Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]3[OH:36])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:45])[CH:19]=1)[CH2:9][CH2:10][C:11](=[O:13])[NH2:12])C1C=CC=CC=1>CO.[C].[Pd]>[C:11]([CH2:10][CH2:9][NH:8][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]3[OH:36])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:45])[CH:19]=1)(=[O:13])[NH2:12]
Reactant: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OCCCNCCC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.9 %

Procedure:
4-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]-propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.5 g) was dissolved in methanol (8 mL). To the solution was added 10% palladium-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. A part (0.1 g) of the residue was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (1.5 mL). To the solution was added a seed crystal, and the mixture was stirred at room temperature for 3 days. The precipitated crystals were collected by filtration. The crystals were washed with a mixed solvent of methanol and ethyl acetate (⅔), and dried under reduced pressure to give the title compound (85 mg).
Reaction SMILES: C1(O[C:8](=[O:42])[O:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[C:40]6[CH:39]=[CH:38][S:37][C:36]=6[CH:35]=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:41])C=CC=CC=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.O>C1COCC1>[S:37]1[CH:38]=[CH:39][C:40]2[C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]4[CH:19]=[C:20]5[C:15]([CH:14]=[CH:13][C:12](=[O:41])[N:11]5[CH2:10][O:9][C:8]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])=[CH:16][CH:17]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=[CH:35][C:36]1=2
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Reactant: C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (0.44 g) synthesized in the same manner as in Example 7 in THF was added piperidine (0.76 ml), and the mixture was stirred at room temperature for 3.5 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to give the title compound (0.44 g, yield quantitative) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]3([CH2:35][CH2:34]3)[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]3([CH2:35][CH2:34]3)[CH2:32]2)[N:3]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC12CC2
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC12CC2
Yield: 57.1 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0961 g, 0.165 mmol) in 4:1 HOAc-water (5 mL) was stirred for 3 days. The solution was concentrated in vacuo and diluted with DCM (100 mL). The solution was washed with sat. aq. NaHCO3 (25 mL), and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC, and the desired fractions were concentrated in vacuo and azeotroped first with MeOH and then with EtOAc. The residue was crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0469 g, 57%, mixture of diastereomers) as a white solid. LCMS: (M+H)+: 498.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NCC1CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1cncc(NCC2CC2)n1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-dichloropyrazine (2.99 g), 1-cyclopropylmethanamine (2.14 g), potassium carbonate (4.14 g) and DMA (20 mL) was stirred at 80° C. for 23 hr. Water (15 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. This was used without purification for the next reaction.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:39](Cl)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH2:35]([S:39]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A29 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), butane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.98 (t,3H), 1.51 (m,2H), 1.83 (m,2H), 2.07 (m,4H), 2.97 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.58 (m, 2H), 5.68 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C20H27N5O7S2 513.14, found 514.4 (MH+).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[CH2:12]Br>CO>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH2:12][NH:1][C:4]2=[O:3]
Reactant: N
Reactant: COC(=O)c1cccc(Br)c1CBr
Solvent: CO
Product: O=C1NCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL microwave tube 3-bromo-2-bromomethyl-benzoic acid methyl ester is dissolved in methanol (15 mL) and mixed with 7.0M methanolic ammonia (6.3 mL) and 17.0M aqueous ammonia (7.3 mL). The microwave tube is sealed and the mixture is stirred overnight at room temperature. The precipitate formed is filtered out and washed with cold water, then dried under vacuum to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:31]([F:34])([F:33])[F:32])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[OH-].[Na+]>CO.C1COCC1>[F:40][C:35]1[CH:36]=[C:37]([F:39])[CH:38]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]3)=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:31]([F:34])([F:32])[F:33])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(=O)C[C@H]1CCCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CCCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of methyl ((3R)-1-{4-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}piperidin-3-yl)acetate (0.045 g, 0.08 mmol) in CH3OH-THF (1:1, v/v) containing 0.5 mL of 1 N NaOH was stirred overnight at ambient temperature. Then it was neutralized with dilute acid and partitioned with ethyl acetate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was crystallized from ether/petroleum ether to give 0.036 g of title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:3](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1>[CH3:1][C@H:2]([C@@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[CH2:3][OH:4]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
A solution of 6.8 g (20 mmol) of 3(2(R),3(S),7-trimethyl-6-octenoyl)-4(R)-phenylmethyl-2-oxazolidinone in 30 mL of THF was added dropwise to a suspension of 1.634 g (43 mmol) of lithium aluminum hydride in 40 mL of THF at 0° C. The reaction mixture was then stirred 6 h at ambient temperature The reaction mixture was then recooled in ice bath and 5 mL of methanol was added dropwise very cautiously. After the effervescence subsided, the reaction mixture was concentrated to about 30% of the original volume The reaction mixture was then stirred with saturated solution of potassium sodium tartrate and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. Solvent removal afforded a crude oil, which was purified on silica gel using 10% ethyl acetate in hexane as solvent to give 2.0 g (62%) of the desired alcohol as a colorless oil.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[C:17]([N+:23]([O-])=O)=[CH:16][C:15]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.NN>[Pd].C(O)C>[CH2:1]([O:13][C:14]1[CH:19]=[C:18]([NH2:20])[C:17]([NH2:23])=[CH:16][C:15]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCCCCCCCCCCCC
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1cc(N)c(N)cc1OCCCCCCCCCCCC
Yield: 75 %

Procedure:
This compound was synthesized according to a literature procedure.24 In a Schlenk tube, 1,2-Bis-dodecyloxy-4,5-dinitro benzene BK2—13 (2.36 g, 4.39 mmol), hydrazine monohydrate (8.25 ml, 48.5 mmol), 131 mg of Pd/C, and 65 ml of absolute ethanol were placed. The reaction mixture was refluxed under argon for 22 hours. Hot filtration under argon was then performed. Upon cooling, a white solid formed. The solid was washed with O2-free methanol and was dried overnight under nitrogen to yield 1.57 g (75%) of white solid. 1H (300 MHz, CDCl3) δ 6.353 (s, 2H), 3.880-3.835 (t, J=6.6 Hz, 4H), 3.062 (br s, 4H, NH2), 1.767-1.673 (pentet, J=7.2 Hz, 4H), 1.43-1.36 (m, 4H), 1.358-1.080 (m, 32H), 0.878-0.833 (t, J=7.2 Hz, 6H).13C (CDCl3, 75 MHz) δ 143.20, 128.20, 106.69, 70.67, 32.00, 29.78, 29.73, 29.67, 29.55, 29.45, 26.17, 22.78, 14.22 ppm. HRMS-E1 (m/z): [M]+ calcd. for C30H56N2O2, 476.43418. found 476.43449.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([OH:15])[CH:13]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([O:15][C:34]3[CH:44]=[CH:43][C:37]([C:38](=[O:39])[N:40]([CH3:41])[CH3:42])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:19][CH:18]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(=O)N(C)C)cn3)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1

Procedure:
1-(4-tert-Butylphenyl)-6-chloro-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (120 mg, 0.26 mmol, see step (b) above), 6-chloro-N,N-dimethylnicotinamide (72 mg, 0.39 mmol), K2CO3 (181 mg, 1.31 mmol) and DMF (3 mL) was heated at 115° C. for 96 h and filtered through Celite®. The solids were washed with EtOAc and the combined filtrates concentrated and purified by chromatography to give the sub-title compound. Yield 48 mg (78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[F:23].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])=[CH:4][C:3]=1[F:23]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BR) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 497.0260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]=2[CH:24]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:22][C:23]=2[CH:24]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Brc1cnc2c(c1)CNCC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ncc(Br)cc2C1
Yield: 66 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[C:35]([CH3:42])[C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[C:35]([CH3:42])=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(C(F)(F)F)c(C)cc21
Yield: 95.8 %

Procedure:
A solution of (S)-5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.920 g, 1.50 mmol) (Example 110) in 1:1 TFA/DCM (10.0 ml) was stirred at room temperature for 2 hours. The solvents were evaporated on a (rotary evaporation). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.736 g, 96%) as white solid. MS (ES+): 513 (M+H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc2ccccc2s1
Product: FC(F)(F)Oc1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The title compound was synthesised from 2-chloro-benzothiazole (commercially available) and 4-trifluoromethoxyaniline (commercially available) according to the procedure described for Example A. MS (m/z): 310.0 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (906 mg, 1.978 mmol), pyridin-3-ylboronic acid (267 mg, 2.176 mmol), potassium carbonate (1367 mg, 9.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.099 mmol). The vial was flushed with argon and dioxane (9.89 mL) and water (5.1 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 4 h. The mixture was cooled to rt, diluted with EtOAc (45 mL), and brine (45 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×35 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of CH2Cl2/MeOH/NH4OH in CH2Cl2 to give (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11]1(=O)[O:15][CH2:14][CH2:13][CH2:12]1>>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([N:6]3[CH2:11][CH2:12][CH2:13][C:14]3=[O:15])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C1CCCO1
Reactant: Nc1ccc2c(c1)OCO2
Product: O=C1CCCN1c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 51 %

Procedure:
A mixture of 3,4-(methylenedioxy)aniline (200 g, 1.46 mole) and γ-butyrolactone (225 ml) was heated (in a dry nitrogen atmosphere) with stirring in a 200° oil bath for 2 days. Product was isolated from the reaction mixture by distillation under reduced pressure (b.p. 156°, 33 μ). Product was filtered over Silica Gel 60 (Trade Name) eluting with ethylacetate. The eluant was concentrated and the crystalline product was collected and washed with ether and petroleum ether affording 1-(1,3-benzodioxol-5-yl)-2-pyrrolidinone (153.4 g; 51%), m.p. 89°-91° which was one spot on tlc analysis.
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH:20][C:23](=[O:26])[CH2:24][CH3:25])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCN)=C(Cc1ccccc1)C2
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)NCCC1=C(Cc2ccccc2)Cc2ccc(OC)cc21

Procedure:
Starting with 2-(2-benzyl-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 98%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:15]2/[C:14](=[O:16])[NH:13][C:12](=[O:17])[S:11]/2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C=O)n1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1nccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A 40 mL round-bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([I:9])=[CH:7][N:8]=1>O.CO>[NH2:2][C:3]1[C:4]([C:10]([NH2:1])=[O:12])=[N:5][C:6]([I:9])=[CH:7][N:8]=1
Reactant: COC(=O)c1nc(I)cnc1N
Reactant: N
Solvent: O
Solvent: CO
Product: NC(=O)c1nc(I)cnc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
30 ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate in 150 ml of methanol. The reaction medium is stirred at 25° C. for 48 hours. After evaporation of the solvents, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 12.50 g of 3-amino-6-iodopyrazine-2-carboxamide (88%) in the form of a beige solid.