Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:44][CH2:45]4)=[O:42])[N:39]=3)[N:36]=2)[CH:28]=1)=[O:6]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1Cl
Yield: 66.6 %

Procedure:
Using 2-chloro-3-(trifluoromethyl)benzoic acid (88 mg, 0.39 mmol), oxalyl chloride (42 μL, 0.49 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol) and N-methylpyrrolidone (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 68%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)#[CH:2].Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[CH:19][CH:18]=1.[Al]>C(N(CC)CC)C.C(OCC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:25][CH:24]([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([F:15])=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:8]=2)=[CH:18][CH:19]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: C#Cc1ccc(F)c(N2CCOCC2)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(C#Cc2ccc(OC(F)F)cc2)cc1N1CCOCC1
Yield: 96 %

Procedure:
In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane was dissolved 4-(5-ethynyl-2-fluorophenyl)morpholine (540 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (54 mg, 0.283 mmol) and Tetrakis(triphenylphosphine) palladium (105 mg, 0.091 mmol) were added. Lastly 1-bromo-4-(difluoromethoxy)benzene (0.750 g, 3.36 mmol) was added, the vial was covered with a teflon septa, an aluminum cap was crimped in place, and the assembly was set on a Biotage Emrys microwave instrument to irradiate at 80° C. for 30 minutes. The crude reaction was diluted with diethylether, washed with saturated ammonium chloride, and purified via column chromatography on a Yamazen W-Prep 2XY using 25% EtOAc in hexanes. Concentration by rotary evaporation afforded 500 mg of oil (96%); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.03 (t, J=4.6 Hz, 4H) 3.73 (t, J=4.6 Hz, 4H) 7.13-7.14 (m, 1H) 7.16 (d, J=2.6 Hz, 1H) 7.17-7.19 (m, 2H) 7.22 (d, J=8.8 Hz, 2H) 7.24 (t, J=73.8 Hz, 1H) 7.60 (d, J=8.8 Hz, 2H); MS (ES) m/z 348.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid is dissolved in 5 ml. of acetic acid. 1 ml. of concentrated hydrochloric acid is added and the mixture is allowed to stand for 2 hours at 20° and poured onto ice. After the customary work up, 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid, m.p. 193-195°, is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][S:18][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:8]=[C:3]([C:1]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:2]=2)[N:4]=1
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Yield: 56.9 %

Procedure:
tert-Butyl 3-[2-cyano-6-(methylthio)-4-pyridyl]propanoate (0.70 g, 2.50 mmol) and methyl thiosalicylate (0.84 g, 5.00 mmol) were dissolved in toluene (50 ml), and triethylamine (1.40 ml, 10.0 mmol) was added thereto. The reaction mixture was refluxed for 18 hrs, and the solvent was evaporated. The residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.59 g, 57%) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24](Br)=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12].C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C>C(#N)C.[Cu]I>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24]([C:45]#[CH:46])=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccc(Br)o2)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1ccc(C(=O)Nc2cc(C(=O)NCCCN3CCCC3=O)ccc2N2CCN(c3ccccc3C)CC2)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 14.1 %

Procedure:
In a 20 mL scintillation vial, 5-bromo-furan-2-carboxylic acid [5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.1 g, 0.231 mmol) was taken in acetonitrile (5.0 mL). Trimethylsilyl acetylene (0.045 g, 0.462 mmol), CuI (0.009 g, 0.046 mmol), triethylamine (0.116 g, 1.155 mmol) and PdCl2(Ph3P) (0.032 g, 0.046 mmol) were added to this, and the solution was evacuated for 5 min and nitrogen purged and stirred at 80° C. for 4 h. LC-MS indicated the completion of the reaction. It was diluted with acetonitrile and filtered through celite and concentrated. The crude was dissolved in THF and stirred with TBAF (2.0 mL of 2 M solution in THF) at room temperature for 16 h. The reaction was concentrated and dissolved in methanol and purified on preparative HPLC using methanol/water as eluent to give the desired product (0.018 g, 14% yield).
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[F:21][C:22]1([F:26])[CH2:25][N:24]([CH:2]2[CH2:19][CH2:18][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CC(F)(F)C3)CC2)CC1
Reaction time: 0.08 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine-F43) (1 g, 3.74 mmol) was added to 3,3-difluoroazetidine hydrochloride (0.484 g, 3.74 mmol) and triethylamine (0.52 ml, 3.74 mmol) in 1,2-dichloroethane (15 ml). The mixture was stirred for 5 min, and then sodium triacetoxyborohydride (1.1 g, 5.23 mmol) was added and stirring was carried out for 3 d at room temperature. Saturated sodium hydrogen carbonate solution was added and, after phase separation, the aqueous phase was extracted with dichloromethane (2×). The combined organic phases were washed with saturated sodium chloride solution (1×), dried over magnesium sulfate and concentrated under vacuum. Yield: 1.26 g (98%)
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH2:14][C@@H:15]([OH:18])[CH:16]=[O:17])=[N+:12]=[N-:13].[OH-].[Na+]>C(O)C(N)(CO)CO>[N:11]([CH2:14][C@@H:15]([OH:18])[C@H:16]([OH:17])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NC[C@@H](O)C=O
Reactant: O=C(CO)COP(=O)(O)O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Product: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of (R)-3-azido-2-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added fuculose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for 1 hour at 35° C., to form a mixture and the mixture stirred slowly for 2 days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MEOH and filtered to remove the insoluble material. The MEOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 6-azido-6-deoxy-D-xylo-hexulose in 30% yield.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[S:21](O)=O)=[CH:6][CH:5]=1.[N+](C1C(SC2C=CC=CC=2)=C(S(O)=O)C=C(C=1)C(O)=O)([O-])=O>>[NH2:18][C:17]1[C:9]([O:8][C:7]2[CH:24]=[CH:25][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)=[C:10]([SH:21])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)O)cc1
Agent: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccccc2)c(S(=O)O)c1
Agent: [Na]
Product: COc1ccc(Oc2c(N)cc(C(=O)O)cc2S)cc1

Procedure:
By replacing mono sodium salt of 4-(p-methoxyphenoxy)-5-nitro-3-sulfinobenzoic acid (12 g) for the momo sodium salt of 5-nitro-4-phenylthio-3-sulfinobenzoic acid (11 g) in Example 11B, 5-amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid is obtained with a melting point of 182° - 184°C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([O:39][C:40]([CH:42]1[CH2:49][C:45]2([CH2:48][CH2:47][CH2:46]2)[O:44][NH:43]1)=[O:41])[CH3:38].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:37]([O:39][C:40]([CH:42]1[CH2:49][C:45]2([CH2:46][CH2:47][CH2:48]2)[O:44][N:43]1[C:7](=[O:9])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])=[O:41])[CH3:38]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CCOC(=O)C1CC2(CCC2)ON1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC2(CCC2)ON1C(=O)C(NC(=O)OC)C(C)C
Temperature: 60 °C
Yield: 72.2 %

Procedure:
To a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (1.11 g, 6.33 mmol) and HATU (2.41 g, 6.34 mmol) in dimethylformamide (13 mL) was added a solution of 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (980 mg, 5.3 mmol) in dimethylformamide (13 mL). To the resulting reaction mixture was added diisopropylethylamine (1.85 mL, 10.6 mmol) and the reaction was heated to 60° C. for 16 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by flash chromatography to give 6-(2-methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (1.31 g, 72%). LCMS-ESI+: calculated for C16H26N2O6: 342.18; observed [M+1]+: 342.90.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)OCO2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
About 600 ml of 1.5M methyllithium (solution in ether) was added to 500 ml of tetrahydrofuran. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added thereto under cooling at -20° C. The mixture was stirred under these conditions for 1 h. Water was added to the reaction mixture. The product was extracted with ethyl acetate, washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 97 g of the intended compound in the form of an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[S:10][C:9]([CH:11]([N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH3:12])=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Product: CC(c1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica yielded 300. NMR: (CDCl3): 1.44 (3 H, d, J 7.1, Me), 2.52-2.64 (4 H, m, CH2), 2.73 (3 H, s, Me), 3.21-3.23 (4 H, m, CH2), 3.80-3.83 (4 H, m, CH2), 3.94-4.06 (5 H, m), 5.16 (2 H, s, NH2) and 9.20 (2 H, s, Ar). MS: (ESI+): MH+=505.20
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([OH:37])[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.[N:39]1([CH2:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]([CH3:38])([O:37][C:48]3[CH:47]=[CH:46][C:45]([CH2:44][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:50][CH:49]=3)[CH3:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: CC(C)(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
131 mg (0.5 mmol) triphenylphosphane are added to a solution of 136 mg (0.5 mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-yl]-2-methyl-but-3-yn-2-ol and 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 20 ml THF. Then 0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCc1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
4-Phenyl-butanoic acid (0.83 moles, 13.57 g) is added to thionyl chloride (0.114 moles, 8.27 ml) and warmed to dissolve the solid. The mixture is stirred for 30' at r.t., then refluxed for 10', finally recovered as in example 3a). A 100% yield is obtained (0.083 moles, 15.09 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:28]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(N3CCOCC3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-Morpholin-4-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:20])[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:4]>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6](=[O:20])[CH:7]([C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9])[CH2:7][C:8](=[O:9])[C:10]1[CH:19]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:4]
Reactant: CCOC(=O)CC(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A suspension of NaH (60% in mineral oil, 323 mg, 8.07 mmol) in toluene (20 mL) was treated with 3-Naphthalen-1-yl-3-oxo-propionic acid ethyl ester (1.63 g, 6.7 mmol). The resulting suspension was stirred at rt under Ar for 1 h, then treated with 2-bromocetophenone (1.61 g, 8.07 mmol). The suspension was immersed in a 70° C. oil bath and stirred under Ar for 4 h, cooled to rt, diluted with toluene and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (SiO2, 10-20% EtOAc/Heptane) to afford 2-(Naphthalene-1-carbonyl)-4-oxo-4-phenyl-butyric acid ethyl ester (1.2 g) contaminated with a small amount of unidentified aromatic impurity: 11H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.03 (t, 3H, J=7.25 Hz), 3.72 (dd, 1H, J=18.8 Hz, J=5.4 Hz), 3.96 (dd, 1H, J=18.8 Hz, J=8.05 Hz), 4.09 (m, 2H), 5.16 (m, 1H), 7.45-7.63 (m, 6H), 7.88 (d, 1H, J=7.9 Hz), 8.0-8.07 (m, 3H), 8.24 (d, 1H, J=7.2 Hz)), 8,48 (d, 1H, J=8.7 Hz).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1.O>CCO>[NH2:3][C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nn(-c2ncccn2)cc1C(=O)O
Temperature: 50 °C

Procedure:
A 1 N aqueous sodium hydroxide solution (3.0 mL) is added to a suspension of ethyl 3-amino-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (500 mg, 2.14 mmol) in 6.0 mL of EtOH. The reaction mixture is heated to 50° C. for 16 h. After cooling to RT, water is added, and the mixture is extracted with EtOAc (3×20 mL). The aqueous layer is cooled to 0° C. and acidified to pH=2 with conc. HCl. The precipitated solid is collected by vacuum filtration and dried in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:15])[CH3:16])=[C:11]([Cl:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester (0.74 g, 2.65 mmol) from step 3 above was added ethanol (10 mL) and Pd(OH)2/C (0.37 g). The reaction was placed under a hydrogen atmosphere using a balloon filled with hydrogen. The slurry was stirred vigorously for 1 hour. The reaction was filtered to remove all of the solids, and the liquid was concentrated to an white solid which was used in next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=7.7 Hz, 3 H), 1.85 (s, 6 H), 2.62-2.66 (m, 2 H), 2.92-2.98 (m, 2H), 4.15 (q, J=14, 7.7 Hz, 2 H), 7.61 (d, J=2 Hz, 1 H), 8.3 (d, J=2 Hz, 1 H). ESIMS (MH+): 289.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([NH:27][CH2:28][CH2:29][OH:30])[N:19]=2)[CH2:14][CH2:13]1>ClCCl>[C:1]([O:30][CH2:29][CH2:28][NH:27][C:20]1[N:19]=[C:18]([N:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCc1nc(NCCO)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(NCCOC(C)=O)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
4.3 g (0.055 mole) of acetyl chloride, dissolved in 50 ml of dichloromethane, and 5.5 g (0.055 mole) of triethylamine, dissolved in 50 ml of dichloromethane, are simultaneously introduced, between 0° and 5° C., into a solution of 13.4 g (0.05 mole) of 2-[(4-morpholino-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol (compound 1) in 200 ml of dichloromethane. The addition of these two reagents is regulated in a manner such that the acid chloride is always present in the reaction mixture in excess with respect to the triethylamine. The mixture is stirred for one hour at 5° C. and then for 12 hours at room temperature. The reaction mixture is washed successively with an aqueous solution of sodium bicarbonate and with water. It is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue crystallizes in a mixture of toluene-hexane 1:2. The product obtained is first purified by chromatography on silica (eluent: 95:5 (v/v) dichloromethane-ethanol) and is then finally recrystallized from a mixture of toluene-hexane 1:1. 9.3 g of 2-[[2-(acetoxy)ethyl]amino]-4-morpholino-6-propyl-1,3,5-triazine are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][CH:14]3[C:22]4[C:17](=[C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>CO>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][C@@H:14]3[C:22]4[C:17](=[C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(Nc1cccc2[nH]ncc12)NC1CCc2c1cccc2N1CCCCC1
Agent: Cl
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)N[C@H]1CCc2c1cccc2N1CCCCC1

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound 1-(1H-Indazol-4-yl)-3-(4-piperidin-1-yl-indan-1-yl)-urea (Ex. 56E) using a chiral column ChiralCel OD. [α]D: −98.5° (HCl salt, c: 1.02, MeOH). MS (ESI) m/z: 376.00 [M+H]+. 1H NMR (DMSO-d6) δ: 1.56 (m, 2H), 1.65 (m, 4H), 1.78 (m, 1H), 2.44 (m, 1H), 2.77 (m, 1H), 2.85 (m, 3H), 2.95 (m, 2H), 5.16 (q, 1H), 6.66 (d, 1H), 6.81 (d, 1H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (m, 2H), 7.68 (d, 1H), 8.05 (s, 1H), 8.62 (s, 1H), 13.00 (s, 1H). Anal Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.18; H, 6.93; N, 18.42.