Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C1COCC1.CC(O)C.O>[CH3:9][NH:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:7]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a room temperature solution of 0.943 g (5 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 25 mL THF is added a solution of 1.96 g (11 mmol) of 4-(4-aminophenyl)morpholine in 100 mL of 2-propanol, and the resulting mixture is heated and stirred at 50° C. for 30 minutes. The mixture is then diluted with water, the solid precipitate is collected, washed with water, and dried, to give 1.62 g (98%) of the title compound: mp (EtOH) 240–241° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.[OH-:15].[Na+].C(O)(=[O:19])C>>[F:12][C:2]([F:11])([F:1])[S:3]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)(=[O:19])=[O:15]
Reactant: [OH-]
Reactant: CC(=O)O
Reactant: Oc1ccc(SC(F)(F)F)cc1
Agent: OO
Agent: [Na+]
Product: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Temperature: 65 °C

Procedure:
A mixture of 4-[(trifluoromethyl)thio]phenol (4.5 g, 23.2 mmol), Na2WO4.2H2O (0.08 g, 0.24 mmol) and hydrogen peroxide (6 ml, 59 mmol) in acetic acid (25 ml) was heated at 65° C. for overnight. Na2S2O5 (sat.) and NaOH (20%) was added (until pH 8) and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to dryness to give the crude title compound (6.0 g). MS m/z (rel. intensity, 70 eV) 226 (M+, 18), 157 (bp), 109 (14), 93 (52), 65 (53).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.Cl[CH2:31][C:32](=O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]2[S:21][CH:31]=[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:22]=2)=[CH:17][CH:18]=1
Reactant: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.5 g (0.0037 mol) of the compound from Example III and 1.5 ml=1.83 g (0.011 mol) of ethyl chloroacetoacetate were heated together with 30 ml of toluene and 10 ml of water at 100° C. for 1 hour. The mixture was neutralised with 10% strength sodium bicarbonate solution, the organic phase was separated off, dried with sodium sulphate and concentrated to a small volume in vacuo, and the residue was separated by column chromatography. A yellow oil was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C)C1C=CC=CC=1>CO.O.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNCCNC(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 93.6 %

Procedure:
To a flask was added 20% Pd(OH)2 on carbon (3.1 g), compound B (3.3 g, 12.5 mmol) in MeOH (200 mL) and water (10 mL), while being exposed to H2 (40 psi). After 2.5 h, the reaction mixture was filtered through celite and concentrated in vacuo. Water was then added (50 mL) and the mixture brought to pH 12 (by addition of 1 N NaOH) and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give compound C (2.0 g, 11.7 mmol, 94%) as a colorless oil. LC-MS [M+H] 686.5 (C35H51N5O7S+H, calc: 685.9). Compound C was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(C#N)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=386.2 [M+H]+.
Reaction SMILES: C(NC(=O)O[CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:20]([NH:23][C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)(=[O:22])=[O:21])[CH2:14][CH2:13]1)C1C=CC=CC=1.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:56]=[C:57]=[O:58])[CH:53]=[CH:54][CH:55]=1.C(N=C=[O:68])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(N(CC)CC)C>[CH3:48][O:49][C:50]1[CH:51]=[C:52]([NH:56][C:57](=[O:68])[O:58][CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:20]([NH:23][C:24](=[O:39])[C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=3)(=[O:21])=[O:22])[CH2:14][CH2:13]2)[CH:53]=[CH:54][CH:55]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(NCc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: COc1cccc(N=C=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)OCC2CCC(CN(Cc3ccccc3)S(=O)(=O)NC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c1

Procedure:
Following procedure to make (9), 3-methoxyphenyl isocyanate was substituted for benzyl isocyanate and diisopropylethylamine substituted for triethylamine to give the title compound after purification. 1H NMR (500 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.45 (s, 2H), 8.10 (s, 1H), 7.38 (d, 2H), 7.24 (t, 2H), 7.14 (m, 3H), 6.96 (d, 1H), 6.52 (d, 1H), 4.35 (s, 2H), 3.75 (d, 2H), 3.68 (s, 3H), 3.30 (water), 2.89 (d, 2H), 2.48 (DMSO), 1.63 (m, 4H), 1.42 (m, 1H), 1.29 (m, 1H), 0.66 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14]O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][Cl:19])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCCl
Yield: 88 %

Procedure:
A mixture of 23 parts of 7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione, 32 parts of thionyl chloride and 150 parts of trichloromethane is stirred and refluxed for 4 hours. The reaction mixture is cooled. The precipitated product is filtered off, washed with trichloromethane and with petroleumether, and dried, yielding 22 parts (88%) of 7-chloro-3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[CH3:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[CH3:19]N(C=O)C.CC(N(C)C)=O>>[Br:1][C:2]1[C:3]([CH2:13][CH3:19])=[CH:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[CH:8]=[CH:9][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1c([N+](=O)[O-])ccc(C)c1Br
Reactant: C1CCNC1
Reactant: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Br

Procedure:
The product of Step 2 (13 g, 53 mmol) and pyrrolidine (2.3 mL) in DMF/DMA (150 ml) were heated at reflux overnight. The mixture was cooled and then concentrated to give the crude title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@@H:16]([NH:19]C(=O)C(F)(F)F)[CH2:17][CH3:18].O1CCCC1.CO.[OH-].[Na+]>ClCCl>[NH2:19][C@@H:16]([CH2:17][CH3:18])[C:15]([NH:14][CH2:13][CH2:12][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:26]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](N)C(=O)NCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 20 mL cintillation vial was charged with N-(3-(1-methyl-1H-indol-2-yl)propyl)-2-(S)-(2,2,2-trifluoro-acetylamino)butanamide (57.0 mg, 0.154 mmol), tetrahydrofuran (0.77 mL), and methanol (0.20 mL). 3N Sodium hydroxide (0.15 mL, 0.450 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The resulting mixture was then diluted with dichloromethane and extracted with 1 N HCl. The aqueous layer was neutralized to pH 8 and extracted with dichlormethane. The organic layer was dried with MgSO4, filter, and concentrate in vacuo. The resulting solid was taken up in water and lyophilized to yield (S)-2-amino-N-(3-(1-methyl-1H-indol-2-yl)propyl)butanamide. 1H NMR (300 MHz, CD3OD) δ 7.42 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.05-7.11 (m, 1H), 6.94-7.02 (m, 1H), 6.23 (s, 1H), 3.60-3.75 (m, 4H), 3.31-3.46 (m, 2H), 2.69-2.86 (m, 2H), 1.91-2.03 (m, 2H), 1.71-1.89 (m, 2H), and 1.02 (t, J=7.4 Hz, 3H); MS (ES+) 274 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1)=[O:4].[BH4-].[Na+].Cl>CO>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:16])(=[O:17])[N:13]([CH3:14])[CH3:15])[CH:6]=1)[OH:4]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc(C(O)CBr)ccc1Cl

Procedure:
To a solution of 6.4 g of 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone in 28 ml of methanol were added dropwise, at a reaction temperature of 5° C., a solution of 0.6 g of sodium borohydride in 5 ml of methanol and the solution was then stirred for 1 hour at room temperature. The reaction mixture was acidified while cooling (+5° C.) with 2 N HCl and the solvent was distilled off under reduced pressure. After adding 70 ml of water, extraction followed with 200 ml of diethyl ether, the organic phase was dried over sodium sulfate, the solvent was distilled off and 2-bromo-1-(4-chloro-3-dimethylsulfamoylphenyl)-ethanol was obtained as fair yellow to colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[H-].[Na+].BrC[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C1COCC1>[C:37]([O:36][C:34](=[O:35])[CH2:33][NH:28][C:25]1[CH:26]=[CH:27][C:20]2[O:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][N:12]=4)[S:23][C:22]=3[C:21]=2[N:24]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 0 °C
Yield: 88 %

Procedure:
Compound 134 (800 mg, 2.0 mmol) was dissolved in THF (20 mL). It was stirred at 0° C. and NaH (58 mg, 2.4 mmol) was added. Then the mixture was warmed to r.t. and stirred for further 0.5 h. The mixture was cooled to 0° C. and tert-butyl 3-bromopropanoate (502 mg, 2.4 mmol) was added. Later, it was warmed to 80° C. for 2 h. The reaction mixture was filtered to gather the solution. Then water was added into the solution. It was extracted by DCM (20 mL×3). The combined organics were dried over Na2SO4, concentrated in vacuo, and separated by prep TLC (DCM) to give {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-acetic acid tert-butyl ester (900 mg, yield: 90%)1HNMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 7.45-7.52 (m, 1H), 7.42 (s, 1H), 7.06-6.93 (m, 4H). 4.25-4.15 (m, 2H), 4.08-3.99 (m, 2H), 3.06 (s, 2H), 1.38 (s, 9H). LC-MS (ESI): m/z=512 [M+H]+
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](N(OC)C)=[O:19])[CH2:14][CH2:13]1)=[O:11].[CH3:43][Li].Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1([F:42])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:19])[CH3:43])[CH2:16][CH2:17]1)=[O:11]
Reactant: [Li]C
Reactant: CON(C)C(=O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
To a solution of 140 mg of (Z)-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-N-methoxy-N-methylcarboxamide in 10 ml of tetrahydrofuran was added 280 μl of a solution of 1.05N methyl lithium in diethyl ether at −30° C. This was stirred at −30° C. for three hours together while adding 200 μl of the above-mentioned methyl lithium solution thereto every 40 minutes. To the reaction solution was added 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) to give 20 mg of (Z)-4,4-difluoro-5-[2-(4-acetylpiperidino)-2-oxoethylidene]-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine as a yellow amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17](O)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:45][C:46]1[C:50]([CH:51]([NH2:53])[CH3:52])=[C:49]([CH3:54])[NH:48][N:47]=1>CN(C=O)C>[CH3:45][C:46]1[C:50]([C@@H:51]([NH:53][C:17](=[O:18])[CH2:16][O:15][C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:5]3=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[CH3:52])=[C:49]([CH3:54])[NH:48][N:47]=1
Reactant: Cc1n[nH]c(C)c1C(C)N
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1[C@H](C)NC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Reaction time: 8 h
Yield: 9.1 %

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (1.35 g, 3.843 mmol), DIC (727 mg, 5.769 mmol) and HOBt (674 mg, 4.996 mmol) in DMF (15 ml) was stirred at rt for 15 min. 1-(3,5-dimethyl-1H-pyrazole-4-yl)ethanamine (642 mg, 4.612 mmol) was added to the solution at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water was added to the reaction mixture and the mixture was stirred for 10 min. The precipitate was collected by filtration and dried under vacuum. The racemic mixture was subjected to chiral preparative chromatographic separation to yield the enantiomeric pure title compound (165 mg) and the R enantiomer (165 mg, see example 1.62). [1H-NMR (CDCl3, 300 MHz) δ 7.62-7.48 (m, 5H), 6.99 (s, 1H), 6.55 (d, 1H), 5.33-4.92 (m, 3H), 4.1 (s, 3H), 2.25 (s, 6H), 1.55 (d, 3H); HPLC RtE=6.194 min. (98%); LCMS RtA=1.382, [M+H]+=473.1; Mp=145-147° C.]
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[Br:11][C:12](Br)([F:14])[F:13]>CN1C(=O)CCC1>[Br:3][C:4]1[C:9]([O:10][C:12]([Br:11])([F:14])[F:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: FC(F)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: FC(F)(Br)Oc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a suspension of sodium hydride (1.72 g, 43.1 mmol) in NMP (50 mL) was added a solution of 2-bromo-3-hydroxypyridine (5 g, 28.74 mmol) in NMP (50 mL). This mixture was stirred at room temperature for 30 minutes followed by heating at 50° C. for 45 minutes before cooling to room temperature. Dibromodifluoromethane (3.15 mL, 34.5 mmol) was slowly added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was slowly quenched into saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (3×100 mL), brine (2×100 mL), dried over MgSO4 and concentrated in vacuo to afford a brown gum. This residue was purified using silica gel column chromatography eluting with 70/30 Heptane/EtOAc to give the title compound as a colourless oil (1.2 g, 14%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15](C)=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:22]([C:24]1[C:29]2[CH:30]=[C:31]([C:33]([O:35]CC)=[O:34])[O:32][C:28]=2[C:27]([O:38][CH3:39])=[CH:26][CH:25]=1)=[O:23]>C1COCC1.CCCCCC>[Cl:20][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:1][C:22]([C:24]1[C:29]2[CH:30]=[C:31]([C:33]([OH:35])=[O:34])[O:32][C:28]=2[C:27]([O:38][CH3:39])=[CH:26][CH:25]=1)=[O:23]
Reactant: CCOC(=O)c1cc2c(C=O)ccc(OC)c2o1
Reactant: Cc1ncc(Cl)cc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 87 %

Procedure:
N,N-Diisopropylamine (8.5 ml) was dissolved in anhydrous THF (150 ml), n-butyl lithium (a 1.65 mol/l solution in hexane, 32 ml) was dropwise added thereto at −78° C. in an argon atmosphere, and the mixture was stirred for 5 minutes. The mixture was stirred at room temperature for 3 minutes and then cooled again to −78° C., 3,5-dichloropicoline (7.2 g) was added thereto, and the mixture was stirred for 30 minutes, which was dropwise added at −78° C. over 1 hour in an argon atmosphere to a solution in anhydrous THF (500 ml) of ethyl 4-formyl-7-methoxybenzofuran-2-carboxylate (10 g) obtained in step 1 of Reference Example 1. The mixture was stirred at −78° C. for 2.5 hours and returned to room temperature, and the reaction was quenched by adding water. The reaction mixture was diluted with ethyl acetate, which was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was suspended in isopropanol and the precipitated crystals were collected by filtration to give the desired compound (14.3 g, 87%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH3:13].O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:13])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: N
Reactant: Clc1ccnc2cc(Br)cnc12
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccnc2cc(Br)cnc12
Temperature: 160 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
In a sealed reactor, 500 mg (2.04 mmol, 1 eq) of 7-bromo-4-chloro-1,5-naphthyridine (G. B. Barlin et al. Aust. J. Chem. 1985, 38, 459-465) and 12 mL (71.3 mmol, 35 eq) of 20% aqueous ammonia solution were introduced in 12 mL of dioxane. The mixture was stirred at 160° C. for 24 h. The mixture was allowed to reach rt and water was added. Aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 350 mg of white powder with 76% yield.
Reaction SMILES: CS[C:3](=[N:12][C:13]#[N:14])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>N1C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:5]([NH:4][C:3]([NH:12][C:13]#[N:14])=[N:24][CH2:23][CH2:22][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[N:7][CH:8]=1
Reactant: CSC(=NC#N)Nc1cncc(Br)c1
Reactant: NCCSc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CNC(=NCCSc1ccccc1)Nc1cncc(Br)c1

Procedure:
S-Methyl N-(5-bromo-3-pyridyl)-N'-cyanoisothiourea (650 mg) and 2-phenylthioethylamine (740 mg) in pyridine (0.5 ml) were heated to 50° C. for 5 hours. To the resulting clear solution was added ether (10 ml), and the desired pure compound was collected by filtration and washed with ether.
Reaction SMILES: [CH2:1]1C2NC(=CC=2)CC2NC(=CC=2)CC2NC(=CC=2)CC2NC1=CC=2.[C:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])[CH3:26].Cl>CO>[CH3:1][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)CCCC(=O)O
Reactant: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Agent: Cl
Solvent: CO
Product: COC(=O)CCCC(C)=O
Yield: 84 %

Procedure:
Calix[4]pyrrole meso-monoester 3. 4-Acetylbutyric acid (3.8 g, 29 mmol) was dissolved in methanol (50 mL) in a 100 mL round bottomed flask with magnetic stirring. Concentrated hydrochloric acid (1 mL, 37%) was added and the mixture heated at reflux for 12 hr. The solvent was then removed in vacuo and the residue redissolved in dichloromethane (50 mL). The solution was then washed with saturated NaHCO3 (aq) solution (2×50 mL) and then brine (1×100 mL). The organic layer was separated and then dried over MgSO4 and reduced in vacuo to give the methyl ester, methyl-4-acetylbutyrate, as a yellow oil (3.5 g, 24.3 mmol) corresponding to a yield of 84%. 1H NMR (CDCl3) 3.64 (s, 3, OCH3), 2.49 (t, J=7.2 Hz, 2, CH2), 2.32 (t, J=7.2 Hz, 2, CH2), 2.12 (s, 3, CH3), 1.86 (m, 2, CH2). 13C NMR (CDCl3) 207.0, 172.8, 50.7, 41.7, 32.3, 29.1, 18.25. Cl MS m/z @145 (MH+)
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]#[C:14][C:15](OCC)=[O:16])[CH3:10]>CO>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([OH:16])[C:4]2[C:3](=[CH:2][C:1]([CH3:8])=[CH:6][CH:5]=2)[N:7]=1)=[O:20])[CH3:10]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1cccc(N)c1
Solvent: CO
Product: CCOC(=O)c1cc(O)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.5 g of m-Tolylamine in 130 ml of methanol, 24.6 g of but-2-ynedioic acid diethyl ester was added drop-wise over 30 min at 0° C. and stirred for 3 h at RT. Then, the solvents were removed under reduced pressure and the residue was dissolved in 70 ml of Dowtherm® and heated to 250° C. for 2 h. Then, the reaction mixture was allowed to cool to RT and 300 ml of n-heptane was added to precipitate the crude product, which was collected by filtration. The title compound was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.7 g.