Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[OH:1][C:2]1[C:9]([Br:15])=[CH:8][C:7]([C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1Cl
Yield: 99.6 %

Procedure:
A solution of 1.97 g (9.26 mmol) of 2-hydroxy-5-(1,1-dimethylethyl)-6-chlorobenzaldehyde and 1.98 g (11.1 mmol) of N-bromosuccinimide in 30 ml of methylene chloride was stirred for 2 hours. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on 150 g of silica gel eluted with 1:99 (v/v) ether:hexane. There was obtained 2.69 g (9.22 mmol, 99%) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)-6-chlorobenzaldehyde as a white solid after recrystallization from hexane; mp 103°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)[CH3:2].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([N:10]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
O-Ethyl-L-tyrosine (IV, EXAMPLE 3, 20.9 g, 100 mmol) and N-carbethoxyphthalimide (23.0 g, 105 mmol) are suspended in water (210 mL). Sodium carbonate (11.1 g, 105 mmol) is added and the mixture is stirred at 20-25° for 24 hr. Hydrochloric acid (1N, 200 mL) is added to the resulting mixture and stirred for 2 hr. The mixture is filtered, washed with water (100 mL) and dried to give the title compound, NMR (MeOH-d4) δ7.78-7.72, 7.14, 6.68, 5.11, 3.90, 3.47 and 1.28; CMR (MeOH-d4) δ172.2, 169.0, 159.2, 135.6, 132.8, 130.9, 130.3, 124.2, 115.5, 64.3, 54.8, 34.7 and 15.0.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: CCCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 3 h
Yield: 58.1 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-undecadienoic acid methyl ester (5.9 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 3 hours the reaction was worked up in the usual way and the crude acid was crystallized from hexane to give 3.27 g of (E,E)-5-(4-methoxyphenyl)-2,4-undecadienoic acid, mp 88°-89.5° C.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[C:1]([O:24][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 130 °C

Procedure:
A four-necked round-bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 1 mole of behenic acid per 1 mole of behenyl alcohol. The ingredients in the flask were heated at 130° C. for 3 hours under a nitrogen atmosphere, to carry out an esterification reaction. The reaction product was purified with methyl ether, to give behenyl behenate. Here, the resulting compound had an acid value of 0.1 mgKOH/g, and a hydroxyl value of 1.2 mgKOH/g.
Reaction SMILES: [C:1]([C:6]1[S:13][C:12]2[C:11]3[S:14][C:15]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:18]([C:41]([O:43]CC)=[O:42])[S:17][C:16]=4[C:10]=3[S:9][C:8]=2[C:7]=1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:3]CC)=[O:2].CO.[OH-].[Li+]>O1CCCC1.O>[CH2:20]([C:19]1[C:15]2[S:14][C:11]3[C:12]4[S:13][C:6]([C:1]([OH:3])=[O:2])=[C:7]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:8]=4[S:9][C:10]=3[C:16]=2[S:17][C:18]=1[C:41]([OH:43])=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c3sc(C(=O)OCC)c(CCCCCCCCCCCCCCCCCCCCC)c3sc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCCCCCCCCCCCCC)c3sc21
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Ester deprotection (Step C) The 2,6,-dicarboethoxy-3,7-diheneicosylthieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene (10 mmol) product of Example 10, is dissolved in tetrahydrofuran (THF) (280 mL) then methanol (40 mL) is added. Lithium hydroxide (40 mmol) is dissolved in water (10 mL) and added to the stirred methanol and THF solution. A condenser is fitted and the reaction mixture is heated in an oil bath at 90° C. for 16 hr. The THF and methanol are removed under reduced pressure. 60 ml, of methanol and 10 mL of conc. hydrochloric acid are added then stirred for 4 h. Next 50 mL of water is added and the solid is filtered off. The product is dried under vacuum to give the 3,7-diheneicosyl thieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene-2,6-dicarboxylic acid. 1H NMR (D8-THF) δ 0.89 (6H, t, J=6.9 Hz), 1.17-1.45 (72H, m), 1.68-1.85 (4H, m), and 3.18-3.28 (4H, m).
Reaction SMILES: [OH:1][C@@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][CH:8]([CH2:12]C)[C:9]([OH:11])=[O:10])[CH2:3]1>CCOC(C)=O.CCCCCC>[OH:1][C@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH2:3]1
Reactant: CCC(O[C@H]1C=C[C@@H](O)C1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(O[C@H]1C=C[C@H](O)C1)C(=O)O
Yield: 89 %

Procedure:
Compound 15 was subjected to general procedure J. Yield=89%. TLC: Rf=0.31 (25% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ1.30 (t, 3H), 2.35 (m, 2H), 4.10 (s, 2H), 4.25 (q, 2H), 4.90 (m, 1H), 6.05 (m, 1H), 6.20 (m, 1H), 6.30 (m, 1H), 8.20 (d, 2H), 8.30 (d, 2H). Subsequent subjection of the product to general procedure E gave compound 30. Yield=91%. TLC: Rf=0.18 (50% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ2.00 (m, 1H), 2.25 (m, 1H), 3.75 (s, 3H), 4.05 (s, 2H), 4.80 (m, 1H), 5.05 (m, 1H), 6.05 (s, 2H).
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9](=O)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH2:17][CH2:16][C:15]=3[CH:19]=2)[CH2:5]1)#[N:2].C1(C)C=CC=CC=1.[BH4-].[Na+].[B-](F)(F)(F)[O+]1CCCC1.N1CCNCC1>O1CCCC1>[O:18]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][C@@H:4]([C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:1]#[N:2])[CH2:5]3)=[CH:19][C:15]=2[CH2:16][CH2:17]1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(C(=O)Cc2ccc3c(c2)CCO3)C1
Agent: C1CNCCN1
Agent: F[B-](F)(F)[O+]1CCCC1
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][CH:30]=[CH:29][C:5]=1[NH:6][CH2:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O>C(O)C.[Pd]>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C:8]3([CH2:7][NH:6][C:5]4[C:4]([NH2:1])=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1

Procedure:
A solution of 2-nitro-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)aniline (570 mg, 1.3 mmol) in ethanol (40 mL) was hydrogenated for 5 hours at room temperature at 50 psi in the presence of 10% Pd/C (60 mg, 10% w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated in vacuo to give the title compound as a gum, used without further purification (500 mg, 94%). HRMS ESI+ m/z 410.2791 [MH]+.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>[Ru]>[N:17]1[CH:18]=[CH:19][C:14]([C@H:11]([OH:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccncc1
Agent: [Ru]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1ccncc1
Temperature: 28 °C
Yield: 55.7 %

Procedure:
Triethylamine (315 mL, 2.26 mol) was added dropwise to formic acid (150 mL, 3.91 mol) with overhead stirring while maintaining the internal temperature below 60° C. with ice-bath cooling. Neat 4-acetylpyridine (100 mL, 0.904 mol) was then added rapidly while maintaining the temperature below 50° C. Following this addition, the reaction was allowed to cool to 28° C. and the chiral ruthenium catalyst [N-[(1R,2R)-2-(amino-N)-1,2-diphenylethyl]-2,4,6-trimethylbenzenesulfonamidato-N]chloro[(1,2,3,4,5,6-n)-1-methyl-4-(1-methylethyl)benzene]ruthenium (CAS #177552-91-9; for catalyst preparation, see: Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.; J. Am. Chem. Soc. 1996, 118, 4916-4917) (3 g, 4.46 mmol) was added. The mixture was stirred under house vacuum for 4 h and then overnight under an atmosphere of nitrogen. The reaction mixture was added dropwise to a stirred solution of 10% Na2CO3 (4 L) and then extracted with EtOAc (3×1 L). The combined EtOAc layers were washed once with brine (1 L), treated with MgSO4 and Darco G-60 decolorizing charcoal and filtered through a 100 g plug of silica gel washing with 10% MeOH/EtOAc (1 L). The filtrate was concentrated to provide a dark oil that crystallized upon standing. The solid was dissolved in warm t-butyl methyl ether (250 mL) and the warm solution was filtered to remove a small amount of insoluble material. The filtrate was allowed to stir with cooling to room temperature and then to −15° C. The solids were collected by filtration, washing with cold t-butyl methyl ether and heptane, and then dried under high vacuum to yield (1R)-1-(4-pyridinyl)ethanol as a dark beige solid (62 g, 52.9% yield). This solid material was 96% ee based on chiral HPLC (HPLC conditions: AS-H column, 5% MeOH/CO2, 40° C., 140 bar, 2 mL/min). The filtrate was combined with the insoluble solid from the crystallization and concentrated in vacuo to yield additional (1R)-1-(4-pyridinyl)ethanol as a dark oil (37.5 g, 32% yield). This oily material was 78% ee based on chiral HPLC (see HPLC conditions above). 1H NMR (400 MHz, DMSO-d6): δ 8.47-8.43 (m, 2H), 7.32-7.28 (m, 2H), 5.37 (d, 1H, J=4.4 Hz), 4.72-4.64 (m, 1H), 1.44 (d, 3H, J=6.6 Hz).
Reaction SMILES: [BH4-].[Na+].[ClH:3].Cl.[CH2:5]([N:7]([CH2:33][CH3:34])[CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:18][CH:19]=3)[C:14](=[O:32])[C:13]=2[CH:12]=1)[CH3:6]>CO>[ClH:3].[ClH:3].[CH2:30]([N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][O:24][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH2:33][CH3:34])[CH2:5][CH3:6])=[CH:23][CH:22]=3)[CH:14]([OH:32])[C:15]=2[CH:16]=1)[CH3:31]
Reactant: CCN(CC)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(CC)CC)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCOc1ccc2c(c1)C(O)c1cc(OCCN(CC)CC)ccc1-2
Temperature: 0 °C

Procedure:
A total of 2.3 g (0.06 mole) of sodium borohydride is added in small portions to a stirred solution of 9.7 g (0.02 mole) of 2,7-bis(2-diethylaminoethoxy)fluoren-9-one dihydrochloride in 200 ml or methanol, maintaining the mixture at 0°C throughout the addition. The mixture is allowed to warm to room temperature and the solvent removed in vacuo. The residue is taken up in 10% hydrochloric acid, the mixture extracted with ether, and the aqueous acidic solution evaporated in vacuo. The residue is dissolved in methanol, cooled at -20°C, and the inorganic material which precipitates removed by filtration. The filtrate is evaporated in vacuo, the residue dissolved in water and made basic with 10% aqueous sodium hydroxide. The liberated free base is extracted into ether, the ether extract washed with water and dried over anhydrous magnesium sulfate. The mixture is filtered, the filtrate evaporated, the residue taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The precipitated product is collected and recrystallized three times from a mixture of isopropyl alcohol and methanol to give 2,7-bis(2-diethylaminoethoxy)fluoren-9-ol dihydrochloride. M.P. 192°-194°C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:27]3[CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]=3[O+]=[C:20]3[C:15]=2[CH2:16][CH2:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=23)=[CH:10][CH:9]=1.[NH3:36]>C(O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:27]3[CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]=3[N:36]=[C:20]3[C:15]=2[CH2:16][CH2:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=23)=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2c3c([o+]c4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Reactant: N
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1ccc(-c2c3c(nc4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
16 (6.63 g, 13.9 mmol, 1 eq) was suspended in ethanol (175 mL, denaturated with 1% methylethyl ketone). Under vigorously stirring an ammonia solution (32% aqueous solution, 18.3 g NH3, 1.075 mol, 77 eq) was added dropwise and the mixture was stirred at ambient temperature for 171/2 hours to obtain a lavender suspension. The product was isolated by filtration and purified by successive washing with ethanol (250 mL). A lavender solid (91% yield) could be obtained. The compound was directly used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccncc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 100 mg, 0.305 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.610 mmol) in NMP (1 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 9%). 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=6.1 Hz, 2H), 6.08 (s, 1H), 4.28 (br. s., 2H), 3.88 (br. s., 2H), 3.15 (d, J=3.0 Hz, 2H), 2.40-2.47 (m, 2H), 2.30-2.37 (m, 3H), 1.85-1.96 (m, 2H), 1.81 (s, 3H), 1.46-1.62 (m, 3H). ESI-MS: m/z 434.0 (M+H)+.
Reaction SMILES: [C:1]([N:4]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([F:28])[F:27])=[CH:20][C:19]=1[C:29](OC)=[O:30])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:3])[NH2:2].[OH-].[Na+]>O1CCOCC1>[F:27][CH:26]([F:28])[CH2:25][O:24][C:21]1[CH:20]=[C:19]2[C:18](=[CH:23][CH:22]=1)[N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[C:1](=[O:3])[NH:2][C:29]2=[O:30]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1N(C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1

Procedure:
2.5 g of 1,1-dimethylethyl 4-{carbamoyl[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.4 in solution in a mixture of 10 ml of dioxane and 5 ml of a 1N aqueous NaOH solution are irradiated under a microwave field at 130° C. for 30 min. Extraction is carried out with AcOEt and the extract is neutralized with a 1N aqueous HCl solution, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The residue obtained is triturated in an AcOEt/pentane mixture to give the expected product. The same reaction is reproduced with 2 other lots of 2.5 g of 1,1-dimethylethyl 4-{carbamoyl[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.4 to give, in total, 5.63 g of expected product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1F
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccccc4F)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.1 g, 0.218 mmol) and 2-fluorophenol (0.025 g, 0.436 mmol) were dissolved in DMF (5 mL). Potassium carbonate (0.06 g, 0.436 mmol) was added and the mixture was heated to 80° C. overnight then at 130° C. for 7 h. The mixture was left to stand at room temperature overnight and the solvent removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to produce a brown oil. The crude product was purified by MDAP to yield the formic acid salt. The salt was taken up in DCM and washed with sat. NaHCO3. The DCM layer was dried and concentrated to yield the title compound as a colourless oil (0.038 g). δH (CDCl3, 400 MHz) 8.02 (1H, d), 7.68 (1H, dd), 7.23 (2H, d), 7.15 (4H, m), 6.98 (2H, d), 6.78 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([OH:18])[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)[CH3:2].[CH2:20](I)[CH3:21]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:18][CH2:20][CH3:21])[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C(O)c1nc(C)n(-c2ccccc2)n1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OCC)c1nc(C)n(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a stirred solution of (RS)-hydroxy-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (1.12 g) at r.t. in toluene (30 ml) under an argon atmosphere were added silver (I) oxide (2.99 g) and ethyl iodide (1.74 ml). The mixture was heated to reflux and stirring was continued for 16 h. The solids were filtered off and washed with EtOAc. The filtrate was concentrated. The product was isolated by chromatography (silica gel, gradient cyclohexane=>EtOAc) to give (RS)-ethoxy-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (0.87 g) as orange oil. MS 290.1 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]CC)=[O:11])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O>[CH3:1][N:2]([CH3:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(N(C)C)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ncc(C(=O)O)c(=O)[nH]1
Yield: 93.7 %

Procedure:
Ethyl 3,4-dihydro-2-dimethylamino-4-oxopyrimidine-5-carboxylate (P. Dostert, T Imbert, J F Ancher, M Langlois, B Bucher and G Mocquet, Eur. J. Med. Chem.-Chim. Ther. (1982), 17, 437-44) (0.64 g) was refluxed with NaOH (304 mg) in water (16 ml) for 2 hours. The cooled solution was acidified to pH2 with 1N HCl, solid filtered off and dried under vacuum at 75° C. to give title compound (0.52 g). MS (−ve ion chemical ionisation) m/z 182 ([M−H]−, 100%).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:18](=O)[CH2:19][CH2:20][C:21]=2[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li][CH3:26]>>[CH3:22][C:21]1[CH2:20][CH:19]=[C:18]([CH3:26])[C:17]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:24])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC1=C(c2ccccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1
Reactant: [Li]C
Product: CC1=CCC(C)=C1c1ccccc1NS(=O)(=O)c1ccc(C)cc1

Procedure:
The same experiment as in Example 17 was carried out, using 1.000 g (2.93 mmol) of 2-(2-(p-toluenesulfonyl)aminophenyl)-3-methyl-2-cyclopenten-1-one and 3.660 ml (5.860 mmol) of MeLi (1.6 M in diethyl ether) (0.617 g, 62%).