Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[N:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reaction time: 23 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol I-(4A-7)b (2.49 g, 6.97 mmol) was suspended in 50 ml of toluene. Triethylamine (1.07 ml, 7.68 mmol) was added followed by addition of POCl3 (720 μl, 7.72 mmol) at room temperature. The reaction was warmed to reflux and stirred for 23 hours to give a clear orange solution. After cooling the reaction to room temperature it was concentrated under reduced pressure, diluted with isopropanol (50 ml) and then concentrated further under reduced pressure until copious amount of precipitate came out of solution. The concentrated suspension was cooled in an ice bath and stirred for 2 hours. The precipitate was collected on a sintered glass funnel and rinsed with cold isopropanol to afford, after drying in vacuo, I-(4A-7)c as an off-white solid (2.13 g, 82%): +ESI MS (M+1) 375.1; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.76 (dd, J=7.46, 1.2 Hz, 1H), 7.58–7.40 (m, 7H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:46][C@@H:47]2[CH2:49][O:48]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:46][C@@H:47]4[CH2:49][O:48]4)[CH3:21])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@@H]2CO2)c1=O

Procedure:
The subtitle compound was prepared using a similar method to Example 299a from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 252j) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][CH2:32][CH2:33][S:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)(=[O:36])=[O:35].O>CN(C=O)C>[N:37]1([S:34]([CH2:33][CH2:32][CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)(=[O:36])=[O:35])[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12)c1cccnc1
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055, 250 mg, 0.001 mol) and K2CO3 (1.1 g, 0.008 mol) in DMF (5 ml) was added 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E, 204.0 mg, 0.001 mol) to a sealed tube and heated to 120° C. for 3 h. The reaction was poured into water and extracted with CH2Cl2. Organic layers dried with MgSO4, filtered and concentrated. The residue was purified using silica gel flash chromatography (100% EtOAc, then 0-20% MeOH/CH2Cl2) to provide the title compound (130 mg, 33%). TLC: Rf=0.21 in 10% MeOH/CH2Cl2, HPLC MS RT=1.81 min., MW=499.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22 (2H, m), 3.17 (4H, m), 3.26 (2H, m), 3.64 (4H, m), 4.18-4.29 (4H, m), 4.56 (2H, m), 7.22 (1H, d), 7.74 (1H, s), 7.89 (1H, m), 8.12 (1H, d), 8.81 (1H, m), 8.95 (1H, dd), 9.44 (1H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]=[N:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH:12]=[CH2:13]>>[N:1]1([CH2:6][CH2:7][C:8]2[CH2:13][CH:12]([CH2:11][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=CCCN1CCCC1
Reactant: C=CCN1CCCC1=O
Product: O=C1CCCN1CC1CC(CCN2CCCC2)=NO1
Yield: 19.8 %

Procedure:
The desired compound was prepared by the method of Example 8 from 400 mg (2.813 mmol) of 3-pyrrolidin-1-yl-propionaldehyde oxime prepared in Example 1 and 704 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 7:1) as eluent to obtain 148 mg (20% yield) of 1-[3-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: C(O)(=O)C.[C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH2:14])=[NH:13].C[O:22][C:23](=O)/[C:24](/[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:25](\O)/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C[O-].[Na+]>CO>[C:29]([O:28][C:26]([C:25]1[C:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:23]([OH:22])[N:14]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)Cc1ccccc1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirred solution of 2-biphenyl-2-yl-acetamidine acetate salt (5-01) (2.5 g, 9.2 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (4.2 g, 13.88 mmol) in methanol (60 mL) was added sodium methoxide (1.5 g, 27.77 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, it was quenched with 1N HCl, evaporated and w ater was added. The mixture was extracted with ethyl acetate and the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get a crude product, which was purified using a normal silica column using 30% ethyl acetate in hexane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01) (2.5 g, 57.63%) as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9]C)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:11](O)(=O)C(C)O.C(O)CCC>Cl.O.C(O)CCC>[C:1]([O:6][CH2:7][CH:8]([CH3:9])[CH3:11])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCOC(=O)C(C)O
Reactant: CC(O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(C)COC(=O)C(C)O

Procedure:
The composition of matter of 1-butyl lactate is and its preparation are disclosed in Gabriel et al. U.S. Pat. No. 1,668,806 (1928). They prepared 1-butyl lactate by dehydrating 70% lactic acid with excess 1-butanol at 117° C., followed by addition of HCl catalyst, followed by refluxing and esterification with addition excess 1-butanol and drawing a 1-butanol water azeotrope overhead. Nakanishi and Tsuda (Japanese Patent JP 46/30176 [71/30176]) consider production of 1-butyl lactate by extraction of an acidified crude fermentation broth with 1-butanol, followed by esterification of the extract phase. BASF (EP 159-285) considers production of isobutyl lactate by extraction of an acidified crude fermentation broth with isobutanol, followed by esterification of the extract phase, which was then distilled in vacuum 80° C./25 mbar to give a purified isobutyl lactate.
Reaction SMILES: [OH-].[Na+].[C:3]([N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([C:19]#[N:20])[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].N[CH:22]([C:25]([OH:27])=[O:26])[CH2:23][SH:24]>C(O)C>[C:3]([N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:10]([C:19]2[S:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[N:20]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: NC(CS)C(=O)O
Reactant: CC(C)(C)n1ncc(C#N)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixed solution of 1N aqueous sodium hydroxide solution (2.65 ml, 2.65 mmol) of the compound (430 mg, 1.77 mmol) obtained in step 1 and DL-cysteine (321 mg, 2.65 mmol), and ethanol (5.3 mL) was stirred at 80° C. for 3 hr. DL-cysteine (200 mg) and 1N aqueous sodium hydroxide solution (1.5 mL) were further added thereto, and the mixture was stirred at 80° C. for 14 hr. DL-cysteine (321 mg) and 1N aqueous sodium hydroxide solution (2.65 mL) were further added thereto, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid and ethyl acetate were added thereto. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether to give 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid (385 mg, 1.108 mmol, 62.7%) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1N
Yield: 85.9 %

Procedure:
A solution of [3-(4-Chloro-2-nitro-phenoxy)-propyl]-carbamic acid tert-butyl ester (1.78 g) was hydrogenated in ethanol (50 ml) in presence of Platinum oxide (178 mg) for 2 hours. The mixture was filtrated over a pad of celite and concentrated under vacuum. The crude reaction was purified by flash chromatography to afford [3-(2-Amino-4-chloro-phenoxy)-propyl]-carbamic acid tert-butyl ester (1.39 g, yield=86%) as a viscous oil which solidified slowly:
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35](Cl)=[O:36])[N:23]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:6][CH2:5]3)=[O:36])[N:23]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccnc1N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
126 mg 2-piperazin-1-yl-nicotinonitrile was added to 216 mg (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 150 μL triethylamine in 10 mL dichlormethane. The reaction was stirred 1 day at RT, the solvant was evaporated and the residue was purified by HPLC to give 93 mg of the desired product. (M+H)+: 486
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl>>[Cl:1][C:2]1[NH:10][C:9](=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(=O)[nH]c1Cl
Temperature: 129 °C
Yield: 88 %

Procedure:
A 500-mL round-bottom flask was charged with 2,6-dichloronicotinic acid (25.0 g, 130 mmol), NaOH solution (325 mL, 2N) and the solution was refluxed at 129° C. for 4 hours. The reaction mixture was cooled to room temperature and acidified with a 6N aq. HCl solution. The resulting precipitate was filtered and dried under reduced pressure yielding to the desired product (19.87 g, 88%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:25]>>[Cl:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=c1n(-c2ccc(CO)cc2)nc2n1CNc1ccccc1-2
Reactant: O=S(Cl)Cl
Product: O=c1n(-c2ccc(CCl)cc2)nc2n1CNc1ccccc1-2
Temperature: 50 °C

Procedure:
A mixture of 2-[4-(hydroxymethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 19) (500 mg, 1.6 mmol) and excess SOCl2 was heated at 50° C. for 1 hour. SOCl2 was evaporated under reduced pressure and the residue was washed with ether to afford 2-[4-(chloromethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 20).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]([C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH4-].[Na+].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH:18][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:36][CH:37]=3)[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CNCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
A solution of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (500 mg, 1.29 mmol) and 4-phenoxybenzaldehyde (256 mg, 1.29 mmol) was heated to 50° C. in ethanol (50 ml) for 1 hour in the presence of molecular sieves (4 A, 5 ml). The reaction mixture was cooled on an ice bath before sodium borohydride (98 mg, 2.59 mmol) was added in three portions over 45 min. The cooling bath was removed and the reaction mixture was allowed to reach room temperature. The mixture was filtered through a plug of Celite and the filter cage was washed with dichloromethane (3×25 ml). The solvent was removed in vacuo and the residue was redissolved in ethyl acetate (50 ml), washed with sodium bicarbonate (50 ml) and dried (MgSO4). The solvent was removed in vacuo before the residue was redissolved in acetonitrile (20 ml). Triethylamine (130 mg, 1.29 mmol), di-tert-butyl dicarbonate (282 mg, 1.29 mmol) and 4-(N,N-dimethyl-amino)pyridine (5 mg, cat.) was added and the reaction mixture was stirred for 16 hours at room temperature. The volatiles were removed in vacuo and ethyl acetate (50 ml) was added and the solution was washed with saturated sodium bicarbonate (50 ml) and dried (MgSO4). The crude product was purified by column chromatography (SiO2, petroleum ether-ethyl acetate (9:1)) to give 325 mg (38% overall) of 2-amino-5-(S)-((4-phenoxy-benzylamino)methyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:25]([CH2:27][C:28](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:29])#[N:26]>CN(C=O)C>[C:7]1([CH:4]2[CH2:3][CH2:2][N:1]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:6][CH2:5]2)[N:11]2[C:12]3[CH:18]=[CH:17][NH:16][C:13]=3[N:14]=[CH:15][C:10]2=[N:9][N:8]=1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#CCC(=O)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added perfluorophenyl 2-cyanoacetate (0.14 g, 0.56 mmol, Preparation #6). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyophilized to afford 3-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.005 g, 4%): LC/MS (Table 2, Method a) Rt=1.24 min; MS m/z: 310 (M+H)+.
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].Cl.O>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:13])([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)I
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: OC(c1ccccc1Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
74 g (0.3 mol) of phosphorous acid trisdiethylamide in 150 ml of CH2Cl2 were initially introduced into a round-bottomed flask with the exclusion of moisture. 74 g (0.3 mol) of pentafluoroethyl iodide and 26.4 g (0.15 mol) of o-chlorobenzoyl chloride were added at about -20° C. The mixture was warmed to 0° C. and stirred for about 8 hours at this temperature. 10 g of hydrogen chloride gas were then introduced, and the mixture was stirred for a further hour at 0° C. The reaction mixture was freed from solvent under reduced pressure and introduced into 3 times the volume of water. The organic phase was separated off, dried and distilled. 34.6 g (62%) of 3-(2-chlorophenyl)-1,1,1,2,2,4,4,5,5,5-decafluoropentan-3-ol of b.p. 66° C./2 mbar were obtained.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
tert-Butyl 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate [Example 34a, step b] (13.2 g) was stirred in dichloromethane (150 mL) and trifluoroacetic acid (50 mL) was added. The solution was stirred for 1 hour. The solvents were evaporated under reduced pressure and the residue dissolved in acetonitrile and the solution evaporated under reduced pressure to afford the subtitled compound. Yield 14.4 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (55 mg, yield 46%). 1H NMR (400 MHz, MeOD) δ 9.39 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.0 Hz, 1H), 8.89 (t, J=2.0 Hz, 1H), 8.07-8.03 (m, 2H), 7.81 (s, 1H), 7.26-7.22 (m, 2H), 3.78-3.75 (t, J=6.9 Hz, 2H), 2.97-2.94 (t, J=6.9 Hz, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O3: 447.10. found: 448.2 (M+H)+.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[CH:13]1([N:9]2[C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]=3[C:11]([I:12])=[CH:10]2)[CH2:16][CH2:15][CH2:14]1
Reactant: N
Reactant: Clc1ncnc2c1c(I)cn2C1CCC1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ncnc2c1c(I)cn2C1CCC1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (70.7 mg, 0.8115 mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.83-1.95 (m, 2H), 2.34-2.47 (m, 2H), 2.48-2.58 (m, 2H), 5.22 (quint, J=8.7 Hz, 1H), 5.63 (brs, 2H), 7.26 (s, 1H), 8.26 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.92 (−), 31.05 (2C, −), 48.50 (+), 48.82 (Cquart), 104.11 (Cquart), 126.39 (+), 149.82 (Cquart), 152.00 (+), 156.94 (Cquart). MS (ES+): m/z 315.0 (100) [MH+]. HPLC: tR=2.4 min (OpenLynx, polar—5 min).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[N:23]1[N:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]2=[C:25]([C:32](O)=[O:33])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[OH:22][CH2:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:32]([C:25]2[CH:24]=[N:23][N:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:26]=23)=[O:33])[CH:12]=1
Reactant: COc1ccc(/C=C/CO)cc1N
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(/C=C/CO)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of diisopropylethylamine (0.25 mL), (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol (90 mg), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (65 mg), HOBT (85 mg) and HBTU (0.20 g) in anhydrous acetonitrile (5 mL) was heated to 80° C. overnight. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/EtOAc, 3/97) to give an oil. This residue was triturated with ethyl acetate to give, upon standing for 1 hour, 20 mg of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol as a light brown solid which was collected by filtration. MS=325 [M+H]+.