Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)([CH3:29])[C:26](=[O:28])[NH:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)=[CH:18]1
Reactant: NCCc1ccccn1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccccn1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.400 g, 1.01 mmol) in ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.03 mmol). This mixture was stirred 2 hours and 2(2-aminoethyl)pyridine (0.16 mL, 1.3 mmol) was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, aqueous saturated sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (SiO2, 230-400 mesh, ethyl acetate eluant). After concentration, the residue was dried under vacuum at 60° C. for 48 hours to provide 0.365 g (72%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.56 (3H, s), 1.65-1.95 (12H, m), 2.88 (2H, t, J 6 Hz), 3.39 (2H, d, J 5 Hz), 3.50-3.70 (2H, m), 4.75 (1H, br s), 5.35 (1H, br s), 6.40 (1H, d, J 2 Hz), 7.00-7.20 (4H, m), 7.22-7.35 (2H, m), 7.52-7.60 (2H, m), 8.20 (1H, br s), 8.40-8.45 (1H, m).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:18][C:17]3=[CH:19][S:20][CH:21]=[C:16]3[NH:15][C:14]2=[O:22])[CH2:9][CH2:8]1)=O)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[NH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:18][C:17]3=[CH:19][S:20][CH:21]=[C:16]3[NH:15][C:14]2=[O:22])[CH2:11][CH2:12]1.[F:24][C:25]([F:30])([F:29])[C:26]([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cscc3NC2=O)CC1
Reactant: O=C(O)C(F)(F)F
Product: O=C([O-])C(F)(F)F
Product: O=C1Nc2cscc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.0 g (0.0296 mol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one and 50 ml of trifluoroacetic acid was stirred at room temperature for 30 minutes. The residue remaining after removal of the excess trifluoroacetic acid was triturated with diethylether and suction filtered. 5.8 g (55.8% of theory) of colourless crystals were obtained, which were used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=C[CH:9]=1)C#N.Cl.[NH2:11][OH:12].C([N:16]([CH2:20][CH3:21])C(C)C)(C)C.[Cl-].[NH4+]>C(O)C>[OH:12][N:11]=[C:20]([NH2:16])[C:21]1[CH:7]=[CH:4][CH:3]=[C:2]([I:1])[CH:9]=1
Reactant: N#Cc1cccc(I)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=NO)c1cccc(I)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
3-Iodobenzonitrile (7.00 g, 30.6 mmol) was dissolved in ethanol (153 mL), and the mixture was stirred at 90° C. for 2 hours after adding hydroxylamine hydrochloride (4.30 g, 61.2 mmol) and N,N-diisopropylethylamine (10.5 mL, 61.2 mmol). After adding an aqueous ammonium chloride solution, insoluble were separated by filtration through sellite. The organic layer of the filtrate was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography to give N′-hydroxy-3-iodobenzamidine (8.37 g, quantitative).
Reaction SMILES: [OH:1][N:2]([CH:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20])[CH3:13])[C:3]([N:5]([C:7](OCC)=O)C)=[O:4].[BH4-].[Li+].C1C[O:26][CH2:25]C1>>[OH:1][N:2]([CH:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20])[CH3:13])[C:3]([NH:5][CH2:7][CH2:25][OH:26])=[O:4]
Reactant: CCOC(=O)N(C)C(=O)N(O)C(C)c1cc(C)sc1C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: Cc1cc(C(C)N(O)C(=O)NCCO)c(C)s1
Reaction time: 8 h

Procedure:
To a stirred solution of ester from Example 59 (1.84 g, 6.13 mmol) in dry THF (15 mL) was added 2M lithium borohydride in THF (5.0 mL, 10.0 mmol) dropwise under nitrogen. The solution was stirred overnight, then quenched by the dropwise addition of methanol (25 mL) and stirred 4 h. The reaction was concentrated, poured into 10% aqueous citric acid (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography (silica gel, ethyl acetate-hexanes, 50:50, 75:25), followed by crystallization from ethyl acetate-hexanes to provide the desired product. (510 mg). m.p=122°-123.5° C.; NMR (300 MHz, DMSO-d6) 1.29 (3H, d, J=7.0 Hz), 2.28 (3H, s), 2.32 (3H, s), 3.08 (2H, m), 3.35 (2H, m), 4.65 (1H, t, J=5.3 Hz), 5.23 (1H, q, J=7.0 Hz), 6.70 (1H, t, J=5.9 Hz), 6.73 (1H, m), 9.03 (1H, s); MS: (M+H)+ =259
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])C=C.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:22][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[NH:4][C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCn1c(C#N)c(-c2ccccc2)c2cc(OC)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1

Procedure:
Allyl ether 88 (0.5 g, 1.6 mmol) was dissolved in dioxane (10 mL). Triethylamine (0.55 mL, 4 mmol) and formic acid (0.12 mL, 3.2 mmol) were added and the reaction mixture purged with argon. Pd(PPh3)4 (91 mg, 0.08 mmol) was added and the mixture heat to 100 C under a stream of Ar for 1.5 h. A precipitate formed upon cooling. It was isolated by filtration to give 97 as a white solid.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:30])[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:22]([NH:30][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CCCCCC#CCN
Product: CCCCCC#CCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-octyn-1-ylamine to obtain 4-(2-octyn-1ylamino)-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 422.3.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@@H:7]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:8]([OH:10])=O)[C:4](=[O:22])O1.[OH:24][NH:25]C(=O)[C@@H](O)[C@@H](C(N1CCN(C2SN=C(C3C=CC=CC=3)N=2)CC1)=O)CC(C)C.BrC1C=CC(OC)=CC=1.[CH2:63]([CH:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH2:64][CH3:65]>>[OH:24][NH:25][C:4](=[O:22])[C@@H:5]([OH:6])[C@H:7]([C:8]([N:69]1[CH2:70][CH2:71][CH:66]([CH2:63][CH2:64][CH3:65])[CH2:67][CH2:68]1)=[O:10])[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)[C@H](O)C(=O)NO
Reactant: CCCC1CCNCC1
Reactant: COc1ccc(CCC[C@@H](C(=O)O)[C@@H]2OC(C)(C)OC2=O)cc1
Agent: COc1ccc(Br)cc1
Product: CCCC1CCN(C(=O)[C@H](CCCc2ccc(OC)cc2)[C@H](O)C(=O)NO)CC1

Procedure:
The title product was prepared following the procedure of Example 64 (step a and b) but starting from (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-(4-methoxyphenyl)pentanoic acid (prepared following the procedure of Intermediate 2 but using 4-bromoanisole in step b) and 4-propylpiperidine (Aldrich). Purification by reverse-phase chromatography gave the title product as a yellow powder. M−(ESI): 405.4; M+(ESI): 407.4. HPLC (Condition A): Rt: 3.6 min (HPLC purity: 94.9%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.CS(C)=O.[C:23](=O)([O-:25])[O-:24].[Na+].[Na+]>O>[C:4]([OH:6])(=[O:5])/[CH:3]=[CH:2]/[C:23]([OH:25])=[O:24].[NH2:1][CH2:2][CH2:3][C:4]([O:6][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:5]
Reactant: NCCC(=O)O
Reactant: O=C([O-])[O-]
Reactant: ClCc1cccc2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCC(=O)OCc1cccc2ccccc12
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 0.89 g. (10 mmole) of 3-aminopropionic acid and 1.77 g. (10 mmole) of 1-chloromethylnaphthalene in 10 ml. dimethylsulfoxide is stirred at 60° C. for 7 hours. Water, 80 ml., is added to the cooled reaction mixture followed by a saturated sodium carbonate solution until a pH of 8 is obtained. The product is extracted into 50 ml. ethyl ether which is then washed with three 20 ml.. portions of water. After drying the ether extract over 12 g. anhydrous sodium sulfate and filtering directly into a solution of 1.0 g. fumaric acid in 30 ml. methanol, solvents are removed under reduced pressure (15-20 mm.) at 35°-40° C. The residue is recrystallized by dissolving in 25 ml. warm methanol and precipitating with 50 ml. ethyl acetate to give 1-naphthylmethyl 3-aminopropionate hydrogen fumarate, m.p. 160.7°-162.7° C. An analytical sample, m.p. 159.2°-161.2° C., is obtained after recrystallization from a similar methanol-ethyl acetate mixture.
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2.C([Li])(C)(C)C.CN(C)P(N(C)C)(N(C)C)=O.CN(C)[CH:36]=[O:37]>C1COCC1>[OH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:36]=[O:37])[CH:16]=[CH:15]2
Reactant: CN(C)C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [CH2-]CCC
Agent: [Li+]
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc2cc(O)ccc2c1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
Step a) N-Butyllithium (35.9 mL, 89.7 mmol) was added dropwise to a cold (-78° C.) solution of 6-bromo-2-naphthol (20.0 g, 89.7 mmol) in THF (200 mL). After stirring for 10 minutes, tertbutyllithium (52.76 mL, 89.7 mmol) was added dropwise. The mixture was stirred for 30 min at -78° C, and two hours at -20° C. Then, hexamethylphosphoramide (15.6 mL, 89.7 mmol) was added to the reaction mixture. After stirring for 20 minutes. N,N-dimethylformamide (6.94 mL, 89.7 mmol) was added dropwise. The mixture was allowed to come to room temperature, stirred for 1 hour, and quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with 2N HCL and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 3/1 ), gave a yellow solid (12.5 g, 81% yield, m.p. 173°-174 ° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(C(c2ccc(F)cc2)N2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(C(c2ccc(F)cc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 1-((4-fluorophenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.343 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.073 g (0.343 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.13 g of desired product.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>C(#N)C.C(OCC)(=O)C>[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CCc1cccc(N)c1C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h

Procedure:
At RT, 1.38 g (10.3 mmol) of N-chlorosuccinimide were added to a solution of 2.0 g (10.3 mmol) of methyl 3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile. The reaction mixture was stirred for 30 min and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1), 279 mg of the target product (11.8% of theory).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[C:20]([CH2:22][CH2:23][C:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH:25]=O)#[N:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:25]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:23][CH2:22][C:20]#[N:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCC(C=O)(CC)CCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(CC)(CCC#N)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
Benzotriazole, 4-chlorobenzamide, 4-cyano-2,2-diethylbutanal, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH2:16]1>>[ClH:6].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[C:23]([NH:27][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH2:16]1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1
Product: Cl
Yield: 80.4 %

Procedure:
Using a method similar to example 1, using 2,4,6-trifluorobenzoyl chloride (127 mg, 0.655 mmol) and 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (preparation 2, 118 mg, 0.545 mmol) provides the title compound (free base, 180 mg, 88%). Free base: MS (ES): m/z=375.2 (M+H)+; 1H NMR (CDCl3): δ 7.78 (s, br, 1H), 7.67 (s, 1H), 7.48 (d, 1H), 7.32 (t, 1H), 7.22 (d, 1H), 6.78 (m, 2H), 6.12 (m, 1H), 2.50 (m, 4H), 2.37 (s, 6H), 2.15 (m, 2H), 1.57 (m, 1H). Hydrochloride salt: Anal. cal'd for C21H21F3N2O.HCl.H2O: C, 58.81; H, 5.64; N, 6.53. Found: C, 58.95; H, 5.30; N, 6.55.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.O>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[CH2:12][CH2:11][CH2:10]3)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of 0.18 grams (0.538 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide in 25 mL pyridine was added 0.052 grams (0.511 mmole) acetic anhydride. The reaction mixture was stirred at 23° C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with 0.5M hydrochloric acid, water, and saturated aqueous sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. N-[6-(3-Fluoro-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide was obtained as a crystalline solid from ethyl acetate/ethyl ether, 0.18 grams (89%), m.p. 136-137° C., M+H=377.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]>CO.O>[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26]([O:2][CH3:1])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]
Reactant: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(Cl)nn3)cc2)C(=O)N(C)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nn1

Procedure:
The equimolar amount of sodium methylate is added at room temperature to 1.0 g (0.0025 mole) of 1,3-dimethyl-5-[4-(6-chloropyridazin-3-yloxy)phenylcarbamoyl]barbituric acid in 20 ml of methanol. The mixture is heated under reflux for 5 hours, then cooled, diluted with water and filtered. The filtrate is washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:41][C:42]4[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=4)[C:24]4[N:29]=[CH:28][C:27]([C:30]5[CH:31]=[N:32][N:33](C6CCCCO6)[CH:34]=5)=[CH:26][N:25]=4)[CH2:20][C@H:19]3[CH2:56][CH3:57])[C:15]([Cl:58])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.CO.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:41][C:42]4[CH:47]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:45]=[C:44]([C:52]([F:54])([F:55])[F:53])[CH:43]=4)[C:24]4[N:25]=[CH:26][C:27]([C:30]5[CH:34]=[N:33][NH:32][CH:31]=5)=[CH:28][N:29]=4)[CH2:20][C@H:19]3[CH2:56][CH3:57])[C:15]([Cl:58])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cnn(C6CCCCO6)c5)cn4)C[C@H]3CC)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cn[nH]c5)cn4)C[C@H]3CC)n2)CC1
Temperature: 25 °C

Procedure:
A 25 ml round-bottom flask was charged with 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester (70 mg, 0.084 mmol), 1N HCl (0.8 ml, 0.8 mmol) and MeOH (2 ml). The mixture is then heated to 60 degree for 30 minutes. After cooling down to rt, Saturated NaHCO3 and dichloromethane are added, then organic layer is collected. Removal of solvent give 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester and it is used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=O.C(N(CC)CC)C.C1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.CN(C=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCCCCCCCCCC(=O)O
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCN
Reaction time: 16 h

Procedure:
In this example, the spacer unit is 11-amino-undecanoic acid. The spacer (411 mg, 2.04 mmol, 4 eq) is suspended in a dry organic solvent, for example tetrahydrofuran (THF). Depending on its solubility and the stability of the Raman marker unit, the suspension temperature can be varied between −78° C. and reflux. First, an auxiliary base (2.1 ml triethylamine) is added. Then, the activated marker unit in a suitable organic solvent, for example DTNB-NHS (300 mg, 0.51 mmol in 10 ml THF and 5 ml DMF), is added dropwise. Depending on the reactivity, the reaction mixture is stirred 10 to 48 h, in this case 16 h. The solvent is removed by vacuum, the remaining solid is washed with NaHSO4 solution and a suitable organic solvent. Further purification can be achieved by column chromatography, preferably on reversed phase silica (yield: 260 mg, 0.34 mmol, 67%).
Reaction SMILES: Br[C:2]([CH2:11][C:12](Cl)([Cl:14])[Cl:13])([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(C(=CC(Cl)(Cl)Cl)C(OCC)=O)(C)C.[H][H]>C(Cl)(Cl)Cl.C(OCC)C.C(O)C.[Pd]>[Cl:13][C:12]([Cl:14])=[CH:11][CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(Br)(CC(Cl)(Cl)Cl)C(C)C
Agent: [Pd]
Agent: CCOC(=O)C(=CC(Cl)(Cl)Cl)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(C=C(Cl)Cl)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
In 20 g of chloroform were dissolved 6.0 g of the ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate and, after the addition of 3.5 g of 1,5-diazabicyclo[5,4,0]undecene-5(DBU), the solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was removed by distillation, whereupon 4.6 g of oily product were obtained. Based on its NMR spectrum and GC-mass spectrum, this product was identified to be ethyl α-isopropyl-β-trichloromethylacrylate containing a certain amount of ethyl α-bromo-α-(2,2-dichlorovinyl) isovalerate. In 50 ml of ethanol were dissolved 4.6 g of the oily product obtained above and, following the addition of 0.4 g of 5% palladium-on-carbon, the solution was stirred in an atmosphere of hydrogen gas at 55° C. for 6 hours. Thereafter, the reaction mixture was filtered to remove the catalyst and the ethanol was distilled off. By the above procedure there were obtained 3.9 g of ethyl α-(2,2-dichlorovinyl)isovalerate as an oil. Then, 3.9 g of this ethyl α-(2,2-dichlorovinyl)isovalerate were dissolved in 20 ml of ethanol and a solution of 2.0 g of sodium hydroxide in 10 ml of water was added to the above ethanol solution. The mixture was stirred at room temperature for 10 hours, at the end of which time the ethanol was distilled off. The residue was neutralized with aqueous hydrogen chloride and extracted with diethyl ether. The ethereal solution yielded 2.9 g of α-(2,2-dichlorovinyl)isovaleric acid having the following NMR spectrum [yield: 84% based on ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate].