Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18]>[Ti](Cl)(Cl)(Cl)Cl.ClC1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH3:18])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Yield: 55.4 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester 0.5 g (2.27 mmol) was added 15 mL of chlorobenzene, 0.27 g (3.4 mmol) of acetyl chloride and 0.63 mL (5.7 mmol) of titanium tetrachloride. The mixture was sealed in a pressure tube and the tube was placed in 95° C. oil bath for 5 h with stirring. The reaction mixture was washed with 0.5N HCl and was extracted with ethyl acetate. Removal of the solvents gave the crude product, which was purified by column chromatography to give 0.33 g (59% yield) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.OCC([C:31]1[C:36]([N+:37]([O-])=O)=[C:35]([CH3:40])[CH:34]=[CH:33][C:32]=1[S:41]([NH2:44])(=[O:43])=[O:42])(C)C>>[OH:13][CH2:12][C:11]([NH:44][S:41]([C:32]1[CH:33]=[CH:34][C:35]([CH3:40])=[C:36]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:31]=1)(=[O:42])=[O:43])([CH3:10])[CH3:7]
Reactant: Cc1ccc(S(N)(=O)=O)c(C(C)(C)CO)c1[N+](=O)[O-]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B.11) according to general procedure II. Light yellow solid. MS (ISP) 596.1 [(M−H−]; mp 214° C.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[N:30]#[N:31].[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@@H:16]([N:30]=[N+:31]=[N-:32])[CH2:15][N:14]1[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N1C[C@H](N=[N+]=[N-])C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 75 °C
Yield: 78.8 %

Procedure:
0.5 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide was dissolved in 10 ml of dry dimethylformamide and treated with 0.330 g of sodium azide. The heterogeneous mixture was stirred and heated at 75° C. for 18 hours. The mixture was evaporated under an oil pump vacuum to give a solid which was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.345 g of N2 -(benzyloxycarbonyl)-4(R)-azido-N1 -tert.butyl-L-prolinamide in the form of a gum.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: O=C(O)c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(SCc2ccccn2)cc1
Yield: 40.9 %

Procedure:
An ethanol/water mixed solution (2/1, 60 mL) of 4-mercaptobenzenecarboxylic acid (1.0 g), 2-chloromethylpyridine hydrochloride (2.1 g) and potassium carbonate (4.5 g) was heated under reflux for 4 hours. The organic solvent was evaporated off under reduced pressure, and aqueous 5 N hydrochloric acid solution was added to the residue until it became acidic. Water was evaporated off under reduced pressure, and DMF was added to the resulting residue and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=9/1 to 4/1) to obtain the entitled compound (650 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][C:8](=[O:10])[O:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>ClCCl>[O:1]1[C:5]2([CH2:9][CH:8]([OH:10])[O:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CC2(CO1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC1CC2(CO1)OCCO2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A solution of 1,4,7-trioxaspiro[4.4]nonan-8-one (prepared from tetronic acid and ethylene glycol) (3.81 g, 26.5 mmol) in dichloromethane (20 mL) at -78° C. was treated with 32 mL of 1.0 M DIBAL in dichloromethane (32.0 mmol). The mixture was stirred one hour, quenched at -78° C. with water (12 mL total) and stirred at 25° C. until complete decomposition of the aluminum complex (two hours). The granular precipitate of alumina was filtered off, and the product was purified by flash chromatography (ether) to give Compound 7 (3.32 g, 84 percent) as a low melting solid; Rf =0.16 (Et2O); IR (thin film) νmax 3446 (bs), 1720 (w) cm-1 ; 1H NMR (500 MHz, CDCl3) δ 5.51 (bd, J =4.7 Hz, 1 H, OCHOH), 3.96-3.73 (m, 7 H, CH2 --O, OCH2CH2O, OH), 2.27 (dd, J =5.4, 13.7 Hz, 1 H, CHH), 2.05 (dd, J = 1.8, 13.7 Hz, 1 H, CHH); 13C NMR (125 MHz, CDCl3) δ 114.8, 98.2, 72.5, 64.8, 64.7, 43.1; FAB HRMS (NBA/NaI) m/e 169.0477, M+NA+ calcd for C6H10O4 169.0477.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([OH:23])=[C:16]([CH2:24][CH2:25][CH3:26])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:27])[CH:3]=1.Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:36]([CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)[O:23][C:17]1[C:16]([CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:27])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:19][C:18]=1[CH2:20][CH2:21][CH3:22])([O:38][CH3:39])=[O:37]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)OC)c1ccccc1
Yield: 96 %

Procedure:
To a solution of (4.72 mmol) of the product of Step G and (5.19 mmol) of methyl 2-bromophenylacetate in 10 mL of acetone was added (9.44 mmol) of K2CO3 and the mixture was stirred and refluxed for 14 hours. The mixture was cooled, filtered and evaporated in vacuo and the residue was purified on a silica gel flash chromatography column to afford a 96% yield of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].C(OCC)C.[CH3:9][C:10](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=O>O>[CH3:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3][N:2]=[CH:11]1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: CC1C=NNC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.22 ml (1 equiv.) hydrazine hydrate was added to 100 mL diethylether. The emulsion was cooled with an ice bath. 15.0 mL 2-Methyl-3-phenyl-propenal was added dropwise, and the mixture was stirred overnight at room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum distillation yielded 5.9 g of desired product (mixture of diastereomeric pairs) as a clear fluid (76-82° C., 0.2-0.3 mbar). 1H NMR (400 MHz, CDCl3) of first diastereomeric pair; δ 0.71 (d, J=7 Hz), 3H), 3.20-3.31 (m, 1H), 4.77 (d, J=10 Hz, 1H), 6.73 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 1H NMR (400 MHz, CDCl3) of second diastereomeric pair: δ 1.24 (d, J=7 Hz), 3H), 2.90-3.11 (m, 1H), 4.22 (d, J=11 Hz, 1H), 6.71 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][N:4]=1
Reactant: CC(=O)NCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCc2sccc21
Temperature: 0 °C

Procedure:
To 5.70 g (0.0337 mol) of 2-acetylaminoethylthiophene (f-l) was added 157 ml of dry benzene; and while being refluxed, a mixture of 13.80 g (0.09 mol) of phosphorus oxychloride and 63 ml of dry benzene was added dropwise to the solution. After being refluxed for 2 hr., the mixture was cooled with ice, and the reaction solution was poured into 315 g of ice. Under ice-cooling, the mixture was adjusted to pH 10 or more with 48% aqueous NaOH, and the solution was extracted with ether. After being washed with saturated brine, the ether layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 4.45 g (Yield : 87.3%) of the objective product, 4-methyl-6, 7-dihydrothieno[3, 2-c]pyridine (g-l) as dark red liquid.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2)(=[O:4])[CH3:3].Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:9]2)(=[O:4])[CH3:3]
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: CC(=O)Oc1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Oc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 26.3 %

Procedure:
Using 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (76 mg, 0.41 mmol), triethylamine (0.23 ml, 1.6 mmol), and ethanol (6 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (34 mg, 0.10 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH:14]=O>C(O)C.[Pd]>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(N)ccc1F
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(NCC(OC)OC)ccc1F
Yield: 101.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyaniline (0.98 g 6.9 mmol) in ethanol (20 ml) was added glyoxal 1,1-dimethyl acetal (0.89 g 8.27 mmol). Pd/C 5% (50 mg) was added and the mixture hydrogenated. Removal of the catalyst by filtration and evaporation of solvent in vacuo gave N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline 1.6 g
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([O:11][CH:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 18.3 %

Procedure:
The procedure is as in Example 7, but starting with 5-hydroxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g) in methylene chloride (80 cc), triethylamine (5.05 g), methacryloyl chloride (3.14 g) and 4-dimethylaminopyridine (50 mg). The residue obtained is purified by recrystallization in acetonitrile followed by chromatography on neutral alumina (50 g) contained in a column 1.5 cm in diameter, eluting with methylene chloride and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 6-(7-Chloro-1,8-naphthyridin-2yl)-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b]-pyrazin-5yl methacrylate (1.4 g), m.p. 255° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH2:13]O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:9]1[N:10]=[CH:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncoc1-c1ccc(Cl)cc1
Product: ClCc1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
269 mg (0.77 mmol) of the compound from Example 38A are initially charged in 0.43 ml (5.85 mmol) of thionyl chloride. The reaction mixture is stirred at RT for 12 h, and excess thionyl chloride is then removed under reduced pressure. The residue is taken up in 5 ml of ethyl acetate and washed once with 2 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reactions.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF (250 mL) at room temperature, was added potassium tert-butoxide (11.1 g, 99 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzylchloride (16.9 g, 108 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The DMF was evaporated under vacuum, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL). The organic phase was dried with Na2SO4 and evaporated to give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][CH:7]=1)=[O:5].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[C:18]1([S:24][C:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:3]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:2]=3[OH:1])=[CH:7][CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1ccccc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Sc2ccccc2)cc1)c1ccc(O)cc1O
Yield: 42.8 %

Procedure:
A mixture of 39 g (156 mmol) of 2,4-dihydroxy-4′-chlorobenzophenone, 22.4 g (204 mmol) of thiophenol and 26 g (188 mmol) of potassium carbonate is stirred in 300 ml of N-methyl-2-pyrrolidone for 24 hours at a temperature of 210° C. After cooling the reaction mixture is neutralized with hydrochloric acid (10%) and extracted with 4×250 ml of ethyl acetate. The solution so obtained is washed with water and afterwards with a saturated solution of sodium chloride. The residue which is obtained, after drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent is subjected to chromatography on silica gel (ethyl acetate/hexane 1:5). The product is recrystallized from ethyl acetate/hexane. 21.5 g of the compound are obtained as yellow crystals with a melting point of 117-118° C.
Reaction SMILES: C[O-].[Na+].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1)=O.[CH3:20][O:21][C:22](=[O:27])[CH2:23][N:24]=[N+:25]=[N-:26]>CO>[N:24](/[C:23](=[CH:4]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])=[CH:8][CH:7]=1)/[C:22]([O:21][CH3:20])=[O:27])=[N+:25]=[N-:26]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C\c1ccc(NC(=O)OC(C)(C)C)cc1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
To a solution 13.45 mmol of sodium methoxide in 6 mL absolute methanol at 0° C. was added a solution of 717 mg (3.24 mmol) of tert-butyl 4-formylphenylcarbamate and 1.49 g (12.96 mmol) methylazidoacetate dissolved in 6 mL absolute methanol dropwise over 5 minutes. The mixture was stirred at 0° C. for 6 h, then partitioned between ethyl acetate and acetic acid until neutral. The organic phase was dried over magnesium sulfate, concentrated and purified by column chromatography, eluting with 25% ethyl acetate/hexane to provide 551 mg of methyl (2E)-2-azido-3-{4-[(tert-butoxycarbonyl)amino]phenyl}prop-2-enoate as a yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[O:13]1>CC(C)=O.C1COCC1>[CH3:6][C:7]1[N:8]=[C:9]([C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]([OH:22])=[O:13])=[O:21])[S:10][CH:11]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1csc(C(=O)c2ccccc2C(=O)O)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A dry 250 mL RBF under nitrogen was charged with THF (35.3 mL, 0.4 M), and cooled to −78° C., via dry ice bath in acetone. n-Butyllithium (6.3 mL, 15.8 mmol) was added via syringe. While keeping reaction mixture at −78° C., 4-methylthiazole (1.4 g, 15.1 mmol) in 40 mL of THF was added via addition funnel over 15 minutes. The reaction mixture was stirred at −78° C. for 2 hrs, allowed to warm up to 0° C. over half an hour, then cooled back to −78° C. and isobenzofuran-1,3-dione (3.4 g, 22.7 mmol) in 25 ml of THF rapidly added. The reaction was allowed to warm up to RT and stirred overnight. Reaction mixture was concentrated down to 30 mL, diluted with 60 mL of water, cooled to 0° C. and acidified with 6N HCl to pH4, and extracted with DCM (3×100 mL). The organic layers were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was triturated with DCM to afford 2-(4-methylthiazole-2-carbonyl)benzoic acid. MS m/z=248 [M+H]+. Calc'd for C12H9NO3S: 247.3.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>CCCCCC.COCCOC>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[C:15]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
After 903 mg (20.7 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 60 ml of 1,2-dimethoxyethane, and 4.63 g (20.7 mmol) of triethyl phosphonoacetate were added dropwise thereto while the suspension was stirred at 0° C. under nitrogen atmosphere. After 15 minutes, 2.00 g (11.5 mmol) of 4-(trifluoromethyl)benzaldehyde were added to the resulting mixture at the same temperature, followed by stirring of the mixture for 15 minutes. Ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water. After drying, an oily residue obtained by evaporation of the solvent was subjected to column chromatography using silica gel and eluted with 4% ethyl acetate-hexane to obtain the title compound having a melting point of 31 to 32.5° C. in a yield of 98%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:16])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:6]([CH3:16])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:15])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: CCc1cnn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (106 mg, 0.45 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (164 mg, 0.43 mmol) [prepared according to Preparation 6] and PyBrop (254 mg, 0.54 mmol) in Chloroform (6 mL). DIEA (400 μL, 2.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (182 mg, 0.32 mmol, 71%): LC-MS (ES) m/z=567 (M+H)+.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH3:9][O:10][CH2:11][CH2:12][C:13](OC)=[O:14]>C1COCC1>[CH3:9][O:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:7][C:6]#[N:8]
Reactant: COCCC(=O)OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC(=O)CC#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification.