Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]2)=[CH:6][CH:5]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[O:29][CH2:28][CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:20]([NH:19][C:11]2[N:10]([CH2:9][C:7]3[O:8][C:4]([CH3:3])=[CH:5][CH:6]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(Cn2c(NC3CCCN(CCO)CC3)nc3cccnc32)o1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2c(NC3CCCN(CCOc4ncccn4)CC3)nc3cccnc32)o1
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a stirred mixture of 1 part of a sodium hydride dispersion 50% and 94 parts of N,N-dimethylformamide is added dropwise a solution of 5.5 parts of hexahydro-4-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1H-azepine-1-ethanol in N,N-dimethylformamide. Upon complete addition, stirring is continued for 15 minutes at room temperature. 1.9 Parts of 2-chloropyrimidine are added portionwise and upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is decomposed with water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent was evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and dried, yielding 3.4 parts (34.8%) of N-[hexahydro-1-[2-(2-pyrimidinyloxy)ethyl]-1H-azepin-4-yl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine (compound 169).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]1([C@H:12]([NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[C:6]1([C@H:12]([N:14]2[CH2:15][CH2:16][C@@H:17]3[CH2:18][C@H:2]2[C:1](=[O:4])[O:5]3)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCCN[C@H](C)c1ccccc1
Reactant: O=CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Temperature: 60 °C

Procedure:
Glyoxylic acid (7.43 mL) was added dropwise to a solution of (R)—N-(1-phenylethyl)but-3-en-1-amine (7.80 g) in tetrahydrofuran (30 mL) at 60° C. over a period of 1.5 h. The reaction was heated at 60° C. for a further 7 h. Water (30 mL) and brine (30 mL) were added and the pH adjusted with 2M NaOH solution to pH 9. The aqueous was extracted with ethyl acetate (3×50 mL), the organics combined, washed with saturated aqueous NaHCO3 solution, water, brine, dried (MgSO4), filtered and evaporated to afford an orange oil (9.5 g). Purification (SiO2 chromatography using elution gradient 25% ethyl acetate in isohexane) afforded the subtitle product (3.10 g) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[S:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([S:5][C:4](=[O:14])[C:3]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:2]2[O:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:7][CH2:8]1
Reactant: CON1CCC2(CC1)SC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)SC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
94 mg 4-Hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-2-one (from Step 7) and 43 mg triethylamine were dissolved in 10 ml tetrahydrofuran, and a solution of 32 mg ethyl chloroformate in 5 ml tetrahydrofuran was added dropwise. The mixture was stirred at ambient temperature for 18 hours, then partitioned between saturated aqueous sodium bicarbonate and t-butylmethyl ether, the organic layer dried over sodium sulfate, and the solvent evaporated. The residue was purified by chromatography on silica gel with ethylacetate/cyclohexane (1:2) as a solvent, to give 34 mg carbonic acid ethyl ester 8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.7) as a solid, mp 87-89° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]([CH3:10])[CH3:9].[CH:16](=O)[CH2:17][CH2:18][CH3:19]>>[CH:16](/[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:17]\[CH2:18][CH3:19]
Reactant: CCCC=O
Reactant: CC(C)CNCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC/C=C/N(CC(C)C)CC(C)C
Temperature: -7 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
Potassium carbonate (4.8 g, 35 mmol) was added to diisobutylamine (17.5 mL, 0.10 mol) under a nitrogen atmosphere, and the mixture was then cooled to −7° C. Butanal (9.0 mL, 0.10 mol) was added dropwise thereto over 10 minutes. The reaction mixture was gradually heated to room temperature and stirred for 19 hours. Insoluble matter was filtered off, and the filtrate was then concentrated under reduced pressure to obtain the title compound (13.6 g, yield: 74%) as a colorless oil substance.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClCCl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:19])[CH3:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
An argon filled RB flask containing carbazole (0.500 g, 2.99 mmol) at 0° C. was treated with dichloromethane (12.5 mL) and triethylamine (2.5 mL), followed by slow addition of ethyl chloroformate (0.59 mL, 5.98 mmol). The mixture was stirred at ambient temperature for 16 h, poured into 25 mL of 2N HCl, and extracted with chloroform. The organic portion was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was treated with methanol (4 mL) and filtered. The filtrate was concentrated to give carbazole-9-carboxylic acid ethyl ester (169 mg). Carbazole-9-carboxylic acid ethyl ester (95 mg, 0.39 mmol) was converted to hydroxamic acid by procedure A. Purification by HPLC gave the title compound (19 mg). 1H NMR (400 MHz, CD3CN): δ 9.43 (br, 1H), 8.08 (d, 2H, J=7.7 Hz), 7.50 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.1 Hz), 7.22 (t, 2H, J=7.1 Hz). 13C NMR APT (100 MHz, CD3OD): δ 125.8 (down), 120.3 (down), 119.4 (down), 110.6 (down). ESI-MS (m/z): [M+Na]+249.6. Analytical HPLC: Purity=99%, tR=8.51 min, Method A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][N:24]([CH2:37][CH2:38][CH2:39]O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:39][CH2:38][CH2:37][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:27]=2[Cl:36])[CH2:23][CH:22]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirring solution of N-(3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (1.9 g, 9.0 mmol) in anhydrous toluene (60 mL) was added N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (2.36 g, 5.3 mmol). Polymer bound triphenylphosphine (2.8 g, 8.4 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.28 mL, 6.5 mmol) was added in a dropwise fashion. After stirring at room temperature for 60 hours, the crude reaction mixture was filtered and the resulting solid was washed with toluene. The filtrate was concentrated and the crude product was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 30 min; detection at 214 nm) to give 2.0 g (3.1 mmol, 59% yield) of the title compound as a white foam. MS (ESI) 639.4
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[O:21]>C1COCC1.CCOC(C)=O.Cl>[O:21]=[C:16]1[NH:15][CH2:20][CH2:19][N:18]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:17]1
Reactant: O=C1CNCCN1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(N3CCNC(=O)C3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (750 mg, 3.54 mmol) and piperazin-2-one (780 mg, 7.79 mmol) in THF (60 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and 1 N HCl (25 ml). The aqueous layer was separated, basified with 1 N NaOH and extracted with EtOAc (6×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give methyl 2-(3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (690 mg, 72%). 1H NMR consistent.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1COCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])[CH2:11][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH:19]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 407.9 %

Procedure:
A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to −78° C. under a nitrogen atmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) was added dropwise to the stirred solution over 0.5 hour. The reaction was held at −78° C. for 1 hour, warmed to −10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to −78° C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at −78° C. for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/conc HCl (222 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added and crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1° C. 1H NMR (CDCl3/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98 (d, 1H, J=8.9 Hz), 4.25 (q, 2H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 Hz). FABLRMS m/z 249 (M+Li). EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11ClO4: C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[N:15]1([CH2:14][CH2:13][NH:12][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: NCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccnc1NCCN1CCCC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To the solution of 2-fluoro-3-(trifluoromethyl)pyridine (990 mg, 6 mmole) in 5 ml of NMP, 2-aminoethylpyrrolidine (1.13 ml, 9 mmole) and triethylamine (1 ml, 7.2 mmole) were added. The reaction solution was stirred at 85° C. for overnight. The reaction mixture was poured into 40 ml of saturated NaHCO3 and extracted with ethyl acetate (2×80 ml). The combined organic layers were washed with water (2×30 ml) and brine (30 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown oily N-(2-(pyrrolidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (1.61 g). ES/MS m/z 260.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][N:37]=[C:36]2[NH:35][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:20]([Cl:19])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester is prepared by adding prop-2-ynyl-carbamic acid tert-butyl ester (0.978 g, 6.31 mmol), diisopropylamine (1.77 ml, 12.63 mmol), Pd(PPh3)2Cl2 (210 mg, 0.30 mmol) and CuI (57 mg, 0.30 mmol) to a stirred solution of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine (3.11 g, 5.74 mmol) in THF (40 ml). After stirring the reaction mixture at rt under N2 for 3 h, the THF is removed under reduced pressured and methylene chloride is added. The organic layer is washed with NH4Cl (sat) and brine, and dried (Na2SO4). The solvent is evaporated and the residual solid is used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[N:36][N:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[CH:37]=[N:36]1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCn1ncc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (2.20 g; compound B50) is reacted with 4-(chloromethyl)-2-ethyl-2H-1,2,3-triazole (748 mg; compound D19) in the presence of potassium carbonate (1.42 g) in DMF (39 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 1/1 (v/v)] as a solid.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:25])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-chlorophenyl)carbamoyl)benzylthio)propanoate (350 mg, 0.51 mmol, 1.00 equiv) in dichloromethane (5.0 mL), and trifluoroacetic acid (581.4 mg, 5.10 mmol, 10.00 equiv). The resulting solution was stirred overnight at 15° C. The resulting mixture was concentrated under vacuum. The crude product (340 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained 250 mg (78%) of a white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.988 (s, 1H), 12.228 (s, 1H), 9.595-9.560 (m, 1H), 9.020-9.003 (d, J=5.1 Hz, 1H), 8.631-8.601 (d, J=9.0 Hz, 1H), 8.448 (s, 1H), 8.118-8.126 (d, J=2.4 Hz, 1H), 7.917-7.899 (d, J=5.4 Hz, 2H), 7.837-7.812 (d, J=7.5 Hz, 1H), 7.727-7.510 (m, 6H), 4.662-4.643 (d, J=5.7 Hz, 2H), 3.904 (s, 2H), 2.637-2.594 (m, 2H), 2.538 (m, 2H). MS (ES, m/z): 628 [M+H]+
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH:1]([N:19]([CH2:20][C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:2]
Reactant: C=CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold solution of HCO2H (3.2 mL) and dichloromethane (10 mL) at 0° C. was added acetic anhydride (1.2 mL, 12.9 mmol). The mixture was stirred for 1 hour at 0° C. To the resulting mixture was added slowly a solution of (2R)-2-({N-benzoxy-amino}methyl)-7-octenoic acid (358 mg, 1.29 mmol) in dichloromethane (10 mL). The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (20 mL) was added to it. It was washed with brine (20 mL×2), and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound. MH+306.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][OH:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:14][O:15][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(CCO)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCCN1Cc1ccccc1
Temperature: 27.5 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 l) was stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 l of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reaction mixture was then stirred at room temperature for 90 minutes. Ice-cold water (6 l) was added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which was used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+ @ Rt 1.00 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:16]([C@@H:19]1[CH2:20][O:21][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=2)[O:15][CH2:22]1)[CH2:17][CH3:18]
Reactant: O=Cc1ccc(-c2ccc(F)cc2)nc1
Reactant: CCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H](c2ccc(-c3ccc(F)cc3)nc2)OC1
Reaction time: 1.5 h

Procedure:
A solution of 1.51 g of 6-(4-fluorophenyl)-3-pyridinecarboxaldehyde and 1.10 g of 2-propyl-1,3-propanediol in 50 ml of toluene was treated with 10 drops of 10 percent (v/v) sulphuric acid. The mixture was heated to boiling for 1.5 hours, whereby moist toluene was distilled off and replaced by fresh toluene. Then, the reaction mixture was neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 60 g of silica gel with toluene/acetone (vol. 99:1) and two-fold recrystallization of the trans/cis mixture from hexane/ethyl acetate (vol. 1:1) gave 0.51 g of pure 5-(trans-5-propyl-1,3-dioxan-2-yl)-2-(4-fluorophenyl)pyridine; m.p. (C-SA) 106.5° C., SA -N 117.5° C., cl.p. (N-I) 163° C.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:14][CH:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH:12]([CH2:37][CH3:38])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>CO>[C:1]([O:9][CH:10]1[CH2:14][CH:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][NH:24][C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH:12]([CH2:37][CH3:38])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CC(OC(=O)c2ccccc2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CCC1CC(OC(=O)c2ccccc2)CC1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (5.00 g, 7.84 mmol, prepared using II from Example #4 Step J with benzoic acid and B) in MeOH (16 mL) was added a solution of potassium cyanide (0.74 mL, 17 mmol) in MeOH (16 mL). The reaction was stirred at ambient temperature for about 16 h. The reaction mixture was concd under reduced pressure to afford a residue. The residue was partitioned between water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The extract was then washed with saturated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford a crude oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to 3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (2.30 g, 78%) as a solid. LC/MS (Table 1, Method a) Rt=2.08 min; MS m/z: 376 (M+H)+.