59](=[CH:60][CH:61]=[C:62]([C:66](O)=[O:67])[CH:63]=1)[CH2:58]2>CN(C)C=O>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:37]([C:40]3([C:43]([F:46])([F:44])[F:45])[CH2:42][CH2:41]3)=[CH:38][N:39]=[C:34]2[C@H:33]([NH:47][C:66]([C:62]2[CH:63]=[C:64]3[C:59](=[CH:60][CH:61]=2)[CH2:58][C:50]2([C:51]4[C:52](=[N:53][CH:54]=[CH:55][CH:56]=4)[NH:57][C:49]2=[O:48])[CH2:65]3)=[O:67])[CH2:32][CH2:31]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
Triethylamine (18.0 μL, 0.129 mmol), EDC (17 mg, 0.086 mmol), and HOBT (7.0 mg, 0.043 mmol) were added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine from Step A (16 mg, 0.043 mmol) and the hydrochloride salt of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (14.0 mg, 0.043 mmol, described in Intermediate 2) in N,N-dimethylformamide (1 mL). After 18 h, the reaction mixture was filtered and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—95:5:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=634 (M+1). HRMS: m/z=634.2265; calculated m/z=634.2236 for C34H29F5N5O2.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]1[CH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])=[O:20])(=[O:5])=[O:4]>CC(OC(C)=O)=O>[CH3:1][N:2]([CH3:31])[S:3]([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]1[CH2:17][CH2:18][C:19]1[O:20][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CCC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CCc1nc2ccccc2c(=O)o1
Yield: 69.5 %

Procedure:
A solution of 2-(3-(1-(N,N-dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)propanamido)benzoic acid (150 mg, 0.339 mmol) in Ac2O (10 mL) was stirred at reflux for 5 h. The reaction mixture was then concentrated to give a white solid (100 mg), which was used for the next step without further purification. LC-MS: m/z 425 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[CH3:39][C:35]1([CH3:40])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]2[CH:30]=[C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:38]=[CH:37][C:36]1=2
Reactant: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 106 mg (0.304 mmol) of 4-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]butan-1-ol and 116 mg (0.334 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The crude product is purified by means of RP flash chromatography on C18 silica gel. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[C:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:39]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])([O-:41])=[O:40]>CC(C)=O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[C:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][CH:50]=[C:42]([N+:39]([O-:41])=[O:40])[CH:43]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
2-[3,4-Bis-(1-benzyl-1H-tetrazol-5-yl)phenoxy]phenylamine (37 mg, 0.07 mmol) and TEA (19 mg, 0.18 mmol) were mixed in acetone (10 ml), and 3-nitrobenzoyl chloride (15 mg, 0.08 mmol) was added. The reaction mixture was stirred for 120 hours at room temperature. The reaction mixture was evaporated in vacuo to an oil. The oil was purified on a silica column with methylene chloride/methanol (39:1) as eluent. The title compound was isolated as yellow oil (yield: 30 mg (62%). 1H-NMR (CDCl3 in ppm): 5.6 (4H,2xs); 7.0 (1H,d,d); 7.15 (1H,d,d); 7.2 (1H,d,d); 7.25-7.4 (11H,m); 7.6 (1H,d,d); 7.73 (1H,d); 7.9 (1H,d); 8.1 (1H,d,d); 8.35 (1H,d,d); 8.45 (1H,broad s); 8.55 (1H,d,d); 8.7 (1H,d,d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:26]([O:33][C:34](=[O:48])[C@H:35]([CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[NH2:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[CH2:26]([O:33][C:34](=[O:48])[C@H:35]([CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[NH:36][C:12]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11]1)=[O:14])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.7 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)aminocyclopropanecarboxylic acid (257 mg, 1.28 mmol), L-aspartic acid dibenzyl ester tosylate (806 mg, 1.66 mmol), WSC hydrochloride (367 mg, 1.92 mmol), and 1-hydroxybenzotriazole (291 mg, 1.92 mmol) in dichloromethane (4.0 ml) was added N,N-diisopropylethylamine (1.30 mL, 7.66 mmol), and the mixture was stirred at room temperature for 7 hours. 1N Hydrochloric acid was added to the reaction mixture, the mixture was extracted 3 times with dichloromethane, and the obtained dichloromethane layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (598 mg, 1.20 mmol, 94%).
Reaction SMILES: [OH-].[K+].C([O-])(=O)C1C=CC=CC=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1/[C:23](/[CH3:36])=[CH:24]/[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=1>C(O)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:15][C:14]=1/[C:23](/[CH3:36])=[CH:24]/[C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc(C(C)(C)C)ccc2C)cc1
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)ccc1C
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide in ethanol was added to 41 mg (0.12 mmol) of ethyl 4-[(E)-2-2-methyl-5-tert-butylphenyl)propen-1-yl]benzoate (Compound 26) and the resulting mixture stirred at room temperature. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a yellow solid.
Reaction SMILES: [S:1]([C:5]1[S:14][C:13]2[S:12](=[O:16])(=[O:15])[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(#N)C.O1CCCC1>[C:17]([N:9]1[CH2:8][C:7]2[CH:6]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[S:14][C:13]=2[S:12](=[O:15])(=[O:16])[CH2:11][CH2:10]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCNC2
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A solution of 7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepin-1,1-dioxide (240 mg, 0.85 mmole) in acetonitrile (5 mL) and tetrahydrofuran (5 mL) containing acetic anhydride (100 mg, 0.94 mmol) and triethylamine (0.17 mL, 1.22 mmol) was stirred at ambient temperature for 1.5 hours. The solvents were evaporated and the residue chromatographed on silica gel. Elution with 10% methanol-methylene chloride gave 250 mg (77%) of the title compound. This material was used as is.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5](N)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:16]([NH:1][C:2]([NH2:4])=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: CCCCCCCCCCCCN
Reactant: NC(N)=O
Product: CCCCCCCCCCCCNC(N)=O

Procedure:
250 g of urea were continuously introduced into a decomposer in the course of 2 hours. The pyrolysis gases were introduced into a melt of 1200 g of dodecylamine at a temperature of 80 to 90° C. After completion of the reaction, the excess dodecylamine was distilled off in vacuo and the residue was recrystallized from chloroform. 598.9 g, i.e. 63% of theory, of dodecylurea having a melting point of 105 to 107° C were obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[CH:7]=1.[CH3:11][C:12]1([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:13]1>CC(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[C:7]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:12]1([CH3:11])[CH2:14][CH2:13]1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: CC1(c2cc3ccccc3[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(c2[nH]c3ccccc3c2C2=C(Cl)C(=O)C=C(Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 2,5-dichloro-1,4-benzoquinone (0.177 g, 1.00 mmol) in AcOH (2 mL) was added 2-(1methyl-cyclopropyl)indole (0.081 g, 0.47 mmol). After the reaction mixture was stirred for 2 h at 50° C. under nitrogen protection, Ag2CO3 on Celite® (50%, 0.500 g, 0.90 mmol) was added. After stirring for 4 h at room temperature, the solution was diluted with ethyl acetate (100 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford 2,5-dichloro-3-[2-(1-methyl-cyclopropyl)-1H-indol-3-yl]-[1,4]benzoquinone (0.148 g, 90%) as blue needles from benzene/hexane. Melting Point 170–171° C. 1H NMR (d6-acetone): 0.53–0.60 (1H, m), 0.64–0.70 (1H, m), 0.70–0.77 (1H, m), 0.92–0.98 (1H, m), 1.48 (3H, s), 7.01 (1H, dt, J=1.2, 7.5 Hz), 7.10 (1H, dt, J=1.2, 7.5 Hz), 7.24 (1H, dd, J=0.6, 7.2 Hz), 7.37 (1H, d, J=7.8 Hz), 7.39 (1H, s), 10.70 (1H, s). 13C NMR (d6-acetone): 13.3, 14.1, 15.1, 24.5, 103.6, 111.4, 119.7, 119.9, 121.9, 126.8, 133.8, 136.0, 140.4, 140.8, 143.9, 144.0, 177.1, 177.9. IR (KBr): 3409, 3059, 3004, 2966, 2927, 1662, 1620, 1567, 1435, 1270, 1241, 1028, 755 cm−1. Anal. Calcd. for C18H13Cl2NO2: C, 62.45; H, 3.78; N, 4.05. Found: C, 62.30; H, 3.77; N, 3.94.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@H:4]([CH2:12][CH2:13][CH2:14][CH3:15])[NH:5][C:6](=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10].[OH-].[Na+].Cl>C1COCC1>[C:6]([NH:5][C@H:4]([C:3]([OH:16])=[O:2])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCC(=O)N[C@@H](CCCC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCC(=O)N[C@@H](CCCC)C(=O)O
Reaction time: 3 h
Yield: 88.8 %

Procedure:
N-Pent-4-enoyl-L-norleucine methyl ester (0.30 g, 1.32 mmol) was dissolved in THF (3 mL) and 1 M NaOH (3 mL) was added at RT. The reaction mixture was stirred for 3 h, poured onto ethyl acetate and 1 M HCl and the layers were separated. The organic layer was washed with water, dried over NaSO4, filtered and concentrated to give N-pent-4-enoyl-L-norleucine (0.25 g, 89% yield): 1H NMR (400 MHz, CD3OD) 8 ppm 5.81 (m, 1H), 5.02 (d, 1H), 4.95 (d, 1H), 4.82 (br s, 1H), 4.27 (m, 1H), 2.32 (br s, 4H), 1.80 (m, 1H), 1.65 (m, 1H), 1.37 (m, 4H), 0.9 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[NH4+]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]=[C:13]=[S:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)N=C=S
Temperature: 50 °C

Procedure:
To a solution of crude 1a (27.4 g, 159 mmol) from the previous step in MeCN (159 mL) was added ammonium thiocyanate (12.69 g, 167 mmol, 1.05 eq.). The fine yellow slurry was heated at 50° C. for 1 h. After cooling down to 0° C., the reaction mixture was filtered through a Celite pad and the cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to a volume of 30-40 mL, cooled again to 0° C. and filtered through a Celite pad. The cake was washed with MeCN (10 mL). The filtrate and washings were combined and concentrated to the same volume of 30-40 mL. The resultant solution contained 2-(4-fluorophenyl)acetyl isothiocyanate (2, assumed quantitative yield, Method B). Half of this solution was used in the next step.
Reaction SMILES: Cl.[CH2:2]([CH:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7]1)[CH2:3][CH2:4][CH3:5].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl-].C[N+](CCCC)(CCCC)CCCC.O>[CH2:2]([C:6]1[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1NC(=O)C2(CCCC2)N1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2.2 h
Yield: 85.6 %

Procedure:
A mixture of 0.231 g (1.0 mmol) of 2-butyl-1,3-diazaspiro [4.4]nonan-4-one, hydrochloride, 0.272 g (1.0 mmol) of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile, 24.4 μL (0.075 mmol) of 75% aqueous solution of methyl-tributylammonium chloride, 2.0 mL of toluene and 2.0 mL of 50% aqueous solution of sodium hydroxide was vigorously stirred at room temperature for 2.2 hours. Then the reaction mixture was diluted with 2 mL of water and the two phases separated. The organic phase was extracted twice with 2 mL of water, evaporated under vacuum to give 0.33 g (85.7%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH:30](OC)[O:31]C)[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]2[CH2:25][CH2:26][CH:27]([CH:30]=[O:31])[CH2:28][CH2:29]2)(=[O:22])=[O:23])=[CH:19][CH:20]=1)=[O:13]
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(NC(=O)NCCc3cc(F)ccc3F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)NCCc3cc(F)ccc3F)cc2)CC1

Procedure:
A solution of 1-[2-(2,5-difluoro-phenyl)-ethyl]-3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-urea (0.170 g, 0.3 mmol) in 2 mL TFA was stirred for 15 minutes at ambient temperature. The excess TFA was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic base was dried (Na2SO4) and the solvent evaporated to provide the title compound which was used directly in the next step.