Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3](O)([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[N:6][OH:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OC)(C)(C)C>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH2:4][C:3]([C:2]([F:26])([F:27])[F:1])([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[O:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)=NO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one oxime (0.45 g) and triphenylphosphine (0.60 g) in tetrahydrofuran (10 mL), diethyl azodicarboxilate (0.44 g) was added, and the mixture was stirred for 24 hours at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield 3-(4-methylphenyl)-5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole (0.11 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[C@H:30]([OH:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[C:17]1([CH2:23]C(Cl)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl>[C:17]1([CH2:23][C:4](=[O:5])[CH2:6][C:7]([O:9][CH3:2])=[O:8])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Cc1ccccc1
Temperature: 0 °C
Yield: 91.6 %

Procedure:
In 70 ml of methylene chloride was dissolved 36.03 g (0.25 mol) of Meldrum's acid. Pyridine (38.17 g, 0.48 mol) was used as a base. To the solution was added dropwise 42.52 g (0.275 mol) of phenylacetyl chloride in an ice bath while stirring. After the reaction, ice-water and diluted hydrochloric acid were added to wash. Methylene chloride was evaporated, methanol was added, followed by refluxing, and the solvent was evaporated to give 44 g (91.7%) of methyl 4-phenyl-3-oxobutyrate.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:20])[CH:9]([CH3:19])[CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:6])[O:4][CH3:5]>[Pd].CO>[CH3:1][O:2][P:3]([CH2:7][C:8](=[O:20])[CH:9]([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(=O)C(C)CC#Cc1ccccc1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(CC(=O)C(C)CCCc1ccccc1)OC
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A mixture consisting of (±)-dimethyl(3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15db(i)/15dc(i)), (1.0 g, 3.4 mmol) and 10% palladium on activated carbon (15 mg) in methanol (30 mL) was stirred under an atmosphere of hydrogen overnight. The hydrogen was evacuated and the mixture was filtered through a micropore filter. The filtrate was concentrated in vacuo to afford the title compound (1.0 g, quantitative yield) as a clear oil; 1H-NMR (CDCl3) δ 7.3-7.25 (m, 2H), 7.2-7.1 (m, 3H), 3.8-3.7 (m, 6H), 3.1 (d, 2H), 2.8-2.75 (m, 1H), 2.7-2.5 (m, 2H), 1.8-1.65 (m, 1H), 1.65-1.5 (m, 2H), 1.4-1.3 (m, 1H), 1.1 (d, 3H); MS (ESI+) m/z 299 (M+1).
Reaction SMILES: [Li].[C:2]([O:5][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([OH:18])=[C:10]([C:13]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[O:12])(=[O:4])[CH3:3].Br[CH:24]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:2]([O:5][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([OH:18])=[C:10]([CH:11]([OH:12])[CH:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])[C:13]=1[C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)(C)C
Reactant: CC(C)CCC(Br)CCC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(CCC(C)C)CCC(C)C)c1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Lithium (2.8 g) was added to a solution of 5-acetoxy-4,6-di-tert-butyl-2-hydroxybenzaldehyde (24.3 g) and 5-bromo-2,8-dimethylnonane (47.0 g) in tetrahydrofuran (200 ml) under ice cooling under a nitrogen atmosphere and the mixture was stirred overnight. The reaction mixture was poured into ice water, neutralized with a saturated aqueous solution of ammonium chloride and subjected to extraction with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica Gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2,2-diisoamyl-1-hydroxyethyl)phenol [17.0 g (yield, 46%)] as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([CH2:17][S:18][CH3:19])=[CH:3]1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([CH2:17][S:18]([CH3:19])=[O:28])=[CH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
To a stirred solution of 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone (6.5 g.) in dichloromethane (150 ml.) at -10° was added a solution of 3-chloroperbenzoic acid (85%, 4.2 g.) in dichloromethane (90 ml.) during 30 minutes. The solution was extracted with saturated aqueous sodium bicarbonate until free of per-acid. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give a solid product. This was crystallised from ethyl acetate:dichloromethane to give the novel 1-methyl-3-methylsulphinylmethyl-7-trifluoromethyl-4-quinolone, m.p. 208°-210°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH2:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:28]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3Nc3cccc(-c4ccccc4)n3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using [4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-acetic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:21])C(Cl)(Cl)Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[C:27]([F:33])[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:9]([O:8][C:6]([CH:5]1[N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16](=[O:21])[N:30]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][C:27]=2[F:33])[C:4]1=[O:22])=[O:7])[CH3:10]
Reactant: NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1C(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester (40.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (29.0 g) and triethylamine (54.8 g, 75.0 ml) in anhydrous dimethylformamide (100 ml) was stirred under the stream of nitrogen at 70° C. for 1 hour. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (38.0 g, 86.0%) as colorless crystals, mp 114°-115° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[F:39])[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:39][C:16]1[CH:17]=[CH:18][C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2F)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(F)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of product from Step E (2.1 g, 3.74 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL). The resulting solution was stirred for 2 hours, then poured onto saturated aqueous sodium bicarbonate, and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title product without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1.[OH-].[Na+]>C1COCC1.CO>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([OH:43])=[O:31])=[CH:34][C:35]=1[O:41][CH3:42])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)-quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-3-methoxy-benzoic acid methyl ester following the procedure of Example 478 then hydrolysis using sodium hydroxide in THF:MeOH (1:2) at RT for 12 hr, the reaction mixture was acidified and concentrated. The crude residue was purified by reverse phase HPLC to provide the desired compound: mp 100-110° C.; MS (ES) m/z 555.8; HRMS: calcd for C32H22F3NO5+H+, 558.15228; found (ESI, [M+H]+), 558.154.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][S:19]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)(=[O:21])=[O:20])([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+:33]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([O-:28])=[O:27])=[CH:30][CH:31]=3)(=[O:21])=[O:20])([OH:17])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2].[Na+:33]
Reactant: COC(=O)c1ccc(S(=O)(=O)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(CCN2CCC(O)(CS(=O)(=O)c3ccc(C(=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the compound (70 mg) obtained in Example 46 in methanol (2.0 mL) was added 2 N aqueous sodium hydroxide solution (0.080 mL), followed by stirring at room temperature for three days. The solvent was removed under reduced pressure, the residue was mixed with ethyl acetate (4 mL) and was stirred for one hour. Insoluble matter was collected by filtration, and dried to yield the titled compound (56 mg) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]([OH:29])([CH3:28])[CH2:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:17]2[CH:16]=[N:15][N:14]([CH2:13][C:12]([CH3:28])([OH:29])[CH3:11])[CH:18]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnn(CC(C)(C)O)c2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (1.00 g), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1.11 g), and 2 M aqueous Na2CO3 solution (4.0 mL) in N,N-dimethylformamide is purged with argon for 3 min. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (85 mg) is added and the mixture is stirred at 60° C. for 3 h. After cooling to room temperature the mixture is diluted with water and ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 11): tR=1.12 min; Mass spectrum (ESI+): m/z=323, 325 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[O:21].C1N2CCN(CC2)C1>>[OH:21][CH:20]([C:16]1[S:15][CH:19]=[CH:18][N:17]=1)[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[O:4]
Reactant: O=Cc1nccs1
Reactant: C=CC(=O)OCc1ccc(Cl)c(Cl)c1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCc1ccc(Cl)c(Cl)c1)C(O)c1nccs1
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 59 mg (0.26 mmol) of 3,4-dichlorophenylmethyl acrylate, 27 mg (0.24 mmol) of 2-thiazolecarboxaldehyde, and 31 mg (0.28 mmol) of DABCO was thoroughly shaken on a Vortex mixer, and then stored at 0° C. overnight. The product was purified by prep HPLC to give 34 mg (0.10 mmol; 42% yield) of the desired Baylis-Hillman adduct, 3,4-dichlorophenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate. 1H NMR (CDCl3): δ 5.12 (2H), 5.76 (1H), 6.07 (1H), 6.49 (1H), 7.12 (d of d, 1H), 7.71 ppm (d, 1H) MS m/z: 344.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[OH:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[OH:12]
Reactant: O=[N+]([O-])O
Reactant: Oc1cnnc2ccc(Br)cc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nnc2ccc(Br)cc2c1O
Temperature: 60 °C
Yield: 58.7 %

Procedure:
Under N2, an orange solution of 6-bromocinnolin-4-ol (18.5 g, 82 mmol) in HNO3 (90 mL, 82 mmol) was cooled to 0° C., and H2SO4 (30 mL) was added. The resulting mixture was then heated at 60° C. for 3 h. After the reaction went to completion as monitored by LC-MS, the reaction mixture was cooled to 0° C., and was then quenched with H2O (20 mL). The mixture was diluted with EtOAc (25 mL). Following general workup procedures, the crude residue was added to silica gel, and eluted with PE/EtOAc to give 6-bromo-3-nitrocinnolin-4-ol as a pale yellow solid (13 g, yield 58.6%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide give the desired product as a colorless foam (44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([NH:21]C(=O)C)[N:10]([CH3:25])[N:9]=1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([NH2:21])[N:10]([CH3:25])[N:9]=1
Reactant: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccccc2Cl)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2ccccc2Cl)c(C#Cc2ccccc2)c1N
Yield: 90.2 %

Procedure:
A solution of N-(3-(2-chlorophenyl)-1-methyl-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (170 mg, 0.49 mmol) in ethanol (1 mL) and 25% NaOH (1.4 mL) was heated to 85° C. for 30 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the organic phases combined, dried over MgSO4, filtered and evaporated to give 3-(2-chlorophenyl)-1-methyl-4-(phenylethynyl)-1H-pyrazol-5-amine as a solid (136 mg), which was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:17][CH2:18]Cl)=[CH:12][CH:13]=2)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[CH3:36][NH:37][CH3:38]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:17][CH2:18][N:37]([CH3:38])[CH3:36])=[CH:12][CH:13]=2)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[N:7]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(COCCCl)cc12
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCOCc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A mixture of 1-(3-chlorobenzyl)-5-(2-chloroethoxymethy)-3-(1-naphthylsulfony)-1H-indazole (0.08 g, 0.16 mmoles) and dimethylamine (0.28 ml, 0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc to afford the title compound (0.08 g, 0.15 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of methyl 2-fluoro-5-[(hexylamino)methyl]benzoate in DCM (13 mL) were added 4-bromobenzenesulfonyl chloride (200 mg; 0.79 mmol) and TEA (0.13 mL; 0.94 mmol). The reaction mixture was stirred at room temperature for 2 hours under N2 atmosphere. The mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×100 mL). The combined organic layers were then washed with a saturated solution of NH4Cl (150 mL) and with brine (150 mL), dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (c-Hex/EtOAc, 95:5) gave 96 mg (25%) of the title compound as a colorless oil. HPLC, Rt: 5.13 min (purity=99.1%). LC/MS: M+(ESI): 486.23; 1H NMR (CDCl3) δ: 7.78 (m, 1H), 7.72 (m, 4H), 7.55 (m, 1H), 7.12 (m, 1H), 4.31 (s, 2H), 3.93 (s, 3H), 3.09 (t, J=7.5 Hz, 2H), 1.85 to 1.05 (m, 8H), 0.81 (t, J=6.9 Hz, 3H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:37][C:38]([F:49])([F:48])[O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:45][CH2:44][C:43]4[CH:46]=[CH:47][C:40]([O:39][C:38]([F:48])([F:49])[F:37])=[CH:41][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(OC(F)(F)F)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-trifluoromethoxy benzylamine, m.p. 147-149° C. MS [(+)ESI, m/z]: 608 [M+H]+ Anal. Calcd for C36H30F3N3O3: C, 70.94; H, 4.96; N, 6.89. Found: C, 70.75; H, 5.13; N, 6.74.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)=[O:18])=[CH:12][CH:11]=1)(C)(C)C.Cl>O1CCOCC1>[CH2:28]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)=[O:18])=[CH:14][CH:15]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)Nc2cnc(C#N)cn2)cc1)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnc(NC(=O)Nc2ccc(CCNCc3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl-(2-{4-[3-(5-cyano-pyrazin-2-yl)-ureido]-phenyl}-ethyl)-carbamic acid tert-butyl ester (1 mmol) was treated with 4N HCl in dioxane (10 ml) and stirred overnight at room temperature. The product was precipitated by addition of dry ether. The crude was purified by column using 0-100% 7 N NH3/MeOH in DCM to afford the title compound as a free base.