Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([O:21]/[N:22]=[C:23](/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])\[C:24](O)=[O:25])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:43][C@@H:44]1[C:51](=[O:52])[N:50]2[C@@H:45]1[S:46][CH2:47][C:48]([CH2:69][Cl:70])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[C@H:45]([S:46][CH2:47][C:48]=1[CH2:69][Cl:70])[C@H:44]([NH:43][C:24](=[O:25])/[C:23](=[N:22]\[O:21][C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])[C:51]2=[O:52])=[O:54])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)O)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a suspension of (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (16.7 g, 27.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (12.89 g, 28.6 mmol) in Dichloromethane (DCM) (210 mL) at −30° C. was added phenyl phosphorodichloridate (4.95 mL, 32.6 mmol), followed by dropwise N-methylmorpholine (8.97 mL, 82 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (85 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (26 g, 25.7 mmol, 95% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1010.6
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:29]=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([OH:30])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: CCC[Mg]Br
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 0.25 mL, 0.50 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (179 mg, 0.453 mmol) in tetrahydrofuran (2.0 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 2-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (rotamer 1; 72.3 mg, 0.165 mmol, 36%, rotamer 2; 68.7 mg, 0.157 mmol, 35%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[I:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:9]([CH:10]=O)[C:8]=1[OH:19].C(N(CC)CC)C>C(Cl)Cl>[O:3]=[S:1]1(=[O:4])[N:2]=[CH:10][C:9]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=[C:7]([I:6])[C:8]=2[O:19]1
Reactant: CC(C)(C)c1cc(I)c(O)c(C=O)c1
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Temperature: 20 °C
Yield: 13.7 %

Procedure:
To a solution of sulfamoyl chloride (13.8 g, 0.12 mole) in anhydrous methylene chloride (75 ml) is added a solution of 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (6 g., 0.02 mole) and triethylamine (12.1 g, 0.12 mole) in anhydrous methylene chloride (100 ml.) dropwise with stirring at 20° C. Upon completing the addition, the resulting reaction mixture is stirred at 20° C. for 3 days. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and 2 N hydrochloric acid. After separating the phases, the organic phase is washed with water and saturated brime, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves an oily residue (6 g.) which is chromatographed on silica gel (300 g.) with benzene. Elution with benzene (840 ml.) gives recovered 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (2.2 g., 37% recovery), m.p. 76°-78° C. Continued elution with benzene (500 ml.) provides an impure solid (2.4 g.) which is triturated with hexane (20 ml.) and filtered to afford the title compound as a pale yellow solid (1.0 g, 14%), m.p. 130°-134° C. Crystallization from hexane benzene (9.1; viv) gives an analytical sample of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine, m.p. 135°-136° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:29])=[O:28]>COCCOC.CCO.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>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:27]([OH:29])=[O:28])[CH:36]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1cccc(B(O)O)c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1951 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (10 ml) were added 3-carboxymethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[CH:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([OH:17])[CH:11]=1>CN(C)C=O>[OH:17][C:12]1[CH:13]=[CH:14][C:15]([N:16]2[C:6](=[O:8])[CH2:7][C:2]([CH3:1])([CH3:9])[C:3]2=[O:5])=[CH:10][CH:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(O)cc2)C1=O
Yield: 70 %

Procedure:
A solution of 2,2-dimethylsuccinic anhydride (128 g, 1 mol) in dimethylformamide (150 ml) was added slowly for a time of 1 h at a temperature of 25° C. to a stirred solution of p-aminophenol (109 g, 1 mol) in dimethylformamide (150 ml) present in a reactor. By continuing the procedure as described in Example 1, N-(4-hydroxyphenyl)-2,2-dimethylsuccinimide was obtained in a yield of 70% and with a purity of more than 95%.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[N:2].Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:20][NH:19][C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[NH:2]
Reactant: N#C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
Part A. Benzyl (S)-2-cyanopyrrolidine-1-carboxylate (500 mg, 2.17 mmol) was dissolved in aqueous ethanol (3 m-L) and water (1 mL). Hydroxylamine hydrochloride (152 mg, 2.17 mmol) and Na2CO3 (115 mg, 1.08 mmol) were added and the reaction mixture heated to 100° C. for 1 h. The ethanol was removed and the aqueous residue was extracted with dichloromethane (3×25 mL), dried over Na2SO4 decanted and concentrated yielding benzyl (S)-2-(N-hydroxycarbamimidoyl)pyrrolidine-1-carboxylate as a pale yellow gum (428 mg, 75% yield): HPLC (method 1) tR=1.40 min, Purity 76%; LCMS (method 4) tR=0.81 min, m/z 264 (M+H).
Reaction SMILES: C([O:4][CH:5]=[CH:6][C@@H:7]([CH3:14])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.P(=O)(O)(O)O.O>C1(C)C=CC=CC=1>[CH3:13][C:11]1([CH3:12])[CH2:10][CH2:9][CH2:8][C@H:7]([CH3:14])[C@H:6]1[CH:5]=[O:4]
Reactant: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1CCCC(C)(C)[C@@H]1C=O
Temperature: 100 °C

Procedure:
A solution of crude product of Example 1a (6.36 g, 32.4 mmol) in toluene (11 mL) (15.7 g) was added 85% phosphoric acid (12 mL). The mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled to room temperature and toluene (12 mL) along with water (24 mL) was added and the layers were separated. The aqueous layer was extracted with toluene (12 mL×2). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL×2) and brine (50 mL×2). Concentration and distillation under reduced pressure (b.p. 65-70° C.) afforded the title compound as a 9:1 mixture of epimers as a colorless oil (2.51 g, Yield: 50%). 1H NMR (400 MHz, CDCl3) (Major) δ 9.63 (d, J=5.2 Hz, 1H), 2.03-1.91 (m, 1H), 1.83-1.75 (m, 1H), 1.64-1.60 (m, 1H), 1.54-1.48 (m, 1H), 1.40-1.35 (m, 1H), 1.24-1.14 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.95-0.84 (m, 2H), 0.81 (d, J=6.4 Hz, 3H) ppm. [α]D24=+5.20° (c=1.00, dichloromethane).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH3:21])=[O:19])(C)C.[Si]([O:29][C@H:30]1[C:35](=[CH2:36])[C@H:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][C:32](=O)[CH2:31]1)(C(C)(C)C)(C)C>O1CCCC1>[Si:38]([O:37][C@H:34]1[C:35](=[CH2:36])[C@H:30]([OH:29])[CH2:31]/[C:32](=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])/[CH2:33]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C1[C@H](O)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of diisopropylamine (1.2 mL, 9.4 mmol) in 10 mL of tetrahydrofuran was cooled to −78° C.; n-butyllithium (2.5 M in hexanes, 3.6 mL) was added, followed after 5 minutes by methyl trimethylsilylacetate (1.7 mL). The resultant solution was stirred at −78° C. for 30 minutes, and then a solution of the compound of Example 13E (2.0 g, 4 mmol) in 10 mL of tetrahydrofuran was added over 5 minutes. Stirring was continued for 4 hours. The reaction was quenched by addition of saturated aqueous NH4Cl; the mixture was warmed to ambient temperature, and partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl and brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 5% to 10% ethyl acetate in hexanes. The product (1.9 g) was dissolved in 17 mL of ethanol; 1.3 mL of concentrated HCl was added, and the resultant solution was stirred overnight at ambient temperature. The solvents were removed in vacuo, the residue was taken up in saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 2% to 3% dichloromethane in acetonitrile to afford the titled compound (0.76 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C(=O)OC)c2ccccc2)c([N+](=O)[O-])c1
Yield: 89.6 %

Procedure:
A solution of methyl 2-amino-2-phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4-fluoro-3-nitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DIEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30° C. in a 100-mL round-bottom flask. The reaction was then quenched by the addition of 200 mL of water, and the solids were collected by filtration. Purification via silica gel column (petroleum ether/EtOAc (50:1)) yielded 3.82 g (90%) of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.O>CO>[CH:12]1([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: ClCCCOc1cccnc1
Reactant: NC1CC1
Solvent: CO
Solvent: O
Product: c1cncc(OCCCNC2CC2)c1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
An Ace Glass pressure tube (185 mL) was charged with 3-chloro-1-(3-pyridyloxy)propane (0.762 g, 4.437 mmol), cyclopropylamine (8.24 g, 194.3 mmol), water (20 mL) and methanol (20 mL). The resulting light-brown solution was heated at 120° C. (oil bath temperature) for 2.5 h and allowed to cool to ambient temperature over 16 h. The solution was concentrated by rotary evaporation to an oily residue that was diluted with saturated NaCl solution (25 mL). The mixture was acidified to pH 1.0 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 6 with 10% NaOH solution and extracted (4×25 mL) to remove other impurities. The aqueous phase was basified to pH 10 with 10% NaOH solution and extracted with CHCl3 (4×50 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated (rotary evaporator) and briefly dried under high vacuum to give 0.250 g of a brown oil. The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (100:2) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2) to remove the product. Selected fractions were combined to give 220 mg (25.8%) of a brown semi-solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(C)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 1-carbethoxy4-cyclopropylamino-3-methylpiperidine. Yield 6.0 g (70%), C12H22N2O2, m/z 227 (M+1), PMR (CDCl3): 0.38 (m, 4H), 0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H), 2.32 (m, 1), 2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m, 2H).
Reaction SMILES: [Zn](CC)[CH2:2][CH3:3].[CH3:6][C:7](=[CH:10][CH2:11][CH3:12])[CH:8]=[O:9]>>[CH3:6][C:7](=[CH:10][CH2:11][CH3:12])[C@@H:8]([OH:9])[CH2:2][CH3:3]
Reactant: CC[Zn]CC
Reactant: CCC=C(C)C=O
Product: CCC=C(C)[C@@H](O)CC
Yield: 73 %

Procedure:
The product was prepared by General procedure L using 1.0 mL (2.0 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 114 μL (1.0 mmol) 2-methyl-2-pentenal. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 73% yield (93 mg, 0.73 mmol). [α]D20=−5.8 (c=0.73, CHCl3, 95% ee); 1H NMR (CDCl3, 500 MHz) δ 0.77 (t, 3H, J=7.4 Hz), 0.89 (t, 3H, J=7.5 Hz), 1.45-1.49 (m, 2H), 1.51 (s, 3H), 1.61 (br s, 1H), 1.96 (q, 2H, J=7.4 Hz), 3.81 (t, 1H, J=6.7 Hz), and 5.29 (t, 1H, J=6.9 Hz) ppm; 13C {1H} NMR (CDCl3, 125 MHz) δ.10.0, 10.8, 14.0, 20.7, 27.6, 79.4, 128.6, and 136.1 ppm; IR (neat) 3360, 2962, 2932, 2875, 2348, 1722, 1670, 1461, 1376, 1335, 1308, 1261, 1097, 1054, and 1008 cm−1; HRMS-CI m/z 128.1206 [M+; calcd for C8H16O: 128.1201].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[N:11][C:3]=12.C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1>O1CCOCC1>[Cl:8][C:5]1[N:6]=[N:7][C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[C:3]2[N:11]=[CH:10][NH:9][C:4]=12
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: Clc1nnc(Cl)c2[nH]cnc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4[nH]cnc34)CC2)nc1
Temperature: 80 °C
Yield: 36.4 %

Procedure:
4,7-Dichloro-1H-imidazo[4,5-d]pyridazine (250 mg, 1.32 mmol) is combined with triethylamine (270 μL), dioxane (2 mL), and 1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (290 mg, 1.26 mmol). The reaction mixture is heated to 80° C. for 70 h. Concentrate in vacuo to remove dioxane. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (176 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:20]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Product: CS(=O)(=O)c1cccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 3-(methanesulfonyl)benzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonyl)benzamide. MS (Q1) 387.2 (M)+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1.FC(F)(F)C(O)=O>>[Cl:5][C:6]1[N:11]=[C:10]([O:4][CH2:1][C:2]#[CH:3])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1nc(Cl)ncc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
3.97 ml (68.2 mmol) Prop-2-yn-1-ol are slowly added to 3.40 g (15.6 mmol) of 2,4-Dichloro-5-trifluoromethyl-pyrimidine at 0° C. under a nitrogen atmosphere. 0.79 ml Trifluoro-acetic acid are added dropwise and the batch is stirred for 6 hours at 0° C. The batch is poured on ice and extracted with ethyl acetate (3×). The combined organic phases are washed with water, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 95:5). 591 mg (2.5 mmol, corresponding to 16% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.[OH-:32].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:32])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (51.2 mg), toluene (0.47 ml), water (0.2 ml), tetra-n-butylammonium bromide (49.9 mg), and sodium hydroxide (54.3 m) were added under a nitrogen atmosphere at room temperature, and stirred at 120° C. for 4 hours. Then, the organic layer was removed. 3.5% by weight of hydrochloric acid (4 ml) was added to the mixture at room temperature, and extracted with tert-butyl methyl ether. Then, the organic layer was concentrated under reduced pressure to give 40.8 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][CH2:65][N:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:63][CH2:64][CH2:65][N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN2CCOCC2)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 4-(2-Aminoethyl)morpholine (82 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was recrystallised from DMSO to yield white solid (0.040 g, 62%).