Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2](=[CH2:5])[CH:3]=O.BrBr.[NH2:8][C:9]1[C:18]([Br:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:20][CH3:21])[CH:10]=1>CC(O)=O>[Br:1][C:2]1[CH:3]=[N:8][C:9]2[C:10]([CH:5]=1)=[C:11]([O:20][CH3:21])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]=2[Br:19]
Reactant: COC(=O)c1cc(Br)c(N)cc1OC
Reactant: C=C(Br)C=O
Agent: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c2ncc(Br)cc2c1OC
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
step 1—Bromine (4.48 mL, 86.9 mmol) in HOAc (50 mL) was added to a solution of 2-bromoacrylaldehyde (11.7 g, 86.9 mmol, CASRN 111049-68-4) in HOAc (100 mL) at RT until the solution showed faint Br2 color. To this solution was added methyl 4-amino-5-bromo-2-methoxybenzoate (22.6 g, 86.9 mmol) and the resulting solution was gradually heated to 100° C. After the temperature reached 100° C., stirring was continued for 15 min then the solution was cooled and concentrated in vacuo. The reaction mixture was neutralized with satd. aq. NaHCO3 and the resulting solid was filtered and washed with water. The solid was washed with ether followed by 10% MeOH/DCM to afford 11.04 g of 122a. The filtrate was absorbed onto SiO2 and purified on a flash column eluting with a DCM/hexane gradient (50 to 100% DCM to afford an additional 3.46 g of 122a.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1nc(C)no1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 35 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid methyl ester with heating for 5 days to afford the title compound as an off-white solid (49 mg, 35%). LC/MS (Method B) 3.80 min, [M+1]+ 477.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](Cl)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(N3CCOCC3)c2CC1
Temperature: 60 °C

Procedure:
To 0.15 g 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester (0.42 mmol), in a sealed tube in 8 mL ethanol, was added 78 μL (0.88 mmol) morpholine, and the reaction was heated at 60° C. for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:23][CH2:22][O:21][CH2:20]C1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:8]([C:3]1[CH:2]=[CH:7][C:22]([O:21][CH3:20])=[C:23]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])[CH:4]=1)=[O:9]
Reactant: O=Cc1cnccc1Br
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1-c1ccncc1C=O
Reaction time: 8 h

Procedure:
A flask was charged with 4-bromo-pyridine-3-carbaldehyde (93 mg, 0.5 mmol), 5-formal-2-methoxylphenelboronic acid (88 mg, 0.6 mmol), tetrakis(triphenylphosphine) palladium(0) (29 mg, 0.025 mmol), potassium phosphate (160 mg, 0.75 mmol) and 1,4-dioxane (5 mL). The reaction mixture was kept at 50° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with water then brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 4-(5-formyl-2-methoxy-phenyl)-pyridine-3-carbaldehyde as a yellow solid.
Reaction SMILES: ClC1C(Cl)=CN=C([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[N:31][N:30]=[N:29]5)=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)N=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH2:37]([O:36][C:34]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[CH:24][CH:23]=3)[N:19]=2)[CH2:11][CH2:10]1)=[O:35])[CH:38]=[CH2:39]
Reactant: Clc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1Cl
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
Example 209 was prepared from 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (Intermediate 4) and allyl chloroformate in a manner similar to that described in Example 22. 1H NMR (CDCl3): δ 8.96 (1H, s), 7.63 (2H, m), 7.20 (1H, s), 7.18 (2H, m), 5.96 (1H, m), 5.31 (1H, m), 5.22 (3H, m), 4.61 (2H, m), 4.29 (2H, m), 3.21 (1H, m), 2.97 (2H, m), 2.15 (2H, m), 1.78 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[S:44][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][C:26]=3[F:43])[C:8](=[O:23])[N:9]([CH2:12][CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:45]([O:22][CH:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:44][C:6]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][C:26]=2[F:43])[C:8]1=[O:23])(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc2c(=O)n(CC(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CC(OC(C)=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 6-ethyl-1-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[2-hydroxy-2-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), acetic anhydride (0.07 mL), triethylamine (0.1 mL), N,N-dimethylpyridin-4-amine (0.006 g) and methylene chloride (20 mL) was stirred at room temperature for 16 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.23 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCCl
Product: NC(=O)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid (9.1 g, 50 mmol) in CH2Cl2 (500 mL) was added EDC (12 gram, 60 mmol), HOBt (6.8 g, 50 mmol), DIEA (12 mL), and NH3 in MeOH (2M, 40 mL). The reaction was stirred at RT for overnight, and a precipitation formed. The solid was isolated via vacuum filtration.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][OH:5]>[Ni]>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][OH:5]
Reactant: CCCCCCC(C)=CCO
Agent: [Ni]
Product: CCCCCCC(C)CCO

Procedure:
52 G. of 3-methyl-2-nonen-1-ol were hydrogenated for 4 hours in the presence of Raney nickel catalyst at an initial pressure of 50 pounds per square inch until the theoretical amount of hydrogen was consumed. The hydrogenated material was fractionated through a 1/2 foot Vigreux column. 48.6 G. distilled at 108° C. under 10 mm. pressure, representing the desired 3-methylnonan-1-ol. The product had a refractive index at 20° C. of 1.4384. There was a residue of 3.4 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]([CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[CH2:26]([C@@H:13]([C@@:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:25]=[CH2:24]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@H](C(=O)OC)[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
500 mg (1.71 mmol) of methyl(S)-3-benzyloxycarbonylamino-3-isobutyl-butanoate, prepared according to the procedure described in Liebigs Ann., pp 1217-1228 (1995), is dissolved in 10 mL of dry THF and cooled under Argon to -80° C. 1.881 mL (3.762 mmol) of 2M LDA is added, and the mixture is stirred at -40° C. for 20 minutes. The reaction is cooled to -78° C., and 828 mg (6.84 mmol) of allyl bromide are added. The mixture is stirred at -78° C. for 5 hours and at room temperature overnight. The reaction is quenched with 20 mL of 1M pH 7 phosphate buffer. The pH is lowered to 2 with 1N HCl. The water layer is extracted with EtOAc. The combined organic layers are dried over MgSO4, and concentrated to provide the crude product, which is purified by chromatography using 70% hexanes/30% EtOAc as eluant to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(COS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
(4-Methyl-3-nitro-phenyl)-methanol (3.00 g, 17.95 mmol) was taken up in anhydrous DCM, under argon, and triethyl amine (5.45 g, 53.85 mmol, 7.51 mL) was added. The solution was cooled to 0° C. and methanesulfonyl chloride (2.26 g, 19.74 mmol, 1.53 mL) was added slowly via syringe. The solution was allowed to warm to room temp and stir for 12 h. The reaction mixture poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (5:1 hexane/ethyl acetate) Yield 2.00 g. 1H NMR (CDCl3, 300 MHz): δ 2.62 (s, 3H), 4.61 (s, 2H), 7.36 (d, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3](=[O:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(Cl)Cl>[N:15]1([CH2:2][C:3](=[O:14])[CH2:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(CBr)CS(=O)(=O)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: O=C(Cn1ccnc1)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 50 g (0.180 mole) finely ground 1-bromo-3-phenylsulfonylpropan-2-one (the product of Example 10) in 125 ml methylene chloride cooled to about 0°-5° C., 36.8 g (0.54 mole) imidazole in 300 ml methylene chloride were added dropwise. The reaction mixture was maintained at 0°-5° C. for one hour, allowed to warm to room temperature and was stirred overnight. The methylene chloride was removed in vacuo at room temperature. The resulting oil was partitioned with 200 ml water and 200 ml ethyl acetate. The aqueous phase was extracted with ethyl acetate (four times 125 ml). The combined ethyl acetate extracts were treated with decolorizing charcoal, dried, filtered and concentrated. The precipitate which formed was triturated with methanol-isopropyl alcohol yielding 17.9 g of the above-identified product, as an off-white solid, melting point 137°-140° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:7]([C:8](=[O:24])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:12][C:11]=2[F:23])[CH:6]1[C:25](=[O:34])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:25]([CH:6]2[CH:7]([C:8](=[O:24])[NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]4=[O:22])=[CH:12][C:11]=3[F:23])[CH:5]2[C:3]([OH:4])=[O:2])=[O:34])=[N:28][CH:29]=1
Reactant: COC(=O)C1C(C(=O)Nc2ccc(Cl)cn2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1C(C(=O)Nc2ccc(Cl)cn2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of 68 mg (0.14 mmol) of (1RS,2SR,3RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid methyl ester (example 114, step 5) in 1.5 ml of THF was treated with 0.2 ml of a 1M aqueous LiOH solution, stirred at RT during 2 hrs and acidified to pH ca. 2 with aqueous HCl. Extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave 45 mg (68%) of (1RS,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid. Light yellow crystalline. MS: 469 (M−H)−.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N)=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:30][OH:31]>>[ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:31][CH3:30])=[O:17])=[CH:11][CH:10]=1
Reactant: NC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1

Procedure:
(R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (0.45 g) was heated under reflux in methanol (20 ml) containing concentrated sulphuric acid (0.5 ml) for 18 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and washed successively with water (20 ml), 5% NaHCO3 solution (50 ml) and water (20 ml), dried over MgSO4 and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate (20 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate hydrochloride (0.25 g), m.p. 181°-183° C.; microanalysis: found, C, 62.6; H, 6.6; N, 3.8; Cl, 9.9%; required for C19H24ClNO4 : C, 62.4; H, 6.6; N, 3.8; Cl, 9.7%; [α]25D =-25.3° (c=0.99 in methanol).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[CH2:13]([N:15]1[C:20]2[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=2[C:18](=O)[O:17]C1=O)[CH3:14]>CN(C=O)C>[NH2:4][C:3]1[N:15]([CH2:13][CH3:14])[C:20]2[C:19]([C:18](=[O:17])[C:2]=1[C:1]#[N:5])=[CH:24][CH:23]=[C:22]([I:25])[CH:21]=2
Reactant: CCn1c(=O)oc(=O)c2ccc(I)cc21
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C#N)c(=O)c2ccc(I)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
0.32 g (6.31 mmol) of malononitrile and 1.45 g (14.35 mmol) triethylamine were added to 2 g (6.31 mmol) of 1-ethyl-7-iodo-1H-benzo[d][1,3]oxazine-2,4-dione dissolved in 25 mL of DMF. The solution was stirred for 2 hours at 120° C. and after addition of 0.73 g (7.17 mmol) of triethylamine, for another 1 hour at 110° C. The DMF was then evaporated under reduced pressure and the residue taken over with a mixture of water and dichloromethane. Filtration of this mixture gave a first fraction of the expected compound: 0.55 g (1.62 mmol).
Reaction SMILES: [C:1]([CH:4]([S:6][C:7](=[N:9][OH:10])[CH3:8])[CH3:5])(=[O:3])[NH2:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CC(C)=O>[CH3:11][NH:12][C:13]([O:10][N:9]=[C:7]([S:6][CH:4]([C:1](=[O:3])[NH2:2])[CH3:5])[CH3:8])=[O:14]
Reactant: CC(=NO)SC(C)C(N)=O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C(C)SC(C)C(N)=O
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of 4.0 g (0.0247 m) of 1-(1-carbamoylethylthio)acetaldoxime, 75 ml of dry acetone, 4.0 g (0.07 m) of methyl isocyanate, and 2 drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for two days. The acetone and excess methyl isocyanate were removed from the product under reduced pressure. The white solid residue was recrystallized from ethanol and then dried at room temperature to give 4.0 g (74% yield) of 1-(1-carbamoylethylthio]acetaldehyde O-(methylcarbamoyl)oxime; melting point=161°-163° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94 %

Procedure:
3-Nitrobenzoyl chloride (7.00 g, 37.7 mmol) was dissolved in tetrahydrofuran (300 mL) and a 2.0 M solution of methylamine in tetrahydrofuran (41.5 mL, 82.9 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate and concentrated to provide a solid (6.38 g, 94%). 1H NMR (300 MHz, CDCl3), δ8.84 (bs, 1H), 8.67 (m, 1H), 8.37 (dd, J=8, 2 Hz, 1H), 8.28 (d, J=7 Hz, 1H), 7.78 (dd, J=8, 7 Hz, 1H), 2.83 (m, 3H). Mass spec (ES+) m+/z 181 (M+H+).
Reaction SMILES: [C:1]1(=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[N:10]O.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:22])=CC=1>>[C:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:1]([OH:12])=[O:22])#[N:10]
Reactant: O=C1C(=NO)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#CCc1ccccc1C(=O)O
Temperature: 50 °C
Yield: 73.3 %

Procedure:
Indan-1,2-dione-2-oxime (35 g, 0.22 mol) was added to a solution of 402.5 ml 8% NaOH, and the mixture was heated to 50° C. Then p-toluenesulfonyl chloride (54.25, 0.28 mol) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed from the mixture. The filtrate was acidified with concentrated HCl to pH=3-4 and the precipitate was collected and dried to give colorless solid (26 g, 74% yield). LC-MS: 162 (MH+)
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[N:29]1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)[CH:38]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3cccc(-n4cccn4)c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 3-(1H-pyrazol-1-yl)phenylboronic acid, the title compound was synthesized following the procedures described Example 108.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:31][CH3:30])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
To a solution of the benzoxazinone product of Example 6, Step D (4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 mL) was added methylamine (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 4.09 g of the title compound, a compound of the present invention, as a white solid melting at 185-186° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=4)[N:22]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
16 mg (0.39 mmol) of 60% sodium hydride were added at 0° C. to a solution of 80 mg (0.37 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 100 mg (0.37 mmol) 2-chloromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (WO 2004/007439) were given to the reaction mixture and stirring continued at r.t for 2 days. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was dried at 40° C. to give 101 mg (60%) of the title compound as white powder.