Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]1=[O:17].C(N(CC)CC)C.[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH2:35]>C(Cl)(Cl)Cl>[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH:35][C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([OH:7])[C:9]1=[O:17]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: O=C(O)CN1CCC(O)C1=O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Reaction time: 0.2 h

Procedure:
1.2 ml of ethyl chloroformate are placed in 12 ml of chloroform, whereupon there are added dropwise at -30° within 30 minutes 2.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.74 ml of triethylamine dissolved in 50 ml of chloroform. After stirring at a temperature between -2° and -10° for 12 minutes, 2.07 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 10 ml of chloroform are added dropwise. The mixture is left to stand at room temperature overnight. Thereupon, the mixture is evaporated and the residue (6 g) is chromatographed on 120 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with acetonitrile and ethanol has a melting point of 128°-130° after repeated chromatography on aluminum oxide and recrystallization from ethyl acetate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.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>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:30]=[N:29][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
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: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 56.4 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.1 g, 0.354 mmol), commercially available 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]morpholine (0.206 g, 0.709 mmol), K2CO3 (0.147 g, 1.063 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 35 micomol) in 3 mL of MeOH and 1 mL of DCM was degassed by bubbling argon through the mixture. It was then stirred at 110° C. for 25 minutes under microwave irradiation before being cooled to RT. And evaporated. The residue was adsorbed onto SiO2 and purified twice by SiO2 chromatography (hexanes/EtOAc 0-50% EtOAc, followed by DCM/MeOH 0-4% MeOH) to give 0.073 g of 2,2-Dimethyl-1-[2-(6-morpholin-4-yl-pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (56% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH2:29]C)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C(C)=NN(C)C=3Cl)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:31]OC1C=CC(C)=CC=1B(O)O.BrC1C=CC([C@H](N)C)=CC=1>>[CH3:29][O:28][C:5]1[CH:4]=[CH:3][C:2]([CH3:31])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:12][CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2Cl)cc1
Reactant: COc1ccc(C)cc1B(O)O
Agent: C[C@@H](N)c1ccc(Br)cc1
Product: COc1ccc(C)cc1-c1ccc([C@@H](C)N)cc1

Procedure:
Prepared in a similar manner to (R)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid [1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethyl]-amide (Example 1) using 2-methoxy-5-methylphenylboronic acid and (R)-1-(4-bromophenyl)ethylamine to give (R)-1-(2′-methoxy-5′-methyl-biphenyl-4-yl)-ethylamine which was then reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride. Title compound: 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.27 (d, 2H), 7.20 (d, 2H), 7.12 (d, 1H), 7.02 (s, 1H), 6.97 (d, 1H), 4.35 (q, 1H), 3.72 (s, 3H), 3.55 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.33 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Yield: 83.9 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate are suspended in 27 ml of methanol, and 4.9 ml of 2N sodium hydroxide solution are added thereto. The mixture is refluxed for 20 minutes under heating. After cooling, the mixture is concentrated under reduced pressure to remove methanol. The residue is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove solvent. Then, the residue thus obtained is crystallized with ether and collected by filtration. 2.15 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:5]([S:2](=[O:4])(=[O:3])[N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:26])[CH:6]=1
Reactant: CNC1CCCCC1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (2.0 g, 7.56 mmol) and diisopropylethylamine (1.94 ml, 11.34 mmol) in DCM (50 ml) is treated with N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) at 0° C. The solution is stirred at room temperature for 3 hours and N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) is added. The solution is partitioned between DCM (250 ml) and 0.5 N HCl (100 ml). The organic layer is washed with 0.5 N HCl (2×100 ml), sat. aq. NaHCO3 (2×100 ml) and water (100 ml), dried over MgSO4, and the solvent removed in vacuo to yield a yellow oil. Crystallisation (iPr2O/EtOAc) yields 3-(Cyclohexyl-methyl-sulfamoyl)-4-m ethoxy-benzoic acid methyl ester as yellow crystals; [M+H] 342.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:25])CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:34]1[N:38]2[CH:39]=[C:40]([O:43][C@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C@@H:47]([NH2:54])[CH2:46][CH2:45]3)[CH:41]=[CH:42][C:37]2=[N:36][N:35]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[Cl:1][CH2:2][Cl:25].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:54][C@@H:47]2[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:44]([O:43][C:40]3[CH:41]=[CH:42][C:37]4[N:38]([C:34]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:28]5[CH3:27])=[N:35][N:36]=4)[CH:39]=3)[CH2:45][CH2:46]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A red-brown solution of Intermediate 33a (883 mg, 2.10 mmol), Intermediate 81d (755 mg, 2.00 mmol) and DIPEA (0.44 mL, 2.5 mmol) in dry dioxane (20 mL) was stirred at 70° C. for 16 h, and at 80° C. for 5 h. The cooled solution was concentrated in vacuo, suspended in water (15 mL) and extracted with DCM (2×15 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. Flash chromatography (silica 80 g, 4-8% MeOH in DCM) gave the title compound as a pale yellow foam (1.27 g, 87%). LCMS (Method 3): Rt 3.61 min, m/z 649 [MH+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(O)CNc1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccccc2F)nc1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 79 mg (0.21 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 35.7 mg (0.42 mmol) piperidine. Yield: 4.3 mg.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C(Cl)Cl>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry TIIF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O—[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Following General Procedure C, ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 278 mg, 1.07 mmol) in DMF (15 ml) was added K2CO3 (590 mg, 4.28 mmol) and 2-(bromomethyl)pyridine (914 mg, 5.35 mmol). The reaction was stirred at 60° C. for 5 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]([NH2:17])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]#[N:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(C#N)N2C(C)=O
Temperature: 25 °C

Procedure:
2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid methyl ester (0.084 mole) and 2M NH3 in methanol (500 ml) were combined and stirred at room temperature under argon over the weekend. The solution was concentrated to 100 ml, cooled in an ice bath, and filtered. The solid was rinsed with a small amount of cold methanol and dried. The residue was triturated in methanol/ACN and filtered, yielding 4.56 g of 2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 21, mp. 228-229° C.). b) Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196-197° C.). c) To a suspension of intermediate (22) (0.022 mole) in DCM (150 ml), cooled in an ice bath under argon, was added triethylamine (0.066 mole) then trichloroacetyl chloride (0.033 mole). The mixture was allowed to slowly warmed to room temperature overnight. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic phase was dried, concentrated and triturated in ether and the solid collected, yielding 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carbonitrile (intermediate 23, mp. 108-110° C.). d) To a solution of intermediate (23) (0.0154 mole) and ethanol (0.0231 mole) in 1M HCl/diethylether (200 ml), cooled in an ice bath was bubbled HCl (gas) for 60 minutes. The ice bath was maintained for 45 minutes, and the mixture was concentrated at room temperature under vacuum to 200 ml of an oily precipitate. The residue was triturated to a brown solid that became an oil after decanting off the diethylether. The residue was washed with diethylether twice, dissolved in methanol, and used without further purification for further synthesis, yielding ethyl 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboximidate monohydrochloride (intermediate 24).
Reaction SMILES: NCCCCCCCCCCCC(O)=O.S(Cl)([Cl:18])=O.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].Cl.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(N(CC)CC)C>ClCCl.C(O)C>[ClH:18].[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[N+:31]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:29][CH:28]=[CH:27][CH:26]=2)([O-:33])=[O:32]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: CCOC(=O)CCCCCCCCCCCN
Agent: Cl
Agent: NCCCCCCCCCCCC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Ethyl 12-aminododecanoate hydrochloride was prepared from 12-aminododecanoic acid, thionyl chloride, and ethanol by the general method of C. Temple, Jr., R. D. Elliott, and J. A. Montgomery, J. Med. Chem., 1988, 31, 697-700. The general method described in Step 1 of Example 15 was used to react 4-chloro-3-nitroquinoline (15.5 g, 74.4 mmol), ethyl 12-aminododecanoate hydrochloride (25.0 g, 89.3 mmol), and triethylamine (18.8 g, 186 mmol) in dichloromethane for 15 hours to provide ethyl 12-(3-nitroquinolin-4-ylamino)dodecanoate (30.0 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Br:30].C(N(CC)CC)C.[CH3:43][O:44][C:45](Cl)=[O:46]>CC(N(C)C)=O>[Br:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:45](=[O:46])[O:44][CH3:43]
Reactant: COC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Br)c(=O)n1-c1c(F)cccc1F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.12 g, 0.00021 mol) in dimethylacetamide (2.0 mL) at 0° C., was added triethylamine (0.06 mL, 0.00043 mol) followed by the addition of methylchloroformate (0.05 mL). The reaction mixture was stirred at room temperature for 30 min under argon atmosphere. Dimethylacetamide was distilled in vacuo and the residue was partitioned between dichloromethane (10 mL) and 5% citric acid (10 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness. The resulting residue was purified by flash chromatography (60% EtOAc in hexane) to afford the title compound (0.09 g, 75%) as a white amorphous powder: 1H NMR (DMSO-d6/400 MHz) δ 7.68 (m, 1H), 7.62 (m, 1H), 7.59 (m, 1H) 7.38 (m, 2H), 7.115 (m, 2H), 6.78 (s, 1H), 5.38 (s, 2H), 4.31 (d, 2H, J=6.0 Hz), 3.53 (s, 3H), and 2.03 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ−113.77 (m), and −120.33 (m); ES-HRMS m/z 511.0508 (M+H C22H19N2O4F3Br requires 511.0475).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:13].[K+].[K+].Cl[C:19]1C=C[CH:22]=[CH:21][CH:20]=1>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[CH2:22][CH2:21][CH:20]([OH:13])[CH2:19]3)[C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: Clc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc2c1OCCO2
Agent: [K+]
Product: OC1CCN(c2cccc3c2OCCO3)C1

Procedure:
10 g (66 mmol) of 5-amino-2,3-dihydro[1,4]benzodioxin, 7.65 ml of ω, ω'-dibromo-butan-2-ol and 18.25 g of K2CO3 in 125 ml of chlorobenzene are heated at reflux for 18 hours. After removal of the solvent by evaporation, the residue is taken up in methylene chloride and washed with water. Drying and evaporation yield 17.6 g of an oil which corresponds to the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2cccc(OCC(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of methyl 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetate (75 mg, 0.19 mmol) in EtOH (4.0 mL) and H2O (4.0 mL) was added 3M aqueous NaOH (0.30 mL, 1.0 mmol). The reaction mixture was left to stir at rt overnight. Then, the mixture was acidified with 1M HCl aqueous to pH=2. Vacuum filtration afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=4.80 (s, 2H), 6.93 (dd, J=7.7, 2.1 Hz, 1H), 7.25-7.29 (m, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.55-7.62 (m, 1H), 8.15 (dd, J=18.4, 7.6 Hz, 2H), 8.31 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.3 Hz, 1H), 13.06 (br. s., 1H). MS (ES+): m/z=378.07 (100) [MH+]. HPLC: tR=3.50 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[OH-:18].[Na+]>S(=O)(=O)(O)O.O>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCN(CC)CC#CCCCc1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCC(=O)CCCc1ccccc1

Procedure:
Add to a solution of 1-diethylamino-6-phenylhex-2-yne (27.1 g) in concentrated sulphuric acid (7.6 cc) diluted with water (77 cc) at 70° mercuric sulphate (1.6 g), and keep the solution under nitrogen for one hour; cool, make basic with sodium hydroxide solution, and filter through glass wool to remove mercuric oxide. Extract the product with ether and evaporate the washed and dried ethereal solution, leaving crude 1-diethylamino-6-phenylhexan-3-one. Distil under reduced pressure with this ketoamine undergoing partial elimination of diethylamine, to obtain a mixture of the ketoamine, and 6-phenylhex-1-en-3-one (18.9 g), b.p. 96°/0.003 mm.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2csc(-c3ccccn3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccn3)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogen carbonate (1.26 g) and dimethyl sulfoxide (18 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-6-oxo-1-[(2-pyridin-2-yl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.80 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.44 g, 49%).