Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CN(C)CCBr
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (54 mg, 0.126 mmol) in DMF (5 mL) were added K2CO3 (26.2 mg, 0.189 mmol) and 2-bromo-N,N-dimethylethanamine (28.8 mg, 0.189 mmol). The resulting mixture was stirred at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(dimethylamino)ethyl 6-((2R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (16.5 mg, 24%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.69 min, MH+=499.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nn(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 179.6 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (5.02 g, 39.5 mmol) in DMF (80 mL) were added CH3I (10.01 mg, 70.52 mmol) and K2CO3 (9.97 g). The mixture was stirred at 60° C. for 2 h, quenched with water (100 mL), and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as brown oil (10.01 g, 89.79%).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][NH:8][C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[CH:7][N:8]([CH3:14])[C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: O=c1cc2scc(Br)c2c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c(Br)csc2cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 3-bromothieno[3,2-c]pyridin-6(5H)-one (235 mg, 1.02 mmol) in DMF (3.9 mL) was added sodium hydride (25.7 mg, 1.07 mmol). The mixture stirred 1 h at room temperature, and then methyl iodide (69.9 μL, 1.12 mmol) was added. The reaction stirred a further 1 h at room temperature and then was poured into water (100 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic fractions were washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated. Trituration with diethyl ether (˜5 mL) and filtration to collect the resultant solid afforded 120 mg (48%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1 H), 6.91 (s, 1 H), 6.89 (d, J=0.8 Hz, 1 H), 3.75 (s, 3 H); MS (ESI): 244.03, 245.98 [M+H]+; HPLC tR=2.76 min (ZQ3, polar—4 min).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[C:16]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][C:13]([NH2:14])=[C:12]([F:23])[CH:11]=1>C(OCC)(=O)C>[Cl:9][C:10]1[C:16]([C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18])=[CH:15][C:13]([N:14]=[C:2]=[O:3])=[C:12]([F:23])[CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Temperature: 0 °C
Yield: 133.3 %

Procedure:
5.4 ml (0.045 mol) of trichloromethyl chloroformate were added to 30 ml of ethyl acetate. The resulting solution was cooled to 0° C. A solution of 13.9 g (0.06 mol) of 4-chloro-2-fluoro-5-isopropoxycarbonylaniline in 25 ml of ethyl acetate were added dropwise to the above cooled solution over a period of 15 minutes. The mixture was stirred at a temperature of 0° to 10° C. for an hour, and then refluxed for two hours. The reaction mixture was concentrated to give 15.45 g (yield 99.9%) of the desired product as nearly white crystals with a melting point of 41°-43° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:28](=[O:30])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]3[C:9]3[O:10][C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:26]=2)=[CH:38][CH:39]=1
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(O)cc1)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a mixture of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (300 mg, 0.690 mmol) and tyramine (123 mg, 0.897 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (140 mg, 1.04 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38mmol). After stirring the resulting mixture at room temperature for 3 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 3:2 elution) to give (±)-N-[2-(4-hydroxyphenyl)ethyl]-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (358.4 mg, 94%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18][CH3:21])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Oc1cccc2cccc(Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cccc(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 g of 8-benzyl-1-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 24.2 g of sodium hydride (55% suspension in oil) was added to the solution under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes. Methyl iodide was added to the resulting mixture under cooling with ice. The obtained mixture was stirred for 30 minutes under cooling with ice and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride twice, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography (developer: 5% ethyl acetate/hexane) to give 73 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(Nc2cnccn2)c(N)cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cn1)nnn2-c1cnccn1
Yield: 23.2 %

Procedure:
To a solution of 6-methyl-N4-(pyrazin-2-yl)pyridine-3,4-diamine (520 mg, 2.58 mmol) in THF (30 mL) was added acetic acid (0.44 mL, 7.75 mmol) and tert-butyl nitrite (0.51 mL, 3.88 mmol). The reaction was heated to reflux. After 30 min the reaction was cooled and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-7% [2M NH3 in MeOH]CH2Cl2) to give the desired product (127 mg, 25%). MS (ESI) mass calcd. C11H9N5, 212.08. m/z found, 213.1 [M+H]+.
Reaction SMILES: [C:1](OCC)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12].CC(C1OC(=O)CC1)CCC>>[CH3:4][CH:3]1[CH:11]([CH:10]([CH2:13][CH2:14][CH3:15])[CH3:9])[O:12][C:1](=[O:5])[CH2:2]1
Reactant: CCCC(C)C=O
Reactant: C/C=C/C(=O)OCC
Agent: CCCC(C)C1CCC(=O)O1
Product: CCCC(C)C1OC(=O)CC1C

Procedure:
Ethyl crotonate (6.7% by weight) and 2-methylpentanal (5.9% by weight) were reacted electrochemically by a method analogous to example 3 (all % by weight are based on the total aqueous reaction electrolyte). A yield of 4-(2-pentyl)butyrolactone of 66.7% and a yield of the corresponding ethyl γ-hydroxycarboxylate of 26.6% were achieved. This corresponded to a total yield of target products of 93.2% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17]N(C)C[C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[C:32]([N:39]1CCC(=O)[CH2:41][CH2:40]1)(OC(C)(C)C)=O.O=C1CCCCN(C(OC(C)(C)C)=O)C1.FC1C=C(F)C(F)=CC=1C(Cl)=O.FC1C=C(C=CC=1F)C(Cl)=O>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[N:39]([CH3:32])[CH2:40][CH2:41][CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:30])[CH3:31])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)N1CCCCC(=O)C1
Agent: O=C(Cl)c1cc(F)c(F)cc1F
Agent: O=C(Cl)c1ccc(F)c(F)c1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCCCN2C)C(C)(C)C

Procedure:
Compound 69 was prepared according to the procedure described above for the synthesis of compound 37 except that 1-Boc-4-piperidone was replaced with tert-butyl 3-oxoazepane-1-carboxylate and 2,4,5-trifluorobenzoyl-chloride was replaced with 3,4-difluorobenzoylchloride. LCMS (+ESI) m/z=434.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[CH2:28](OP(Cl)(Cl)=O)C>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[C:14](=[CH2:28])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CCOP(=O)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(C)=O)[C@@]2(C)CCC(=O)C=C12

Procedure:
Analogously to Example 42, 1.0 g of 17α-acetoxy-4-pregnene-3,20-dione is reacted with 3.8 ml of ethyldichlorophosphate and worked up, thus obtaining 510 mg of 17α-acetoxy-6-methylene-4-pregnene-3,20-dione, mp 231°-233° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[N:7][CH:8]=1.[Cl:20][C:21]1[C:26]([C:27]([N:29]=[C:30]=[O:31])=O)=[C:25]([F:32])[C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([F:32])[C:26]=1[C:27]1[NH:29][C:30](=[O:31])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cn3)c(=O)[nH]2)c1F
Yield: 14.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate (Intermediate-60, 0.050 g, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.120 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.012 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 4.30 (d, J=5.6 Hz, 2H), 7.11 (br s, 1H), 7.46 (1, J=8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.14 (m, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.35 (dd, J=7.2 Hz, 1H), 8.87 (s, 1H); MS (m/z): 472.24 (M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][I:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(OCCOCCO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCCOCCI)c1ccccc1
Reaction time: 14 h
Yield: 64.1 %

Procedure:
To a solution of 2,2′-oxydiethanol (2.12 g) in pyridine (20 mL) was added benzoic anhydride (4.52 g) by small portions under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 18 hrs. Pyridine was evaporated under reduced pressure and the obtained residue was diluted with diethyl ether (20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with diethyl ether (100 mL×3). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→40/60). The object fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane (10 mL) were added 1-iodopyrrolidine-2,5-dione (2.70 g) and triphenylphosphine (3.14 g) by small portions under ice-cooling, and the mixture was stirred for 14 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mL×3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=100/0→60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(2-iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:16]([OH:18])=[O:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 4-Fluoro-2-trifluoromethyl-benzaldehyde (2 g, 10.2 mmol), malonic acid (1.2 g, 11.2 mmol), piperidine (0.087 g, 1 mmol) and pyridine (7 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 40 g ice and 20 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 1.16 g (49%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[C:29]([CH3:30])=[CH:28][C:27](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][C:25]=1[CH3:38].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.CCCCP(CCCC)CCCC>C1COCC1>[CH3:38][C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:28]=[C:29]([CH3:30])[C:24]=1[O:20][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)/C=C/c1cc(C)c(O)c(C)c1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1c(C)cc(/C=C/C(=O)OCC)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and ethyl (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-2-propenoate (79 mg, 0.36 mmol) in THF (4 mL) at 0° C. under nitrogen was added ADDP (101 mg, 0.40 mmol) followed by tri-N-butylphosphine (0.100 mL, 0.40 mmol). The resulting mixture was then allowed to warm slowly to ambient temperature overnight. After 66 h the solvent was removed under vacuum (Genevac) and the resulting solid partitioned between DCM (5 mL) and water (5 mL), the layers separated and the aqueous re-extracted with DCM (5 mL). The combined organic layer was then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 1:1) to give the title compound (35 mg).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:10])[C:7](O)=[O:8].[NH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:5][CH:6]([F:10])[C:7]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH3:16])=[O:8]
Reactant: CCOC(N)=O
Reactant: O=C(O)C(F)F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)NC(=O)C(F)F
Temperature: 25 °C
Yield: 93.3 %

Procedure:
During a thirty minute period 65.4 g (0.55 mole) of thionyl chloride was added dropwise to 50.0 g (0.52 mole) of difluoroacetic acid with stirring, while maintaining a reaction temperature of 20°-25° C. After complete addition the mixture was stirred at room temperature for 1.5 hours and 46.4 g (0.52 mole) of urethane was added. The resultant mixture was heated at reflux for approximately three hours then allowed to cool to room temperature and stir for approximately 18 hours. The reaction mixture was again heated at 77° C. for two hours. Unreacted materials were removed from the reaction mixture by evaporation under reduced pressure leaving 81.1 g of ethyl difluoroacetylcarbamate as a semi-solid residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reaction time: 2.5 h
Yield: 165.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (0.52 g) ad N,N-dimethylaniline (0.97 g) in methylene chloride (15 ml) is added dimethylaminoacetyl chloride hydrochloride (0.63 g) under ice cooling, and the mixture is stirred at the same temperature for 2.5 hours. To the reaction mixture is added aqueous sodium hydrogen carbonate solution, and is extracted with chloroform. The chloroform layer is washed, dried and distilled to remove the solvent. The residue is treated with hydrochloric acid and the resulting salt is recrystallized from ethanol-ether to give 2-(4-chlorophenyl)-4-(dimethylamino)acetyl-3,4-dihyro-2H-1,4-benzothiazine hydrochloride (0.63 g, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:33]#[C:32][C:30]([OH:34])([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)[CH3:31])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCC(O)CO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(O)CO)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol (80 mg, 0.21 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg, 1.06 mol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.22 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred for 5 h at 70° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a frit filter. The filtrate was purified by preparative HPLC to afford 23 mg (24%) of 3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol as a white solid. 1H NMR (300 MHz, DMSO) delta 8.38 (d, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.07-7.05 (m, 3H), 6.46 (s, 1H), 6.38 (s, 1H), 5.19 (d, J=5.4 Hz, 1H), 4.83-4.80 (m, 1H), 4.64 (d, J=3.6 Hz, 1H), 4.52 (d, J=6.3 Hz, 1H), 3.93 (d, J=4.5 Hz, 1H), 3.52-3.49 (m, 3H), 2.40 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=451 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[N:14]=2)=[CH:2]1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: OCc1ccsc1
Product: c1cc(COc2cncc(N3CCNCC3)n2)cs1
Temperature: 105 °C
Reaction time: 7.5 h
Yield: 64.7 %

Procedure:
The title compound was prepared according to the procedure of Example 20 starting from 3-thiophenemethanol (6.05 g, 53.0 mmol), K-t-BuO (0.897 g, 7.99 mmol) and 6-chloro-2-(1-piperazinyl)pyrazine (0.845 g, 4.25 mmol: obtained in Example 13, step 2). The reaction mixture was stirred at 105° C. for 7.5 h. Following chromatography on silica, solvents were evaporated off. The remaining oil was redissolved in ethyl acetetate and filtered through a short plug of alumina (5×3 cm) using ether/MeOH (96:4) as eluent. Solvent removal in vacuo gave 0.76 g (64%) of the title compound as a colorless oil. HRMS m/z for C13H16N4OS (M)+ calcd for 276.1045, found 276.1037. Anal. (C13H16N4OS.0.25 H2O) C, H, N.