Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C@H:9]([OH:22])[CH2:10][NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:25][S:26]([O:22][C@@H:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])(=[O:28])=[O:27]
Reactant: N#Cc1ccc(OC[C@H](O)CNC(=O)OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H](CNC(=O)OCc1ccccc1)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
4-(Dimethylamino)pyridine (0.22 g, 1.77 mmol) was added to a solution of benzyl (2R)-3-(4-cyanophenoxy)-2-hydroxypropylcarbamate (see step (iii) above; 5.79 g, 17.7 mmol) in pyridine (15 mL). The mixture was cooled to 0° C., and methanesulfonyl chloride (2.23 g, 19.5 mmol) was added slowly at 0° C. The mixture was allowed to reach rt, at which temperature it was then stirred for 4 h. The solvent was evaporated. DCM (100 mL) was added, washed with water, 1 N H2SO4 and brine, dried (Na2SO4) and evaporated giving 6.0 g (84%) of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.C(N=C=N[CH2:20][CH2:21][CH2:22][N:23]([CH3:25])C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N1CCCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:23]1[CH2:22][CH2:21][CH2:20][CH2:25]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-indole-2-carboxylic acid (1.0 g, 4.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (1.1 g, 5.9 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (0.62 g, 4.6 mmol) in THF (20 mL) was added 4-methylmorpholine (NMM) (0.65 mL, 5.9 mmol). After 10 minutes, pyrrolidine (0.73 mL, 8.8 mmol) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. The solvent was removed under reduced pressure. Water was added, stirred for 0.5 hours. The solid was filtered, washed with water, and dried in air to afford (5-bromo-1H-indol-2-yl)-pyrrolidin-1-yl-methanone as a pale yellow solid. Yield: 1.2 g (95%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:40][CH2:41]1
Reactant: O=S1(=O)CCNCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCS(=O)(=O)CC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, thiomorpholine 1,1-dioxide was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 507.
Reaction SMILES: P(=O)([O-])[O-].[CH:5]([NH:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].[Li+:12].CCC[CH2-].[C:17]12([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH:30]=[O:31])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C1COCC1>[CH:5]([N-:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].[Li+:12].[C:17]12([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH:30]=[O:31])[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: CC(C)NC(C)C
Agent: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=[PH]([O-])[O-]
Agent: [CH2-]CCC
Solvent: C1CCOC1
Product: CC(C)[N-]C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
11.42 g (30.51 moles) of the phosphonate obtained in EXAMPLE II(b) are dissolved in 50 ml of THF. This solution is then cooled to -78° C. and there is slowly added thereto a solution of lithium di-isopropylamide which was prepared in a conventional manner starting with 3.4 g (33.58 mmoles) of di-isopropylamine and 2.1 ml (33.56 mmole) of a solution of N-butyllithium (1.6M in hexane). The red-orange solution thus obtained is stirred for 30 minutes at -78° C. and a suspension of 3-(1-adamantyl)-4-methoxybenzaldehyde obtained above in part (a) (7.5 g 27.74 moles) in 140 ml of THF is added in fractions thereto. This addition lasts for about 10 minutes. The reaction mixture is then stirred initially for 20 minutes at -78° C. and then for 2 hours at 25° C. The mixture is poured into water and extracted three times with 100ml ethylether. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and the solvents evaporated. The residue in chromatographed on a silica column, as in Example II(c), yielding a mixture of two isomers, E and Z, of the methyl ester of p-[1-(2,2-dimethoxyethyl)-2-[3-(1-adamantyl)-4methoxyphenyl]-vinyl]benzoic acid (7.5 g, 53% yield) in the form of a partially crystallized light yellow oil. This mixture is used as such in the continuation of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][O:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(N(CC)CC)C>[Cl:14][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[N:17]([O:16][CH3:15])[CH3:21])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: CON(C)C(=O)Cl
Reactant: Nc1ccc(N2CCOC2=O)c(Cl)c1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(N2CCOC2=O)c(Cl)c1
Reaction time: 12 h

Procedure:
10.1 g of triethyamine was added to the solution of 1C, then 13.6 g of N-methoxy-N-methylcarbamoyl chloride was added drop-by-drop. After 12 hours at room temperature, the mixture was washed with water and extracted with ether. The extract was dried and the ether was evaporated under reduced pressure. The residue was chromatographed over silica gel to give 1, as a white solid, mp: 151°-153° C.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH3:21]
Reactant: COC(=O)Cl
Reactant: CC1=C(O)C(=O)C(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)OC1=C(C)OC(C)C1=O
Yield: 29.3 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 44.0 g, 0.33 mole) and triethylamine (50.5 g, 0.5 mole) in methylene chloride (220 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.0 hours, a solution of methyl chloroformate (38.6 g, 0.41 mole) in methylene chloride (200 g), which is then stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 18 g of methyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product, b.p. 105° C.; IR (neat film) 2960(M), 1770(S), 1710(S), 1640(S), 1250(S), 1200(S) cm-1 ; 'H NMR δ1.55(d, J=8 Hz,3), 2.28 (s,3), 3.95 (s,3), 4.70 (q, J=8 Hz,1).
Reaction SMILES: C(O[C@@H:5]([CH2:8][CH2:9][C@@H:10]([OH:23])[CH2:11][O:12]S(C1C=CC(C)=CC=1)(=O)=O)[C:6]#[CH:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO>[C:6]([C@H:5]1[O:23][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8]1)#[CH:7]
Reactant: C#C[C@H](CC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CC[C@H](CO)O1
Reaction time: 2 h
Yield: 120.1 %

Procedure:
To a solution of (3S,6R)-3-acetoxy-6-hydroxy-7-p-toluene sulfonyloxy-hept-1-yne 48 (0.9 g, 2.64 mmol) in MeOH (15 mL) at room temperature, K2CO3 (0.805 g, 5.83 mmol) was added and the mixture was stirred for 2h. It was treated with NH4Cl solution, evaporated MeOH and the residue extracted with EtOAc (3×20 mL). Organic layer was washed with water (10 mL), brine (10 mL), dried (Na2SO4) evaporated. The residue obtained was purified by column chromatography (Si-gel, 20% EtOAc-hexane) to furnish (2R,5S)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 49 (0.4 g) in 95% yield as a colorless liquid. [α]D −10.5 (c 1.0, CHCl3); 1HNMR (CDCl3, 200 MHz): δ 1.50-2.3 (m, 4H, H-3,4), 2.4 (br.s, 1H, OH), 2.42 (d, 1H, J 2.2 Hz, H-7), 3.5 (dd, 1H, J 4.5, 11.3 Hz, H-1), 3.75 (dd, 1H, J 3.3, 11.35 Hz, H-1a), 4.16-4.34 (m, 1H, H-2), 4.6-4.74 (m, 1H, H-5)
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O)[CH3:8].Cl>C1C=CC=CC=1>[CH2:7]([O:9][C:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[C:2]1/[C:1](=[O:6])[CH2:5][CH2:4][CH2:3]/1)=[O:21])[CH3:8]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)COc1ccccc1C=O
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)COc1ccccc1/C=C1\CCCC1=O
Reaction time: 2 h

Procedure:
A solution of 21.2 g of morpholine enamine of cyclopentanone, 24.0 g of 2-formylphenoxyacetic acid ethyl ester, and 200 ml of benzene was refluxed through a condenser equipped with a Dean-Stark trap for about 4.5 hours. The resulting solution was cooled to about room temperature, and treated with 35 ml of 6 normal (N) hydrochloric acid. After stirring for about 2 hours at about room temperature, the benzene layer was separated and the aqueous layer was extracted with two 15 ml portions of benzene. The combined benzene layer and extracts were washed with 5% sodium bicarbonate and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo, 27.6 g of nearly pure product was obtained. The product was crystallized in 50% ethanol to give 26.0 g of 2-(E)-(2-ethoxycarbonylmethoxyl-benzylidene) cyclopentanone as colorless crystals. The melting point of this intermediate compound was determined to be 77°-79° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:18])[CH2:10]3)=[CH:6][CH:7]=2)[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
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: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(C(=C3CC(C)(C)CC(C)(C)C3)c3ccccc3)cc2)cn1
Yield: 88.4 %

Procedure:
The procedure described for 22 (Example 11) was employed using 16 (192 mg, 0.5 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.0 mmol), 2N aqueous Na2CO3 (0.5 mL, 1.0 mmol), and THF (3 mL). The reaction mixture was refluxed for 12 h. Aqueous work-up followed by flash column chromatography afforded 170 mg (88%) of the title product 23 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.56 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.20-7.16 (m, 4H), 3.92 (s, 3H), 2.02 (s, 2H), 1.97 (s, 2H), 1.29 (s, 2H), 0.95 (s, 6H), 0.93 (s, 6H). LCMS (APCI): m/z 385 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Product: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 102.7 %

Procedure:
A flame-dried 1 L 3-necked flask, fitted with a 30 cm Vigreux column topped with a distillation head, an argon inlet tube and a magnetic stirring bar, was charged with 36.8 g (0.189 mol) of (3E,6R)-6,10-dimethyl-3,9-undecadien-2-one (GC purity 93.6%), 500 mL of iospropanol and 40.0 g (0.196 mol) of aluminum isopropoxide. The reaction mixture was stirred and heated to gentle reflux under argon. Acetone was allowed to distill off at a rate of about 30 drops/min. While maintaining a head temperature of ca. 80° C. After 3.5 hours the reaction was shown by GC to be almost complete with 5% of starting material remaining. The reaction was cooled in an ice bath and the pressure was reduced to ca. 54 mmHg. Isopropanol was distilled off at a head temperature of 30° C.-31° C. until the reaction mixture was concentrated to a volume of about 200 mL. The residual oil was cooled in an ice bath, 200 mL of 2N HCl were carefully added with stirring and the mixture was poured into a separatory funnel containing 200 mL of ether. An additional 200 mL of 2N HCl were added to dissolve some remaining white solid material. The layers were separated and the aqueous phase was extracted with 2×200 mL of ether. The combined organic layers were washed successively with 200 mL of sat. NaHCO3 -solution and 200 mL of brine, dried over MgSO4, filtered and concentrated on the rotovapor. The residue was dried at 0.1 mm for 30 minutes to afford 38.1 g (102.6%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol as a light yellow liquid. GC analysis indicated a purity of 94.6%. This material was used as is in Example 2.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:25])([CH2:23][CH3:24])[C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:25])[CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(C)(N)C(N)=O
Product: CCC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-methyl-butanamide (CAN 59209-90-4) as starting materials, LC-MS (UV peak area/ESI) 96%, 332.1982 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromopicolinaldehyde (500 mg, 2.70 mmol) was dissolved in THF (9.0 mL) and the flask was then sealed with a septum, flushed with argon, and cooled to 0° C. (Trifluoromethyl)trimethylsilane (0.44 mL, 3.0 mmol) was then added followed by TBAF (2.7 mL, 2.7 mmol, 1M in THF). The resulting mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was then quenched with water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 10-20% EtOAc/hexanes) to afford the title compound. LRMS (ESI) calc'd for C8H6BrF3O [M+H]+: 256. Found: 256.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:18]>CC(C)=O>[CH3:23][O:22][C:20]([CH2:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18])=[O:21]
Reactant: COC(=O)CC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(C)=O
Product: COC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 51.4 %

Procedure:
20.3 g (100 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 16.4 g (120 millimoles) of methyl chloroformylacetate and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 15.6 g (52%) of 6-[p-(methoxycarbonylacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 228°-230° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c2c1CCCC2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(O)c2c1CCCC2

Procedure:
1.15 g (3.41 mmol) of the above prepared (E)-3-(4-benzyloxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-acrylic acid ethyl ester was dissolved in 20 ml of tetrahydrofuran and hydrogenated over 0.3 g of 10% of palladium on charcoal as catalyst at ambient temperature and atmospheric pressure. Filtering off the catalyst and evaporating the solvent yielded 0.84 g of the title compound as grey solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:27])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:27])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Agent: [Pd]
Solvent: CCO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F

Procedure:
The product of Example 10, Step D, 3,4-Difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)-benzamide was hydrogenated in absolute EtOH in the presence of 5% Pd/C by the procedure of Example 1, Step D. An off-white solid was isolated which was purified by filtration through a plug of silica gel (EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a crystalline cream solid (52 mg, 73%); m.p. (EtOAc/Et2O) 115–116° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.83 (br s, 1 H), 7.44–7.37 (m, 1 H), 7.13–7.05 (m, 1 H), 7.03 (dd, J=12.6, 1.6 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1 H), 6.81 (ddd, J=8.7, 8.7, 4.5 Hz, 1 H), 4.76 (br s, 1H), 4.46 (t, J=5.1 Hz, 1 H), 3.86 (t, J=4.8 Hz, 2 H), 3.57 (t, J=5.0 Hz, 2 H), 3.43–3.35 (m, 2 H), 2.58–2.52 (m, 2 H), 1.72–1.64 (m, 2 H). Anal. calcd. for C18H19F3N2O4.0.5Et2O: C, 57.0; H, 5.7; N, 6.7. Found C, 56.6; H, 5.5; N, 6.8.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]#[CH:17].Cl>>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:16]#[CH:15])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: C#CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCC(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 93 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml; 20 mmoles) was added to 1.64 g (10 mmoles) of phenylpyruvic acid to form a solution. Then, 1.19 g (10 mmoles) of propargyl bromide was added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with three 50 ml portions of ether. The ether layers were dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give a pale yellowish white solid. The NMR spectral analysis of this product led to the determination that nearly pure 2-oxo-3-phenyl-5-hexynoic acid (1.88 g; yield 93 %).
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([N:26]([CH:34]([CH3:36])[CH3:35])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:25]>CN(C=O)C>[O:15]=[C:11]1[N:10]([CH2:23][C:24]([N:26]([CH:34]([CH3:36])[CH3:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:25])[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13](=[O:14])[CH2:12]1
Reactant: Cc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred solution of 700 mg (2.78 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 15 mL DMF is added 144 mg (3.61 mmol, 1.3 equiv) 60 wt % NaH at ambient temperature and stirred 0.5 h. To this solution is added 750 mg (2.78 mmol, 1.0 equiv) 2-Bromo-N-isopropyl-N-p-tolyl-acetamide, prepared as in Part B, in 1 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc and washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a yellow oil. The crude product is purified by flash chromatography on 27 g silica gel eluted successively with EtOAc/Hexanes (2:3, 500 mL), (1:1, 100 mL). Appropriate fractions were combined and concentrated in vacuo to give 554 mg (1.25 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-p-tolyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.43-7.07 (m, 12H), 6.90 (d, 1H, J=8.3), 5.03 (m, 1H), 4.37 (d, 1H, J=16.6), 4.04 (d, 1H, J=16.6), 3.58 (d, 1H, J=11.9), 3.49 (d, 1H, J=11.7), 2.41 (s, 3H), 1.10 (d, 6H, J=6.6); TLC Rf =0.27 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10]1([S:20](Cl)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:10]1([S:20]([N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
1-Acetylpiperazine (0.500 g, 3.9 mmol), 1-naphthalenesulfonyl chloride (0.884 g, 3.9 mmol) and DMAP (0.095 g, 0.70 mmol) were dissolved in pyridine (6 mL). After stirring overnight, the reaction mixture was concentrated in vacuo, and quenched with an ice cold solution of 1.0 M HCl (15 mL). The resulting precipitate was filtered and rinsed with water. Trituration with ether followed by filtration provided the 1.06 g (85%) of the title compound as a white solid. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 2.00 (s, 3 H), 3.12-3.21 (m, 4 H), 3.45-3.54 (m, 2 H), 3.57-3.67 (m, 2 H), 7.56-7.67 (m, 3 H), 7.94 (d, J=7.58 Hz, 1 H), 8.10 (d, J=8.08 Hz, 1 H), 8.20 (d, J=7.58 Hz, 1 H), 8.73 (d, J=9.09 Hz, 1 H); ESI-MS: m/z 319.4 (M+H)+.