Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
30.5 mg (0.11 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 23.1 mg (0.11 mmol) of 4-methoxycarbonylbenzhydrazide were dissolved in 3.0 ml of DMF and stirred at 100° C. for 3 hours. After cooling and evaporation of the solvent, the crude product was recrystallized from ethyl acetate/n-hexane to give 32.9 mg of the desired product as a yellow solid (yield 66%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67-11.81 (bs, 1H), 8.38-8.41 (m, 1H), 7.85-7.98 (m, 2H), 7.25-7.32 (m, 1H), 7.20-7.24 (m, 2H), 7.09-7.19 (m, 4H), 3.75 (s, 2H), 2.37 (s, 3H), 2.05 (s, 3H); MS (APCI+) M/Z 420 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].P([O-])([O-])([O-])=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>C(OCC)(=O)C>[C:1]([NH:8][CH:9]([CH:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)C1CCCCC1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(O)C1CCCCC1
Reaction time: 2 h

Procedure:
The reducing activity against ethyl N-Boc-2-amino-3-cyclohexyl-3-oxopropionate was calculated in the following manner. First, an appropriate amount of a crude enzyme solution and 100 mM phosphate buffer (pH 6.5) were added to a test tube to make a total volume of 0.5 ml. Further, 0.25 mg of ethyl N-Boc-2-amino-3-cyclohexyl-3-oxopropionate and 1 mg of NADH were added, and the reaction was allowed to proceed at 30° C. for 2 hours with shaking. After the reaction, 1 ml of ethyl acetate was added and extraction was carried out. The quantitation of the product ethyl N-Boc-2-amino-3-cyclohexyl-3-hydroxypropionate was carried by capillary gas chromatography (column: GL Sciences InertCAP 5 (ID 0.25 mm×30 m), column temperature: 200° C.; carrier gas: helium (70 kPa), detection: FID). The enzyme activity was calculated from the amount of the ethyl N-Boc-2-amino-3-cyclohexyl-3-hydroxypropionate formed. The activity such that 1 μmol of ethyl N-Boc-2-amino-3-cyclohexyl-3-hydroxypropionate is formed in 1 minute under the reaction conditions mentioned above is defined as 1 unit.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]\[C:30]#[N:31])[CH:23]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[N:12]=[C:11]2[CH:10]=[C:28]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:29]=[C:30]([NH2:31])[N:15]2[N:14]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: N#C/C=C\c1cccnc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):288 (M+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-pyridin-3-yl-acrylonitrile.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>C1COCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@@H:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1cccc(Cl)c1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(Cl)c3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a solution of 9.70 g (22.0 mmol) of enone 13 in 60 mL of THF at -23° C. was added dropwise a solution of 11.1 g (34.6 mmol) of (-)-B-chlorodiisopino-campheylborane in 30 mL of THF. After 4 h, the reaction was quenched by the dropwise addition of 5 mL of methanol and then warmed to room temperature. After pouring into 200 mL of a 2/1 mixture of ethyl acetate/saturated NH4Cl, the layers were separated, and the aqueous phase was extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, concentrated, and the residue was chromatographed on silica gel eluting with ethyl acetate/hexanes, 3/2, to afford 4.7 g (48%) of 14 as a white solid, m.p. 101.0°-102.5° C. 1H NMR δ 8.05-7.95 (m, 2 H), 7.62-7.40 (m, 3 H), 7.18 (t, J=8.0 Hz, 1 H), 7.0-6.92 (m, 1 H), 6.85 (t, J=2.1 Hz, 1 H), 6.77-6.70 (m, 1 H), 5.85 (d of d, J=6.2, 15.5 Hz, 1 H), 5.72 (d of d, J=4.5, 15.5 Hz, 1 H), 5.30 (q, J=5.8 Hz, 1 H), 5.12-5.04 (m, 1 H), 4.58-4.48 (m, 1 H), 3.92 (d of d, J=3.5, 9.3 Hz, 1 H), 3.80 (d of d, J=7.3, 9.4 Hz, 1 H), 2.9-2.2 (m, 8 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:20])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH-].[Na+]>O.C(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[F:1][C:2]1[C:3]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[S:20][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=S)Nc2ccccc2F)cc1OC
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3c(F)cccc3s2)cc1OC
Temperature: 95 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A solution of N-(2-fluorophenyl)-3,4-dimethoxythiobenzamide (0.850 g, 2.92 mmol) and sodium hydroxide (0.93 g, 23.3 mmol) in water (10 mL) and ethanol (0.5 mL) was added dropwise to a solution of potassium ferricyanide (3.84 g, 11.7 mmol) in water (5 mL) at 95° C. The resulting solution was stirred at 95° C. for a further 2 h and then cooled in an ice bath. The precipitate was collected by vacuum filtration, washed with water and dissolved in ethyl acetate (10 mL) and insoluble material was removed by filtration. The filtrate was concentrated in vacuo and the crude product purified by column chromatography (dichloromethane) to give the required product as a pale yellow powder (0.46 g, 55% yield), mp 129° C.; 1H NMR (DMSO-d6) δ 7.95 (1H, m, ArH), 7.65 (2H, m, ArH), 7.42 (2H, m, ArH), 7.15 (1H, m, ArH), 3.90 (3H, s, OMe), 3.88 (3H, s, OMe); m/z (CI) 290 (M++1); Anal. (C15H12FNO2S) C, H, N. C: found 62.36%, calc. 62.27%; H: found 4.19%, calc.4.18%; N: found 4.93%, calc. 4.84%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)CO
Solvent: c1ccncc1
Solvent: O
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
10 g of 2-ethoxypropanol was dissolved in 59 ml of pyridine and the solution was cooled to below 5° C. To the solution under stirring was added 22 g of p-toluenesulfonic acid chloride. After that, the mixture was stirred for 5 hours at room temperature and left standing overnight. Cold water was added thereto, and the mixture was subjected to extraction with ether. The ether extract was washed with water, followed by distilling-off of the ether to obtain 24 g of p-toluenesulfonic acid 2-ethoxypropyl ester.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC(=O)O)C(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a 0° C. solution of ethyl 2-(N-methyl-3-phenylprop-2-ynoylamino)acetate (prepared according to the procedure described for Intermediate A, 124.4 g, 0.507 mol) in MeOH (750 mL) was added a solution of NaOH (30.4 g, 0.760 mol, 1.5 equiv) in water (1000 mL). The resulting red reaction mixture was stirred for 20 min, then allowed to warm to room temperature and stirred for 2 h. The reaction was washed with CH2Cl2 (3×500 mL). The aqueous layer was cooled in an ice bath and acidified to pH 3 using conc. HCl. A light orange oil formed, which was extracted into EtOAc (4×500 mL). The combined EtOAc layers were washed with water (3×200 mL) and a saturated NaCl solution (2×300 mL), dried (Na2SO4) and concentrated under reduced pressure to give 2-(N-methyl-3-phenylprop-2-ynoylamino)acetic acid (102.5 g, 93%) as an orange solid: TLC (1% AcOH/5% MeOH/CH2Cl2) Rf 0.20; 1H NMR (CDCl3) δ 3.09 (s, 1.1H, N—CH3), 3.36 (s, 1.9H, N—CH3), 4.27 (s, 1.2H, N—CH3), 4.45 (s, 0.8H, N—CH3), 7.30-7.56 (m, 5H), 9.58 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:16]([C:18]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:23]=3)=[CH:17][C:10]=12>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:16]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of P-5-I (2.4 g) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, solvents were removed under reduced pressure and saturated NaHCO3 (60 mL) solution was added to the residue. Extraction was carried out using EtOAc (50 mL×3); the combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained (1.9 g, quantitative) was used without any purification. LCMS: m/z; 388.2 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 339 mg (1.79 mmol) 1-bromomethyl-3-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][C:30]1(C)[C:34](C)(C)OB(C(C)=C)O1>COCCOC.C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([C:30]([CH3:34])=[CH2:29])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(Br)cccc3[C@@H]1CN(Cc1ccccc1)C2
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 160 °C
Yield: 75.2 %

Procedure:
trans-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in DME (1 ml) and Ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml) was added along with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.842 mmol, 141 mg) and tetrakis(triphenylphosphine)Pd(0) (0.028 mmol, 32.4 mg). The reaction mixture was heated at 160° C. for 15 minutes in a microwave reactor and then diluted with water. The resulting mixture was extracted with DCM and the combined organic extracts were concentrated in vacuo to give a crude residue that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford trans-2-benzyl-3a-methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (134 mg), m/z: 318.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[N:21]1.C(Cl)CCl.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:29][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][N:21]=[CH:22]3)=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 80 °C
Yield: 28.2 %

Procedure:
The product of step 2 (252 mg, 0.890 mmol, 1.00 equiv), 1H-indazol-5-amine (142 mg, 1.07 mmol, 1.20 equiv), EDC (229 mg, 1.07 mmol, 1.20 equiv), and DMAP (10 mg, catalytic) were suspended in 4.0 mL DMF. Et3N (0.298 mL, 2.14 mmol, 1.00 equiv) was added and the solution was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (100% EtOAc) to provide 0.100 g (28%) of the title compound as a white solid. MS (ES+) m/e 399 [M+H]+
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]2[CH:25]=[C:26]([Cl:28])[CH:27]=[C:7]2[C:6]=1[OH:29])=[O:4].[NH2:30][C@H:31]([C:33]([OH:35])=[O:34])[CH3:32].C[O-].[Na+]>>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:5]([C:3]([NH:30][C@@H:31]([CH3:32])[C:33]([OH:35])=[O:34])=[O:4])=[C:6]([OH:29])[C:7]3=[CH:27][C:26]([Cl:28])=[CH:25][N:8]23)=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 1-biphenyl-4-ylmethyl-6-chloro-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 466 (M+H)+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl>CN1CCCC1=O>[CH2:9]([N:8]1[C:6](=[O:7])[NH:5][NH:4][C:1]1=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCN
Reactant: NC(=O)NNC(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
60 g of hydrazodicarbonamide and 56 g of n-hexylamine are stirred in 100 ml of N-methy pyrrolidone for 6 hours at 150° C., for 20 hours at 175° C. and for 20 hours at 180° C. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of 10% sodium hydroxide solution. The deposit is isolated by filtration under suction and the filtrate is neutralised with 10% hydrochloric acid. A deposit is precipitated and is isolated by filtration under suction, washed with water and dried in vacuo, giving 75 g (81% of the theoretical yield) of 4-(n-hexyl)-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 144° C. to 145° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:15]([F:14])([F:25])[F:26])=[O:19])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.19 (s, 3 H) 2.21 (s, 3 H) 3.90-3.96 (m, 2 H) 5.99 (s, 1 H) 7.52-7.61 (m, 2 H) 7.66-7.71 (m, 1 H) 7.72-7.77 (m, 1 H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+:21].[ClH:22].[OH-].[Na+]>>[ClH:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Product: NC(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 190 °C
Reaction time: 10 h
Yield: 65.6 %

Procedure:
A mixture of 1,2-bis(4-fluorophenyl)-1-oxoethane (2.13 g) and ammonium formate (3.78 g) was stirred for 10 hours at 190° C.. After cooling, concentrated hydrochloric acid (12 ml) was added to the reaction mixture and the mixture was refluxed for 5 hours. After cooling, aqueous sodium hydroxide solution was added to the mixture and alkalized. The product was extracted with ethyl acetate and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in methanol. To the solution, HCl/methanol was added and the solution was concentrated in vacuo. Separated crystals were collected by filtration to give 1.77 g (65.6%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[I:16][CH2:17][C:18]#[C:19]O.N1C=CC=CC=1.C1(C)C=CC=CC=1>C1CCCCC1.S(Cl)(Cl)=O.C(OCC)C>[I:16][CH:17]([O:14][C:13](=[O:15])[CH2:12][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])[C:18]#[CH:19]
Reactant: OC#CCI
Reactant: O=C(O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C#CC(I)OC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 30 °C
Yield: 61.7 %

Procedure:
15 g (0.06 moles) of 2,6-dichloro-3-nitrophenylacetic acid were suspended in 30 ml of cyclohexane and 20 ml of thionyl chloride. The whole was refluxed until the evolution of gas was complete. Subsequently, excess thionyl chloride and cyclohexane were distilled off. The resulting acid chloride was dissolved in 50 ml of absolute toluene and, while stirring, at a temperature of 30° C., added dropwise to a mixture of 11 g (0.06 moles) of 3-iodopropynol, 4.75 g of pyridine and 50 g of toluene. After 1 hour the reaction mixture was taken up in diethyl ether and the ethereal solution was extracted with 1N hydrochloric acid and then with saturated sodium bicarbonate solution. Finally, the organic phase was washed with water, dried with sodium sulfate and concentrated by evaporation. The crude product (22.7 g) was further purified by chromatography over silica gel. 15.5 g (0.037 moles) of 2,6-dichloro-3-nitrophenylacetic acid iodopropargyl ester corresponding to 63% of the theoretical yield, were obtained. Melting range 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)[CH2:15][CH2:16]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 100 °C
Reaction time: 25.5 h
Yield: 23.4 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyrimidine (0.58 g, 3.60 mmol) and tert-butyl 3-amino-9-azaspiro[5.5]undecane-9-carboxylate (1.44 g, 5.37 mmol) in EtOH (25 mL) was added Et3N (0.86 g, 8.50 mmol). After addition, the reaction mixture was stirred at 100° C. in a sealed tube for 25.5 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a yellow solid (332.2 mg, 24%).