Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C

Procedure:
13-(Quinolin-2-ylmethoxy)-phenol (5.2 g, 21 mmol, example 3), methyl 2-bromomethyl-6-methyl-benzoate (example 2) (5.0 g, 21 mmol) and potassium carbonate (4.4 g, 32 mmol) are combined in DMF (50 mL) and heated at 85° C. for 3 h. The reaction is poured into ethyl acetate (500 mL) and washed with water (4×120 mL) and brine (100 mL). The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to provide a residue which is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexane) to provide the title compound. MS (ESI) 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:23]=[C:24]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:33](/[C:31]1[O:32][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])[CH:23]=2)=[CH:29][CH:30]=1)\[CH3:34]
Reactant: CC(=O)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C/C(=C1\C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Yield: 42 %

Procedure:
A solution of 5-chlorooxindole (668 mg, 4 mmol), 1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (1.7 g of oil) and piperidine (394 μL, 4 mmol) in toluene (15 mL) was heated at reflux with a Dean-Stark receiver for 24 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave (E)-5-chloro-3-(1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (800 mg) as a E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: [NH4+].[OH-].[NH2:3][C:4]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH:19]=2)=[O:9])=[C:6](Cl)[CH:5]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O1CCOCC1>[NH2:3][C:4]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH:19]=2)=[O:9])=[C:6]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[CH:5]=1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3scnc3c2)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3scnc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of the amide from above (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 4-amino-N-benzothiazol-5-yl-2-chloro-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (12 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-5-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][N:28]([CH3:27])[C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:13]
Reactant: CNOC
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
3-Methyl-3H-benzotriazole-5-carboxylic acid (1.67 g, 5.6 mmol) was suspended in 25 ml N,N-dimethylformamide. 1,1′-carbonyldiimidazole (1.0 g, 6.2 mmol) was added and the reaction stirred at room temperature for 90 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (593 mg, 6.2 mmol) was added and the reaction stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride solution and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using chloroform/methanol gradient system (100:0 to 97:3, respectively) as eluent to afford 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (1.0 g, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8].[C:12](O)(=O)[CH2:13][C:14]([OH:16])=[O:15].CCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:11])[C@@H:4](/[CH:5]=[C:13](/[C:14]([OH:16])=[O:15])\[CH3:12])[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: O=C(O)CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H](/C=C(\C)C(=O)O)C1(C)C
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 0.666 g of methyl (±)-trans-2,2-dimethyl-3-formylcyclopropanecarboxylate was dissolved in 10 mL of a designated solvent. A designated amount of an amine and 1.000 g of malonic acid was then added thereto, and the resulting mixture was stirred under heating. After the mixture was allowed to cool to room temperature, 50 mL of ethyl acetate was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel chromatography, wherein the eluent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1. Methyl(±)-trans-2,2-dimethyl-3-{2-carboxy-(E)-1-propenyl}cyclopropanecarboxylate was obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
Intermediate 1 was prepared as shown in Scheme 2. Esterification of 4-bromomethylbenzoic acid 4 (25 grams) was carried out in refluxing methanol (500 ml) in the presence of concentrated H2SO4 (5 ml) to yield methyl 4-bromomethylbenzoate 5. TLC (thin layer chromatography) monitoring of the reaction mixture showed formation, over time, of a side-product (about 15-20%), which according to 1H-NMR analysis, was identified as methyl 4-methoxymethylbenzoate. The mixture of methyl 4-bromomethylbenzoate 5 and the side-product (4.56 grams; 1 equiv) was reacted with commercially available 4-boc-aminopiperidine 6 (Aldrich™) (4.0 grams) in 100 ml of DCM or 100 ml of methanol in the presence of potassium carbonate (4.14 grams; 1.5 equiv) at room temperature to yield compound 7. Reaction in methanol afforded compound 7, as identified by 1H NMR, in 72% yield compared to 57% obtained with DCM.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[NH:16][C:15]2=[O:22])=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH2:26][CH2:25][CH2:24][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][S:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[C:15]2=[O:22])=[CH:30][CH:31]=1
Reactant: ClCCCCSc1ccncc1
Reactant: CC1(C)NC(=O)N(CCCCSc2ccncc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CCCCSc2ccncc2)C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a suspension of 96 mg (2.4 mmol) of 60% sodium hydride (oily) in 15 ml of dimethylformamide, 587 mg (2.0 mmol) of 3-[4-(4-pyridylthio)butyl]-5,5-dimethylhydantoin was added, and the mixture was stirred at room temperature for 10 minutes. To this reaction mixture, 807 mg (4.0 mmol) of 4-(4-chlorobutylthio)pyridine was added with stirring under ice-cooling, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to give 0.74 g of the desired product (80.7% yield, yellow oil).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CN(C=O)C>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-hydroxybenzoate (13.4 kg, 88 mol) in DMF (52 L) was added dropwise to a mixture of NaOMe (4.8 kg, 89 mol) and DMF (50 L) at room temperature under a gentle stream of nitrogen. The reaction mixture was heated at 60°-70° for 1 hr with stirring and then cooled to room temperature. To this mixture was added dropwise a solution of 4-phenylbutyl bromide (16.92 kg, 79.4 mol) in DMF (5 L). The resulting mixture was heated at 60°-70° for 1 hr with constant stirring and cooled to room temperature. After an addition of 1N-NaOH (110 L) was added, and the product was extracted twice with ethyl acetate (50 L and 80 L). The extracts were washed with 1N-NaOH (110 L) and saturated brine (20 L) successively, and then concentrated to dryness in vacuo to give the title compound in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[NH:26][C:25]([CH:27]=O)=[CH:24][N:23]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:25]3[NH:26][C:22]([CH3:21])=[N:23][CH:24]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: Cc1ncc(C=O)[nH]1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1ncc(CNc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)[nH]1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 2-methyl-3H-imidazole-4-carbaldehyde using decaborane yielded the title compound as a white solid. MS (ESI): m/z=373.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O.C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To a solution of 4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl ester oxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg, 0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) at room temperature. The solution was stirred for 2 days when it was quenched by addition of saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115 mg (96%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s, 3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54 (s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 27.8 ppm; MS (m/z) 542.3 [M+H]+, 564.2 [M+Na]+.
Reaction SMILES: C(C1C=CC=CC=1C([NH:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12)=O)(O)=O.C(N(CC)CC)C.ClC(OCC)=O.CNN>O1CCCC1>[NH2:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([CH2:16][S:17][C:18]3[S:19][C:20]([CH3:23])=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Agent: CCOC(=O)Cl
Agent: CNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 0.33 h

Procedure:
A solution of benzhydryl 7-(2-carboxybenzamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 30 ml. of dry tetrahydrofuran is cooled in an ice-salt bath, and 0.28 ml. (2 mmol.) of triethylamine and 0.20 ml. (2 mmol.) of ethyl chloroformate are added. After cooling and stirring for 20 minutes, 0.106 ml. (2 mmol.) of N-methylhydrazine in 5 ml. of tetrahydrofuran is added. Stirring is continued for about 10 minutes. The Et3N.HCl salt is filtered, and the filtrate is evaporated to dryness. The residue is taken up in about 15 ml. of chloroform, and the mixture is allowed to stand at room temperature for about one hour during which time methylphthalhydrazide (m.p. 243°-245° C.) precipitates. Filtration and evaporation in vacuo of the filtrate gives crude benzhydryl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[N:13]=[C:12]4[N:14]([CH2:17][C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[N:15]=[N:16][C:11]4=[N:10][CH:9]=3)[CH2:4]2)[CH2:2]1.CO.[CH3:30][NH2:31].[I-].[K+]>CS(C)=O>[CH3:30][NH:31][CH2:2][C:3]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH2:4]1
Reactant: CN
Reactant: c1cnc2ccc(Cn3nnc4ncc(N5CCC6(CO6)C5)nc43)cc2c1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CNCC1(O)CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a solution of 6-{[6-(1-oxa-5-azaspiro[2.4]hept-5-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}quinoline (130 mg, 0.36 mmol) in 2:1 MeOH:DMSO (3 ml) were added methylamine (24.7 mg, 0.80 mmol) and potassium iodide (300.4 mg, 1.81 mmol) at R.T. After heating at 80° C. for 3.5 h, the reaction mixture was cooled to R.T. and concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 0-5% 7N N3 in MeOH: CH2Cl2 to give the desired product (35 mg, 25%).
Reaction SMILES: Cl.[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:15][CH:14]=1)[NH2:11])[CH3:7])(=[O:4])[CH3:3].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:17][CH:18]=1)[NH:11][C:34]([C:33]1[C:32]([Cl:31])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:41])=[O:35])[CH3:7])(=[O:4])[CH3:3]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester hydrochloride salt (0.723 mmol, 399 mg) and 2,6-dichlorobenzoyl chloride (0.8 mmol, 0.17 g) in dichloromethane (5 mL) was added diisopropylethylamine (3.2 mmol, 0.45 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 48 h at room temperature. The resulting light brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.312 g (67% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as a white solid: mp 168-170° C. ES-HRMS m/e calcd for C27H27Cl2N3O7 (M+Na) 598.1118, found 598.1122.
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=3[O:27][CH3:28])[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>>[CH3:28][O:27][C:20]1[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:12]2[O:11][CH:10]([CH2:8][NH:9][C:39](=[O:40])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cccc(-c2cccc3c2OC(C(N)Cc2ccccc2)C3)c1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1OC
Yield: 91.2 %

Procedure:
Treatment of (±)-benzyl[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.7 g, 8.39 mmol) with diisopropylethylamine (1.63 g, 12.59 mmol) and benzyl chloroformate (1.72 g, 10.07 mmol) generally according to the procedure described for Intermediate 12 provided 3.21 g (91%) of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:21][CH3:22])[C:19]#[CH:20].O>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][O:21][CH2:18][C:19]#[C:20][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C#CCOC
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Nitrogen was bubbled through a solution of Ethyl 5-bromo-2-phenylthiazole-4-carboxylate (13.1 g, 41.9 mmol) and methyl propargyl ether (7.1 mL, 83.9 mmol) in dimethoxyethane (DME) (200 mL). Dichlorobis(triphenylphosphine)palladium (II) (1.47 g, 2.2 mmol), copper (I) iodide (0.2 g, 1.1 mmol), and TEA (29 mL, 210 mmol) were added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-50% gradient) to give ethyl 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylate as a tan solid (11 g, 88% yield).
Reaction SMILES: [CH3:1][S:2]([CH:5]([S:7]([O-:10])(=O)=[O:8])[CH3:6])(=[O:4])=[O:3].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:13].Cl>ClCCl>[CH3:1][S:2]([CH:5]([S:7]([Cl:13])(=[O:10])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(S(C)(=O)=O)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(S(C)(=O)=O)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 g of sodium 1-(methylsulfonyl)ethanesulfonate (Formula II, X=R=CH3, Y=Na) and 5.34 g of phosphorus pentachloride was stirred under an inert atmosphere at room temperature. After about 20 minutes, the evolution of hydrogen chloride and the generation of heat were observed, and shortly thereafter the mixture became liquid. The mixture was maintained at 80°-100° C. overnight, cooled, and diluted with dichloromethane. The mixture was filtered, the residue was washed with dichloromethane, and the solvent was evaporated from the dichloromethane solution (combined portions) with a stream of nitrogen. The residual oil was concentrated further with a vacuum pump: weight of oil, 3.8 g. The mass spectrum and the proton NMR showed that this material was principally 1-(methylsulfonyl)ethanesulfonyl chloride (Formula III, R=X=CH3 and Z=Cl): MS (electron-impact, direct-probe temperature 20° C.), m/e 207 (M+1), 171 (M - Cl); 1H NMR (300.6 MHz, CDCl3), δ 2.07 (d, CH3CH), 3.32 (s, CH3SO2), 4.84 (q, CHCH3). The infrared spectrum (KBr) included strong bands at 1375, 1325, 1170, 1150, 960, 760, 715, 595, 535, 505, 490 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.O>CN(C=O)C>[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: OCCC1CCCCN1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
In DMF (3ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200mg), and to the mixture was added 2-(2-hydroxyethyl)piperidine (214mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(2-hydroxyethyl)piperidinomethyl]phenyl]-3-(4-methyl-phenyl)cinnamamide (Compound 69) (202mg) as colorless crystals.