Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29](I)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:35][S:36]([N:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1)(=[O:38])=[O:37]>>[CH3:32][C:31]1[CH:30]=[C:29]([C:42]2[CH2:41][CH2:40][N:39]([S:36]([CH3:35])(=[O:37])=[O:38])[CH2:44][CH:43]=2)[CH:28]=[C:27]([CH3:34])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCN(S(C)(=O)=O)CC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Step 4 of Intermediate 2. LC (method 8): tR=0.79 min; Mass spectrum (ESI+): m/z=628 [M+Na]+.
Reaction SMILES: C([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@:7]([OH:33])([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[OH:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@:7]([OH:33])([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@H]4[C@@H]3CC[C@@]2(O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 3β-acetoxy-5α,25-dihydroxy-cholestane (IV) in 40 cc of methanol and 10 cc of dioxane was treated with 6 cc of a 10% solution of sodium hydroxide and refluxed for 3 hours. The reaction mixture was neutralized with a solution of 5% aqueous hydrochloric acid, extracted with ether and washed with water. The ether solution was evaporated in vacuo and the residue was recrystallized from ether to give 850 mg of the 3β, 5α,25-tri-hydroxy-cholestane (VI) m.p. 202°-204° Nmr δ 0.67 (s, 3H), 0.9 (d, J=5 cps, 3H), 1.22 (s, 6H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](SC)[N:6]=1>CCO>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:2][NH2:3])[N:6]=1
Reactant: NN
Reactant: CSc1nccc(C)n1
Solvent: CCO
Solvent: O
Product: Cc1ccnc(NN)n1
Temperature: 0 °C
Reaction time: 50 h
Yield: 21562.2 %

Procedure:
Based on a reported procedure (Vanderhaeghe, Claesen, Bull. Soc. Chim. Belg. 1959, 68, 30). Hydrazine monohydrate (334.7 ml, 6.90 mmol) was added in one portion to a solution of 4-Methyl-2-methylsulfanyl-pyrimidine (357.9 g, 2.55 mol) in abs. EtOH (890 ml). The resulting mixture was refluxed for 50 h, then hydrazine monohydrate (200 ml) was added and refluxing was continued for 50 h (the reaction was monitored by 1H NMR). Then it was cooled to 0° C. to crystallize and 213 g of crude product was isolated by filtration. Recrystallization from ethanol gave the title compound (184.7 g, 59%) as a white solid.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].[CH2:20](Br)[C:21]#[CH:22].CO>CN(C)C=O>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:22][C:21]#[CH:20])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a stirred solution of compound 15 (1.39 g, 5.91 mmol) in N,N-dimethylformamide (25 mL) was added NaH (0.33 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature and then cooled to 0° C. Propargyl bromide 4 (1.24 mL, 11.13 mmol) was added, and stirring was continued for 0.5 h at 0° C., then for 2 h at room temperature. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 16 as a solid (591 mg, 36.6%) having an RF of 0.41 (solvent 3:2 hexane-ethyl acetate). See FIG. 9.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=2[S:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]2[S:26][CH:25]=[C:24]([CH2:23][N:3]3[C:4]4=[N:9][C:8]([N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][C@@:2]3([CH3:1])[C:18]([F:21])([F:19])[F:20])[C:28]=2[CH:29]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1csc2ccc(Cl)cc12

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 103 mg of 3-(bromomethyl)-5-chloro-1-benzothiophene, replacing the sodium hydride with caesium carbonate. After purification by preparative HPLC/MS (method C), 49 mg of (2S)-1-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:20]3[C:21]4([CH2:24][O:25][CH2:26][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]4)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:28](=[O:30])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:20]4[C:21]5([CH2:24][O:25][CH2:26][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]5)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)COC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 214.5 %

Procedure:
To a solution of 2-methyl-N1-[6-(1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-yloxy)-3-pyridinyl]alaninamide (34 mg, 0.096 mmol) in dry Dichloromethane (DCM) (5 mL) TEA (0.067 mL, 0.481 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (12.85 mg, 0.043 mmol) in dry Dichloromethane (DCM) (2 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (5 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 10 g and Dichloromethane/methanol 99:1 to Dichloromethane/methanol 95:5 as eluents affording the title compound (35 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1.C(OCC)C>[N:1]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3Cl)[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:34][CH:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(N)CC
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
[(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enyl]-propionyl-carbamic acid tert-butyl ester (700 mg, 1.64 mmol) is dissolved in THF (15 mL) under an atmosphere of argon. 3-Pentylamine (315 mg, 3.61 mmol) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The reaction mixture is partitioned between DCM (50 mL) and 0.1 M HCl (50 mL). The organic layer is washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:8]=1.C[CH:14]([S:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1)[C:15]1[CH2:16][S:17][C@@H:18]2[C@H:38]([NH:39]C(=O)CC3SC=CC=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CO>C(Cl)Cl>[NH2:39][C@@H:38]1[C:37](=[O:48])[N:19]2[C:20]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:15]([CH2:14][S:49][C:50]3[N:54]([CH3:8])[N:53]=[N:52][N:51]=3)[CH2:16][S:17][C@H:18]12
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 81.5 %

Procedure:
A suspension of phosphorus pentachloride (416 mg) in dry methylene dichloride (10 ml.) was stirred at 23° and a solution of pyridine (0.16 ml.) added. The warm suspension was stirred for 10 minutes, and cooled to 0°, and treated, over 10 minutes, with a solution of diphenylmethyl 3-(1-methyltetrazol-5-ylthiomethyl)-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (619 mg) in methylene dichloride (15 ml.). After stirring for a further 45 minutes, during which time the temperature was allowed to rise to 23°, the solution was added, over 5 minutes, to a stirred and cooled (0°) mixture of methanol (5 ml.) and methylene dichloride (15 ml.). The resulting solution was stirred for a further 10 minutes, and washed with N-hydrochloric acid (20 ml.), and stirred for 30 minutes with saturated sodium bicarbonate solution (50 ml.). The organic phase was separated, and washed with saturated aqueous sodium bicarbonate (25 ml.), and treated with some charcoal. The mixture was filtered through a pad of kieselguhr, and the filtrate evaporated to a gum (640 mg.), which was triturated with ether (20 ml) to give the amine as an off-white solid (403 mg, 81.5%), λmax. (CHCl3) 268.5 nm (ε 7,700), νmax. (CHBr3) 3416 and 3350 (NH2), 1780 (β-lactam), and 1720 cm.-1 (CO2R), τ (CDCl3) values include 5.00 and 5.15 (C-6H and C-7 H, two doublets, J 5 Hz.), 6.14 (CH3 -), and 7.59 (NH2).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:79])C=1>ClCCl.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@H:21]3[S:20](=[O:79])[CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS(=O)[C@H]23)cs1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (511 mg: 0.5 mMol.) in a mixture of dichloromethane (10 ml) and methanol (10 ml) is added m-chloroperbenzoic acid (purity: 80%: 54 mg: 0.25 mMol.) at -30° C., and the mixture is stirred for 1 hour. The reaction mixture is diluted with aqueous 5% sodium thiosulfate and extracted with ethyl acetate. The extract solution was washed with aqueous sodium hydrogencarbonate, diluted hydrochloric acid, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (toluene-ethyl acetate=2:1 to 1:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (232 mg). Yield: 45%. A part of the starting material (236 mg: 48%) was recovered.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(C)[C:10](S(O)(=O)=O)=[CH:11][CH:12]=[CH:13][CH:14]=1.CC(CCC)=C.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:11]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:10][CH2:9][CH2:14][CH2:13][CH3:12]
Reactant: Oc1ccc(S)cc1
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: C=C(C)CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCSc1ccc(O)cc1
Temperature: 60 °C

Procedure:
A 4-(hexylthio)phenol was prepared as follows. In a one liter flask equipped with thermometer, stirring rod and water condenser was added 126 grams of 4-mercaptophenol and 7 grams of toluenesulfonic acid. The flask contents were heated to 60° C. and 93 grams of 2-methyl-1-pentene were added over a fifty minute period. The flask contents were neutralized with 9 grams of Na2CO3 in aqueous solution and decanted. The reaction product was stripped to a pot temperature of 80° C. at 20 millimeters of mercury. It weighed 216 grams.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[CH:34](=O)[CH2:35][CH:36]([CH3:38])[CH3:37]>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2](/[N:1]=[CH:34]/[CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Reactant: CC(C)CC=O
Solvent: CC(=O)N(C)C
Product: CC(C)C/C=N/n1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 71.1 %

Procedure:
The product of Example 304F (0.220 g, 0.48 mmol) and isovaleraldehyde (0.77 mL, 7.18 mmol) in N,N-dimethylacetamide (1.5 mL) were reacted at 130° C. for 35 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.181 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[CH2:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:5][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1Cl
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(CN1CCCC1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)acrylic acid methyl ester (0.70 mmol) in 2 mL THF was added pyrrolidine (0.77 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 min, diluted with DCM and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired compound as pinkish oil;
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:14])C1.C([O-])(O)=O.[Na+]>O>[CH3:8][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: CSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccccc1
Yield: 95.9 %

Procedure:
Methyl phenyl sulphide (20 g, 161.03 mmol) was added to a mixture of methanol (100 ml) and water (20 mL). NBS (34.39 g, 1.2 eq) was added in portions maintaining the temperature between 0° and 5° C. The mixture was stirred at the same temperature until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 60 ml). The pH of the resulting reaction mixture was adjusted to a value between 7 and 8 with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (2×125 mL). The combined organic layer was washed with water (2×125 mL) and concentrated to ⅓ of the volume. Heptane (20 mL) was added and then removed by distillation to give 21.64 g (95.9%) of the desired product as colourless oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].[Br-].[Na+].C([Li])CCC.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:23]1([CH2:22][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: ClCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Tetrahydrofuran (125 mL), N-(1,1- dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) and sodium bromide (1.3 g) are charged and cooled to -40° C. under nitrogen. Two equivalents of nbutyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Benzyl chloride (1.05 equivalents) is then added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 ml) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product may crystallize. Product yield of 94% determined by internal standard assay on gas chromatograph.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:47][C:48](=[NH:68])[C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][N:53]=[C:54]2[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:47]=[C:48]([C:49]3[CH:58]=[CH:57][CH:56]=[C:55]4[C:50]=3[CH:51]=[CH:52][N:53]=[C:54]4[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[N:68]=2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
3-Cyano-4-fluorobenzoic acid (D31; 0.288 g, 1.744 mmol) was stirred at room temperature in 5 ml of DMF with HATU (0.723 g, 1.903 mmol) and DIPEA (0.831 ml, 4.76 mmol) for 10 mins. 1,1-Dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36, 0.5 g, 1.585 mmol) and 5 ml of DMF were added, and the resulting mixture was stirred in a Biotage Initiator microwave at 120° C. for 30 mins. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane, to give the title compound as a white solid (67 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH2:33][N:17]1[CH2:18][CH2:19][N:14]([C:12]2[N:11]=[C:10]([NH2:20])[C:9]3[N:8]([N:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:21]=3)[CH:13]=2)[CH2:15][CH2:16]1
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nc(C(F)(F)F)c(CN2CCN(c3cn4nc(-c5ccco5)nc4c(N)n3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 5-chloro-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxaldehyde (45 mg, 0.21 mmol), sodium triacetoxyborohydride (65 mg, 0.31 mmol) and acetic acid (12 μL, 0.2 mmol). The reaction was stirred at room temperature overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=40:60) to afford 6-[4-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (9 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1ccc(F)c(NN)c1
Product: CCOC(=O)C(C)=NNc1cc(C)ccc1F

Procedure:
The title compoundwas prepared in accordance with the general method of example 25b) from (2-fluoro-5-methyl-phenyl)-hydrazine and ethyl pyruvate.