Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[O:16][CH3:17].[CH3:19][C:20]([CH3:23])([O-:22])C.[Na+]>O1CCCC1.CCOCC.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]>[O:16]1[C:20]2([CH2:19][CH2:11][N:10]([C:2]3[CH:3]=[CH:4][C:5]([F:18])=[C:6]4[C:11]=3[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]4[O:16][CH3:17])[CH2:9][CH2:23]2)[O:22][CH2:6][CH2:7]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(F)(F)F)nc2c(N3CCC4(CC3)OCCO4)ccc(F)c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 126.8 %

Procedure:
To a solution of 8-chloro-5-fluoro-4-methoxy-2-(trifluoromethyl)quinoline (Step 2, 1.24 g, 4.45 mmol, 1 eq.) in anhydrous tetrahydrofuran (44 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3, 0.125 g, 0.14 mmol, 0.03 eq.), sodium tert-butoxide (0.69 g, 7.18 mmol, 1.61 eq.), 2-dicyclohexyl-phosphino-2′-(N,N-dimethylamino)biphenyl (CYMAP, 0.054 g, 0.14 mmol, 0.03 eq.), and 1,4-dioxo-8-azaspiro-4,5-decane (0.8 mL, 6.24 mmol, 1.4 eq.). The resulting mixture was stirred at 70° C. overnight (approximately 18 hours) under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered through a plug of silica gel and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1.09 g (64% yield) of the desired product as a beige solid; MP=101-103° C.; MS (ES) m/z (relative intensity): 387 (M+H)+ (100).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:16]2[CH:15]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:19]=[CH:18][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(NC2CCNCC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6c (104 mg, 0.21 mmol) and triethylamine (0.1 mL, 3.3 eq) in 1 mL of DCM, was added isopropyl chloroformate (0.24 mL, 1.1 eq). The mixture was stirred at room temperature for 2 h. The crude mixture was poured onto silica and eluted with ethyl acetate/hexane then chromatographed over a silica gel column (elution with 25-100% ethyl acetate and 0.1% TEA in hexanes) and finally purified on preparative HPLC to give 6-1, LC-MS 460.4 (MH+), tR=4.50 (Method 4). EC50: 611 nM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[C:54]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=4[C:48]4[C:43]3=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:40]2[CH:41]=[CH:36][CH:37]=[C:38]([N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=4[C:49]4[C:54]3=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:39]=2)[CH:5]=[C:4]([Si:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (4.02 g, 8.12 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (1.500 g, 4.06 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol), K2CO3 (1.123 g, 8.12 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen for 24 h. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (9/1 to 4/1, v/v) as eluent and recrystallized from hexane/DCM (9/1, v/v) to yield 9-(3′-Bromo-5′-(triphenylsilyl)-[1,1′-biphenyl]-3-yl)-9H-carbazole (2.1 g, 79%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](NC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=O)(C)(C)C.[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:41])=[O:40]>>[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44]([CH2:1][O:5][CH3:6])[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:40])=[O:41]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropylamine IV k3 is allowed to react and worked up by the same procedure as described in (4). m.p. 41.5°-43° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12]>O.C(O)(C)(C)C>[C:2]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:1])[CH3:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (45 g, 345 mmol) and Triton-B (40%, weight % solution in water, 1.08 mg, 6.90 mmol) in tert-BuOH (54 mL) was added tert-butyl acrylate (100.72 g, 691 mmol) dropwise over a period of 30 min under N2 atmosphere. The solution was stirred at room temperature for 24 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer washed with EtOAc (2×50 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to provide compound D28-1 (140 g, quant) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.20 (q, J=7.2 Hz 2H), 2.24-2.09 (m, 8H), 1.58 (s, 3H), 1.43 (s, 18H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N:21]1[C:30](=[O:31])[C:29]2[C:24](=[N:25][C:26]([S:32][CH3:33])=[N:27][CH:28]=2)[N:23]([CH3:34])[C:22]1=[O:35].CN(C=[O:40])C.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[CH3:33][S:32]([C:26]1[N:25]=[C:24]2[N:23]([CH3:34])[C:22](=[O:35])[N:21]([C:3]3[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])[C:30](=[O:31])[C:29]2=[CH:28][N:27]=1)=[O:40]
Reactant: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Reactant: CN(C)C=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-n1c(=O)c2cnc(S(C)=O)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of N-[4-Methyl-3-(1-methyl-7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (184 mg, 0.37 mmol) in the mixed solvent of DMF (4 mL) and chloroform (4 mL) is added m-chloroperoxybenzoic acid (77% max., 97 mg, 44 mmol) and the mixture is stirred for 1 h at room temperature. The mixture is diluted with chloroform, and washed with 5% aqueous Na2S2O3 solution and saturated NaHCO3 solution. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give N-[3-(7-Methanesulfinyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (167 mg, 88%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=2)[NH:22][N:21]=1.[CH2:30]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][C:36](=O)[CH2:37]2)[CH2:31][CH3:32].N>ClC(Cl)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][CH:36]3[CH2:35][CH:34]4[N:33]([CH2:30][CH2:31][CH3:32])[CH:38]([CH2:39][CH2:40]4)[CH2:37]3)[CH:27]=2)[NH:22][N:21]=1
Reactant: CCCN1C2CCC1CC(=O)C2
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCN1C2CCC1CC(Nc1ccc3[nH]nc(Br)c3c1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.1 %

Procedure:
Sodium triacetoxyborohydride (159 mg, 0.750 mmol) and then acetic acid (29 μl, 0.507 mmol) were added to a suspension of 3-bromo-1H-indazol-5-amine (106 mg, 0.500 mmol) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (100 mg, 0.598 mmol) in dichloroethane (3 ml), and the resulting mixture was stirred at room temperature for 1 day. Aqueous ammonia was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (chloroform/methanol/triethylamine=100/10/5) and a preparative thin-layer chromatography (200×200×0.5 mm, eluent: chloroform/methanol/triethylamine=100/5/5) to obtain 3-bromo-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (2 mg, 1%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:30](=[O:32])[CH3:31])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirred solution containing 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (WO 2009/102736) (0.272 g, 0.849 mmol) and pyridine (0.137 mL, 1.90 mmol) dissolved in dichloromethane (2.1 mL) at 0° C. was added acetyl chloride (0.079 mL, 1.10 mmol) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The solution was diluted with dichloromethane (20 mL) and washed successively with hydrogen chloride (1 N, 1×15 mL), saturated aqueous sodium bicarbonate (1×15 mL) and saturated sodium chloride solution (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (0.291 g, 95%): mp 169-171° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.28 (s, 1H), 2.22 (s, 3H). ESIMS m/z 362 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22]C)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(O)=O.Br>O.[OH-].[Na+]>[NH2:21][C:19]1[CH2:18][O:17][CH2:16][C@:15]2([C:14]3[CH:13]=[C:12]([OH:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:20]=1
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
(S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.611 g, 1.624 mmol) was dissolved in HOAc (6.14 mL, 107 mmol). Hydrobromic acid (48% aq.; 6.06 mL, 53.6 mmol) was added and the reaction was stirred at 100° C. for two hours. The reaction was diluted with water, slowly neutralized to pH 7 with 6N NaOH, and stirred overnight, during which a light pink solid crashed out of solution. The solution was filtered, and the solid was air dried to afford (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.554 g, 1.530 mmol, 94% yield) as an off-white solid. [M+H]+=363.9 Step 2: A flask was charged with (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.250 g, 0.690 mmol), cesium fluoride (9.17 mg, 0.069 mmol), and acetonitrile (6.90 mL). Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.272 mL, 1.381 mmol) was added slowly and the reaction was stirred for 15 minutes. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM), to afford (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol, 19.68% yield) as a light yellow solid. [M+H]+=411.9 Step 3: A microwave vial was charged with (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol). 2-fluoropyridin-3-ylboronic acid (0.038 g, 0.272 mmol), potassium phosphate (0.087 g, 0.408 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.81 mg, 6.79 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.509 mL) and water (0.170 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM) to afford (S)-3-(difluoromethoxy)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.042 g, 0.098 mmol) as a light yellow solid. [M+H]+=429.0
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-(pyrrolidin-1-yl)pyridazine (7.2 g, 33 mmol) and hydrazine hydrate (9.96 g, 0.2 mol) were heated at reflux in dioxan (130 ml) for 6 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (4.1 g, 58%). 1H NMR (250 MHz, d6-DMSO) 1.79-1.84 (4H, m), 3.25-3.40 (4H, m), 4.12 (2H, br), 6.09 (1H, s), 7.47 (1H, s). MS (ES+) 214 [MH]+, 216 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:3]1=[O:12].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[N:2]([CH3:1])[C:3](=[O:12])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]2=[O:7])=[CH:17][CH:16]=1)#[N:14]
Reactant: CN1CC(=O)N(CC(=O)O)C1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)N(CC(=O)O)C(=O)C1=Cc1ccc(C#N)cc1

Procedure:
2.6 g (15 mmol) of (1-methyl-2,4-dioxoimidazolidin-3-yl)-acetic acid, 2.9 g (22 mmol) of 4-cyanobenzaldehyde, 1.8 g (22 mmol) of sodium acetate and 2.1 ml (22 mmol) of acetic anhydride are heated under reflux in 25 ml of acetic acid for 6 hours. After cooling, the mixture is poured onto ice and extracted with ethyl acetate. The ethyl acetate phase is extracted with sodium bicarbonate solution and the aqueous phase is acidified. The product which has precipitated is filtered off with suction and dried.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccc(Cl)cc1
Product: O=[N+]([O-])c1cccnc1COc1ccc(Cl)cc1
Yield: 90 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-chlorophenol, the titled compound was obtained as yellow solid. (Yield: 90%)
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:26]([F:29])([F:28])[F:27])[C:2]#[CH:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:16]1[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:18][C:19](=[O:20])[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:7]3[N:6]=[C:5]([C:26]([F:27])([F:28])[F:29])[N:4]([CH2:1][C:2]#[CH:3])[C:8]=3[CH:9]=2)[C:15]1=[O:25]
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 69.1 %

Procedure:
A solution of 0.6 gram (0.001 mole) of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, 0.4 gram (0.003 mole) of potassium carbonate, and 0.17 mL (0.003 mole) of methyl iodide in 30 mL of acetone was stirred at ambient temperature for about 18 hours, after which the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in diethyl ether and washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily residue, which was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 104°-105° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][CH:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:15][CH:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:17]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2C2=CCOCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2C2CCOCC2)C1
Temperature: 30 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of tert-butyl (3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate (346 mg, 1 mmol) and wet Pd—C (50%, 200 mg) in MeOH (100 mL) was stirred under H2 (40 psi) at 30° C. overnight then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated to give tert-butyl (3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate (331 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 349 calc. for C19H28N2O4 348.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:32])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([OH:17])=[O:16])=[O:4].[Na].[SH:34][C:35]1[N:40]2[N:41]=[C:42]([C:44]3[CH:45]=[C:46]([OH:51])[C:47](=[CH:49][CH:50]=3)[OH:48])[N:43]=[C:39]2[N:38]=[C:37]([CH3:52])[CH:36]=1>CN(C)C=O>[OH:51][C:46]1[CH:45]=[C:44]([C:42]2[N:43]=[C:39]3[N:38]=[C:37]([CH3:52])[CH:36]=[C:35]([S:34][CH2:2][C:3]([NH:5][C@@H:6]4[C:13](=[O:14])[N:12]5[C@@H:7]4[S:8][CH2:9][C:10](/[CH:18]=[C:19]4/[C:20](=[O:32])[N:21]([CH2:24][C:25]6[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=6)[CH2:22][CH2:23]/4)=[C:11]5[C:15]([OH:17])=[O:16])=[O:4])[N:40]3[N:41]=2)[CH:50]=[CH:49][C:47]=1[OH:48]
Reactant: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12
Reactant: Cc1cc(S)n2nc(-c3ccc(O)c(O)c3)nc2n1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(SCC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(Cc5ccc(O)cc5)C4=O)CS[C@H]23)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 1 h

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (see ex. C34a) (200.0 mg, 0.38 mmol) was dissolved in 4 ml N,N-dimethylformamide and 4-[7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl]pyrocatechol sodium salt (124.0 mg, 0.42 mmol) was added. After 5 h the reaction mixture was poured on diethyl ether and the suspension was filtered. The solid material was digerated with 10 ml ethyl acetate:water (1:1) for 1 h, filtered and dried in high vacuum.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[S:3][C:4]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:23])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(N)sc1Sc1ccccn1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)sc1S(=O)c1ccccn1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 52.1 %

Procedure:
A mixture of 2-amino-4-methyl-5-(2-pyridylthio)thiazole (1.7 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (20 ml) and dichloromethane (50 ml) was stirred at 5° C. for 3.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyridylsulfinyl)thiazole (0.95 g, yield: 52.2 %). mp: 190°-193° C. (dec.)
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:17][O:18]C(=O)C)[O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15])(=O)C.C(O)C.[O-]CC.[Na+]>CO>[OH:18][CH2:17][CH:6]([CH2:5][OH:4])[O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)OCC(COC(C)=O)OCn1ccnc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1nccn1COC(CO)CO
Temperature: 25 °C
Yield: 130.4 %

Procedure:
3.01 g of 1-[2-acetoxy-1-(acetoxynethyl)ethoxy]- methyl-2-nitroimidazol (compound (1)) was dissolved in 50 ml of absolute methanol, and stirred at room temperature while being added with 5% absolute ethanol solution of sodium ethoxide dropwise until pH reached 9.0. Stirred at room temperature over 3 hours. Then Dowex 50 W (H+, made by Dow Chemical) was slowly added until the liquid had a pH of 7.0. Dowex 50 W was removed by suction filtration, and the solvent was distilled off under reduced pressure. The residue was subjected to recrystallization by ethanol to obtain 2.83 g of the title compound as light yellow needles (yield: 94%).