Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:19]([NH2:20])=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:17]=1)[CH:14]=[CH2:15].C(O)=O>CO>[CH2:13]([C:16]1[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:19]([N:20]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:20][C:19]3[C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:16]([CH2:13][CH:14]=[CH2:15])=[CH:17][C:18]=3[CH:26]([CH3:28])[CH3:27])[CH3:11])[N:5]=2)[CH3:2])=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:22]=1)[CH:14]=[CH2:15]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: C=CCc1cc(C(C)C)c(N)c(C(C)C)c1
Solvent: O=CO
Solvent: CO
Product: C=CCc1cc(C(C)C)c(N=C(C)c2cccc(C(C)=Nc3c(C(C)C)cc(CC=C)cc3C(C)C)n2)c(C(C)C)c1

Procedure:
A solution containing 2,6-diacetylpyridine (0.30 g, 1.84 mmol), 4-allyl-2,6-diisopropylaniline (0.80 g, 3.68 mmol), and formic acid (2 ml) in 30 ml dry methanol was refluxed under argon for 14 hours. Yellow solid was collected by filtration and washed with cold methanol (3×5 ml). Recrystallization from CH2Cl2:hexane (1:4) yielded 0.70 g (68%) of yellow, 2,6-bis[1-(4-allyl-2,6-diisopropylphenylimino)ethyl]pyridine crystals. IR (KBr): v(C═N) 1639 cm−1. 1H-NMR (CDCl3): 8.47(d, 2H, Py-Hm), 7.92(t, 1H, Py-Hp), 6.98(s, 4H, Ph-Hm), 6.04(m, 2H, CH═C), 5.12(m, 4H, C═CH2), 3.40(d, 4H, CH2—C═C), 2.75(m, 4H, CH(Me)2), 2.27(s, 6H, CH3), 1.15(d, 24H, C(CH3)2); 13C-NMR(CDCl3): 167.04(C═N), 155.15(Py-C), 144.57(Ph-C), 138.12(Ph-C), 136.79(Py-C), 135.69(Ph-C), 134.75(—CH═), 123.16(Py-C), 122.12(Ph-C), 115.34(═CH2), 40.25(—CH2—), 28.31(C(Me)2), 23.24(CH3), 22.92(CH3), 17.14(CH3). C39H51N3 (561.86 g·mol-1): Anal. Calcd: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.03; H, 9.13; N, 7.55.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[CH3:16][C:5]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)n(S(=O)(=O)c2cccnc2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 106.6 %

Procedure:
A suspension of ethyl 5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.26 g), phenylboronic acid (1.54 g), dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate (1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 80° C. for 40 min. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→6:4) to give the title compound as a colorless oil (yield 2.39 g, about 100%).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].CO[C:25](OC)([N:27]([CH3:29])[CH3:28])[CH3:26]>>[CH3:28][N:27]([CH3:29])/[C:25](/[CH3:26])=[CH:2]/[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Product: C/C(=C\C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12)N(C)C
Yield: 57.4 %

Procedure:
A solution of N-(2-acetylthiophen-3-yl)-2-(naphthalen-1-yl)acetamide (197 mg, 0.64 mmol) in N,N-dimethylacetamide dimethyl acetal (0.3 mL, 2.05 mmol) was heated at 80° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried (sodium sulfate), filtered and concentrated to give the desired N-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (139 mg, 58%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cncc(Br)c1
Yield: 26.9 %

Procedure:
A solution of 5-bromopyridine-3-sulfonyl chloride (1.5 g, 5.8 mmol)) and 2-methoxyethanamine (1.3 g, 18 mmol) in THF (40 mL) was stirred at room temperature for 16 h. After this time, the resulting reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was dried and evaporated. The resulting residue was purified by flash column chromatography using ethyl acetate/hexanes to yield 5-bromo-N-(2-methoxyethyl)pyridine-3-sulfonamide (460 mg, 27%). LCMS Method T: Retention time 1.13 min; [M+1]=295, 297.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:27][CH3:28])[C:15]([CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=3[O:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:27][CH3:28])[C:15]([CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=2[O:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1ccccc1)C2=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CCl)C2=O
Yield: 89 %

Procedure:
By the method of part E of Example 45 2-phenylthiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.85 g) was reacted with sulfuryl chloride (0.30 g) in dichloromethane and purified with hexane affording 2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin, 0.62 g, 89% yield, mp 131°-133° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([CH:11]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10].CN(C=O)C>O>[Br:8][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]([O:13][CH2:12][CH:11]([CH2:9][CH3:10])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)COc1ccccc1OCC(CC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1ccc(Br)cc1OCC(CC)CCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Solid NBS (26.21 g, 0.147 mol) was added to an ice cold CH2Cl2 solution (250 mL) of 1b under N2 in the absence of light. Just enough DMF was added (30 mL) to dissolve the NBS. The reaction mixture was allowed to warm to room temperature and then stirred for 12 h. The mixture was then poured into water. The organic layer was washed with a saturated LiCl solution and water. After drying with MgSO4 the solvent was removed under reduced pressure. The remaining oil was distilled (160° C./0.01 mmHg) to yield 4-bromo-1,2-di(2-ethylhexyloxy)benzene (2b) in 96% yield as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2].CCN(CC)CC.[O:22]=[C:23]1[NH:32][C:31]2[N:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][CH:37]=O)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:29]3[N:30]=[C:31]4[C:26]([CH2:25][CH2:24][C:23](=[O:22])[NH:32]4)=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(N2CCNCC2)n1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1
Reaction time: 0.08 h
Yield: 47.4 %

Procedure:
To a solution of 1-(6-ethyl-pyridin-2-yl)-piperazine (0.41 g, 2.13 mmol) in dichloroethane (15 mL) was added Et3N (0.22 g, 2.13 mmol) and the mixture was stirred for 5 min. 4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.50 g, 2.13 mmol) was added as a solution in dichloroethane (3 mL) and the mixture was stirred at room temperature for 15 min. NaBH(OAc)3 (0.63 g, 3.00 mmol) was added as a solid and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by liquid chromatography (Biotage 40M, gradient elution 100% CH2Cl2 to 99% CH2Cl2/MeOH) afforded the title compound as a sticky white foam (413 mg, 1.01 mmol, 47%). The foam was dissolved in Et2O and treated with anhydrous HCl gas to give a white precipitate. The mixture was filtered and dried to give a white powder (287 mg). MS: APCI: M+1: 410.3 (Exact Mass: 409.25).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20](O)C1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]([CH:21]2[CH2:22][N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])[CH2:20]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: COc1n[nH]cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nn(C2CN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a cooled (0° C.) suspension of 3-methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mmol, 1.00 eq), tert-butyl-3-hydroxypyrrolidine-1-carboxylate (2.12 g, 12.2 mmol, 1.75 eq), and polystyrene bound triphenylphosphine (4.06 g, 12.2 mmol, 1.75 eq, 3 mmol/gram) in THF (45 mL) was added diethyl azodicarboxylate (2.42 mL, 13.0 mmol, 1.90 eq) in a drop-wise manner over 3 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hr. The reaction mixture was then diluted with EtOAc (60 mL), filtered and the filtrate concentrated. The crude reaction mixture was purified via flash chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane to give the title compound (1.52 g, 72.9% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (s, 1H) 4.87 (tt, J=5.6, 7.5 Hz, 1H) 4.40-4.28 (m, 4H) 4.09 (s, 3H) 1.48 (s, 9H). m/z (APCI+) for C7H11N4O3 198.9 (M−Boc+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added 1-naphthoyl chloride (0.055 g, 0.288 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixtures were filtered through a 2.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 20 mL of methanol, followed by 7N ammonia in methanol (20 mL), and concentrated under vacuum. The crude product was purified over a silica gel column eluting with methanol in dichloromethane (0-10%) over 30 minutes to obtain 0.0247 g (62%) of the compound.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([CH3:22])=[CH:9][C:8]=1[NH:23][C:24](=[O:28])[CH:25]=NO.C([O-])(O)=[O:30].[Na+]>>[CH3:22][C:10]1[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:12][C:7]([CH3:6])=[C:8]2[C:9]=1[C:25](=[O:30])[C:24](=[O:28])[NH:23]2
Reactant: Cc1cc(OCCN2CCOCC2)c(C)cc1NC(=O)C=NO
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(OCCN2CCOCC2)c(C)c2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To concentrated H2SO4 (3.5 mL) at 60° C. was added N-[2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-hydroxyimino-acetamide (1.4 g, 4.36 mmol) in portions with stirring. After the addition was finished, the mixture was heated to 75° C. and kept at this temperature for 15 min. A dark-purple solution was formed and poured upon cracked ice. Then solid NaHCO3 is added and pH was adjusted to 8.0. The mixture was extracted with CH2Cl2, dried (Na2SO4), and crystallized from CH2Cl2-hexane to give 4,7-Dimethyl-5-(2-morpholin-4-yl-ethoxy)-1H-indole-2,3-dione as brown solid 1.15 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccnc(Cl)c1
Product: O=C(Nc1ccnc(Cl)c1)c1cc(Cl)ccc1O
Yield: 12.2 %

Procedure:
Using 5-chlorosalicylic acid and 4-amino-2-chloropyridine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:41])([F:40])[F:42])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C(C)C(N)=O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Acetic anhydride (15 μL, 0.15 mmol) was added to a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 56 (50 mg, 0.10 mmol) in DCM (5 mL) and pyridine (12 μL, 0.15 mmol) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant solid was suspended in water (25 mL) and sonicated for 5 minutes. The solid was collected by filtration and washed with sat. aq. Na2CO3 (20 mL), water (50 mL) then petroleum benzine 40-60° C. to give the title compound 58 as a white solid (42 mg, 77%). LCMS-D: rt 3.176 min; m/z 530.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1)=[O:4].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[C:30](=[O:32])[CH3:31])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 3.5 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 35 ml CH2Cl2 was added 8.4 ml triethylamine, followed by dropwise addition of 4.2 ml acetic anhydride. The resulting solution was stirred at room temperature for two hours and then quenched with water. The organic layer was washed successively with 5% aq. HCl, water, saturated NaHCO3 and brine, and dried (MgSO4). Concentration, trituration with hexane and recrystallization from toluene/hexane gave 3.1 g solid, m.p. 184°-186° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2>>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:7](=[O:9])[CH2:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: Nc1ccc2[nH]ncc2c1
Product: CC(C)C(=O)CC(=O)Nc1ccc2[nH]ncc2c1
Temperature: 180 °C

Procedure:
Methyl isobutyrylacetate (3 mL) was mixed with 5-aminoindazole (0.50 g) and heated In a SmithSynthesizer to 180° C. for 300 seconds. The crude mixture was then purified by silica gel chromatography to yield the title compound as a purple solid. 1H NMR (keto- tautomer) (400 MHz, DMSO-D6) δ ppm 12.98 (s, 1H), 10.06 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 3.62 (s, 2H), 2.78 (sept, 1H), 1.06 (d, 6H). MS m/z 246 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[N:9]=[CH:8]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[O:24][CH3:25].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[N:9]=[C:8]1[C:23]([O:24][CH3:25])=[O:26]
Reactant: COC(=O)Cl
Reactant: COCCCCn1cnc2c1CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCCn1c(C(=O)OC)nc2c1CCCC2
Temperature: -15 °C
Reaction time: 12 h

Procedure:
1-(4-Methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole (625 mg) was dissolved in acetonitrile (5 ml), and the mixture was cooled to −15° C. Triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were added dropwise. The reaction mixture was heated to room temperature and stirred for 12 hr. The reaction mixture was again cooled to −15° C., triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were added dropwise, heated to room temperature and stirred for 12 hr. This operation was further repeated 3 times, aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH:29]=3)[CH:18]=2)[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]2)=[O:38])=[CH:18][C:19]=1[O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:37][O:36][CH2:35]2)[CH:29]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C4COC4)c3)c2)CCC(C(F)(F)F)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(C(F)(F)F)CC2)cc1OCCc1cccc(C2COC2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
77 mg of 1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester were dissolved using 3.5 ml of methanol and 173 μl of a 1M aqueous solution of NaOH added. The mixture was stirred at 60° C. for 8 h. The mixture was then poured into 10 ml of water and acidified to pH=5 using 5% aqueous NaHSO4-solution. The mixture was then extracted three times using 15 ml of EA each. The organic layer was then dried using MgSO4 and evaporated.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]#[N:21])[CH2:16][CH2:15]3)[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1>C(O)C>[OH:2][NH:1][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:9]([C:5]([C:4]([F:23])([F:3])[F:22])=[N:6][N:7]=3)[N:10]=2)[CH2:15][CH2:16]1)=[NH:21]
Reactant: N#CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: NO
Solvent: CCO
Product: N=C(NO)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Hydroxylamine (50% w/v aqueous solution) (0.667 mL, 10.09 mmol) was added to a stirred suspension of 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carbonitrile (2.5 g, 8.41 mmol) in ethanol (16.82 mL) and the suspension was stirred at ambient temperature. Over 20 minutes the starting material largely dissolved and the product began to crystallise. The mixture was stirred for 2 hours and the precipitate was collected by filtration, washed with EtOH followed by ether and dried under vacuum to afford N-hydroxy-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboximidamide (2.410 g, 87%) as a colourless crystalline solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH:8]1[CH2:23][CH2:9]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: Cc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: Cc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.99, 2.08, 2.38, 3.04, 3.25, 4.72, 4.97, 5.45, 7.24–7.31; MS (ESI+) for C17H18BrN3O m/z 362 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[CH:26]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:26][C:17]3[CH:18]=[N:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cnc2ccccc2n1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2cnc3ccccc3n2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 2-quinoxaline-carboxaldehyde in analogy with Example 18. 1H NMR (400 MHz, CDCl3): 8.96 (s, 1H), 8.06-7.98 (m, 2H), 7.72-7.66 (m, 2H), 7.28-7.16 (m, 4H), 7.96-7.92 (m, 1H), 6.42 (s, 1H), 3.85 (s, 2H), 3.48-3.45 (m, 4H), 3.55-3.52 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([CH3:11])[S:8][C:9]=1[CH3:10].O.[NH2:14][NH2:15]>C(O)CCC>[CH3:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([NH:14][NH2:15])=[O:2])[N:6]=1
Reactant: NN
Reactant: COC(=O)Cc1nc(C)sc1C
Solvent: O
Solvent: CCCCO
Product: Cc1nc(CC(=O)NN)c(C)s1
Yield: 68 %

Procedure:
As described for example 112a, (2,5-dimethyl-thiazol-4-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was then heated under reflux for 20 h. Evaporation of all volatiles and crystallization from n-butanol and toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.31 (s, 3H), 2.51 (s, 3H), 3.37 (s, 2H), 4.20 (s, 2H), 9.10 (s, 1H).