Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.C(N1CCCOC(C[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C1)C1C=CC=CC=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:23]1([NH:22][C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)C1CC1
Temperature: 0 °C

Procedure:
Pyridine (3.64 mL, 45.0 mmol) was added to a solution of crude amine 80 (30.0 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then cyclopropyl carbonyl chloride (2.99 mL, 33.0 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature and stirred until the reaction was judged complete by TLC (3.25 h). CH2Cl2 and saturated NaHCO3 were added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by alumina gel chromatography (96:2:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (85) as a pale yellow oil. 1H NMR (CD3OD) 7.46-7.24 (8H, m), 7.13 (2H, broad d, J=7.2 Hz), 3.90 -3.42 (5H, m), 2.92-2.76 (2H, m), 2.62-2.51 (1H, m), 2.30 (1H, dd, 13.7, 8.5 Hz), 1.40-1.20 (2H, m), 0.96-0.82 (3H, m), 0.61 (2H, dd, J=7.9, 2.8 Hz) ppm. 13C NMR (CD3OD) 175.84, 144.04, 140.20, 130.82, 130.54, 129.55, 129.08, 128.43, 77.04, 68.00, 63.63, 59.72, 55.83, 52.94, 31.28, 13.76, 9.34, 9.07 ppm. LRMS: 364.57.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=S)#[N:2].[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: N#CNC(=S)Nc1ccncc1
Reactant: NCCNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CNC(=Nc1ccncc1)NCCNc1ccccc1
Reaction time: 72 h

Procedure:
N-Cyano-N'-4-pyridylthiourea (1.80 g) was suspended in dimethylformamide (5 ml). While stirring in an ice bath N-phenylethylenediamine (1.4 ml) and N,N'-dicyclohexylcarbodiimide (2.50 g) were added, resulting in a clear solution. The mixture was left at room temperature for 3 days, when the suspension formed was evaporated extensively under high vacuum. The residue was triturated repeatedly with ether (15 ml portions), and the residual solid was extracted with 1N hydrochloric acid (50 ml). After filtration, the crude product was precipitated from the filtrate by addition of 9N sodium hydroxide and taken up into ethyl acetate (3×75 ml).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:29]([O:33][N:34]1N=NC2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O>[CH3:29][O:33][N:34]([CH3:35])[C:14]([C@@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
To a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at 0° C. C, was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONMHMe.HCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (˜2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3×10 mL), water (2×10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1H NMR (400 MHz, CDCl3): 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The product from Step 4 above (60 mg, 0.1 mmol) was dissolved in 4 M HCl in dioxane (4 mL). Water (1 mL) was added and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was dissolved 20% aqueous acetonitrile and lyophylization yielded 4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as the hydrochloride salt. 1H NMR: (400 MHZ, DMSO-d6) δ 8.55 (d, J=6 Hz, 1H), 8.45 (d, J=2 Hz, 1H), 8.32 (d, J=2 Hz, 1H), 8.18-8.15 (m, 1H), 8.05 (d, J=2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 2.20 (s, 3H), 2.03 (s, 3H). MS: (M+H)/z=504.
Reaction SMILES: FC1C=C([C@H]2N(CC(OCC)=O)[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11]C2)C=C(F)C=1.[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:30](=[O:33])[CH2:31]Br.Cl.CN([CH:42]=[O:43])C>>[F:26][C:27]1[CH:28]=[C:29]([C:30](=[O:33])[CH2:31][NH:11][C:12]2([C:17]([O:43][CH3:42])=[O:25])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Reactant: CN(C)C=O
Agent: Cl
Product: COC(=O)C1(NCC(=O)c2cc(F)cc(F)c2)CCCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (10.0 g, 55.7 mmol, described in Intermediate 25), 3,5-difluorophenacyl bromide (14.4 g, 61.2 mmol), and Na3PO4 (22.8 g, 139 mmol) in DMF (100 mL) was stirred at ambient temperature for 3.5 h. The reaction mixture was acidified with 1 N aqueous HCl and the mixture was extracted with EtOAc (200 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 8-9 by addition of saturated aqueous NaHCO3 and the mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give the title compound. MS: m/z=298 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55][CH2:56]CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][C:50]([F:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: OCCCOc1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 68.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy-]aniline (71 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (108 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-fluorophenoxy)-1-propanol (61 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (81 mg, yield 64%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].N>>[CH:14]1[CH:15]=[CH:16][C:11]([O:17][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: N
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1
Reaction time: 15 h
Yield: 93.9 %

Procedure:
A steel autoclave was filled with 157.6 g of o-chloronitrobenzene and 116.1 g of sodium phenolate. At room temperature, 150 g of liquid ammonia were pumped into the vessel, the mixture was heated to 600 with stirring for 15 hours and subsequently cooled. Removal of the ammonia by distillation and workup of the distillation residue gave 202 g of 2-nitrodiphenyl ether (94% of the theoretical yield), 98.5% pure.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26]C)=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 247.2 %

Procedure:
A mixture of lithium hydroxide (0.5 g) and methyl cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonyl-amino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 58, 0.217 g) in a mixture of dioxane (13 mL) and water (4 mL) was divided between two microwave vials and the mixtures were irradiated in the microwave at 150° C. for 10 minutes. After cooling, the combined mixture was acidified by addition of 10% aqueous citric acid (2 mL), extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.518 g) as a glass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:30])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:44](OC(=O)C)([F:46])[F:45]>O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:44]([F:46])[F:45])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][C:20]=1[Cl:29])[C:10]([CH3:17])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.34 g), N,N-dimethylformamide (15 mL), potassium carbonate (0.58 g) and acetic acid chlorodifluoromethyl ester (0.4 mL) was stirred at 70° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and then the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (7:3 by volume) gave title compound, 0.37 g.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(S(O)(=O)=O)[CH:13]=CC=C[CH:9]=1.[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)O.CC(C)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:8]([C:25]2[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:18]=2)([CH3:13])[CH3:9])=[CH:3][CH:2]=1
Reactant: Oc1cccc(O)c1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)c1ccccc1
Solvent: CC(C)=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
7.56 g of phenol (0.08 mol) and 0.56 g of benzenesulfonic acid (0.0035 mol) and 2.5 g of the resin prepared according to Example 4 (0.01 mol of resorcinol) were charged into a 30 ml reactor fitted with a magnetic stirrer. The reaction mixture was heated to 50°. When the temperature of the reaction mixture had reached 50° C., 0.58 g of acetone (0.01 mol) was introduced very rapidly with the aid of a syringe. Samples withdrawn at various time intervals were assayed by high performance liquid chromatography to determined the yields of bisphenol A and impurities.
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:31])[CH2:17][N:18]([C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28](=[NH:30])[NH2:29])[CH2:24][CH2:23]2)=[O:21])[CH3:19])=[CH:12][C:11]=1[O:32][CH2:33][C:34]([O-:36])=[O:35])[C:6]([O-:8])=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:28]([C@H:25]1[CH2:26][CH2:27][C@H:22]([C:20]([N:18]([CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:12]=2)=[O:31])[CH3:19])=[O:21])[CH2:23][CH2:24]1)(=[NH:29])[NH2:30]
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Reaction time: 5 h

Procedure:
To the solution of the compound prepared in (d) (50 mg, 0.089 mmole) in anisole was added trifluoroacetic acid under ice-cooling. The mixture was stirred for 5 hours, during which the temperature of the mixture was left rising up to room temperature. After isopropyl ether was added to the reaction mixture, solids deposited were collected to give 31 mg of the title compound as the colorless solid (yield, 62%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[C:10]([C:14]1[CH:15]=[C:16]([NH2:34])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:34][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Reaction time: 3 h
Yield: 72 %

Procedure:
2,2,2-Trichloroethyl chloroformate (0.077 mL, 0.57 mmol) was added to a solution of Intermediate 12c (200 mg, 0.57 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (5 mL), and the mixture stirred for 3 h. The mixture was then partitioned between water (10 mL) and EtOAc (3×15 mL), and the combined organic extracts dried (Na2SO4). The solvent was evaporated and the residue triturated under pentane and filtered to give the title compound as a yellow solid (215 mg, 72%). LCMS (Method 1): Rt 2.89 min, m/z 523/525 [MH+]
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:22]=[CH:23][C:24]=1[C:25]#[N:26].C([N:38](CC)CC)C>C(Cl)Cl.CN(C=O)C.ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]2[O:9][N:38]=[C:25]([C:24]3[CH:23]=[CH:22][C:21]([CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:20][C:19]=3[CH3:18])[N:26]=2)[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 200 mg (1.04 mmol) of 5,6-dichloronicotinic acid in 5.0 mL of CH2Cl2 was added 273 μL (3.13 mmol) of oxalyl chloride and one drop of DMF. After stirring at rt overnight, the mixture was concentrated and dried azeotropically using toluene (3×5 mL). The residue was dissolved in 5.0 mL of dichloroethane and added to a solution of 242 mg (0.87 mmol) of N-HYDROXYAMIDINE 1 and 182 μL (1.30 mmol) of triethylamine in 5.0 mL of dichloroethane. After stirring at rt for 1 hr and at 120° C. overnight, the reaction mixture was cooled to rt and concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 303 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 2.58 (t, J=7.8, 2H), 2.65 (s, 3H), 2.95 (t, J=7.7, 2H), 7.17-7.19 (m, 2H), 8.00 (d, J=8.5, 1H), 8.53 (d, J=2.0, 1H), 9.08 (d, J=2.0, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:19][C:18]=2[F:40])[CH:8]=1)[CH3:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:41]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:19][C:18]=2[F:40])[CH:8]=1)[CH3:42]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)c2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)CC4CCNCC4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of tert-butyl 4-(2-(4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)-2-oxoethyl)piperidine-1-carboxylate (Example 35; 2 mg, 0.00336 mmol) in methylene chloride (3 mL) was added 2,2,2-trifluoroacetic acid (3.83 mg, 0.0336 mmol). The reaction was stirred for 4 hours at room temperature. The reaction mixture was concentrated to dryness to give the product as a clear oil. Yield: 1.2 mg (47%). LRMS (esi pos) m/e 495 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([Si:12](Cl)([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].[Br:18][C:19]1[S:23][C:22]2=[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:26][N:21]2[C:20]=1[CH2:33][OH:34]>CN(C)C=O.C(OCC)(=O)C>[Br:18][C:19]1[S:23][C:22]2=[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:26][N:21]2[C:20]=1[CH2:33][O:34][Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: OCc1c(Br)sc2c(-c3cccnc3)ncn12
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OCc1c(Br)sc2c(-c3cccnc3)ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (3.1 ml) and 3.0 ml of triethylsilylchloride were added in that order to a solution of 4.05 g of 2-bromo-7-(pyridin-3-yl)hydroxymethylimidazo[5,1-b]thiazole in 30 ml of dimethylformamide, and the mixture was stirred at room temperature for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water, a 5% aqueous sodium bicarbonate solution, and a 20% aqueous sodium chloride solution in that order and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (2 to 5% methanol/methylene chloride) to give 5.14 g of 2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:17]O>CCOC(C)=O.O>[CH3:17][O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Br)s1

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid (1.04 g, 5.0 mmol) in 15 mL of methanol, add concentrated sulfuric acid (0.5 ml, 10 mmol). After heating to reflux for an hour, cool the reaction to room temp, and dilute with EtOAc/H2O=50/50. Then, neutralize with 1.0 N NaOH to pH=7, extract the aqueous solution with ethyl acetate (30 ml×3), and dry the combined organic layers over sodium sulfate. Purify the crude material via flash chromatograpgy on sila gel to give the title compound 0.62 g. GC/MS (m/z) 222 (M+1), 191 (M—OMe+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:5][C:4]=1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)cc1COCc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1COCc1ccc(C(F)(F)F)cc1

Procedure:
Using 4-methoxy-3-({[-4-(trifluoromethyl)benzyl]oxy}methyl)benzaldehyde and 2,4-thiazolidinedione, 5-[4-methoxy-3-([4-(trifluoromethyl)benzyl]oxymethyl)benzyl]-1,3-thiazolane-2,4-dione was obtained in the same method as in Production Example 27c) and then in Example 29).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br[CH2:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:24]1[N:4]=[C:1]([CH2:2][CH3:3])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:23]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Product: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 1-bromo-3,3-dimethylbutan-2-one: MS (ESI) m/z 372 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.O([CH3:21])[Na]>C1COCC1>[C:14]1([CH:17]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:15]=[CH:16][CH:21]=[CH:12][CH:13]=1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccncc1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 29 %

Procedure:
2.26 g (16.6 mmol) of 2-hydroxyacetophenone, 1.68 g of 4-pyridine-carboxaldehyde (15.7 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.02 g (29%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 8.72-8.70 (m, 2H), 7.90 (d, d, J=1.5, 7.8 Hz, 1H), 7.80 (s, 2H), 7.56-7.48 (m, 3H), 7.05 (d, d, J=0.9, 8.4 Hz, 1H), 6.97 (d, d, J=7.2, 7.5 Hz, 1H).