Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]2[CH2:26]C[O:24][CH2:23][CH2:22]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5].ClCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CCC)=NC=2N.O1CC[C@@H](N)C1>>[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C@@H:21]2[CH2:22][CH2:23][O:24][CH2:26]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: N[C@@H]1CCOC1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN[C@@H]3CCOC3)c2n1
Temperature: 70 °C

Procedure:
Prepared similarly to Intermediate 36 from 9-(4-chlorobutyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and (3R)-tetrahydro-3-furanamine but with heating at 70° C. for an additional 20 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[N:9]=2)=[CH:4][CH:3]=1.I[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([NH:13][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1N
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1Nc1ccccc1C(=O)O
Temperature: 150 °C
Reaction time: 18 h
Yield: 11.9 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate D, 100 mg, 0.37 mmol) in DMF (3 mL), was added 2-iodobenzoic acid (93 mg, 0.37 mmol), potassium carbonate (62 mg, 0.45 mmol), and copper (II) acetate (3 mg, 0.01 mmol). The mixture was stirred at 150° C. for 18 h and then cooled to rt. The solution was adjusted to pH 4 using glacial acetic acid. The mixture was extracted with dichloromethane (3×5 mL), and then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by HPLC (45-90% acetonitrile in water) to afford the title compound (17 mg, 12%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 6.85 (ddd, 1H), 6.93 (s, 1H), 7.24 (ddd, 2H), 7.42 (m, 6H), 7.84 (dd, 1H), 7.92 (ddd, 2H), 10.02 (s, 1H), 13.23 (s, 1H); ES-MS m/z 388.2 (MH+); HPLC RT (min) 3.47.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:48]>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:32])([C:28]([NH2:48])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@H]2CC[C@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
Methyl (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinate (Intermediate 9, 25 mg, 0.039 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml, 21.0 mmol) and the reaction mixture was stirred for 48 hours at 60° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Companion system; eluent: from 99:1 Dichloromethane/MeOH to 95:5 Dichloromethane/MeOH; 12 g cartridge) affording the title compound (16 mg, 0.026 mmol, 65.5% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.BrBr>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CCCCCC.C(OCC)(=O)C>[CH2:14]([C:13]1[C:12]([O:11][C:9](=[O:10])[C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)[C@@H](Cc2ccccc2)[C@@H]1Cc1ccccc1
Agent: BrBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1OC(=O)C(Cc2ccccc2)=C1Cc1ccccc1
Yield: 25 %

Procedure:
To the suspension of (2S,3S)-2,3-dibenzylsuccinic anhydride thus obtained in anhydrous toluene (3.5 mL) were added triethylamine (361 mg, 2.54 mmol) and trimethylsilyltrifluoromethanesulfonic acid (565 mg, 2.54 mmol) with stirring under ice cooling, and the mixture was stirred at 90° C. for 2 h. To the reaction mixture with stirring under ice cooling was added dropwise a solution of tetrabutylammonium bromide (2.7 mg, 0.00845 mmol) in dichloromethane (3 mL) and bromine (140 mg, 0.876 mmol), and the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 8:1) to give 59 mg of the title compound as a solid (2 step yield: 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[C:4]([CH:8]=[C:9]([O:11][CH2:12][CH:13]=[C:14]([Cl:16])[Cl:15])[CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][CH2:45][CH2:46][OH:47]>C1(C)C=CC=CC=1>[OH:47][CH2:46][CH2:45][NH:44][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[C:14]([Cl:16])[Cl:15])[CH:10]=[C:2]([Cl:1])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=1
Reactant: O=C(O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
0.2 g of 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-[3-(5-trifluoromethylpyrid-2-yloxy)-propyloxy]benzoic acid and 0.065 g of carbonyldiimidazole were allowed to react at room temperature in 4 ml of anhydrous toluene for 1.5 hours. 0.027 g of 2-amino-ethanol was then added, and the mixture was stirred at room temperature for another hour. The reaction mixture was concentrated under reduced pressure and purified by column chromatography. Yield: 0.159 g (73%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21]1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: N#CCC1CCC(N)CC1
Agent: Cl
Product: N#CC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.108 g, 0.36 mmol) was reacted with 2-(4-aminocyclohexyl)acetonitrile (0.120 g, 0.72 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.068 g, 47%) as a white solid. MW=402.36. 1H NMR (DMSO-d6, 500 MHz) δ 13.51 (s, 1H), 7.99-7.96 (m, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.71-7.68 (m, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.14 (s, 1H), 3.95-3.79 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.95-1.88 (m, 2H), 1.85-1.77 (m, 2H), 1.68-1.58 (m, 1H), 1.37-1.22 (m, 2H); APCI MS m/z 366 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][NH2:9])[CH2:4][CH3:5])[CH3:2].Cl[C:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=3)[S:16][C:15]=2[C:14]([N+:34]([O-:36])=[O:35])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:11]2[CH:12]=[CH:13][C:14]([N+:34]([O-:36])=[O:35])=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:21][C:22]=4[C:23]([C:24]=23)=[N:9]1)[CH3:2]
Reactant: CCN(CC)CCNN
Reactant: O=c1c2cc(OCc3ccccc3)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccc(OCc3ccccc3)cc1-2
Yield: 61.1 %

Procedure:
A mixture of 1.2 g (0.0091 mol) of 2-(diethylaminoethyl)hydrazine, 2.7 g (0.0069 mol) of 1-chloro-4-nitro-7-phenylmethoxy-9H-thioxanthen-9-one, and 0.97 g (0.0069 mol) of powdered K2CO3 in 30 ml of xylene was reacted and 2.0 g of the product was isolated as described in Example 58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][C:4]=1[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[C:7]=1[CH:5]([C:4]1[CH:16]=[C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:18]=[CH:19][C:3]=1[O:2][CH3:1])[OH:6]
Reactant: COc1ccc(-n2ccnc2)cc1C(=O)c1c(C)cc(C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2ccnc2)cc1C(O)c1c(C)cc(C)cc1C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a suspension of 4 g of 2-methoxy-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 20 ml of ethanol is added a solution of 0.9 g of sodium borohydride in 5 ml of water. After the whole mixture is stirred at 70°-75° C. for 1.5 hours, the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 2.9 g of α-(2,4,6-trimethylphenyl)-2-methoxy-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 187°-188° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:24][CH2:23]4)[O:19][N:18]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:26].C(OCC)C>C(Cl)Cl>[ClH:26].[CH:22]1([C:20]2[O:19][N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:8]4([NH2:7])[CH2:9][CH2:10]4)=[N:12][CH:13]=3)[N:21]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To the solution of {1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (80 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added 4M HCl (2 mL, 8 mmol). After stirring overnight, more 4M HCl (0.1 mL, 0.4 mmol) was added. After a total of 42 h, diethyl ether (10 mL) was added to the reaction mixture and stirring was continued for 10 min. The reaction suspension was filtered and the solid was washed with ether (10 mL) to afford 1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropylamine HCl salt (40 mg) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([OH:35])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[N+](=[CH2:38])=[N-]>>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:38])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2

Procedure:
Asiatic acid (2) is treated with diazomethane to obtain methyl asiatate (3, R3 =methyl) quantatively, which is then oxidized to give a compound of lactol structure (4, R3 =methyl) in which A-ring have been modified. The compound is treated with catalytic amount of acetic acid/piperidine to obtain methyl A(1)-norursa-2,12-diene-23-hydroxy-2-formyl-28-oate (5, R3 =methyl). [See Scheme 1]
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:15])[C:10](=[CH:13][CH:14]=2)[CH:11]=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:15][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:14]=[CH:13][C:10]=1[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Reactant: [Li]c1ccccc1
Product: O=C(c1ccccc1)c1ccc(N2CCOCC2)cc1O

Procedure:
Following the procedure for preparing Example 34, 4-(4-morpholinyl)-salicylaldehyde (1.0 g, 5 mmol) and phenyllithium (1.8 M solution in tetrahydrofuran, 6.0 mL, 11 mmol) were converted to the product (387 mg, 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].O.[BH4-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)c([N+](=O)[O-])cc1OC
Temperature: 40 °C
Yield: 56.5 %

Procedure:
1011 g of 2-nitro-4,5-dimethoxybenzaldehyde in 10 l of ethanol with 94.8 ml water added was stirred, and a solution of 57 g sodium borohydride in 2 l absolute ethanol was added over 1 hour. The mixture was heated to 40° C. for 2.5 hours, cooled to 5° C. and the mixture filtered. The solid was washed with 4 l of cold 2B alcohol (denatured ethanol) and 8 l cold water, and dried in a 50° C. vacuum oven to yield 570 g, 56.5% yield.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.FC(F)(F)C(O)=O.CCOCC>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.75 h
Yield: 22.3 %

Procedure:
To a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[(Z)- 2(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.28 g) in a mixture of methylene chloride (3.8 ml) and anisole (1.28 ml) was added trifluoroacetic acid (2.6 ml) under ice-cooling. The mixture was stirred for 45 minutes at the same temperature. The mixture was poured into diisopropl ether (200 ml) to give a precipitate. The precipitate was collected, washed with diisopropyl ether and dissolved in a mixture of ethyl acetate and dilute aqueous solution of sodium bicarbonate at pH 5. The insoluble material was filtered off. The aqueous layer was separated and concentrated in vacuo in order to remove ethyl acetate. The aqueous solution was adjusted to pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water. The fractions containing the object compound were combined and concentrated in vacuo to about 20 ml. The concentrated solution was adjusted to pH 2 with dilute hydrochloric acid under ice-cooling to give a precipitate. The precipitate was collected, washed with cold water and dried over phosphorus pentoxide to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (220 mg).
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+].[F:42][C:43]([F:54])([F:53])[C:44]1[C:45]2[CH2:52][O:51][CH2:50][CH2:49][C:46]=2[NH:47][N:48]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:53][C:43]([F:42])([F:54])[C:44]1[C:45]2[CH2:52][O:51][CH2:50][CH2:49][C:46]=2[N:47]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)[N:48]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: FC(F)(F)c1n[nH]c2c1COCC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-n1nc(C(F)(F)F)c2c1CCOC2
Temperature: 150 °C
Reaction time: 18 h

Procedure:
5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 150 mg, 0.282 mmol), copper (1+) iodide (59.1 mg, 0.310 mmol), N,N-dimethylglycine (32.0 mg, 0.310 mmol) and K2CO3 (86 mg, 0.620 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (2 ml) to give a light blue solution with a white precipitate. To this mixture, 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (starting material prepared according to a similar procedure to that described in Prep38 followed by Prep39, 179 mg, 0.931 mmol) was added. After 18 h shaking at 150° C., the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, then filtered and the solvent evaporated. The obtained crude was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. The resulting mixture was further purified by preparative LC-MS to obtain 9.6 mg of the title compound as a free base.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:8])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:18]1[C:19]([C:2]2[S:6][C:5]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[O:8])=[CH:4][CH:3]=2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1
Reactant: O=C(Nc1ccccc1Cl)c1ccc(Br)s1
Reactant: Cc1nc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2cc(Cl)c(-c3ccc(C(=O)Nc4ccccc4Cl)s3)cc2o1
Temperature: 110 °C
Yield: 33.2 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2-chlorophenyl)carboxamide (7) (25 mg, 0.08 mmol), 2-(5-chloro-2-methylbenzoxazol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (23 mg, 0.08 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 12 mg) and sodium carbonate (32 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash column chromatography. The isolated crude product was re-purified on prep HPLC to furnish 10.7 mg of [5-(5-chloro-2-methylbenzoxazol-6-yl)(2-thienyl)]-N-(2-chlorophenyl)carboxamide (8) as white solid (yield: 33.1%; purity>95%). LC-MS: calcd. for C19H12Cl2N2O2S: 404 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:12]([N:14]([CH:22]3[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:8][C:9]=2I)[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.[Pd]>[CH:22]1([N:14]([CH:12]([C:7]2[CH:6]=[C:5]3[C:10]([CH:2]=[N:3][N:4]3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:9][CH:8]=2)[CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: COCCCn1nc(Br)c2c(I)cc(C(C)N(C(=O)OC(C)(C)C)C3CC3)cc21
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1ncc2ccc(C(C)N(C(=O)OC(C)(C)C)C3CC3)cc21
Reaction time: 42 h
Yield: 25.9 %

Procedure:
To a solution of tert-butyl N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}cyclopropylcarbamate (1.0 g) in 1,4-dioxane (20 mL) were added diisopropylethylamine (0.90 mL) and 10% palladium on carbon catalyst (200 mg), and the mixture was stirred under hydrogen for 42 hours. An insoluble was filtered, and then the filtrate was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give tert-butyl cyclopropyl{1-[1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}carbamate [REx(30-1)] (167 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].CO[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:8]2[NH:5][CH2:4][CH:3]=[CH:2][NH:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCN
Reactant: COC(=O)c1ccccc1
Product: C1=CNC(c2ccccc2)NC1
Reaction time: 3 h
Yield: 79 %

Procedure:
With 185 g 1,3-diaminopropane, 136 g benzoic acid methyl ester were reacted under pressure at 200° C. in the reactor. After 3 hours, the excess of diamine was distilled off, and the 2-phenyl-tetrahydropyrimidine was isolated in a 79% yield. Boiling point 165° C./1 mm; melting point=86°-87° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][CH3:35])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Reactant: CN
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Yield: 46.1 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.3 g, 0.63 mmol) and methyl amine (1.3 ml of 1M solution, 1.3 mmol) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.135 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.70 (m, 1H), 8.65 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.41-8.39 (m, 1H), 7.85 (s, 1H), 7.81 (brs, 2H), 7.38 (s, 1H), 7.24-7.22 (m, 2H), 3.61-3.57 (m, 3H), 2.90 (d, J=4.0 Hz, 1H), 2.60 (s, 3H), 1.46 (s, 9H); (ESI) m/z: 465.2 (M+H*).