Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3]C1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.Cl.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C:36]=4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1>>[ClH:3].[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C@@H:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C@@H:36]4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Reactant: Clc1cccc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Agent: Cl
Product: Clc1cccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole dihydrochloride the title compound was prepared: 1H NMR (DMSO-d6) δ 1.35, 1.55, 2.10, 2.71, 3.05, 3.28, 3.97, 4.20, 6.65, 7.12, 7.4-7.5, 8.8. HRMS (FAB) calcd for C18H21ClN2 (MH+) 299.1315, found 299.1306.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([CH2:39][NH:40][C:41]([C@@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH3:48])=[O:42])[CH2:4][CH2:3]2.CN1CCC[C@@H]1C(O)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([CH2:39][NH:40][C:41]([C@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH3:48])=[O:42])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)[C@@H]3CCCN3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN1CCC[C@@H]1C(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)[C@H]3CCCN3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield following the procedure described above in the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(((S)-1-methylpyrrolidine-2-carboxamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 150, using (R)-1-methylpyrrolidine-2-carboxylic acid as the reactant acid. MS: m/e 655.7 (MH+), 1.73 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3H) 0.96 (s, 3H) 1.03 (s, 3H) 1.05 (s, 3H) 1.17 (s, 3H) 1.71 (s, 3H) 0.85-2.25 (m, 24H) 2.14 (dd, J=17.07, 6.27 Hz, 1H) 2.48-2.62 (m, 2H) 2.90 (s, 3H) 3.15-3.25 (m, 2H) 3.50-3.57 (m, 1H) 3.67-3.76 (m, 1H) 4.04 (t, J=8.16 Hz, 1H) 4.61 (s, 1H) 4.73 (d, J=2.01 Hz, 1H) 5.29 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H) 8.24 (t, J=5.90 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[Si:18]([C:22]#[CH:23])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.O.[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>[Br:8][C:6]1[N:7]=[C:2]([C:23]#[C:22][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]([NH2:10])=[N:4][C:5]=1[Cl:9]
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1nc(Br)c(Cl)nc1N
Temperature: -5 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 3,5-dibromo-6-chloro-pyrazin-2-ylamine (5.0 g, 17.42 mmol) in anhydrous THF (40 mL) was added triethylamine (3.52 g, 34.84 mmol) and CuI (0.333 g, 1.74 mmol). The mixture was degassed with bubbling argon for 10 min then evacuated and back-filled with argon. It was purged thoroughly with argon for 20 min and Pd(PPh3)2Cl2 (0.355 g, 0.52 mmol) was added. The reaction mixture was cooled to −5° C., TMS-acetylene (1.90 g, 19.16 mmol) was added very slowly and the temperature was slowly increased to 15° C. during 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were concentrated in vacuo then purified by chromatography (silica, 5% ethyl acetate in hexanes) to give 5-bromo-6-chloro-3-trimethylsilanylethynyl-pyrazin-2-ylamine (4.0 g, 75%) as a yellow solid. LC-MS: 304.0 (M+H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:19])=O>>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([Cl:19])=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(N=[N+]=[N-])cc1
Product: CC(C)C(C(=O)Cl)c1ccc(N=[N+]=[N-])cc1

Procedure:
2-(4-Azidophenyl)-3-methylbutanoic acid, 3.68 g, was dissolved in 15 ml of thionyl chloride. After 45 minutes the solution was heated to a boil, then evaporated in vacuum to a residual oil. The oil was twice dissolved in diethyl ether and evaporated in vacuum to a residual oil, and further dried under a nitrogen stream. The infrared spectrum of the oil showed absorption peaks at 2120 cm-1 (azide) and 1810 cm-1 (acid chloride).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[N:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>C1C=CC=CC=1>[N:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[O:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[C:2]([CH3:1])[C:11]3=[O:12])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cccc(-c2oc3c(C(=O)Cl)cccc3c(=O)c2C)c1
Reactant: NCCCN1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Product: Cc1cccc(-c2oc3c(C(=O)NCCCN4CCCCC4)cccc3c(=O)c2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of 3,3'-dimethylflavone-8-carboxylic acid chloride (prepared from 1.00 g of 3,3'-dimethylflavone-8-carboxylic acid and 0.50 ml of thionyl chloride) in 30 ml of benzene were added 0.44 g of 3-piperidinopropylamine and the mixture was stirred for 2 hours at room temperature. To the mixture was added aqueous HCl soluction and the mixture was shaken. The water layer was separated and made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried, and evaporated, and to the residue was added isopropyl ether. The precipitate was filtered to give 0.80 g of reddish brown crystals, which were recrystallized from a mixture of acetone and water as colorless needles, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20]C)=[C:15]([CH3:22])[CH:14]=1)[CH3:2].Cl.N1C=CC=CC=1>>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:22])[CH:14]=1)[CH3:2]
Reactant: CCc1sc2ccccc2c1C(=O)c1cc(C)c(OC)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1sc2ccccc2c1C(=O)c1cc(C)c(O)c(C)c1

Procedure:
Into a half-litre flask equipped with a condenser, a mechanical stirrer and a thermometer, 25 g (0.777 mol) of 2-ethyl-3-(3,5-dimethyl-4-methoxy-benzoyl)benzo[b]thiophene were introduced with 125 g of pyridine hydrochloride.
Reaction SMILES: C1(C2CC(=O)CC(=O)C2)C=CC=CC=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][C:26](=[O:28])[C:25](=[CH:29][N:30]([CH3:32])[CH3:31])[C:24](=[O:33])[CH2:23]2)=[CH:18][CH:17]=1>>[CH3:32][N:30]([CH:29]=[C:25]1[C:26](=[O:28])[CH2:27][CH:22]([C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:23][C:24]1=[O:33])[CH3:31]
Reactant: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Agent: O=C1CC(=O)CC(c2ccccc2)C1
Product: CN(C)C=C1C(=O)CC(c2ccccc2)CC1=O
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 5-phenylcyclohexane-1,3-dione (1.0 g, 5.3 mmol), following the procedure described for the synthesis of 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was run at ambient temperature for 30 min.
Reaction SMILES: C([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=CC=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[S:41]1[CH:35]=[CH:40][CH:39]=[C:38]1[C@:5]1([O:18][C@H:17]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29])[OH:4]
Reactant: Sc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@](O)(c2cccs2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound [2] (0.31-8.02 g, 0.68-17.7 mmol) is dissolved in 3.2-100 ml of dry dichloromethane, and thiophenol (0.15-3.9 g, 1.36-35.4 mmol) and tin tetrachloride (0.35-9.22 g, 1.36-35.4 mmol) are added and the mixture is stirred until reaction is complete. The reaction mixture is diluted and then washed with saturated sodium bicarbonate solution. The crude product compound [3] obtained in this way is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.27-7.14 g, 0.54-14.2 mmol, about 80%) and is dissolved in anhydrous methanol (3-90 ml) and catalytic amounts of sodium methylate (prepared from 0.002-0.05 g of sodium in 0.1-2 ml of methanol) are added. After the reaction is complete, the mixture is neutralized with an acidic ion exchanger (0.2-5 g Amberlite IR-120, H+ -form) compound [4] (0.21-5.31 g, 0.54-14.1 mmol, about 80% yield). FAB-MS: M+H+ =378. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 112:3695 (1990) and T. J. Caulfield, Ph.D. Dissertation, The University of Pennsylvania (1991).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine in an analogous manner to Example 179 heating at 130° C. Product was isolated as a pink foam (42 mg, 57%). LCMS (m/e) 475 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.60 (d, 1H, J=8.3 Hz), 8.32 (d, 1H, J=7.8 Hz), 8.05 (s, 1H), 7.78 (s, 1H), 7.43 (m, 2H), 7.21 (m, 2H), 6.95 (m, 3H), 4.01 (m, 2H), 3.76 (s, 3H), 2.07 (m, 2H), 1.69 (m, 2H), 1.39 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.N1(C2CCCCCCCCCC2)CCCNCCCCC[CH2:15]1.CI.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CCCCCC(N2CCCCCCNCCC2)CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by MeI (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water (2×), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=2[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O:11]C)=[O:10])=[N:2]1.[OH-].[Na+]>C(O)C>[O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=2[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([OH:11])=[O:10])=[N:2]1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.2 %

Procedure:
To 3.00 g of methyl 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoate were added 10 ml of ethanol and 20 ml of a 1N sodium hydroxide solution to stir at room temperature for 2 days. Ethanol was distilled out under reduced pressure. The remaining solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 2.75 g of the title compound as white crystals. m.p. 182~184.5° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[OH:28].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([OH:28])[CH:22]=1
Reactant: Nc1cc(F)c(F)cc1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)cc1O
Yield: 71306.5 %

Procedure:
The product is prepared according to the procedure described in stage 1 of Example 2, but using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (Example 1, stage 2), 425 mg of 2-amino-4,5-difluorophenol and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of dimethylformamide. 500 g of N-(4,5-difluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: C(OCCOC(=O)C(C)=C)(=O)C(C)=C.C(O)C.[CH3:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21]([CH3:26])([CH3:25])[C:20]=1/[CH:27]=[CH:28]/[C:29](/[CH3:38])=[CH:30]/[CH:31]=[CH:32]/[C:33](/[CH3:37])=[CH:34]/[CH:35]=[O:36]>O>[CH3:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21]([CH3:25])([CH3:26])[C:20]=1/[CH:27]=[CH:28]/[C:29](/[CH3:38])=[CH:30]/[CH:31]=[CH:32]/[C:33](/[CH3:37])=[CH:34]/[CH2:35][OH:36]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Solvent: CCO
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Yield: 96.78 %

Procedure:
50 g of mesoporous polymer beads having a size of 10 nm and made of polymethylmethacrylate crosslinked with ethyleneglycol dimethacrylate was added to ethanol in a 5 L beaker, was stirred for 40 minutes or more using an agi mixer, was mixed with 2 g of butylated hydroxytoluene, and was then dissolved to prepare a first mixed solution. Subsequently, 40 g of retinal (vitamin A) was added to the first mixed solution, was completely dissolved, was mixed with purified water, and was then stirred for 5 minutes or more to prepare a second mixed solution. Subsequently, the second mixed solution was filtered under reduced pressure to obtain retinol-adsorbed mesoporous polymer beads, and then the retinol-adsorbed mesoporous polymer beads were vacuum-dried at 45° C. (yield: 96.78%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C1(=O)O[CH2:16][CH2:15][O:14]1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:16][CH2:15][OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1OCCO1
Reactant: CCCCOc1cccc(O)c1
Product: CCCCOc1cccc(OCCO)c1
Yield: 85 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from 3-n-butoxyphenol (2.0 g, 12 mmol) and ethylene carbonate (0.88 g, 10 mmol). Oil; yield 85%. MS m/z 210 (M)+.
Reaction SMILES: [CH3:1][C:2]([N:8]1[Si:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][Si:9]1([CH3:16])[CH3:15])([CH3:7])[C:3]#[C:4][CH2:5][OH:6].[K].[CH3:18][Si]([NH-])(C)C.CI>O1CCCC1.O>[CH3:18][O:6][CH2:5][C:4]#[C:3][C:2]([N:8]1[Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][Si:12]1([CH3:13])[CH3:14])([CH3:1])[CH3:7]
Reactant: C[Si](C)(C)[NH-]
Reactant: CC(C)(C#CCO)N1[Si](C)(C)CC[Si]1(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COCC#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Methyl-4-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)pent-2-yn-1-ol (2.55 g) in dry tetrahydrofuran (30 ml) was cooled to −10° C. under an atmosphere of nitrogen with stirring and potassium bis(trimethylsilylamide (2.09 g) in dry tetrahydrofaran (25 ml) was added over 5 minutes then the mixture was stirred at −(10 to 5)° C. for 0.75 hours. Methyl iodide (1.49 g) in tetrahydrofuran (10 ml) was added over 5 minutes and the mixture was allowed to warm to ambient temperature over 2 hour then stored for 18 hours. The mixture was diluted with water and extracted with ethyl acetate (three times). The extracts were combined, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give 1-(1-methoxy-4-methylpent-2-yn-4-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as a yellow liquid. This liquid was stirred with dilute aqueous hydrochloric acid (30 ml) for 0.25 hours, washed with diethyl ether (twice) and the aqueous acidic phase separated then evaporated under reduced pressure. The residue was evaporated under reduced pressure with toluene (twice) to remove any water, dissolved in dichloromethane and dried over magnesium sulphate then evaporated under reduced pressure to give 4-amino-1-methoxy-4-methylpent-2-yne hydrochloride, 0.66 g, as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[N:14][C:15]([CH:18]([OH:31])[CH:19]2[CH2:24][CH2:23][C@@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:21]([CH3:30])[CH2:20]2)=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:17]=[N:16][C:15]([C:18]([CH:19]2[CH2:24][CH2:23][C@@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:21]([CH3:30])[CH2:20]2)=[O:31])=[N:14][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CCC(C(O)c2ncc(Cl)cn2)C[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CCC(C(=O)c2ncc(Cl)cn2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (0.37 mL, 3.5 mmol) in dichloromethane (4.4 mL) cooled to −78° C. was added dropwise a solution of dimethylsulfoxide (0.55 mL, 7.1 mmoL) in dichloromethane (10.8 mL). After 5 min, a solution of ethyl rel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]-2-methylcyclohexanecarboxylate (1 g, 3.2 mmol) in dichloromethane (6.5 mL) was added. The reaction mixture was stirred for 15 minutes at −78° C. and triethylamine (2.2 mL, 16 mmol) was added in one portion. After stirring for 10 min at −78° C., the mixture was allowed to warm to room temperature and diluted with dichloromethane (50 mL). The organic layer was successively washed with a saturated aqueous ammonium chloride solution (30 mL) and brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)carbonyl]-2-methylcyclohexanecarboxylate. MS ESI calc'd for C15H20ClN2O3[M+H]+ 311. found 311. 1H NMR: (400 MHz, CDCl3) δ. 8.88-8.84 (m, 2H), 4.17-4.10 (m, 2H), 2.71-2.48 (m, 2H), 2.14-2.01 (m, 1H), 1.90-1.73 (m, 5H), 1.53-1.41 (m, 1H), 1.28-1.24 (m, 3H), 1.06-0.99 (m, 3H).
Reaction SMILES: [CH2:1]([O:51][S:52]([OH:55])(=[O:54])=[O:53])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([OH:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([OH:19])(=[O:18])=[O:17])[C@@H:11]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([OH:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C@@H:4]([O:41][S:42]([OH:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([OH:50])(=[O:49])=[O:48].[OH-].[K+:57]>>[CH2:1]([O:51][S:52]([O-:55])(=[O:53])=[O:54])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([O-:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([O-:19])(=[O:17])=[O:18])[C@@H:11]([O:20][S:21]([O-:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([O-:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([O-:40])(=[O:38])=[O:39])[C@@H:4]([O:41][S:42]([O-:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([O-:50])(=[O:49])=[O:48].[K+:57].[K+:57].[K+:57].[K+:57].[K+:57].[K+:57].[K+:57].[K+:57]
Reactant: O=S(=O)(O)OC[C@H]1O[C@@](COS(=O)(=O)O)(O[C@H]2O[C@H](COS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@H](OS(=O)(=O)O)[C@H]2OS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@@H]1OS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)([O-])OC[C@H]1O[C@@](COS(=O)(=O)[O-])(O[C@H]2O[C@H](COS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H]2OS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@@H]1OS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
One portion of sucrose octasulfate solution prepared as described in I above was adjusted with 10% w/w aqueous potassium hydroxide to pH=9 with stirring at room temperature. The solution was evaporated at 50° C. in vacuo to remove pyridine and water until 880 g were left. The warm solution was filtered, adjusted to pH=9.5, and the substance was precipitated with slow cooling to 5° C. The substance was filtered and washed with 300 ml of 1:1 ion-exchanged water/methanol and 300 ml of methanol. The wet filter cake was dried in vacuo at 50° C. The crude product was dissolved at 40° C. in 700 ml of ion-exchanged water. The liquid was filtered and adjusted to pH=9.5, and the substance was precipitated with slow cooling to 5° C. The precipitated substance was filtered and washed with 300 ml of 1:1 ion-exchanged water/methanol and 300 ml of methanol. The wet filter cake was dried in vacuo at 50° C. The substance was reprecipitated twice as mentioned above.