Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]([Cl:15])([Cl:14])[CH2:10][CH:11]1[O:13][CH2:12]1>C(O)C>[OH:4][CH2:3][CH2:2][N:1]([CH2:12][CH:11]([OH:13])[CH2:10][C:9]([Cl:15])([Cl:14])[Cl:8])[CH2:5][CH2:6][OH:7]
Reactant: ClC(Cl)(Cl)CC1CO1
Reactant: OCCNCCO
Solvent: CCO
Product: OCCN(CCO)CC(O)CC(Cl)(Cl)Cl

Procedure:
To a solution of 52.5g (0.5 mole) diethanolamine in 100 ml ethanol heated to reflux was added 87.7g (0.5 mole) 4,4,4-trichloro-1,2-epoxybutane over a period of 105 minutes. After refluxing with agitation for an additional 5 hours the solvent was removed via vacuum leaving 135.7g (96.5%) of N,N-bis(2-hydroxyethyl)-4,4,4-trichloro-2-hydroxy-1-butylamine, a clear dark, highly viscous liquid; hydroxyl number = 600. This product is soluble in water (pH≈8) and in xylene. Analysis: (Calculated) %N, 5.00; %Cl, 37.96. (Found) %N, 5.00; %Cl, 37.09.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21](Cl)=[O:22]>COCCOC>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:22]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1F

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 3-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 3-fluoro-4-(hexadecylamino)benzoylmalonate.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.[OH-].[Na+].C1C=CC=CC=1>C1COCC1.CO.Cl.O.[Pd]>[C:8]([C:7]1[CH:2]=[N:3][C:4]([NH2:11])=[CH:5][C:6]=1[NH2:10])#[N:9]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(N)cc1N
Reaction time: 168 h
Yield: 69 %

Procedure:
Crude 2-bromo-3-cyano-4,6-diaminopyridine [W. J. Middleton, U.S. Pat. No. 2,790,806 (Apr. 30, 1957), Du Pont; Chem. Abst. 51:P14829 (1957), see also next experimental] (15.1 g, 0.071 mole) is hydrogenated in THF/MeOH (200 mL, 2:1) containing KOAC (7.0 g, 0.071 mole) and 5% Pd/C (4 g) at 55 p.s.i. and 20° C. for 7 days. Filtration over celite, washing with THF/MeOH and removal of the solvent gives a solid, which is dissolved in dilute HCl and water. Adjustment of the solution pH to 10 (conc. NaOH) and cooling gives 3-cyano-4,6-diaminopyridine (6.58 g, 69%) as a yellow solid, mp 197-198° C. [Metzger, R.; Oberdorfer, J.; Schwager, C.; Thielecke, W.; Boldt, P. Liebigs Ann. Chem. 1980, 946-953 record mp (benzene) 205° C.]. Extraction of the remaining liquor with EtOAc (4×200 mL) gives further product (2.12 g, 22w). 1H NMR (DMSO) δ 7.91 (1H, s), 6.26, 6.24 (2H, 2H, brs), 5.63 (1H, s).
Reaction SMILES: N#N.[Cl:3][C:4]1[C:5]([CH:10]([NH:24][C:25]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.CC#N.O=P(Cl)(Cl)Cl>O.CN(C=O)C>[Cl:3][C:4]1[C:5]2[N:6]([C:25]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:24][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CCCC1
Agent: N#N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
In an oven-dried flask filled with N2 was added cyclopentanecarboxylic acid [(3-chloropyrazin-2-yl)-(4-phenoxyphenyl)-methyl]-amide (80 mg, 0.2 mol), MeCN (5 mL) and DMF (0.9 mL). POCl3 was added dropwise at 0° C. The reaction was warmed up to rt and stirred at that temp overnight. The excess of POCl3 was removed under reduced pressure and the residue was quenched with 2 N NH3 in i-PrOH at 0° C. with vigorous stirring to adjust pH to 9. The crude reaction mixture was then charged with water and the aqueous layer was washed with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 42 mg of the title compound as a yellow oil. Compound was carried over to the next step. MS (ES+): m/z 389.88 (30)[MH+]. HPLC: tR=4.29 min (Open Lynx, polar—5 min).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH:7]=[CH:6][C@H:5]([CH2:8][CH3:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].CSC.[OH-:20].[Na+].OO>C1COCC1.CCOC(C)=O>[CH2:1]([C@@H:3]1[CH:7]([OH:20])[CH2:6][C@H:5]([CH2:8][CH3:9])[N:4]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:2]
Reactant: [OH-]
Reactant: CC[C@H]1C=C[C@@H](CC)N1C(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1CC(O)[C@@H](CC)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.7 %

Procedure:
To a solution of tert-butyl (2R,5S)-2,5-diethyl-2,5-dihydropyrrole-1-carboxylate (4.8 g, 10.5 mmol) in THF (50 mL) was added slowly BH3.DMS solution (2M in THF, 6.97 mL, 13.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours and then cooled to 0° C. NaOH solution (5 M, 12.6 mL, 63.2 mmol) was added to the reaction mixture, followed by addition of H2O2 (30%, 6.33 mL, 62.0 mmol). The resulting mixture was stirred for 5 hours before diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4. The organic solvent was removed to give the crude product, which was purified by flash chromatography on silica gel to give the tert-butyl (2R,5S)-2,5-diethyl-3-hydroxy-pyrrolidine-1-carboxylate (3.8 g, 77%). 1HNMR(CDCl3, 300 MHz): 4.35 (s, 1H), 4.0-3.46 (m, 5H), 3.33 (m, 1H), 2.22-2.10 (m, 1H), 1.89-1.73 (m, 1H), 1.39 (s, 9H), 0.82 (s, 18H), −0.01 (s, 6H), −0.03 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>O1CCOCC1>[CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])([C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCCCC(=O)OC)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.50 g (52.22 mmol) of sodium hydride were added carefully to a solution of 2.00 g (69.62 mmol) of diallyl malonate in 700 ml of dioxane. After the evolution of gas had ended, the mixture was stirred at room temperature for 20 min, and a solution of 7.00 g (34.81 mmol) of methyl 5-bromovalerate in 120 ml of dioxane was added dropwise. The solution was stirred at 110° C. for 16 h. The resulting precipitate was filtered off, the solvent was removed and the residue was taken up in water. The mixture was extracted with diethyl ether, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromato-graphically (silica gel, cylcohexane/ethyl acetate 10:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)=[O:4].[NH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[C:21]=1O)[C:17]#[N:18].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[O:12][C:21]3[C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[N:13]=2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=O)nc1
Reactant: CC(C)c1cc(C#N)cc(N)c1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COC(=O)c1cnc(-c2nc3cc(C#N)cc(C(C)C)c3o2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Methyl-2-formylpyrimidine-5-carboxylate (200 mg, 1.205 mmol) and 3-amino-4-hydroxy-5-isopropylbenzonitrile (212 mg, 1.205 mmol) were dissolved in methanol (5 ml). The mixture was concentrated, and then the residue was dissolved in dichloromethane (5 ml). To the above solution was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (300.9 mg, 1.325 mmol) at room temperature. The solution was stirred at room temperature for 30 min, and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (hexanes-ethyl acetate=4:1, then 1:1) to provide of the title compound (139 mg) as a yellow solid. Mass spectrum (ESI) 322.8 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 2H), 8.13 (s, 1H), 7.66 (s, 1H), 4.09 (s, 3H), 3.65 (m, 1H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][NH:8][CH:3]([CH2:4][CH2:5]2)[CH2:2]1.[ClH:9].O.[OH-].[K+].[C:13]1([C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:22][CH2:23]Br)[C:20]#[N:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[ClH:9].[C:25]1([C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH2:22][CH2:23][N:8]2[CH2:7][CH:6]3[CH2:5][CH2:4][CH:3]2[CH2:2][CH2:1]3)[C:20]#[N:21])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CC2CCC1CN2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 0.85 part of 2-azabicyclo-[2.2.2.]octane hydrochloride in 20 parts of water is added 0.71 part of potassium hydroxide under a nitrogen atmosphere. Then, 1.90 parts of 2,2-diphenyl-4-bromobutyronitrile is added, and the mixture heated to reflux for 3.5 hours. This reaction mixture is cooled to about 60° C., whereupon 13 parts of benzene is added. The aqueous layer is separated and extracted with 15 parts of benzene. To the combined benzene extracts is added dropwise 2 parts by volume of a solution of hydrochloric acid in isopropanol. The volume of this solution is reduced by heating on a steam bath. Cooling affords a white precipitate which is washed with benzene and dried at 100° C. for about 2 hours. The resulting product, 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile hydrochloride, is obtained in approximately 76.8% yield. This product melts at about 194° - 197° C., and is represented by the following structural formula. ##STR11##
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][C:7](=[N:12][OH:13])[C:8]([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7](=[N:12][OH:13])[CH2:6][N+:1]([O-:3])=[O:2]
Reactant: CC(C)(C)C(CBr)=NO
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(C[N+](=O)[O-])=NO
Reaction time: 20 h
Yield: 29.2 %

Procedure:
To a stirred solution of 18.2 g (0.26 m) of sodium nitrite in 130 ml of dimethyl sulfoxide is added, in portions, 29.0 g (0.15 m) of 1-bromo-3,3-dimethyl-2-butanone oxime. A mild exotherm results and external cooling is used to keep the temperature below 27° C. Additional solvent is added to maintain stirrability. After 20 hours stirring, the mixture is poured onto ice and water to give a solid which is collected on a filter. The 10 g of solid, m. 115°-120° C, thus obtained is recrystallized from a hot benzene-petroleum ether mixture to give 7 g of white crystals, m. 124°-125° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]#[N:16])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])C.OO.NC(N)=[O:21]>CO.[OH-].[Na+]>[C:15]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:3])=[O:5])=[CH:7][CH:8]=2)[NH:12][CH:11]=1)(=[O:21])[NH2:16]
Reactant: CCOC(=O)c1ccc2c(C#N)c[nH]c2c1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1c[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A suspension of 3-cyano-1H-indole-6-carboxylic acid ethyl ester (100 mg, 1.4 mmol) in methanol (1.12 mL) was added to a solution of urea hydrogen peroxide (453 mg, 4.67 mmol) in 2.5 M sodium hydroxide (1.12 mL, 2.80 mmol) at 0° C. The suspension was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated under reduced pressure. Water was added and the solution was acidified with 3 N aqueous hydrochloric acid to pH=2. A precipitate formed. The reaction mixture was stirred for 1 minute at room temperature and was then filtered to give an orange solid. Additional urea hydrogen peroxide (453 mg) in 2.5 M sodium hydroxide and methanol was added and the mixture was stirred for 2 hours. The reaction was concentrated, diluted with water, acidified to pH=3 and filtered. The solid was washed with water and heptanes and was dried in a vacuum oven to give 3-carbamoyl-1H-indole-6-carboxylic acid as a solid (66.5 mg, 70%). −ESI (M−1) 203.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.45 (br. s., 1 H), 11.78 (br. s., 1 H), 8.83 (d, J=1.6 Hz, 1 H), 8.09 (d, J=2.9 Hz, 1 H), 7.73 (dd, J=8.6, 1.8 Hz, 1 H), 7.51 (br. s., 1 H), 7.45 (d, J=8.4 Hz, 1 H), 6.89 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(C#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Mg+].[Br-].CC[O:22][CH2:23][CH3:24].O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:23](=[O:22])[CH3:24])[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: N#CC1(c2ccc(C(F)(F)F)cc2)CCC1
Reactant: CCOCC
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC1
Temperature: 95 °C
Yield: 88 %

Procedure:
The starting nitrile, 1-(4-Trifluoromethyl-phenyl)-cyclobutanecarbonitrile, has been described (Parke Davis & Co., U.S. Pat. No. 3,536,656; 1970 and Chemical Abstracts 1970, 73, 109539). To the carbonitrile (2 g) in 5 mL of toluene in a pressure tube was added 10 mL of 3M MeMgBr ether solution (3 equiv.). The tube was sealed and the reaction mixture was heated at 95° C. for 24 hr, cooled to room temperature, poured into 50 mL of water, acidified with 25 mL of 5 M HCl, and this solution was heated at 70° C. for 2 h, cooled, and extracted with ether. The extracts were dried, filtered, concentrated, and purified on silica gel to give pure 1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.9 g, 88%). Data for this ketone: MS 242 (M); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, 8.0 Hz, 2H), 7.4 (d, 8.0 Hz, 2H), 2.75-2.85 (m, 2H), 2.35-2.5 (m, 21H), 1.8-2.0 (3H s and 21H m overlapping); 13C NMR (75 M Hz, CDCl3): δ 207.7, 1 47.5, 129.5, 126.9, 126.1, 125.9 (CF3), 59.5, 30.9, 24.6, 16.1.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CC#N
Product: Brc1ccc2nc(-c3ccc(OCCN4CCOCC4)cc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 40 from 4-(6-bromo-benzoxazol-2-yl)-phenol and N-(2-chloroethyl)morpholine hydrochloride with ACN as solv.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[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:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:2].[CH3:27][C:28](N(C)C)=[O:29]>>[CH2:25]([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:23]=[CH:22][C:20]([NH:21][C:28](=[O:29])[CH3:27])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:26]
Reactant: CC(=O)N(C)C
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(C)=O)cc3F)c2s1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
A 20 mL scintillation vial was charged with polystyrene-2,3,5,6-tetrafluoro-4-(methylcarbamoyl)phenyl acetate (0.179 g, 0.238 mmol). 4-(2-(3-(Diethylamino)-prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (Example 6, Step B 0.022 g, 0.0595 mmol) in DMA (2 mL) was added to the resin, and the mixture was heated at 100° C. with shaking for 96 hours. The reaction was cooled to room temperature and filtered using a vacuum master and Jones tubes. The filtrate was collected in 13 mm test tubes. The resin was washed with DMA (2 mL) making the total volume 4 mL. The crude material was dried using a GeneVac DD-4 set at 50° C. for the chamber and vial holder. Vacuum was set to aqua speed and reached a pressure of 7 mm Hg. The crude oil was purified by reverse phase chromatography (see purification method A, below). The final product was a TFA salt and a yellow oil (6.9 mg, 16%). Final Purity: 97%, LRMS (APCI pos) m/e 412.1 (M+1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[S:7][C:8](S(CC)(=O)=O)=[N:9][N:10]=1)(=[O:5])=[O:4])[CH3:2].O.[NH2:17][NH2:18]>CO>[NH:17]([C:8]1[S:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:10][N:9]=1)[NH2:18]
Reactant: CCS(=O)(=O)c1nnc(S(=O)(=O)CC)s1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1nnc(NN)s1
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
2,5-bis(ethanesulphonyl)-1,3,4-thiadiazole (67.5 g) was added portionwise to a stirred solution of hydrazine hydrate (25.8 g) in methanol (1000 ml) at room temperature. The mixture was then stirred for 20 minutes and filtered. The solid was crystallised from methanol to give 2-hydrazino-5-ethylsulphonyl-1,3,4-thiadiazole (16.5 g, mp 166°-167° C.). The corresponding semicarbazone was prepared from this compound by reaction with acetaldehyde, then with methylisocyanate by methods analogous to those of Example 1(c) and 1(d), and the title compound was generated by the method of Example 13, mp 151°-153° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 10 (300 mg, 0.714 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (128 mg, 0.785 mmol) in the presence of EDCI hydrochloride (273 mg, 1.428 mmol), DMAP (80 mg, 0.714 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 27 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.80-1.90 (m, 4H), 1.98-2.08 (m, 2H), 2.66-2.76 (m, 1H), 3.89-3.95 (m, 2H), 7.15-7.25 (m, 3H), 7.40-7.47 (m, 1H), 7.52-7.67 (m, 2H), 7.78 (d, J=15.9 Hz, 1H), 8.00-8.10 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 571.18 (MH)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14]/[C:15](=[N:36]\O)/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCOCC1.CN(C=O)C>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([NH:25][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]3[N:36]=[C:11]([C:9]4[N:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH:8]=4)[O:13][N:14]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(C(=O)O)n1
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(/C(N)=N/O)cc2)c1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(-c3noc(-c4cccc(NC(C)=O)n4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Carbonyldiimidazole (9.78 g) dissolved in dioxane (100 ml) is added dropwise to 6-acetylaminopyridine-2-carboxylic acid (10.86 g) in a mixture of dioxane (100 ml) and DMF (60 ml) and the mixture is stirred at room temperature for 3 h. N-{3-[({4-[(Z)-Amino(hydroxyimino)methyl]phenyl}sulfonyl)amino]phenyl}acetamide is then added as a solid and the reaction mixture is stirred at room temperature for 16 h. Subsequently, the reaction mixture is stirred at 100° C. for 4 h and then poured onto ice/water. The product is left to stand for 10 min, collected by filtration, washed with water (three times) and dried in a vacuum oven. 25.55 g (90% of theory) of product are obtained as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[C:22]([N:28]=[C:29]=[O:30])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([NH:28][C:29](=[O:30])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)N=C=O
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: CCn1c(COC(=O)NC(=O)C(C)(C)C)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the compound 19 (200 mg, 0.580 mmol) in tetrahydrofuran (1 mL) under ice-cooling was added pivaloyl isocyanate (5 eq.), and stirred at the same temperature for 1 hour. After removing condenser, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and phosphate buffer (pH 7.0). The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ether (2:1)) to give the compound 81 (227 mg, 83%) as crystals. Mp. 157-159° C. Rf 0.31 (1:2 EtOAc-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH3:12].CCO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:12])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)c1cc(F)cc(F)c1
Reaction time: 20 h

Procedure:
To a stirred mixture of 3′,5′-difluoroacetophenone (86.8 g, 0.556 mol) and 2 M NH3 in EtOH (1.4 L, 2.8 mol) was added titanium(IV) isopropoxide (326 mL, 1.11 mol) dropwise over 15 min stirring was continued at ambient temperature for 20 h. The mixture was cooled in an ice-water bath and sodium borohydride (31.5 g, 0.834 mol) was added in portions over 60 min. The reaction mixture was stirred for an additional 1 h, and then quenched with aqueous NH4OH (2 M, 1.3 L) followed by EtOAc (1 L). The resulting mixture was aged for 18 h and filtered through a pad of celite, washing with EtOAc (1 L). To the filtrate was added EtOAc (2 L) and H2O (1 L) containing NaCl (ca. 100 g). The mixture was shaken and allowed to separate. The organic layer was concentrated in vacuo to a volume of about 500 mL and partitioned between EtOAc (2 L) and saturated aqueous Na2CO3 (300 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. MS: m/z=182 (M+CH3CN−NH2).