Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([O:37]C)=[O:36])[C:28]=4[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CO.[ClH:41]>C1COCC1>[ClH:41].[ClH:41].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=4[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cccc2sc(-c3ccnc(NCCCN4CCN(C(=O)OC(C)(C)C)CC4)n3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCNc2nccc(-c3cc4c(C(=O)O)cccc4s3)n2)CC1
Reaction time: 0.03 h

Procedure:
Aqueous LiOH solution (2.5 N, 2.0 mL) is added to a stirred solution of 4-{3-[4-(4-methoxycarbonyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.49 mmol) in THF (7 mL)/MeOH (4 mL), the resultant mixture is stirred at 40° C. for 4 hours. At 40° C., 5 N HCl (2.1 mL) is added in one shot to the reaction mixture. Within 2 minutes the mixture becomes a suspension. After filtration and drying, the title compound is obtained as a yellow solid (950 mg, 99% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([O:9][C:10]3[CH:17]=[C:16]([CH3:18])[C:13]([C:14]#[N:15])=[C:12]([CH3:19])[CH:11]=3)=[C:7]([CH:20]3[CH2:22][CH2:21]3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu](I)I>[CH:20]1([C:7]2[C:8]([O:9][C:10]3[CH:17]=[C:16]([CH3:18])[C:13]([C:14]#[N:15])=[C:12]([CH3:19])[CH:11]=3)=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:6]=2)[CH2:22][CH2:21]1
Reactant: Brc1cccnc1
Reactant: Cc1cc(Oc2c(C3CC3)n[nH]c2C2CC2)cc(C)c1C#N
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2c(C3CC3)nn(-c3cccnc3)c2C2CC2)cc(C)c1C#N
Temperature: 110 °C
Yield: 4.4 %

Procedure:
Copper iodide (13 mg, 0.07 mmol) was added to a solution of the benzonitrile of Example 4 (200 mg, 0.68 mmol) and potassium carbonate (197 mg, 1.43 mmol) in toluene (2 ml) in a Reactivial®. The reaction mixture was degassed, then 3-bromopyridine (79 μl, 0.82 mmol) and (1R,2R)-(−)-1,2-bis(methylamino)cyclohexane (20 mg, 0.14 mmol) were added successively. The reaction was then sealed and heated at 110° C. for 24 hours. The reaction mixture was then diluted with ethyl acetate (20 ml), filtered through a pad of silica and then washed with more ethyl acetate (15 ml). The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC to provide the title compound (11 mg, 4%),
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].Cl.[CH:32]1([NH:36][NH2:37])[CH2:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:36]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:37]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1
Reactant: NNC1CCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-thiopropionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow foam.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([CH2:14][O:15]/[N:16]=[C:17](/[C:21]1[N:22]=[C:23]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:24][CH:25]=1)\[C:18]([OH:20])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.[NH2:53][CH:54]1[C:68](=[O:69])[N:56]2[C:57]([C:65]([OH:67])=[O:66])=[C:58]([CH2:61][N:62]=[N+:63]=[N-:64])[CH2:59][S:60][C@H:55]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>ClCCl.O.CN(C=O)C>[N:62]([CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:18](=[O:20])/[C:17](=[N:16]\[O:15][CH2:14][C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])/[C:21]3[N:22]=[C:23]([NH:26][C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[S:24][CH:25]=3)[C:68](=[O:69])[N:56]2[C:57]=1[C:65]([OH:67])=[O:66])=[N+:63]=[N-:64]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
The 3-aminomethylcephalosporin may be prepared as follows:-Oxalyl chloride (337 μl.) and DMF (330 μl.) were added to CH2Cl2 (20 ml.) at -10°, and stirred for 30 minutes. 2((Z)-t-Butoxycarbonylmethoxyimino)-2-(2 tritylaminothiazol-4-yl)acetic acid and N-methylmorpholine (510 μl.) were added and stirring continued for 30 minutes. Meanwhile in a separate flask, a suspension of 7-amino-3-azidomethylceph-3-em-4-carboxylic acid (987 mg.) in dichloromethane (8 ml.) was treated with N,O-bis(trimethylsilyl)acetamide (1.91 ml.), and stirred for 1 hour to give a clear solution, which was transferred by syringe to the acid chloride solution. After stirring the mixture for 1 hour at -10°, the temperature was allowed to rise to ambient. The mixture was poured into water (25 ml.) and organics extracted with EtOAc (3×25 ml.). The crude product was filtered through a short SiO2 column in EtOAc/HOAc 99:1 v/v, and evaporated to give 3-azidomethyl-7-[2-((Z)-t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic acid, having the following n.m.r. in solvent A:-1.4(s, 9H); 3.35(d, 1H); 3.63(d, 1H); 3.86(d, 1H); 4.38(d, 1H); 4.49(s, 2H); 5.09(d, 1H); 5.7(d, 1H); 6.73(s, 1H); 7.29(m, 15H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:22][O:21][C:20]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19]2)[CH2:14][CH2:13]1)=O)C.C1C[O:31][CH2:30]C1>>[O:19]1[C:20]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:21][CH2:22][CH:18]1[CH:15]1[CH2:14][CH2:13][CH:12]([CH2:10][CH2:30][OH:31])[CH2:17][CH2:16]1
Reactant: CCOC(=O)C1CCC(C2COC3(CCCCC3)O2)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dried THF (100 ml) was added to lithium aluminum hydride (17.6 g, 0.464 mol), followed by cooling the mixture down to 0° C., dropwise adding thereto a 800 ml THF solution of the above 4-(1,4-dioxaspiro[4.5]decyl)cyclohexylmethanoic acid ethyl ester (183.2 g, 0.464 mol), stirring at 0° C. for 3 hours, stirring at room temperature for 2 hours, washing the reaction solution successively with 3N HCl, a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, and recrystallizing, to isolate colorless crystals of 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol (50.6 g, 0,179mol). Yield from bicyclohexanedione monoethylene ketal was 38%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.Br[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCCOC(=O)CBr
Product: CCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Yield: 55 %

Procedure:
The procedure of Example 3 was repeated by using 10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (250 mg) and n-propyl bromoacetate (0.1 ml) to obtain the title compound (170 mg, 55%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][N:13]=[N:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2cnns2)cc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(-c2cnns2)ccc1OCC1CO1

Procedure:
To a solution of 0.92 g. of sodium hydroxide in 425 ml. of water is added 4.1 g. of 5-(4-hydroxyphenyl)-1,2,3-thiadiazole and 5.4 ml. of epibromohydrin, stirring the reaction mixture for 20 hours at room temperature. It is then extracted with ethyl acetate, and the organic extract washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel plates using a mixture of chloroform-acetone (95:5) as eluant to yield 5-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole. This product can be further purified by crystallization from methylene chloridehexane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:19][OH:20])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(-c2ccc(O)cc2)ccc1C=O
Agent: Cl
Product: COc1cc(-c2ccc(O)cc2)ccc1C=NO

Procedure:
The title compound was prepared by reacting 4′-hydroxy-3-methoxy-1,1′-biphenyl-4-carbaldehyde (225 mg, 0.986 mmol) with hydroxylamine hydrochloride (137 mg, 1.97 mmol) according to Method C to yield 210 mg (88%) of yellowish solid: mp 228-230° C.; 1H NMR (DMSO-d6): δ 3.91 (3H, s), 6.85 (2H, d, J=8.29 Hz), 7.18 (1H, d, J=8.08 Hz), 7.21 (1H, s), 7.56 (2H, d, J=8.59 Hz), 7.68 (1H, d, J=7.98 Hz), 8.28 (1H, s), 9.63 (1H, s), 11.19 (1H, s); MS (ESI) m/z 242 (M−H)−, 244 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:20]CC1>CC#N.CCOC(C)=O>[CH:2]([C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:20]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C=O)c1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a mixture of (A2) (1.0 eq.) and 4 Å mol. sieves (15 g) in MeCN (0.2M) at RT was added NMMO (2.0 eq.) and the reaction mixture was stirred for 1.5 hr under N2 atmosphere. Then, the mixture was diluted with EtOAc, filtered and the filtrate was washed with H2O, 1N HCl, brine and dried (Na2SO4). Evaporation of the solvent gave (A3) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 9.96 (1H, s), 8.26 (1H, d, J=7.9 Hz), 8.18 (1H, d, J=7.9 Hz), 7.77 (1H, t, J=7.9 Hz), 3.93 (3H, s). MS (ES) C9H7NO5 requires: 209. Found: 208 (M−H)−.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])N)=[CH:14][CH:13]=1.C(OC(OCC)CCCNC)C.ClC1C=C2C(=CC=1)N(C[C:53]([N:55]1[CH2:60][CH2:59][CH:58](C)[CH2:57][CH2:56]1)=O)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[N:18]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[C:57]1[CH2:56][N:55]([CH3:53])[CH2:60][CH2:59][C:58]2=1
Reactant: CC1CCN(C(=O)CN(N)c2ccc(Cl)cc2)CC1
Reactant: CNCCc1cn(CC(=O)N2CCC(C)CC2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3)CC1

Procedure:
The title compound is prepared by following General Methods 1, 3, and 4 by using 4-chlorophenylhydrazine hydrochloride, 1-(N-bromoacetyl)-4-methyl piperidine, and triethylamine (General Method 1), 2-(1-(4-chlorophenyl)hydrazinyl)-1-(4-methylpiperidin-1-yl)ethanone and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3), 2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)-1-(4-methylpiperidin-1-yl)ethanone, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:16]=[CH:15][C:14]([NH:17][CH:18]=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]1[N:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]2=[O:26]
Reactant: CCOC(=O)C(=CNc1ccc(NC2Cc3ccccc3C2)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2ccc(NC3Cc4ccccc4C3)nc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
A solution of diethyl 2-((6-(2,3-dihydro-1H-inden-2-ylamino)pyridin-3-ylamino)methylene)malonate (1.3 g) in dichloromethane (10 ml) was added very carefully into pre-heated (230° C.) diphenyl ether (20 ml) with stiffing and heating was continued with stiffing for another 20 min after addition had been completed. This was then allowed to cool to room temperature, petroleum ether (200 ml) was added, and the solid which separated was filtered off dried to give the crude product (600 mg), which was on-reacted without further characterization other than ascertaining that the compound was one spot by tlc with the expected molecular weight (M+1) of 350.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[F:19][C:20]1[C:25](O)=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:19][C:20]1[C:25]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(C(=O)Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1
Temperature: 0 °C

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane. 10.2 g. (0.05 moles) of phosphorus pentachloride are added and the mixture is stirred for two hours at the boiling point of dichloromethane. The solvent is distilled off and the residue is taken up in carbontetrachloride and the solution is added dropwise to 9.2 g. (0.05 moles) of pentafluorophenol and 4 ml. (0.05 moles) of pyridine-dissolved in 200 ml. of carbontetrachloride. The reaction mixture is cooled to 0° C. and the pyridine chlorohydrate is washed with 2n hydrochloride acid. The organic layer is washed twice with 40 ml. of water, dried over magnesium sulfate and evaporated. The α-cyano-phenylacetic acid-pentafluorophenyl ester is recrystallized from petrolether
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][OH:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:26](I)[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][O:25][CH2:26][CH3:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Add sodium hydride (0.558 g, 14.0 mmol) in portions to (S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (3.075 g, 9.31 mmol) in dimethylformamide (60 mL) and stir for 15 minutes. Cool to 0° C. and add ethyl iodide (1.5 mL, 18.6 mmol) dropwise and stir at 0° C. After 30 minutes warm the mixture to room temperature and stir overnight. Dilute the mixture with ethyl acetate and wash the organics six times with brine. Dry over sodium sulfate and concentrate under reduced pressure to give (S)-2-(2-ethoxyethyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (3.17 g, 95%) as a yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18].[Na+].[Cl-]>CN(C)C=O.C1COCC1>[CH2:1]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCc1ccccc1C(=COC)C(=O)OC
Temperature: 0 °C

Procedure:
7.4 g of n-butanol are dissolved in 50 ml of dimethylformamide, and 2.4 g of sodium hydride are added. The solution is slightly heated until everything has reacted. This solution is gradually added dropwise at -20° C. to 28.4 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate in 150 ml of THF. Once the bromomethyl compound is no longer detectable by thin layer chromatography, 100 g of ice and 100 ml of saturated NaCl solution are added. Extraction with methylene chloride gives 23 g of an oil which is chromatographed. 10 g of a resin are obtained after elution with ethyl acetate/hexane.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]3[C:29]4[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]5[CH2:37][CH2:36]5)[C:28]=4[S:27][CH:26]=3)=[O:24])[CH:16]=2)=[CH:9][C:8]=1[C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:49][C:50]1[N:51]=[CH:52][NH:53][CH:54]=1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([NH:34][C:33]2[C:28]3[S:27][CH:26]=[C:25]([C:23]([NH:22][C:17]4[CH:16]=[C:15]([C:14](=[O:38])[NH:13][C:10]5[CH:11]=[CH:12][C:7]([CH2:6][N:53]6[CH:54]=[C:50]([CH3:49])[N:51]=[CH:52]6)=[C:8]([C:39]([F:42])([F:40])[F:41])[CH:9]=5)[CH:20]=[CH:19][C:18]=4[CH3:21])=[O:24])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:36][CH2:37]1
Reactant: Cc1c[nH]cn1
Reactant: Cc1ccc(C(=O)Nc2ccc(COS(C)(=O)=O)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
4-(3-(4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzamido)-2-(trifluoromethyl)benzyl methanesulfonate (30 mg, 0.048 mmol) was dissolved in DMF (1 mL), K2CO3 (20 mg, 0.145 mmol) and 4-methyl-1H-imidazole (20 mg, 0.242 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (MeOH/DCM=5/95) to obtain the title compound (23 mg, 78% yield).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH:29]=[C:28]([CH:30]=O)[C:27]([CH3:32])=[N:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:1].[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([N:18]3[CH2:23][CH2:22][N:21]([CH2:30][C:28]4[C:27]([CH3:32])=[N:26][N:25]([CH3:24])[CH:29]=4)[CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: Cc1nn(C)cc1C=O
Reactant: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COCc1ccc(-c2nccnc2N2CCN(Cc3cn(C)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
Stir 3′-(4-methoxymethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (312 mg, 0.87 mmol) in dry tetrahydrofuran (10 mL), and add 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (138 mg, 0.87 mmol). Stir at room temperature for 15 min., and then add sodium triacetoxyborohydride (171 mg, 1.04 mmol). Stir the reaction for 17 hr. at room temperature, then at 50° C. for 20 hr. under nitrogen. Pour the reaction mixture into saturated aq. sodium bicarbonate (20 mL), extract with DCM (3×20 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify using silica gel chromatography (eluting with 2:98 to 5:95 methanol:DCM). Dissolve the oil in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize, then free base using an SCX-2® ion exchange cartridge. Further purify by low pH reverse phase HPLC. Form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 3 M ammonia in methanol and concentrate. Dissolve the solid in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a bright yellow solid (80 mg, 22%). MS (ES): m/z=393 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Br[CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(=O)OCC>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH2:27][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:8]4[CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:25])[NH:6][N:7]=4)[CH:24]=[CH:23][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(OC)OC)cc3)oc2c1

Procedure:
100 mg (298 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 38.5 μL (316 μmol) 2-bromo-1,1-dimethoxy-ethane, 125 mg (904 μmol) potassium carbonate and 3 ml DMF are stirred for 6 h at 150° C. and then at RT over the weekend. Then the mixture is diluted with EA, and extracted with 10% sodium carbonate solution and then with sat. saline solution. The solv. of the org. phase is eliminated i.V. The residue is purified on silica gel (eluant: DCM/methanol) the solv. of the corresponding fractions is eliminated i.V. and the residue is recrystallised with EA/cyclohexane.