Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:59][CH2:58][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:56][CH2:55]3)[CH2:50][CH2:49]2)=[CH:40][C:41]([O:45][CH2:46][CH3:47])=[C:42]([NH2:44])[CH:43]=1)[CH3:37].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:42]3[CH:43]=[C:38]([CH2:36][CH3:37])[C:39]([N:48]4[CH2:49][CH2:50][CH:51]([N:54]5[CH2:55][CH2:56][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:58][CH2:59]5)[CH2:52][CH2:53]4)=[CH:40][C:41]=3[O:45][CH2:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 67.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.1 g, 0.203 mmol), (5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amine (0.083 g, 0.203 mmol) and HCl (4N,1,4-Dioxane, 0.102 mL, 0.407 mmol) in Trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. LCMS analysis indicated that the starting materials had been consumed. The reaction was quenched with 7N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.119 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 9.27-9.38 (m, 1H), 8.40 (s, 1H), 8.28 (d, J=5.22 Hz, 1H), 8.13 (d, J=1.92 Hz, 1H), 7.80 (dd, J=8.39, 1.88 Hz, 1H), 7.72 (d, J=8.98 Hz, 1H), 7.58 (s, 1H), 7.35-7.51 (m, 2H), 7.29 (d, J=8.71 Hz, 1H), 7.14-7.25 (m, 2H), 6.88-6.98 (m, 1H), 6.81 (s, 1H), 6.60 (d, J=5.13 Hz, 1H), 4.06 (q, J=6.97 Hz, 2H), 4.00 (s, 3H), 3.07-3.15 (m, 4H), 2.98-3.06 (m, 2H), 2.87 (s, 3H), 2.60-2.74 (m, 6H), 2.52-2.59 (m, 2H), 2.36-2.46 (m, 1H), 1.80-1.87 (m, 2H), 1.50-1.67 (m, 2H), 1.26 (t, J=6.97 Hz, 3H), 1.09 (t, J=7.51 Hz, 3H). MS (M+H, ES+) 866.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Yield: 10.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (774 mg, 2.2 mmole) was added to the suspension of 5-chloro-3-piperidine-4-yl-1H-indole (516 mg, 2.2 mmole) in dioxane (20 ml). The reaction mixture was a suspension also at 100° C., and was boiled under reflux for 40 hours. To work up the suspension the existing precipitate was filtered off, washed with dioxane (1×1 ml) and diethyl ether (3×2 ml) and dried in vacuo. The isolated solid (183 mg, 17%, m.p. 140°-150° C.) was a still unpurified part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide, which was purified by flash chromatography on silica gel [20 g, eluent: methanol (500 ml)]. The mother liquor and the wash phases were concentrated by evaporation in vacuo. The residue contained in addition to phenol, also the two diastereoisomers of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol/EE (1:1; 900 ml) was used as eluent. The non-polar diastereoisomer (335 mg, m.p. 205°-207° C., 31%) and the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (115 mg, m.p. 140°-143° C., 11%) were thereby obtained as pale yellow solids.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH3:8]
Reactant: CCNC(=O)CCCCC(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCCCCC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A stirred suspension of LiAlH4 (2.65 g, 0.0697 mol) in THF (60 ml), under nitrogen, was cooled in an ice bath and treated during 20 minutes with a solution of the product from Step II (4.6 g, 0.0266 mol) in THF (60 ml). The mixture was warmed to ambient temperature during 30 minutes and then refluxed gently for 3.5 hours. It was again cooled in an ice bath and treated cautiously first with H2O (6 ml) and then with 2.5N NaOH (5.1 ml). This mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated and crystallized from hexane to give 2.63 g of ethyl(6-hydroxyheptyl)amine, mp 37°-38° C. The analytical sample had mp 39°-41° C. Anal. calc'd for C9H21NO: C, 67.87; H, 13.29; N, 8.80. Found: C, 67.69; H, 13.45; N, 8.81.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.Cl>C(O)C>[NH2:9][C:4]1[N:3]=[C:2]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(CO)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2ccc(CO)cc2)n1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (6.6 g, 40 mmol), 4-aminobenzyl alcohol (8.0 g, 65 mmol) and N,N-diisopropylethylamine (15 ml) in ethanol (200 ml) was heated under reflux for 72 hours. Concentration under reduced pressure provided a solid which was stirred with 1.0 M hydrochloric acid (200 ml) for 1 hour, filtered, dried under reduced pressure, stirred with ethyl acetate (200 ml) for 2 hours, filtered, and dissolved in methanol (300 ml). Aqueous sodium carbonate solution (1.0 M, 50 ml) was added. After stirring for 2 hours, volatiles were evaporated under reduced pressure and water (200 ml) was added. Filtration and drying provided [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.3 g, 63% yield) as a white powder.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:17]([CH2:19][C:20](OCC)=O)#N.ClC1C=CC=CC=1C=O.[N+](C(C)C)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:19]1([CH3:20])[CH3:17])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(C)[N+](=O)[O-]
Product: CCOC(=O)C1(C#N)C(c2ccccc2Cl)C1(C)C
Yield: 88 %

Procedure:
A mixture of 640 mg (2.7 mmoles) of (E)-ethyl 2-cyano-3-(o-chlorophenyl)-2-propenoate (6) (prepared from ethyl cyanoacetate and o-chlorobenzaldehyde using the procedure described in Example I for an analogous cyanoester), 0.25 mL (2.78 mmoles) of 2-nitropropane, 357 mg (2.6 mmoles) of anhydrous potassium carbonate, and 4.0 mL of absolute ethyl alcohol was heated at reflux for 3 hours. The product was isolated as described in the procedure of Example VIII, affording 664 mg (88% yield) of cyclopropanoid cyanoester 12, stereochemically homogeneous as shown by NMR analysis: δ3.22 (singlet, cyclopropyl H); bp: 122°-155° C. (bath temperature, 0.08 mm).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O>C(O)(=O)C.ClCCl.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([I:16])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Cl)c(-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-4′-fluorobiphenyl-3-ol (Preparation 104, 280 mg, 1.26 mmol) in acetic acid (2.5 mL), dichloromethane (2.5 mL) and concentrated sulfuric acid (25 μL) was added N-iodosuccinimide (272 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (60 mL) was added and the organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography eluting 33% dichloromethane in heptane to afford the title compound (306 mg, 70%) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH:24]=[CH2:25]>>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Product: C=CCOc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (100 mg, 0.45 mmol) and 3-bromoprop-1-ene (133 mg, 0.96 mmol) according to the general procedure IV to give 101 mg (70%) of a pale yellow oily product. Rf=0.55 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.45 (d, J=8.0 Hz, 2H), 7.24 (t, J=1.3 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.06 (t, J=1.9 Hz, 1H) 6.90 (dd, J=8.3 Hz, 2.5 Hz, 1H), 6.10-6.00 (m, 1H), 5.42 (dd, J=17.3 Hz, 1.5 Hz, 1H), 5.30 (dd, J=10.5 Hz, 1.3 Hz, 1H), 4.55 (dt, J=5.3 Hz, 1.3 Hz, 2H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.1, 158.3, 140.9, 133.0, 131.7, 129.4, 128.3, 124.3, 124.3, 121.1, 117.7, 117.2, 115.6, 89.1, 89.0, 68.8, 51.6, 35.4, 30.8; MALDI-MS m/z 343.4 (M+Na+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 95 °C
Yield: 14.9 %

Procedure:
3-Bromo-1-(tetrahydro-2-pyranyl)-1H-indazole-5-carbonitrile (1.00 g, 3.27 mmol), 2-benzofuranboronic acid (795 mg, 4.90 mmol), Pd(dppf)Cl2 CH2Cl2 (266 mg) and potassium phosphate (3.47 g, 16.35 mmol) in 1,2-dimethoxyethane (16.0 mL) was placed into a screw-top pressure tube and heated in a 95° C. oil bath for 21 h. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was separated, washed with satd. NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel with 30% ethyl acetate in hexane (R=0.49) to afford the desired product (167 mg, 15% yield) as a pale orange foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2([C@@H:19]3[CH2:23][CH2:22][N:21](CC4C=CC=CC=4)[CH2:20]3)[CH2:18][CH2:17]2)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:16]2([C@@H:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1([C@@H]2CCNC2)CC1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
(R)-4-{[1-(1-benzyl-pyrrolidin-3-yl)-cyclopropyl]-methyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in 150 mL glacial acetic acid at room temperature in a hydrogenation flask, air was evacuated, and filled with nitrogen. To this was added 30% Pd/C (5 g), flask was mounted to Parr shaker, nitrogen was evacuated and filled with hydrogen, and the mixture was shaken under hydrogen atmosphere at 60 psi in a Parr for 18 h. Reaction mixture was diluted with toluene (300 mL), filtered through a pad of celite. The filtrate was concentrated in vacuo, residue was digested in cold 30% NaOH at 0° C. and the product was extracted with ethyl acetate. The combined ethyl acetate solution was charged with 50 g of charcoal (Darco G-60), allowed to stir for 2 h, filtered, concentrated to give pale yellow oil, which can be vacuum distilled to give a clear oil (9.6 g). 1H NMR (400 MHz, CD3OD) δ 4.04 (br s, 1H), 3.01 (dd, J=10.4 Hz and 7.6 Hz, 1H), 2.84 (dd, J=8.0 Hz and 5.2 Hz, 2H), 2.64-2.55 (m, 3H), 2.48-2.43 (m, 2H), 2.30 (s, 3H), 2.28-2.23 (m, 1H), 2.23-1.74 (m, 3H), 1.40 (s, 9H), 1.35-1.28 (m, 2H), 1.18-1.12 (m, 2H), 0.53-0.45 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:48][CH3:49])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:48][CH3:49])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (229 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:9]([C:12]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[N:15][O:14][N:13]=2)=[N:10][OH:11])[O:5][CH:6]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:22](=[O:23])[O:11][N:10]=[C:9]2[C:12]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[N:15][O:14][N:13]=2)[O:5][CH:6]=1
Reactant: COCCNc1nonc1C(=NO)NCc1cc(Br)co1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Temperature: 65 °C
Yield: 52 %

Procedure:
N-[(4-Bromo-2-furyl)methyl]-N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (7.3 g, 20.4 mmol) and 1,1′-carbonyldiimidazole (5.0 g, 30.5 mmol) were dissolved in ethyl acetate (72 mL). The reaction mixture was heated at 65° C. for 15 minutes. Ethyl acetate (70 mL) was added and the crude reaction was washed with 0.1N hydrogen chloride in water (2×70 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes gave the desired product (4.1 g, 90%). LCMS calculated for C12H13BrN5O5 (M+H)+: m/z=386.0, 388.0. 1H NMR (400 MHz, CD3OD): δ 7.88 (s, 1 H), 6.67 (s, 1 H), 6.39 (t, J=5.7 Hz, 1 H), 5.07 (s, 2 H), 3.50 (m, 2 H), 3.41 (q, J=5.7 Hz, 2 H), 3.25 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[CH2:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[N:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O.CC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[CH2:23][CH:24]([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCN(C(=O)CC(=O)c4ccccc4)CC3)nc(N)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc2nc(N3CCN(C(=O)CC(O)c4ccccc4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3 g of the compound prepared in Example 13 in 50 ml MeOH a solution of 0.43 g of NaBH4 96% in 4 ml iced H2O containing 0.2 ml NaOH 30% is quickly added and the mixture is stirred at room temperature for 8 h. Thereafter 2 g (5×0.4) of NaBH4 are added in 8 h. The suspension is diluted with 10 ml acetone, treated with diluted HCl, neutralized with sodium bicarbonate in 5% solution and concentrated under vacuum. The aqueous suspension is diluted with H2O and extracted with CHCl3 ; the organic phase is washed with H2O, dried on anhydrous Na2SO4 and the residue, obtained by evaporation of the solvent, is purified by flash chromatography on SiO2 column eluting with CH2Cl2 /MeOH 100:5. The crude compound, obtained after pooling the pure fractions and evaporating the solvent, is crystallized from EtOH giving 2.34 g (79%) of the wanted compound; m.p.: 222° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3.74 mmol) and cerium(III) chloride heptahydrate (1.39 g, 3.74 mmol) in methanol (40 mL) was cooled to −78° C. and sodium borohydride (141 mg, 3.74 mmol) was added in 4 portions. The mixture was warmed up to −20° C. and stirred for 30 min. Water was added and the mixture was concentrated in vacuo. The aqueous layer was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated to give 883 mg (88%) of 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[NH4+].CCCCCCCC[N:16](CCCCCCCC)CCCCCCCC.C(O)CCCCCCCCCCC>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[NH4+:16].[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: CC(O)C(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCCCCCCCCO
Product: CC(O)C(=O)O
Temperature: 160 °C

Procedure:
The procedure described in Example 1 was followed except that the reaction solution consisted of 10 g of a 70% solution of ammonium lactate, 45 g tricaprylamine, and 5 g dodecanol. The reaction mixture was heated for 2 hours at 160° C. and atmospheric pressure, resulting in a conversion of about 98% from ammonium lactate to lactic acid. Some of the dodecanol also reacted with lactic acid to form an ester. The conversion from ammonium lactate to lactic acid plus lactic acid ester was about 99%.
Reaction SMILES: Cl.CO[C:4](=[O:8])[CH2:5][NH:6][CH3:7].[C:9]([C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:44])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[C:34]4C(=O)OC(C)(C)[O:36][C:35]4=O)[OH:33])[CH:27]=3)[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH2:47][CH2:48][CH3:49])[C:13]=1[OH:50])(=[O:11])[CH3:10].C(N(CC)CC)C.[OH-].[K+]>C1(C)C=CC=CC=1.O.CO.O>[C:9]([C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:44])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:33])=[C:34]4[C:4](=[O:8])[CH2:5][N:6]([CH3:7])[C:35]4=[O:36])[CH:27]=3)[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH2:47][CH2:48][CH3:49])[C:13]=1[OH:50])(=[O:11])[CH3:10]
Reactant: CNCC(=O)OC
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(O)=C4C(=O)OC(C)(C)OC4=O)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(O)=C4C(=O)CN(C)C4=O)c3)c2)ccc(C(C)=O)c1O
Yield: 8.2 %

Procedure:
Add sarcosine methyl ester hydrochloride (0.156 g, 1.12 mmol) to a solution of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-hydroxy-methyl]-benzamide (0.641 g, 1.12 mmol) in toluene (0.2M). Add triethylamine (0.226 g, 2.23 mmol) and heat the solution at reflux for 24 h. Evaporate solvents and add potassium hydroxide (10 mmol) in 1:1 methanol/water (0.2M). Stir the reaction for 24 h. Precipitate product by diluting reaction mixture with water. Filter to afford the title compound (0.050 g, 0.092 mmol, 8%): 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.0 Hz, 3H), 1.50 (q, J=9.8 Hz, 2H), 2.57 (s, 3H), 2.61 (t, J=7.2 Hz, 2H), 2.81 (s, 1H), 3.31 (m, 3H), 4.03 (s, 4H)(?), 5.25 (s, 2H), 6.72 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.46 (m, 1H), 7.68 (s, 2H), 7.80 (d, J=9.0 Hz, 1H), 7.95 (s, 2H), 8.05 (s, 1H), 10.31 (s, 1H), 12.84 (s, 1H). MS (m/z): 541 (M−1).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].Br[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19]>[O-2].[Zn+2].ClC(Cl)C>[CH2:16]([O:20][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCO
Reactant: BrCc1cccc2ccccc12
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: CC(Cl)Cl
Product: CC#CCOCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask equipped with magnetic stirrer, condenser and drying tube filled with calcium chloride, bromomethylnaphthalene (1.0 g, 4.52 mmol), 2-butyn-1-ol (0.63 g, 9 mmol) and 10 ml of dichloroethane are placed. After the addition of zinc(II) oxide (4.0 g, 4.52 mmol) the suspension is stirred for 1 hour at room temperature, then it is refluxed for 1 hour. The reaction is accompanied by a characteristic change of colour. The mixture is then filtered, the filtrate is evaporated. The residual oil is dissolved in 15 ml of ether, washed with 2×50 ml of water, dried and evaporated. The product is purified by coloumn chromatography. Purity (GC) 95%. IR (CHCl3, cm−1) υ: 3044, 3001, 2945, 2920, 2854, 1598, 1509, 1356, 1166, 1086, 1067; 1H-NMR (400 MHz, CDCl3) δ: 1.93 (3H, t, J=2.3 Hz, C≡C—CH3), 4.22 (2H, q, J=2.1 Hz, O—CH2—C≡C), 5.06 (2H, s, C10H7—CH2—O), 7.45 (1H, t, J=8 Hz), 7.53 (3H, m), 7.84 (1H, d, J=8.1 Hz), 7.88 (3H, m), 7.88 (1H, d, J=7.7 Hz), 8.19 (1H, d, J=8.2 Hz); 13C-NMR (100 MHz, CDCl3) δ: 3.6 (C≡C—CH3), 57.71 (O—CH2—C≡C), 69.72 C10H7—CH2—O), 75.10 (O—CH2—C≡C), 82.76 (O—CH2—C≡C), 124.03, 125.10, 125.72, 126.19, 126.85, 128.43, 128.72, 131.79 (C-8a), 133.06, 133.70.