Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 81.5 %

Procedure:
The solution of 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer 10.8 g.), conc. hydrochloric acid (11 g.) and methanol (350 ml.) was stirred at room temperature for 4 hours. After concentrating the resultant solution under reduced pressure, ethyl acetate was added to the residue. The solution was adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and the aqueous layer was separated and washed with diethyl ether. After nitrogen gas was bubbled in the aqueous solution, the aqueous solution was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitates were collected by filtration and washed with water to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 8.2 g.), m.p.>290° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([C:4]1[C:5]([O:33][CH2:34][O:35][CH3:36])=[CH:6][C:7]([O:29][CH2:30][O:31][CH3:32])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:20][CH:21]=3)[C:12]([S:15][CH3:37])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCOCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F45-03, 2.43 g, 4.72 mmol) and potassium carbonate (653 mg, 4.72 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) and then methyl iodide (0.29 mL, 4.72 mmol) were added. After heating at 80° C. stirring for an hour, the reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The reaction system was mixed with water, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium sulfate, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a pale yellow foam (2.18 g) containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F45-04).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:32]CN(CC)CC.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Product: CN1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reaction time: 16 h
Yield: 111.9 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 290 mg), Et3N (55 mg; 0.55 mmol)cOH (1 drop), and 37% aqueous HCHO (89 mg; 1.1 mmol) in MeOH (10 mL) was added NaBH(OAc)3 (233 mg; 1.05 mmol). The reaction mixture was stirred for 16 h and concentrated. The residue was dissolved in DCM (20 mL) and washed with saturated NaHCO3 (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 270 mg (>100%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)(O)[O-].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][C:45]1=[O:53]>CC(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:41][CH2:42][CH2:43][N:44]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46][C:45]4=[O:53])[CH2:16][CH2:17]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1Cc2ccccc2N1CCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)Cc5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a solution of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassium bicarbonate (0.069 g, 0.69 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)indolin-2-one (0.096 g, 0.46 mmol). After stirring at 78° C. for 2 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.075 g, 27%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=O.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:11][C:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]1[NH:2][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[CH3:21])=[O:10])[CH3:13]
Reactant: CC(C)(C)CC=O
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NCCC(C)(C)C
Reaction time: 18 h
Yield: 1.3 %

Procedure:
To a solution of ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride (1.00 g, 4.6 mmol) in methanol (10 mL) was added triethylamine (0.72 mL, 5.1 mmol), 3,3-dimethylbutyraldehyde (0.67 mL, 5.1 mmol), and sodium cyanoborohydride (213.0 mg, 3.2 mmol) at 25° C. After stirring for 18 h, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-50% ethyl acetate in hexanes) to afford the desired product, cis-2-(3,3-dimethylbutylamino)-cyclohexanecarboxylic acid ethyl ester (31.2 mg, 0.061 mmol, 25%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, s), 1.22-1.29 (1H, m), 1.35 (3H, t, J=7.0 Hz), 1.40-1.51 (1H, m), 1.58-1.77 (5H, m), 1.90-1.94 (1H, m), 2.12-2.15 (1H, m), 2.37-2.40 (1H, m), 2.96 (1H, bs), 3.09 (1H, bs), 3.22-3.33 (2H, m), 4.21-4.35 (2H, m). LC-MS (ESI) calcd for C15H29NO2 255.22, found 256.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25].C(Cl)(Cl)Cl>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:17])[CH3:18])[NH2:8]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Yield: 97 %

Procedure:
N-tert-butoxycarbonyl L-valyl L-valine methyl ester (4) (10.07 g, 30.48 mmol, 1.00 eq.) was treated with a 50% (v/v) TFA solution in CH2Cl2 for 2 hours at room temperature. The solvent and bulk of excess TFA were evaporated affording a clear, crystalline solid which contained TFA as judged by 1H-NMR. Small portions of purified CHCl3 (i.e. without EtOH as stabiliser) were added and evaporated under reduced pressure four times resulting in an off-white solid. The solid was washed with Et2O (3×50 mL) and dried under reduced pressure affording a white solid (10.20 g, 97%). The compound has been mentioned in the literature, but spectral data was not provided55; δH (300 MHz; d6-DMSO) 8.62 (1H, d, J 7, NH), 8.17 (3H, br s, NH3+), 4.19 (1H, dd, J 7 and 6, CαH(Val2)), 3.75 (1H, br d, J 5, CαH(Val1)), 3.64 (3H, s, OCH3), 2.16-2.01 (2H, m, CH(CH3)2), 0.96-0.90 (12H, m, CH(CH3)2); δC (75 MHz; d6-DMSO) 171.4, 168.4, 158.4 (q, JCF 31), 117.1 (q, JCF 297) 57.7, 56.9, 51.7, 29.9, 29.6, 18.8, 18.1, 18.1, 17.4; m/z (ESI) 231.1710 (M+; C11H23N2O3 requires 231.1708)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:28]=2[F:37])[CH2:23][CH2:22]1)=[O:20])C1C=CC=CC=1.C(Cl)(Cl)Cl>[Pd].CO>[F:37][C:28]1[CH:29]=[C:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=[CH:32][C:27]=1[N:24]1[CH2:23][CH2:22][N:21]([C:19]([C:10]2[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[O:20])[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCc3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3O)CC2)c(F)c1
Reaction time: 2 h

Procedure:
A mixture of 0.915 mmol (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone, 0.05 mmol palladium on charcoal (10%) in 12.5 ml methanol was hydrogenated at atmospheric pressure at room temperature for 2 hours. After addition of chloroform, the mixture was filtered, and the solvent was evaporated to provide the title compound. MS (m/e): 474.3 (M+NH4+, 100%)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(CC)CC.CO.C(Cl)Cl>C(O)(C)C.C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[N:11]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3c2CCCC3)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(N(C)c2nc(NCCO)nc3c2CCCC3)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of (2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 0.150 g (0.5 mmol), ethanolamine 0.2 mL (3.0 mmol) with Et3N 0.2 mL in isopropanol 5 mL was stirred at 100° C. for 48 h. The reaction mixture was diluted with CH2Cl2, and directly charged to gradient column chromatography (MeOH/CH2Cl2, 0% to 20%) to give the title compound. For analytical use, it was further purified with preparative HPLC to give the corresponding TFA salt. 1H NMR (CD3OD, 400 MHz) δ 7.19 (d, J=8.0 Hz, 2H,), 6.98 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.76 (t, J=5.6 Hz, 2H), 3.62 (t, J=5.6 Hz, 2H), 3.50 (s, 3H), 2.59 (t, J=6.5 Hz, 2H), 1.60-1.66 (m, 2H), 1.55-1.58 (m, 2H), 1.41-1.46 (m, 2H); HRMS (ES) m/z calcd for C18H24N4O2 (M+H) 329.1972, found 329.1962.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH3:22].[C-:23]#[N:24].[K+].O>CN(C=O)C>[CH3:22][O:21][C:12]1[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][C:23]#[N:24]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(OC)c1OC
Agent: BrCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC#N)c(OC)c1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Phosphortribromide (6.83 g, 25.22 mmol) was added dropwise to a stirred solution of 2,3,4-trimethoxybenzyl alcohol (10 g, 54.44 mmol) in dichloromethane (100 ml), cooled at 0° C. After 30 min of vigorous stirring, the reaction mixture was slowly quenched with 100 g of ice-water. The dichloromethane layer was separated and the aqueous layer was further extracted with dichloromethane (2×100 ml). The combined extracts were twice washed with a saturated solution of sodium chloride (2×150 ml). The organic solution was dried over magnesium sulphate and evaporated to give 10 g (yield 76%) of the benzylbromide 2 as a colourless oil. As soon as isolated, the benzyl bromide compound was directly used for the next step. In fact the compound degradated after one night even at +4° C. The obtained 1-bromomethyl-2,3,4-trimethoxybenzene oil was treated with KCN (6.52 g, 100 mmol) in dry DMF (30 ml), at 0° C. and under nitrogen atmosphere. The obtained mixture was stirred for 3 g at 0° C. and 1 h at 60° C. The cooled reaction mixture was poured into water (80 ml) and extracted with diethylether (3×150 ml). The crude benzylcyanid was chromatographed on silica (diethylether/petroleumether: 1/3) to give 2,3,4-trimethoxyphenyl-acetonitrile as a white crystalline material (Yield: 6.8 g; 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=O)[CH:12]=[O:13].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
4,5-Dichlorophenylenediamine (26.0 g, 147 mmol) and 50% ethyl glyoxylate in toluene (32 mL, 161 mmol) in ethanol (250 mL) was refluxed for 18 h. The reaction was cooled and the crystallized brown product was collected by filtration, then washed with ethanol (50 mL). The obtained product (25.5 g, 81%) was 96% pure via LC/MS. MS (ES) m/e 215[M+H]+.
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[N+:41]([C:38]1[CH:37]=[CH:36][C:35]([CH2:34][O:33][C:31]([N:7]2[CH2:8][C@@H:9]([S:11][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][C@H:6]2[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:32])=[CH:40][CH:39]=1)([O-:43])=[O:42]
Reactant: C1CNCCN1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.0 g) in dimethylformamide (90 ml) was added piperazine (2.0 g) and the mixture was stirred at 80°]90°C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)pyrrolidine (2.52 g).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:32][C:29]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:27])[O:25]2)=[CH:20][CH:19]=1>C(#N)C>[CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[O:9][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([B:24]2[O:25][C:26]([CH3:28])([CH3:27])[C:29]([CH3:31])([CH3:30])[O:32]2)=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Cc1occc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1occc(=O)c1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Maltol (0.50 g, 3.96 mmol) was dissolved in 25 mL of acetonitrile followed by the addition of 1.6 g (11.88 mmol) of K2CO3. The reaction was heated to reflux for 10 min before adding 4-bromomethylphenyl boronic acid pinacol ester (1.3 g, 4.4 mmol). The reaction was left stirring under refluxing conditions for 12 h then cooled to room temperature and filtered rinsing with DCM. The resulting filtrate was concentrated and purified via silica gel chromatography eluting with 0-2% MeOH in DCM. B20 (1.03 g, 3.0 mmol) was collected and dried yielding a pale yellow solid in 76% yield. 1H NMR (400 MHz, CDCl3) δ=7.77 (d, J=7.6 Hz, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.37 (d, J=7.6 Hz, 2H), 6.35 (d, J=5.6 Hz, 1H), 5.19 (s, 2H), 2.06 (s, 3H), 1.34 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=175.3, 160.0, 153.6, 143.9, 140.0, 135.1, 128.5, 117.4, 84.1, 73.6, 25.1, 15.2. ESI-MS(+): m/z 343.18 [M+H]+. Anal. calcd. for C19H23BO5: C, 66.69; H, 6.77. Found: C, 66.34; H, 6.67.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>CCOCC>[Cl:8][C:7]1[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: NN
Reactant: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Solvent: CCOCC
Solvent: O
Product: CN1CCN(c2cnnc(NN)c2Cl)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
3,4-Dichloro-5-(4-methylpiperazin-1-yl)pyridazine (500 mg, 2.023 mmol) was placed in a microwave tube and hydrazine monohydrate (1.772 g, 1.717 mL, 35.40 mmol) was added. The resulting suspension was stirred at 100° C. for ˜10 mins. The brown reaction mixture was allowed to cool to RT, whereupon solid started to precipitate. The suspension was sonicated and the suspended solid was collected by filtration. This material was dissolved in water, basified with saturated NaHCO3 and partitioned with 10% MeOH in DCM. The aqueous layer was extracted with further 10% MeOH in DCM (6×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid. This material was sonicated in ether and the suspended solid was collected by filtration to give [4-chloro-5-(4-methylpiperazin-1-yl)pyridazin-3-yl]hydrazine as an ochre powder (155.9 mg, 32% Yield).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].Br[CH:9]([CH3:13])[C:10](Cl)=[O:11].C(N(CC)CC)C>CC(C)=O>[CH3:13][CH:9]1[O:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[O:1][C:10]1=[O:11]
Reactant: CC(Br)C(=O)Cl
Reactant: CC(C)(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1OC(=O)C(C)(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
5 g α-hydroxyisobutyric acid (48 mmol) and 5.15 mL 2-bromopropionyl chloride (50 mmol) were stirred at 75° C. under nitrogen for 12 h. 300 mL acetone and 14 mL anhydrous triethylamine (100 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium chloride salts, acetone was distilled off and the resulting mixture was dissolved in 450 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from ethyl acetate:hexane mixture (1:10). 1H NMR (500 MHz, CDCl3): δ 5.1 (q, 1H), 1.705 (s, 6H), 1.69 (d, 3H). 13C NMR (500 MHz, CDCl3): δ 168.58, 166.64, 80.54, 72.90, 26.23, 25.27, 17.41. ELEM. ANAL. Calcd. for C7H10O4: C, 53.16; H, 6.33. Found: C, 52.86; H, 6.39. Yield: 46%.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:22].FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:11]([OH:13])=[O:12])[C:6]1=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2O)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2O)C1=O

Procedure:
A solution of Example 145B (0.127 g, 0.35 mmol) in dichloromethane (1.75 mL) was treated with trifluoroacetic acid (1.75 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was azeotroped twice with ethyl acetate to give crude material which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]2[CH:9]1[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)(O)[O-].[Na+].IC>CN(C)C=O>[CH3:25][O:18][C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH3:24])[C:10]=12)=[O:19]
Reactant: O=C([O-])O
Reactant: CC1c2c(C(=O)O)nc(C(F)(F)F)n2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1C(C)N(C(=O)OC(C)(C)C)CC2
Yield: 137.6 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 39a (0.349 g, 1 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and sodium bicarbonate (0.84 g, 10 mmol) was added to the solution under stirring. Iodomethane (0.43 g, 3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 40 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 39b (0.5 g, yield 100%) as a yellow oil.