Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=2)[C:23]([O-:25])=[O:24])=[N:4][N:3]=1.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35](NS(C1C=NC=C(C2C3C(=C(C4C=CC=CC=4)C=CC=3)C(NCC3C=CC=CN=3)=NN=2)C=1)(=O)=O)(C)(C)[CH3:36]>>[C:12]1([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:3][N:4]=[C:5]3[C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=2)[C:23]([O:25][CH2:35][CH3:36])=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccn1
Reactant: O=C([O-])c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Product: CCOC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Yield: 88 %

Procedure:
Ethyl 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinate (3.10 g, 88.0%, brown solid) was prepared from 5-(4-chloro-5-phenylphthalazin-1-yl)nicotinate (3.00 g, 7.70 mmol) and 2-(aminomethyl)pyridine (10.0 mL, 97.0 mmol) by the methods described for the preparation of N-(tert-butyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide in Example 1. The residue was purified by preparative HPLC (Condition 15 as described in general methods). LCMS (Condition 2): retention time 1.90 min, [M+1]=462.2. HPLC (Condition 25): retention time=7.06 min, purity 96.07%. 1H NMR (400 MHz, DMSO-d6) δ 1.38 (t, J=7.2 Hz, 3 H), 4.42 (q, J=7.2 Hz, 2 H), 4.67 (d, J=4.4 Hz, 2 H), 6.35 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.21-7.25 (m, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.50-7.61 (m, 5 H), 7.69-7.73 (m, 2 H), 7.84 (dd, J=1.6 Hz, J=8.4 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.23 (dt, J=0.8 Hz, J=4.8 Hz, 1 H), 8.53 (t, J=2.0 Hz, 1 H), 9.11 (d, J=2.0 Hz, 1 H), 9.24 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:24]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: O=Cc1nccs1
Product: Nc1cc(Br)cc2nc(-c3nccs3)nn12

Procedure:
The title compound, MS m/e (%): 298 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 2-formylthiazole. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31].[H-].[Na+].S(OC)(O[CH3:38])(=O)=O.O>COCCOC>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:38])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.52 g.; 0.01 mol) in 1,2-dimethoxyethane (50 ml.) there is added 57% sodium hydride (0.42 g.; 0.01 mol) (oil dispersion). The mixture is stirred at room temperature for one hour and there is then added dimethyl sulfate (1.26 g.; 0.01 mol). The mixture is stirred at room temperature for one hour and is poured into an excess of water. The suspension is filtered and the filter cake dried to afford 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:7]=1[CH:8]=[O:9].C[O-:20].[Na+].Cl>CO.CS(C)=O.O>[OH:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:7]=1[C:8]([OH:20])=[O:9]
Reactant: C[O-]
Reactant: COCCOc1ccc(O)c(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COCCOc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium chlorite (8.08 g) was added over a period of 30 seconds to a stirred solution 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (see Example 41) and sodium methoxide in methanol (25% by weight solution, 9.68 ml) in dimethylsulphoxide (350 ml) at 15° C. After warming to room temperature and stirring for 3 hours the mixture was added to water (600 mls), acidified with 2M aqueous hydrochloric acid, and extracted with diethyl ether (4×250 mls). The ethereal extracts were combined, washed with water (2×100 ml), dried (MgSO4) and evaporated. The residue was crystallised from toluene to give 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (4.1 g) as solid m.p. 115-116° C.; NMR 3.3(3H,s), 3.65(2H,m), 4.05(2H,m), 6.9(1H,d), 7.15(1H, d of d), 7.25(1H,d); m/z 213(M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10](=O)[CH3:11].[ClH:13].[NH2:14][OH:15].[OH-].[Na+]>CO>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([CH:8]=[CH:9][C:10](=[N:14][OH:15])[CH3:11])=[CH:2][CH:7]=1
Reactant: Cl
Reactant: NO
Reactant: CC(=O)/C=C/c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccc(Cl)cc1)=NO
Yield: 54.7 %

Procedure:
In a 250 ml single neck flask was charged 5.4 g (29.9 mmoles, 1.0 eq.) of (E)-4-(2-chlorophenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.2 g of 4-(4-chlorophenyl)-3-buten-2-one 2-oxime (E/Z mixture of oxime isomers) as an oil in 54.7% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:10]=[C:3]12.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.FC1C=C(F)C=CC=1N1CCN2N=C(COC3C=CC=CC=3)C=C2C1=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:6][CH2:5][N:4]3[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:10]=[C:3]3[C:2]2=[O:1])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)OCc1cc2n(n1)CCNC2=O
Agent: O=C1c2cc(COc3ccccc3)nn2CCN1c1ccc(F)cc1F
Product: CC(=O)OCc1cc2n(n1)CCN(c1ccc(F)cn1)C2=O

Procedure:
The compound was prepared from acetic acid 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester and 2-bromo-5-fluoropyridine using the method described in the preceding example 43 (5-(2,4-difluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].C(Cl)Cl.[C:37]([C@@H:39](O)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)#[N:38]>N1C=CC=CC=1>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[C@H:18]1[C:30]([O:32][C@H:39]([C:37]#[N:38])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=1)=[O:31]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
6.2 g of dicyclohexylcarbodiimide were added to a mixture of 9.5 g of the product of Step B, 30 ml of methylene chloride and 3 ml of pyridine and after stirring for 30 minutes, 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture. The mixture was stirred for 90 minutes and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 16.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzene-ethyl acetate mixture to obtain 12 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:23]([CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>C(O)C>[CH2:34]([N:33]([CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:12]2)=[CH:7][CH:6]=1)[CH2:32][CH2:31][CH2:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: c1ccc(CNCCCCc2cccnc2)cc1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Solvent: CCO
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CN(CCCCc3cccnc3)Cc3ccccc3)ccc12
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)flavone (15 g, 51.0 mmol) and N-(3-nicotinylpropyl)benzylamine (22.5 g, 100 mmol) in ethanol (150 ml) was heated at 60° C. for 3 hours. The ethanol was then evaporated and the residue was washed with cyclohexane (three times) to remove the excess amine. The remaining residue was then extracted with ethyl acetate (twice), and the extracts were evaporated to give a red syrup. Purification of the red syrup by flash column chromatography eluting with EtOAc--MeOH (20:1) gave 8.0 g of a yellow syrup, 30% yield, which is stored in the refrigerator and used for the further reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:48]4[CH2:49][CH2:50][O:45][CH2:46][CH2:47]4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (33 mg, 0.1 mmol) in THF (5 mL) was added PPh3 (78.6 mg, 0.25 mmol) and tetrahydro-2H-pyran-4-ol (10 mg, 0.1 mmol). Then, DIAD (51 mg, 0.25 mmol) was added dropwise to the mixture at 0° C. and stirred at 0° C. for 10 min under N2. The mixture was allowed to warm to it and stirred at RT for 16 hr. The mixture was concentrated in vacuum and partitioned between DCM (20 mL) and brine (20 mL). Organic layer was separated from aqueous layers, dried over sodium sulfate and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 5 mg (12%) of 7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.66-7.58 (m, 2H), 7.58-7.52 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.97 (t, J=7.6 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.23 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 5.21 (s, 2H), 4.66-4.56 (m, 1H), 3.90-3.79 (m, 2H), 3.54-3.43 (m, 2H), 3.25-3.18 (m, 1H), 2.97-2.86 (m, 1H), 2.21-2.07 (m, 2H), 2.02-1.92 (m, 2H), 1.65-1.50 (m, 2H). MS (ESI) m/e [M+1]+ 415.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21].[C:22]([CH2:25][C:26](=O)[CH3:27])(=O)[CH3:23]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:9][C:10]3[N:21]=[C:22]([CH3:23])[CH:25]=[C:26]([CH3:27])[C:11]=3[C:12](=[O:14])[CH2:13]2)[CH:7]=1
Reactant: [NH4+]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCCCO
Product: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=O
Yield: 62.2 %

Procedure:
A mixture of 5-(5-fluoro-2-methylphenyl)-cyclohexane-1,3-dione (1.5 g) and ammonium acetate (1.6 g) in butanol(30 ml) was combined with acetylacetone (2.0 g) and heated under reflux for 3 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to a column chromatography on a silica gel (ethyl acetate-hexane) to obtain 7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][CH2:43][C:44]1[CH:64]=[C:63]([Cl:65])[C:47]2[O:48][C:49]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:50][C:46]=2[C:45]=1[Cl:66]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][CH2:43][C:44]2[CH:64]=[C:63]([Cl:65])[C:47]3[O:48][C:49]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[O:50][C:46]=3[C:45]=2[Cl:66])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Reactant: NOCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2cc(Cl)c3c(c2Cl)OC(c2ccccc2)(c2ccccc2)O3)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.4 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (100 mg) (0.17 mmol) and 93 mg (0.22 mmol) of 5-[(aminooxy)methyl]-4,7-dichloro-2,2-diphenyl-1,3-benzodioxol hydrochloride are dissolved in 2 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is distilled off in a high vacuum at room temperature. The residue is crystallized using diethyl ether. The product is filtered off under suction and washed with diethyl ether and water. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]imino]-acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder after drying in a high vacuum at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=[O:8].[C:25]1([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([NH:37][C:33]4[N:32]=[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:36]=[CH:35][N:34]=4)[CH:3]=[N:4][CH:5]=3)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: Nc1nccc(-c2ccccc2)n1
Reactant: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Nc4nccc(-c5ccccc5)n4)c3)cc2)CC1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
A mixture of 5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide (45.6 mg, 0.1 mmol) and 4-phenylpyrimidin-2-amine (25.7 mg, 0.15 mmol), KOBut (22.4 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 2 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder (20 mg, 38%). MS (ESI+) m/z 479.2 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C1N(P([Cl:43])(N2C(=O)OCC2)=O)C(=O)OC1.O[CH2:45][CH2:46][CH:47]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:48][C:49]([NH:51][NH2:52])=O>C(Cl)Cl.O>[Cl:43][CH2:45][CH2:46][CH:47]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:48][C:49]1[O:28][C:26](/[CH:25]=[CH:24]/[C:14]2[CH:15]=[CH:16][C:17]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:12]([O:11][CH3:10])[CH:13]=2)=[N:52][N:51]=1
Reactant: NNC(=O)CC(CCO)c1ccccc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C/c2nnc(CC(CCCl)c3ccccc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42.7 %

Procedure:
IPEA (2.0 mL), (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (600 mg) and BOPCl (0.71 g) were added to a solution of 5-hydroxy-3-phenylpentanoic acid hydrazide (492 mg) in methylene chloride (20 mL) at room temperature, and the reaction solution was stirred at room temperature for seven hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium bicarbonate solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Phosphorus oxychloride (10 mL) was added to the resulting residue at room temperature, and the reaction solution was heated under reflux for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 445 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C=CC=C[C:12]=1[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH3:12])=[CH:18][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ccccc1-c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
2-chloro-3-nitropyridine (100 mg, 0.63 mmol) was dissolved in dioxane (4 mL) in a round bottom flask to which p-tolylaniline (68 mg, 0.63 mmol) was added followed by addition of diisopropylethylamine (0.22 mL). The reaction mixture was heated to 80° C. for 24 hours and stopped when complete as observed by LCMS. After cooling to room temperature, the solvent was removed under reduced pressure to afford an oily residue. The residue was dissolved in ethyl acetate (20 mL) and washed with water and brine (5 mL each respectively). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was carried on to the next step without further purification. LCMS [M+H]: 230.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>>[CH3:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([CH3:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Yield: 65 %

Procedure:
The title compound is prepared from N-(3-amino-2,4-dimethyl-benzyl)-2,2-dimethyl-propionamide, 1,1′-thiocarbonyldi-2-pyridone in analogy to example Af.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1([C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:10][O:9][CH2:8][O:7][CH2:6]1.Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[CH:21]1([CH2:20][CH:12]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:11]([C:5]2([CH3:4])[CH2:10][O:9][CH2:8][O:7][CH2:6]2)=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C(=O)C(CC2CCCCC2)n2cncn2)COCOC1
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
2.96 g (0.05 mol) of powdered potassium hydroxide and 3 ml of water are added to a solution of 11.0 g (0.05 mol) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 40 ml of dimethylsulphoxide, with stirring. After 10 minutes, 9.6 g (0.05 mol) of bromomethylcyclohexane (90% pure) are added and the mixture is stirred at 50° C. for 6 hours. For working up, the cooled reaction mixture is poured onto 500 ml of water and extracted twice with 200 ml of diethyl ether each time, the combined ether extracts are washed twice with 100 ml of water each time and dried over sodium sulphate and the solvent is removed in vacuo. The oily residue crystallizes from methylene chloride/diethyl ether. 8.0 g (52.1 g of theory) of 3-cyclohexyl-1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-propan-1-one of melting point 68°-71 ° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O2, 433.9