Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].[N:37]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:31](=[O:35])[C:32]([NH2:37])=[O:33])=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 256 mg (0.582 mmol) of [[2-(methylthio)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 9 mL of chloroform was added 0.15 mL of oxalyl chloride followed by 0.07 mL of pyridine. The reaction stirred at ambient temperature and was monitored by nmr for conversion to product. Additional oxalyl chloride (0.200 mL) was added in portions over 3 days. The reaction was quenched into 4.0 mL of dilute ammonium hydroxide and the product was extracted into 4.0 mL of methylene chloride. The organic phase was washed with water, dried with sodium sulfate and concentrated to 420 mg of yellow solid. The residue was purified by flash chromatography (42 g of silica, ethyl acetate) to provide 66 mg (22%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]-methyl]-7H-pyrrolo(2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, dmso-d6) δ1.00 (t, 3H), 2.34 (s, 3H), 2.81 (q, 2H), 3.65 (s, 3H), 4.97 (s, 2H), 5.62 (s, 2H), 6.47 (d, 1H), 7.53 (m, 2H), 7.65 (s, 1H), 7.83 (d, 1H) , 8.06 (s, 1H)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:20]1([C:16]2[N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: N#Cc1cccc(N2CCCCC2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(N3CCCCC3)n2)sc2ccccc12
Yield: 11.8 %

Procedure:
A mixture of methyl thiosalicylate (0.36 g, 2.1 mmol), 2-cyano-6-(1-piperidinyl)pyridine (0.40 g, 2.1 mmol), triethylamine (0.45 ml, 3.1 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The obtained crystals were recrystallized from hexane-ethyl acetate to give the titled compound (0.08 g, 13%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[NH2:14][NH2:15].O>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:14][NH:15]2
Reactant: CC(C)C(=O)c1c(F)cccc1Br
Reactant: NN
Solvent: OCCO
Solvent: O
Product: CC(C)c1n[nH]c2cccc(Br)c12
Temperature: 160 °C

Procedure:
A mixture of 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g, 4.5 mmol) and anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol (10 mL) is heated for 16 h at 160° C. Water is added and the mixture is extracted with CH2Cl2. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography to yield 4-bromo-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 10.1 (br s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d, 6H).
Reaction SMILES: OCCS[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.OO[S:17]([O-:19])=[O:18].[K+].[C:21](OCC)(=[O:23])[CH3:22]>O>[OH:23][CH2:21][CH2:22][S:17]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:7][CH:6]=1)(=[O:19])=[O:18]
Reactant: O=S([O-])OO
Reactant: NS(=O)(=O)c1ccc(SCCO)cc1
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: O
Product: NS(=O)(=O)c1ccc(S(=O)(=O)CCO)cc1

Procedure:
4-(2-Hydroxyethylthio)benzenesulfonamide (94.3 g, 0.40 mol) was added portionwise to a stirred solution of Oxone® (368.9 g, 0.60 mols) in H2O (3600 mL). After 18 hours the white solid was collected, washed with H2O and dried to give 72.6 g, mp 156°-162° C. An additional 12.3 g was obtained from the aqueous filtrate by extraction with ethyl acetate (3×1000 mL). Recrystallization from acetonitrile gave material with mp 163°-165° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(F)cc1

Procedure:
Using a procedure similar to that described in Example 1-A, 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene was acylated with p-fluorobenzoyl choride to afford 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 4-fluorophenyl ketone which was treated with 4-[2-(1-pyrrolidinyl) ethoxy]phenyl magnesium bromide using a procedure similar to that described in Example 1-B to afford title compound in 84% overall yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]#[C:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1)=[O:11].[NH2:26][OH:27].[OH-].[Na+].Cl>C1COCC1.CO>[OH:27][NH:26][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([C:15]#[C:14][CH2:13][NH:12][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Reaction time: 14 h

Procedure:
To a solution of methyl 4-[3-(benzothiophen-2-ylcarbonylamino)prop-1-ynyl]-benzoate (0.5 mmol) in THF/methanol (10 ml/10 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH to 10-11. The reaction mixture was stirred for ˜14 h, neutralized to pH=7-8 with 6M aqueous HCl, and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:25][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)=O)=C(F)C(F)=C(F)C=1F>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)=[CH:36][CH:35]=3)[CH:33]=2)=[O:25])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.01 mmol, 0.25 g) in THF (4.0 mL), was added BH3:THF (2 mL, 1M solution in THF) and stirred for 12 h. All volatiles were removed under reduced pressure. The residue was taken in DCM (2 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.29 mmol, 0.15 g) was added followed by TEA (0.5 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with NaOH (0.5 M) solution (2×5 mL) water (2×5 mL), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (3:7) to provide 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[C:14](=[O:18])[O:13][C:12]2=[O:19]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:15]2[CH2:16][CH2:17][CH:11]2[C:12]([OH:19])=[O:13])=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=C1OC(=O)C2CCC12
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=O)C2CCC2C(=O)O)cc1Cl
Yield: 35.4 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (1229 mg, 8.06 mmol), 3-oxabicyclo[3.2.0]heptane-2,4-dione (1016 mg, 8.06 mmol) and TEA (1.123 mL, 8.06 mmol) in toluene (10 mL) was stirred at 80° C. for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate to give 2-((3-chloro-4-cyanophenyl)carbamoyl)cyclobutanecarboxylic acid (795 mg, 2.85 mmol, 35.4%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C)C=O>[CH2:24]([O:23][C:21]([CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)COc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of ethyl 4′-hydroxybiphenyl-4-carboxylate (2.262 g), ethyl bromoacetate (1.871 g) and potassium carbonate (1.940 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 1 hr. Diethylamine (6.820 g) was added to the reaction mixture. After being stirred at room temperature for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate (3.06 g) as a crude product. A mixture of the crude ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate, sodium borohydride (0.706 g), tetrahydrofuran (40 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture, and stirred at room temperature for additional 30 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (3.000 g)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[N:7]=[C:6]([NH2:13])[N:5]=1)[CH3:2].Br[CH2:15][C:16](=O)[C:17]([O-:19])=[O:18].[CH2:21]1COC[CH2:22]1>>[CH2:21]([O:19][C:17]([C:16]1[N:13]=[C:6]2[N:7]([C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)[CH:15]=1)=[O:18])[CH3:22]
Reactant: C1CCOC1
Reactant: CCOc1nc(N)nc2c1CCC2
Reactant: O=C([O-])C(=O)CBr
Product: CCOC(=O)c1cn2c3c(c(OCC)nc2n1)CCC3
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5.2 gram (29 mmol) 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 100 ml dry THF. Bromopyruvate (5.4 ml,) was then added dropwise with in five minutes. The mixture was stirred at 23° C. for one hour. It was then filtered and washed with ether to give 8.7 gram of solid. This solid was then dissolved in 50 ml ethanol and refluxed for two hours. The reaction mixture was cooled to room temperature and partitioned between 350 ml chloroform and 200 ml saturated sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. Filter off the drying agent and concentrate to give 6.5 gram of product.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: Clc1nccc2[nH]cnc12
Solvent: O
Solvent: CCO
Product: NNc1nccc2[nH]cnc12

Procedure:
A mixture of 200 mg (1.3 mmol) of 4-chloro-1H-imidazo[4,5-c]pyridine [J. A. Montgomery and K. Hewson, J. Med. Chem., 8, 708 (1965)], 0.253 mL (261 mg, 5.2 mmol) of hydrazine hydrate, and 5 mL of ethanol was stirred at room temperature overnight. The precipitate was collected on a filter, washed with a little ethanol, and dried to give the title compound as a solid. LC-MS 150 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:17][C@@H:12]2[CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=3)[CH2:17][C@@H:12]2[CH2:11]1
Reactant: COC(=O)c1cccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of 0.15 g (0.39 mmol) of (7S,8aS)-7-(3-(methoxycarbonyl)phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Example 11j) in 15 mL of anhydrous ethyl ether was added dropwise to an ice-cold suspension of 0.029 g (0.78 mmol) of lithium aluminum hydride in 15 mL of anhydrous ethyl ether and the mixture stirred for 30 min. The reaction was carefully quenched at 0° C. with 0.029 mL of water, 0.029 mL of 15% sodium hydroxide, and 0.087 mL of water. The precipiate which formed was filtered through Celite, the filtrate concentrated in vacuo, and purification of the residue by flash silica gel chromatography with 95:5 chloroform:methanol gave 0.099 g (72%) of the title compound. mp (.HCl) 85°-89° C. HRMS calcd for C19H24FN4O2 (MH+): 359.1883, found: 359.1895.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CCCS(=O)(=O)[O-])CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1ccc(C2(CCN3CCC(C(N)=O)(c4ccccc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Prepared by the methoB of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.55 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (175 mg, 0.73 mmol). Chromatography on silica gel (30 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23].C[O-].[Na+]>CO>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:5]2[C:4]([OH:18])=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:6]=2[OH:8])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(O)c(-c2ccc(C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of diethyl(4-methylphenyl)malonate (9.45 g) and butyramidine hydrochloride (5.00 g) in methanol (25 ml) is added 28% sodium methoxide (19.67 g) under ice-cooling, and the mixture is stirred at room temperature overnight. After the reaction is complete, the reaction solution is concentrated to the half volume thereof, and the resultant is diluted with water. The mixture is acidified with 10% hydrochloric acid, and the precipitated crystals are collected by filtration, washed, and dried to give 5-(4-methylphenyl)-4,6-dihydroxy-2-n-propylpyrimidine (5.17 g) as crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=O)[C:21]([O:26][CH3:27])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[C:19]=3OC)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH3:34][NH2:35].B.[Na].[CH3:38][OH:39]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:35][CH3:34])[C:21]([O:26][CH2:27][O:39][CH3:38])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CO
Reactant: CN
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(OC)c(C(=O)OC)c3OC)cs2)cc1OCC
Agent: B
Agent: [Na]
Product: CCOc1ccc(-c2nc(-c3cc(CNC)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In 30 ml of methanol was dissolved 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxy-methoxy-5-formylphenyl)thiazole. Thereto was added 3 ml of a 30% methylamine solution. The mixture was stirred at room temperature for 14 hours and at 70° C. for 1 hour. Thereto was added 530 ml of sodium boron hydride with stirring under ice-cooling. The mixture was stirred at room temperature for 3 hours. The solvent was removed from the reaction mixture by distillation. The residue was mixed with 40 ml of ethyl acetate and 20 ml of water, and phase separation was conducted. The organic layer was washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was subjected to silica gel chromatography (eluent: dichloromethane/methanol=49/1 by v/v). From the eluate was obtained 150 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethyl-phenyl)thiazole.
Reaction SMILES: CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.C(O)[C@H]1[O:22][C@H:21]([O:23][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:20](O)[C@@H](O)[C@@H]1O.[CH2:39]([N:50]([CH2:55]C(O)=O)CC(O)=O)[CH2:40][N:41](CC(O)=O)CC(O)=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH:40]1[N:41]=[CH:55][NH:50][C:39]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C(O)Cc1cnc[nH]1
Reaction time: 0.33 h

Procedure:
The coding sequence of the VHH was subcloned in vector pET22 using the NcoI and NotI restriction sites according to the manufacturer's instructions (Novagen, Darmstadt, Germany). Transformed E. coli BL 21 (DE3) cells expressed VHHs in the periplasm after induction by IPTG 1 mM for 18 hours at 15° C. Periplasmic extracts were obtained by spheroplasting cells, suspended in 50 mM sodium phosphate buffer pH 8 containing 20% sucrose and 1 mM EDTA, and hydrolysing the peptidoglycan with 5 mg/ml lysozyme for 20 min at 4° C., in the presence of protease inhibitors (Complete™, Boehringer Mannheim, Germany). The suspension was then centrifuged 2 min at 10,000 rpm. The supernatant corresponding to the periplasmic extract was kept at 4° C. Purified VHHs were obtained by IMAC using a chelating agarose column charged with Ni2+ (Superflow Ni-NTA, Qiagen Ltd, UK) according to manufacturer's instructions. Purified VHH were dialysed against PBS and the protein content was measured using the Bradford reagent. The purity of the final preparation was evaluated by SDS-PAGE with Coomassie staining and by Western blot.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][I:22]>CCO>[IH:22].[CH3:19][C:15]1[CH:14]=[C:13]([C@H:12]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CI
Reactant: Cc1cccc([C@H]2NC(=S)N[C@H]2c2cccc(C)c2)c1
Solvent: CCO
Product: CSC1=N[C@@H](c2cccc(C)c2)[C@@H](c2cccc(C)c2)N1
Product: I
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A mixture of cis-4,5-bis-(3-methylphenyl)imidazolidine-2-thione (30) (2.23 g, 0.00825 mol) and methyl iodide (0.77 mL, 0.0124 mol) in abs. EtOH (30 mL) is heated at 95° C. overnight. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue suspended in Et2O. The insoluble material is filtered to give 3.24 g of the product 47. 1H NMR (DMSO-d6) δ 10.71 (s, 2H), 7.10-7.00 (m, 2H), 7.00-6.90 (m, 2H), 6.90-6.75 (m, 4H), 5.73 (s, 2H), 2.80 (s, 3H), 2.13 (s, 6H); MS: m/z 297 (M++1).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:2].CN([CH:20]=[O:21])C.O>C1COCC1.C([Li])CCC>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCOCOC)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCOCOC)c1ccc(C=O)cc1
Reaction time: 0.75 h
Yield: 91 %

Procedure:
68.0 g (0.23 mol) of N-ethyl-N-[2-(methoxymethyl)oxyethyl]-4-bromoaniline was dissolved in 500 ml of anhydrous THF in an atmosphere of nitrogen, and 280 ml (2.2-fold equivalent weight) of a 1.7M n-butyllithium solution (solvent: n-pentane) was dropwise added thereto at -78° C., followed by stirring for 45 minutes. To the reaction solution obtained, 25 ml of anhydrous DMF was added, and the solution was stirred for 8 hours while allowing the temperature to naturally rise to room temperature. Thereafter, 100 ml of water was added to the resulting reaction solution, which was then extracted with dichloromethane (100 ml×2). The organic layer was dried with anhydrous sodium sulfate, and thereafter concentrated under reduced pressure. The residue thus obtained was distilled under reduced pressure to obtain 51.0 g of N-ethyl-N-[2-(methoxymethyl)oxyethyl]-4-formylaniline (yield: 91%).