Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])C.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[CH2:2]([S:4]([N:28]1[CH2:29][CH2:30][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][C:14]3[CH:15]=[CH:16][N:11]4[CH:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[O:31])=[CH:21][CH:22]=2)[CH2:27]1)(=[O:6])=[O:5])[CH3:1]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: CCS(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 557C, substituting ethane sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (t, J=5.9 Hz, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.88 (m, 3H), 7.52 (d, J=1.2 Hz, 1H), 7.45 (m, 2H), 7.38 (s, 1H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H), 3.75 (dd, J=9.5, 7.5 Hz, 1H), 3.50 (m, 2H), 3.38 (m, 1H), 3.26-3.12 (m, 3H), 2.32 (m, 1H), 2.03 (m, 1H), 1.24 (t, J=7.3 Hz, 3H); MS (ESI(+)) m/e 413 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:16]=1[C:17](=O)[CH2:18]Br>>[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:16]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:18]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)c1ccc(-c2nc(-c3c(F)c(F)c(F)c(F)c3F)cs2)cc1
Yield: 60 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 2,3,4,5,6-pentafluorophenacyl bromide to obtain methyl 4-[4-(2,3,4,5,6-pentafluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 60%. Pale yellow prisms. Melting point: 141 to 142° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:14])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt](=O)=O.[H][H]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1

Procedure:
Hydrogenate 18 g of 2-(4-nitrobenzyl)-1-methylpyrrolidine in ethanol with 300 mg of platinum dioxide/hydrogen. Filter the catalyst from the reaction mixture, concentrate the latter and recrystallize the thus-produced residue from n-hexane to obtain the title compound at a yield of 12.7 g (82% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-4-yl]-propionic acid as off-white solid.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1.[Na+].[Cl-]>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:33][N:34]([C:7]([Cl:10])=[O:6])[CH2:35][CH2:36]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NC(=O)C1(c2ccccc2)CCNCC1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)C1(c2ccccc2)CCN(C(=O)Cl)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of triphosgene (172 mg, 0.6 mmol) in dichloromethane (6 mL) at 0° C. under an argon atmosphere was added a solution of pyridine (106 μL, 1.32 mmol) in dichloromethane (3 mL) and a solution of 4-phenyl-piperidine-4-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (195 mg, 0.6 mmol) in dichloromethane (6 ml). After stirring at room temperature for 12 h the reaction mixture was poured into ice water, the aqueous layer was saturated with NaCl, then extracted 6 times with dichloromethane, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography over a 10 g silica gel column with n-heptane and ethyl acetate to yield 233 mg 4-[(S)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-4-phenyl-piperidine-1-carbonyl chloride. MS ISN (m/e): 387.4 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].CC1(C)C(C)(C)O[B:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)O1>O1CCOCC1>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][B:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[O:4][CH2:3]1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Reactant: CC(C)(CO)CO
Solvent: C1COCCO1
Product: CC1(C)COB(c2ccc(-c3ccccc3O)cc2)OC1
Yield: 99 %

Procedure:
A mixture of 2,2-dimethylpropane-1,3-diol (4.0 g, 38 mmol) and 4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-ol (1.0 g, 3.4 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 210° C. for 1 hour. The cooled reaction mixture was partitioned between water (50 mL) and 1:1 EtOAc/heptane (25 mL:25 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (0.95 g, 99% yield). GC/MS, M=282 at 5.31 min. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J=7.81 Hz, 2H), 7.48 (d, J=7.81 Hz, 2H), 7.31-7.26 (m, 2H), 7.03-6.98 (m, 2H), 3.82 (s, 4H), 1.08-1.04 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(F)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
3.7 g (13 mmol) of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 20 ml of sulfuric acid, and 0.9 g (14 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water and then, dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 4.2 g (yield: 98%) of the desired product. Melting point: 115-118° C.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2C(=O)Cn2cncn2)cc1
Yield: 42 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 74, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (189 mg, 42%). 1H-NMR (400 MHz, CDCl3): σ 8.96 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.17-7.14 (m, 2H), 7.01 (t, 2H), 6.96-6.93 (m, 1H), 6.83-6.76 (m, 4H), 5.02 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.63 (t, 1H), 3.23 (t, 1H), 3.03-2.86 (m, 2H), 2.69-2.60 (m, 2H), 2.18 (s, 3H), 1.72-1.57 (m, 1H). MS (EI) for C29H27F2N5O3. found 532.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][O:20]C1C=C([N+]([O-])=O)C=CC=1S(NC1C=CC(C)=CC=1)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[C:4]([O:20][CH3:19])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc(C)cc1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1cc(N)ccc1S(=O)(=O)Nc1ccccc1C
Yield: 93 %

Procedure:
(RK2-065-01) I This compound was prepared according to the procedure described for compound 12a except using 11j to obtain the required product as a yellow solid (63 mg, 93%). Mp=189-191° C.; 1H NMR (400 MHz, CD3OD) δ 7.30 (d, J=8.8 Hz, 1H), 7.10-7.06 (m, 2H), 7.01-6.97 (m, 2H), 6.31 (d, J=1.6 Hz, 1H), 6.12 (dd, J=8.8, 2.0 Hz, 1H), 3.30 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:23][C:16]3([CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:23][C:16]3([CH2:17][CH2:18][N:19]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[CH2:20][CH2:21]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCC2(CC1)SC(c1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccc(Cl)c(Cl)c1)c1ccccc12

Procedure:
A solution of 2.5 g of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine], free base of Example 19, and 1.3 g of phenyl chloroformate in 30 ml of methylene chloride is stirred at ambient temperature for 16 hours. The well stirred solution is washed successively with dilute sodium hydroxide and water and then dried, effecting a crystalling product. The product is recrystallized from an acetone-pentane mixture to give fine needles, m.p. 200°-202° C. of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([C:14]#[N:15])[CH2:11][C@H:10]2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[O:17])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:33]>[Pd].CO>[ClH:33].[N:1]1([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH2:15])[CH2:11][C@H:10]2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)=[O:17])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
A flask was charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (260 mg, 0.599 mmol), prepared as in Reference 11, methanol (4 mL), hydrogen chloride (4N in dioxane, 16 mmol) and palladium on carbon (10%, 100 mg) and the mixture was placed under a hydrogen atmosphere (balloon). The mixture was stirred for 18 hours at ambient temperature, filtered and concentrated to give crude (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-aminomethyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride salt (0.247 g, 0.564 mmol).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1.ClC1N=C(Cl)C2[O:27][CH:26]=[CH:25]C=2N=1.N1CCNCC1.C(Cl)(=O)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:26](=[O:27])[CH3:25])[CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Clc1nc(N2CCNCC2)c2occc2n1
Reactant: Clc1nc(Cl)c2occc2n1
Agent: C1CNCCN1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a flask was added 2-chloro-4-(piperazin-1-yl)furo[3,2-d]pyrimidine, hydrochloride salt (0.325 g, 1.18 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Ark Pharm] with piperazine), DMF (10 mL), TEA (0.543 mL, 3.90 mmol) and acetyl chloride (0.185 mL, 2.60 mmol). The mixture was warmed to about 35° C. and stirred overnight. The mixture was cooled to rt and diluted with DCM (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo and dried in a vacuum oven at about 40° C. to give 1-(4-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperazin-1-yl)ethanone (0.214 g, 64%): LC/MS (Table 2, Method a) Rt=1.04 min; MS m/z 281.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12](OCC)(=[O:18])[C:13]([O:15]CC)=[O:14].CC(C)([O-])C.[K+].O>C(O)C>[CH3:11][C:3]1[C:2]([CH2:1][C:12](=[O:18])[C:13]([OH:15])=[O:14])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
A solution of 15.1 g (0.10 mol) of 2-methyl-3-nitrotoluene and 14.6 g (0.10 mol) of diethyl oxalate in 10 ml of ethanol was added to a solution of 11.2 g (0.10 mol) of potassium tert-butoxide in 50 ml of ethanol. After stirring at room temperature for 1.5 hour, the reaction mixture was refluxed for 1.5 hour. After 60 ml of water was added to the reaction mixture, the mixture was refluxed for further an hour. After cooling, ice water was poured onto the reaction mixture followed by washing twice with ethyl acetate. The aqueous layer was acidified with conc. hydrochloric acid and then extracted three times with chloroform. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 10.4 g (46.6%) of the desired 6-methyl-2-nitrophenylpyruvic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1OB(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to a suspension of 60 mg (0.16 mmol) 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine and 63 mg (0.32 mmol) 2,4-dichlorophenylboric acid in 4 mL 1,4-dioxane and 1 mL 2 M Na2CO3 solution and the reaction mixture is stirred for 1 h at 110° C. The mixture is evaporated down i.vac. and the residue is extracted twice with in each case 15 mL EtOH. The solvent is removed and the residue is purified by HPLC.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH3:33])[C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1)#[N:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(OC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl.CO>[NH2:19][C:10]1[C@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[O:12][CH2:13][C@:8]([C:6]2[N:7]=[C:2]([NH:32][C:30]([C:27]3[C:26]([CH3:33])=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A mixture of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (80 mg, 0.216 mmol), 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (34.8 mg, 0.216 mmol, see Intermediates Amide 1), xantphos (11.26 mg, 0.019 mmol) and cesium carbonate (99 mg, 0.303 mmol) in dioxane (2 ml) was degassed for 5 minutes with argon. Pd2(dba)3 (5.94 mg, 6.48 μmol) was added, the microwave vial was sealed and stirred at 80° C. for 18 hours. The reaction mixture was diluted with water and TBME. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. 173 mg orange solid. Silica gel chromatography (applied on two 20×20 cm plate, 1 mm, dichloromethane:methanol 9:1, rechromatographed with dichloromethane:methanol 95:5 with double evolution of the plates) afforded the titel compound: 15 mg and 21 mg. Combined amount: 36 mg (37% yield). TLC (dichloromethane/methanol 9:1) Rf=0.53; API ES+ MS 451. LCMS RtH4=0.87 min. (100%, ES+ 451), 1H-NMR (400 MHz, CDCl3): 10.80 (br s, 1H), 8.83 (br s, 1H), 8.41 (dd, 1H), 7.93 (br s, 1H), 7.55 (t, 1H), 5.8-4.6 (very broad, 2H), 4.23 (br s, 2H), 2.83 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[C:14](F)(F)[C:15](O)=[O:16]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:12][O:11][C:10]1[C:2]([F:1])=[C:3]2[C:7]([C:15](=[O:16])[CH2:14][O:6][CH2:4]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(C(=O)O)c1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(c1F)COCC2=O
Yield: 32 %

Procedure:
A solution of 2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid from Step 1 (1.96 g, 8.6 mmol) in 4 mL of trifluoroacetic acid and 2 mL of trifluoroacetic anhydride was stirred at room temperature for 1 hour. The solution was concentrated in vacuo, the residue dissolved in ether, and the ethereal solution was washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a solid that was purified by flash chromatography to provide 0.37 g (32%) of the desired ketone. The aqueous phase from the NaHCO3 was acidified, extracted with ether, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide 1.13 g, of recovered 2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid: mp 112°-118° C.; 1H NMR (CDCl3 /300 MHz) 7.86 (dd, J=8.66, 1.41 Hz, 1H), 7.00 (apparent t, J=8.26 Hz, 1H), 4.96 (s, 2H), 4.31 (S, 2H), 3.97 (S, 3H); 19F NMR (CDCl3 /282 MHz) -142.2 (d). Mass spectrum M+ =196.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:33]([O:34][CH3:35])[CH3:32])=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CON(C)C(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1

Procedure:
The product from Example 88A and N,O-dimethylhydroxylamine hydrochloride were processed as described in Example 68D to provide the title compound. MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[C:9](=[O:14])[CH2:10][CH2:11][C:12]=2[CH3:13])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C(c2ccccc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1

Procedure:
0.815 g (4.35 mmol) of 2-(2-aminophenyl)-3-methyl-2-cyclopenten-1-one, pyridine 0.413 g (5.22 mmol), 0.829 g (5.22 mmol) of p-toluenesulfonyl chloride, and 4 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.330 g, 89%).
Reaction SMILES: Cl.NO.C(=O)([O-])[O-:5].[Na+].[Na+].Cl.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH2:20][C:21]([NH2:23])=[NH:22])=[N:12]1>O.C(O)C>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH2:20][C:21](=[N:23][OH:5])[NH2:22])=[N:12]1
Reactant: N=C(N)Cc1noc2ccccc12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.17 g) and sodium carbonate (0.13 g) in water (5 ml) was added a solution of 1,2-benzisoxazole-3-acetamidine hydrochloride (0.21 g) in ethanol (10 ml) and the mixture was heated on water bath at 80°C for 1 hour. The solvent was distilled off under a reduced pressure and to the residue was added water. The mixture was made alkaline with sodium bicarbonate and the precipitated crystalline were separated by filtration, washed with water, dried and recrystallized from ethanol to give the desired compound (0.16 g). m.p. 160° to 162°C.