Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(OCC)C.[Li]CCCC.[CH:16]([C:18]1[N:23]2[CH:24]=[N:25][N:26]=[C:22]2[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:20][CH:19]=1)=[O:17]>C(Cl)Cl>[OH:17][CH:16]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:18]1[N:23]2[CH:24]=[N:25][N:26]=[C:22]2[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)n3cnnc23)CC1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)c3cccs3)n3cnnc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 250 mL 3-necked round bottom flask was charged with thiophene (0.63 g, 7.5 mmol) and dry ethyl ether (10 mL). To the above was added dropwise nBuLi solution (2.5 M in hexane, 3 mL, 7.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, and was then cooled to −78° C. A solution of tert-butyl 4-(5-formyl-[1,2,4]-triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in dry CH2Cl2 (10 mL) was added dropwise at that temperature. The resulting mixture was stirred at −78° C. for 0.5 h, and then quenched by slow addition of methanol (10 mL). The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with ethyl ether (100 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 1% MeOH in CH2Cl2, to afford 0.90 g (72%) of the product as a white solid. MS m/z: 417 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH:25]([NH:28][C:29]([NH:21][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22])=[O:30])([CH3:27])[CH3:26]
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(N)=O
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
2-(4-((3-Chloro-5-(trifluoromethyl)-2-pyridyl)-oxy)phenoxy)propanamide (3.6 g, 0.01 mole) was dissolved in 80 ml. dry toluene. Isopropyl isocyanate (2.55 g, 0.03 mole) was then added and the mixture refluxed for about 16 hours. The toluene was removed by distillation and cold hexane was added. The product precipitated as white crystals, m.p. 135°-137° C.; Yield 3.6 g; 80.7%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:17]([OH:20])[CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.10 mL; 7.85 mmol) (Aldrich) was dissolved in freshly distilled tetrahydrofuran (15 mL) and cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 3.10 mL; 7.75 mmol) (Aldrich) was added dropwise and stirring continued for 30 minutes to give a LDA solution. A solution of 2,4-dichloropyrimidine (0.50 g; 3.36 mmol) (Aldrich) in tetrahydrofuran (3 mL) was added to this freshly prepared LDA solution over 12 minutes. After 30 minutes stirring at −78° C., propionaldehyde (0.48 mL; 6.65 mmol) (Aldrich) was added over 6 minutes and stirring continued for another 35 minutes. The reaction was quenched with the addition of 25% aqueous ammonium chloride solution (15 mL) and was then diluted with ethyl acetate and water. The organic phase was washed with a second portion of ammonium chloride solution and then brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage; 40M; 15:85 to 25:75 ethyl acetate-hexanes gradient) to give (±)-1-(2,4-dichloro-pyrimidin-5-yl)-propan-1-ol. (Yield 0.260 g; 37%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(Cc1ccc2ncccc2c1)NNc1ccc(Cl)nn1
Solvent: CC(=O)O
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 53 %

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (8 g crude, 25.5 mmol) in 250 mL of acetic acid was heated at 50° C. for 5 h. After the reaction was complete, the solvent was evaporated and the residue was taken up in EtOAc. The formed solid (mainly dicyclohexyl urea) was filtered off and the filtrate was evaporated to afford the title compound as yellow solid (4 g, 53%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 8.0 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.53 (m, 1H), 7.42 (d, 1H), 4.79 (s, 2H). LCMS (method B): [MH]+=296.0, tR=1.876 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of (R)-tetrahydrofuran-3-ol (1 g, 11.4 mmole) and TEA (2.3 g, 22.8 mmole) in DCM (20 mL) at 0° C. was added dropwise 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, eluting with 15% ethyl acetate in hexane) to give the title compound (2.3 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].Cl>CS(C)=O>[OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[N+:21]([O-:23])=[O:22])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A solution of 4.38 g (25.8 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (preparation 1), 4.19 mL (38.7 mmol) of 2,5-difluoronitrobenzene, and 5.46 g (51.5 mmol) of sodium carbonate in 25 mL of DMSO was heated at 95° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, and washed with ethyl ether (3×). The aqueous layer was made basic with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×), dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 chloroform: methanol gave 6.19 g (78%) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 724. Product was isolated as a tan solid (0.023 g, 14%). Mp 77-82° C.; LCMS (m/e) 489 (M); 1H-NMR (DMSO, 400 MHz) δ 10.28 (s, 1H), 9.26 (s, 1H), 8.49-8.47 (d, 1H, J=8.34 Hz), 8.16 (s, 1H), 7.92 (s, 1H), 7.63-7.61 (d, 1H, J=7.89 Hz), 7.42-7.40 (t, 1H, J=7.83 Hz), 7.30-7.26 (t, 1H, J=7.58 Hz), 7.22-7.20 (d, 1H, J=8.33 Hz), 7.08 (s, 1H), 6.96-6.94 (d, 1H, J=7.85 Hz), 6.60 (s, 1H), 3.58-3.52 (s, 2H), 3.09-3.03 (q, 2H, J=6.57 Hz), 2.92-2.85 (s, 2H), 2.76-2.70 (s, 2H), 2.40-2.33 (m, 2H), 1.17-1.08 (t, 3H, J=6.57 Hz), 1.05-1.01 (t, 3H, J=6.82 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][C:14]([C:16]2([NH:31]C(=O)OC(C)(C)C)[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[NH2:31][C:16]1([C:14]([NH:13][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][OH:12])=[O:15])[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(C#N)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc([C@H](CCO)NC(=O)C2(N)CCN(c3ncnc4[nH]ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
(S)-4-(1-amino-3-hydroxypropyl)benzonitrile (Intermediate 46) (195 mg, 1.11 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (400 mg, 1.11 mmol) and DIPEA (0.580 mL, 3.32 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (463 mg, 1.22 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 46.4%) as a white solid. (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 0.51 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.769 mL, 22.14 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-cyanophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 15.1%) as a white solid.
Reaction SMILES: C1C=CC(NC2C=CC(N)=CC=2)=CC=1.[OH:15]C1C2N=NNC=2C=CC=1.[CH:25]1([N:31]=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[C:32]([NH:31][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)([NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15]
Reactant: Oc1cccc2[nH]nnc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 15 h
Yield: 65 %

Procedure:
1.65 g (8.98 mmol) of 4-aminodiphenylamine, 1.77 g (8.98 mmol) of intermediate 3.2 and 1.27 g (9.42 mmol) of hydroxybenzotriazole are dissolved in 40 ml of THF in a 100 ml flask, under a nitrogen atmosphere. When all have dissolved, 1.94 g (9.42 mmol) of 1,3-dicyclohexylcarbodiimide is added and the reaction medium is left under agitation for 15 hours. The precipitate of dicyclohexylurea formed is filtered and rinsed with ethyl acetate. The filtrate is evaporated under vacuum and the evaporation residue is taken up in ethyl acetate, it then forms a precipitate which is filtered and rinsed using the same solvent. A greenish solid is obtained with a yield of 65%. The product obtained is sufficiently pure to be used directly in the following stage. Melting point: 192–195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH:16]([CH3:22])[C:17](OCC)=[O:18]>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([CH3:22])=[C:17]([OH:18])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)c1ccccc1F
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1O

Procedure:
Prepared according to procedure R using aniline (0.91 mL, 10 mmol) and ethyl 3-(2-fluorophenyl)-2-methyl-3-oxopropanoate (4 g, 20 mmol) in PPA (4 g, 40 mmol). The resulting precipitate was collected by filtration, washed with water, and dried to give 2-(2-fluorophenyl)-3-methylquinolin-4-ol. Mass Spectrum (ESI) m/e=254 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[C:14]1([NH:20][C:21]([NH2:23])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(O)C>C(O)(=O)C>[C:1]([CH2:3][C:4]([NH:23][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])=[O:6])#[N:2]
Reactant: NC(=O)Nc1ccccc1
Reactant: N#CCC(=O)O
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)Nc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Cyanoacetic acid (28 g, 340 mmol) was taken in 20 ml acetic acid and 40 ml acetic anhydride (400 mmol), stirred at 50° C. until all cyanoacetic acid was solved. Phenyl urea (33.05 g, 247.5 mmol) was added and the mixture was stirred at 95° C. for 60 minute under LC-MS (Liquid Chromatography coupled with Mess Spectrometer) control of the reaction progress. After cooling down to room temperature, dilution with 20 ml 2-propanol and storing at 4° C. for 2 h, solids were separated by filtration, washed with cold 2-propanol and dried under high vacuum giving 40.06 g of white solids (82.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25][CH2:26]O)=[CH:23][CH:22]=[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:26][CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
0.24 g (1.0 mmol) of the above prepared 2-(5-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, 0.31 g (1.10 mmol) of 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (see below example 70E]) and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0° C. and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl azodicarboxylate in 5 ml of THF was added drop by drop. Then, the reaction warmed up to ambient temperature. After 20 hours, the solvent was evaporated and the residue purified by chromatography (SiO2, heptane/EtOAc=95:5 to 9:1) to give 0.23 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1csc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 65.8 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.8 g (24.5 mmol) of 2-amino4-methylthiazole to give 4.8 g of title compound as an off- white solid (95% yield, m.p. 188° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CC(C)([O-])C.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cncc(N2CCCC2)c1
Temperature: 100 °C
Yield: 75.9 %

Procedure:
To a solution of 3,5-dibromopyridine (5.5 g, 23.22 mmol) in toluene (100 mL) was added BINAP (0.840 g, 1.350 mmol), Pd2(dba)3 (0.412 g, 0.45 mmol), sodium tert-butoxide (6.49 g, 67.5 mmol) and pyrrolidine (1.86 mL, 22.50 mmol). The reaction mixture was degassed (N2, 10 min) and then heated at 100° C. for 2 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was evaporated and the residue purified by silica gel chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to afford the title compound (3.88 g). LCMS (A) m/z: 227/229 [M+1]+, Rt 0.87 min (acidic),
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)CC(O)=O.[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19].[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C(O)C(N)(CO)CO>>[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: NC(CO)(CO)CO
Agent: O=C(O)CNC(=O)OCc1ccccc1
Product: C[C@H](N)C(=O)O

Procedure:
The title compound was obtained in quantitative yield by hydrogenation of a solution of Z-Gly-Tris in ethanol at 40 atm. pressure in a Parr hydrogenator in the presence of palladium on carbon (10%). The removal of the benzyloxycarbonyl group was monitored by HPLC (System A). The catalyst was removed by filtration and washed with ethanol. Evaporation of the solvent gave the title product in 95% purity as shown by 1H NMR spectroscopy. Ala-Tris was prepared in an analogous manner. The preparation of Z-Gly-Tris and Z-Ala-Tris are described in Whittaker, R. G., Hayes, P. J.,and Bender, V. J. (1993) Peptide Research 6, 125 and Australian Patent No. 649242.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]([OH:15])=O)[CH:8]=[CH:7][CH:6]=2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:20][NH2:21].FC(F)(F)OC1C=CC(CN)=CC=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28])[CH2:20][NH:21][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(CC(=O)O)cccc2cn1
Agent: NCc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: Cc1cc2c(CC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 222B using (3-methyl-5-isoquinolinyl)acetic acid and 3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.14 (s, 2H), 4.38 (d, J 6.1, 2H), 7.33 (m, 2H), 7.72 (t, J 7.8, 1H), 7.86 (t, J 7.5, 1H), 8.04 (d, J 6.8, 1H), 8.36 (m, 2H), 9.07 (t, J 6.1, 1H), 9.77 (s, 1H); Anal. Calcd for C20H16F4N2O+1.2HCl+0.3 DMF: C, 56.62; H, 4.20; N, 7.48. Found: C, 56.79; H, 4.40; N, 7.29.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chlorobenzaldehyde (28 g) and (carboethoxymethylene)triphenylphosphorane (73 g) in toluene (500 mL) was refluxed for 2 hours. The reaction was cooled to room temperature and concentrated under vacuum to a total volume of 150 mL. Then pure hexane (500 mL) was added and the mixture was left for 18 hours at room temperature. The solid (triphexylphosphine oxide) was filtered, rinsed with hexane and the filtrate evaporated to give crude product which was distilled at 0.5 mm Hg, and the fraction boiling at 130° C. was collected to give ethyl 4-chlorocinnamate, which was reduced as follows: the cinnamate (21 g) was hydrogenated in EtoAc (300 mL) in the presence of 5% Pd on C (2 g) for 3 hours at atmospheric pressure. After completion, the reaction mixture was filtered through a celite pad, rinsed with EtOAc and the filtrate evaporated to dryness to give the title product as an oil.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[CH2:25]([O:24][C:22]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Sodium hydrogencarbonate (0.95 g, 11.32 mmol) was added into a suspension of 30 in THF (120 mL), followed by water (10 mL), affording a clear solution. Benzyl chloroformate (1.21 mL, 8.49 mmol) was then added into the reaction mixture at 0° C. The reaction mixture was then stirred at room temperature overnight. After that, the solvent was removed under reduced pressure. Ethyl acetate (70 mL) was added to the residue and the solution was washed with 2N HCl (2×30 mL) and water (2×50 mL), then dried in vacuum. 1.82 g (98%) of 31 was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (m, 2H), 1.28 (m, 2H), 2.33 (m, 2H), 3.02 (m, 2H), 5.01 (m, 2H), 7.15 (m, 7H), 7.93 (d 2H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(O)c2c(F)ccc(F)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2c(F)ccc(F)c2n1
Temperature: 25 °C

Procedure:
4-Hydroxy-5,8-difluoro-2-methylquinoline (5.4 g) in phosphoryl chloride (60 ml) was boiled for 4 h. The mixture was cooled to room temperature, excess phosphoryl chloride removed at reduced pressure, the residue dissolved in ethyl acetate, washed with sodium hydrogen carbonate, dried (Na2SO4) and solvent removed at reduced pressure. The title compound (5.35 g) was isolated as a brown powder. (Method B). 1H NMR δ: 2.61 (3H, s), 7.46 (1H, m), 7.66 (1H, m), 7.81 (1H, s).