Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:22])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:26][C:27]([OH:29])=[O:28]>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH2:26][C:27]([OH:29])=[O:28])=[N:18][CH:17]=2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 0.08 h

Procedure:
3-Cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 50 mg, 150 μmol) was added to a stirred suspension of NaH (12 mg of a 60% dispersion in mineral oil, 300 μmol) in anhydrous DMF (0.8 mL). After 5 min, a solution of chloroacetic acid (14 mg, 150 μmol) in anhydrous DMF (0.4 mL) was added. The reaction was stirred for 15 min, then more NaH (10 mg of a 60% dispersion in mineral oil, 250 μmol) and chloroacetic acid (14 mg, 150 μmol) were added. After 15 min, the reaction mixture was partitioned between EtOAc (10 mL) and saturated aqueous Na2CO3—H2O (1:1, 15 mL). The aqueous phase was acidified to pH 2.5 with 2M HCl, then the resulting precipitate was extracted into EtOAc (15 mL). The EtOAc solution was washed with brine (5 mL), dried (MgSO4), filtered, concentrated, and recrystallised (CH2Cl2—IH) to give the title compound: RTA=3.52 min; m/z (ES+)=392.2 [M+H]+.
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].[BH3-]C#[N:19].[Na+].O>CO>[NH2:19][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [BH3-]C#N
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(N)CC(=O)OC
Yield: 44.8 %

Procedure:
Dimethyl 3-ketoglutarate (13 g) in methanol (50 ml) was treated with ammonium formate (5 g) and NaCNBH3 (2 g). 10 ml of H2O was added and the excess solvent removed under reduced pressure. The semi-solid was dissolved in 5% aqueous HCl (250 ml), and washed with CH2Cl2 (2×50 ml). The aqueous layer was made basic (pH>9) with K2CO3 and the product was extracted using CH2Cl2 (2×75 ml). The organic layers were combined and dried with Na2SO4. The excess solvent was removed to give 2.5 g of the dimethyl (±)3-aminoglutarate. This was dissolved in methanol (50 ml) and treated with 4N HCl/Dioxane (10 ml). The excess solvent was removed under reduced pressure to give a 2.7 g of dimethyl (±)3-aminoglutarate hydrochloride. MS and 1H-NMR were consistent with the desired product.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: ClCCN1CCCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 1-(2-chloroethyl)-pyrrolidine
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH3:34])[C:8]([C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][N:7]([CH3:34])[C:8]([C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(C)C(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CC(=O)O)C(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 8 from (Z)-3-{1-[3-(N-ethoxycarbonylmethyl-N-methylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone and sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[O:15][CH:16]=[N:17][N:18]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[O:15][CH:16]=[N:17][N:18]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3nnco3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (200 mg) of 5-methansulfonyl-2-([1,3,4]oxadiazol-2-yl)-1H-indole in N,N-dimethylformamide (8 ml), 60% sodium hydride (40 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 5 minutes, followed by addition of 4-fluorobenzyl bromide (215 mg), and the mixture was stirred for 3 hours. To the reaction solution was then added water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 67 mg of the desired product as a white powder.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:33])([F:35])[F:34]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1cc(Cl)c(OC(F)(F)F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (378 mg, 1.58 mmol) and 1,3-dichloro-2-(trifluoromethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (567 mg, 1.74 mmol) in DMF (10 mL) at rt was added TEA (176 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the final desired title compound 5-(5-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (310 mg; 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.91 (s, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 4.46 (d, J=18.4 Hz, 1H), 4.37 (d, J=18.0 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 97.1% at 220 nm and 99.0% at 254 nm; MS: m/z=528.4 (M+, ESI+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C(O)=O)[CH:8]=2)[CH:3]=[CH:2]1.C1C[O:16][CH2:15]C1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O.CO>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:15][OH:16])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
1H-Indole-6-carboxylic acid (1.00 g, 6.23 mmol) was dissolved into anhydrous THF (20 ml) under argon. The solution was cooled in an ice bath and lithium aluminum hydride (13.1 ml of 1M solution in THF, 13.1 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was cooled to 0° C. and ethyl acetate (10 ml) was carefully added, followed by methanol (5 ml) and water (5 ml). The mixture was stirred for 30 min and filtered through celite. The solution was concentrated and dissolved in ethyl acetate (200 ml) and washed with brine (2×100 ml), dried over MgSO4, filtered and concentrated to yield (1H-indol-4-yl)-methanol (471 mg, 52%) as an orange oil: 1H NMR (400 MHz, DMSO-d6) δ 11.04 (bs, 1H), 7.30-7.26 (m, 2H), 7.05-6.98 (m, 2H), 6.48-6.47 (m, 1H), 5.04 (t, J=4.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([NH2:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=O)[C:26]=12)=[O:29])(=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([N:20]3[C:31](=[O:30])[C:26]4[C:27](=[CH:33][CH:34]=[CH:35][C:25]=4[NH:24][C:21](=[O:23])[CH3:22])[C:28]3=[O:29])[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OCC1CC1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OCC1CC1
Yield: 21.2 %

Procedure:
To a solution of 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in acetic acid (10 mL), was added 3-acetamido-phthalic anhydride (1.37 g, 6.7 mmol) and sodium acetate (0.54 g, 6.7 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL×2) and brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give N-{2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (340 mg, 21%): mp 102-104° C.; 1HNMR (CDCl3) δ 0.35-0.37 (m, 2H, c-CH2), 0.62-0.67 (m, 2H, c-CH2), 0.88-0.93 (m, 2H, c-CH2), 1.25-1.32 (m, 1H, c-CH), 2.25 (s, 3H, CH3), 2.87 (s, 3H,CH3), 3.75 (dd, J=4, 15 Hz, 1H, CHH), 3.83-3.85 (m, 5H, OCH2+OCH3), 4.53 (dd, J=10, 15 Hz, 1H, CH2), 5.85 (dd, J=4, 10 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.07-7.10 (m, 2H, Ar), 7.45 (d, J=5 Hz, 1H, Ar), 7.62 (t, J=8 Hz, 1H, Ar), 8.72 (d, J=8 Hz, 1H, Ar), 9.45 (s, 1H, NHCO); 13C NMR (CDCl3) δ 1.6, 3.2, 3.3, 24.7, 41.4, 48.3, 54,2, 55.8, 73.9, 111.5, 113.1, 115.0, 118.0, 120.3, 124.7, 129.1, 130.9, 135.9, 137.2, 148.6, 149.8, 167.2, 169.0, 169.3. Analy. Calculated for C24H26N2O7S: C 59.25; H 5.39; N 5.76. Found: C 59.00; H 5.36; N 5.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.C(OC(=O)C)C>CN(C)C=O>[Br:24][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(c2ccc(Br)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
N,N-bis(4-methoxyphenyl)aniline 1 (9.0 g, 29.5 mmol) was dissolved in 100 mL dimethylformamide in a 250 mL round bottom flask. N-bromosuccinimide (5.25 g, 29.5 mmol) was dissolved in 30 mL dimethylformamide and added dropwise to the reaction mixture. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography (TLC) (Reaction Time=23 h). The reaction mixture was quenched using 600 mL water and extracted with 4×150 mL dichloromethane. The organic layers were combined and washed with 4×150 mL saturated sodium thiosulfate solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified along with materials prepared previously using flash chromatography on silica gel eluting with 5:1 hexanes:ethylacetate (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 4H), 6.90 (d, J=9.0 Hz, 4H), 6.73 (d, J=9.0 Hz, 2H), 3.77 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][O:24]1>>[OH:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:22][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC1(c2ccccc2)CO1
Product: CC(O)(CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O)c1ccccc1

Procedure:
Compound 177 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-methyl-2-phenyloxirane and conditions outlined in general procedure X. M.p.=117° C. (dec); 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8 Hz, 1H), 7.77 (d, J=4 Hz, 2H), 7.56 (d, J=4 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.30 (t, J=7.2 Hz, 2H), 7.19 (t, J=7.2 Hz, 1H), 4.84 (bs, 1H), 3.05 (s, 2H), 2.72-2.34 (m, 2H), 1.96-1.83 (m, 4H), 1.80-1.57 (m, 4H), 1.47 (s, 3H). LCMS: 436 [M+H].
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:13]CC(C1C=C(CC)C=CN=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CCc1ccnc(C(C)=O)c1F
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CCc1ccnc(C(=O)CBr)c1F

Procedure:
The title compound was prepared from 2-acetyl-4-ethyl-3-fluoropyridine according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CCOCC1

Procedure:
The 4-(3-hydroxypropyl)morpholine (Aldrich, 0.18 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[CH3:15][S:16]([O:5][CH:3]1[CH2:4][N:1]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Azetidin-3-ol (3.3 g) and DIPEA (20 mL) are dissolved in dry tetrahydrofuran (40 mL). After 30 min the reaction mixture is cooled to 0° C. and methanesulfonyl chloride (10.9 g) is added dropwise. After stirring for 2 hours at ambient temperature, the mixture is concentrated under vacuum, partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. Chromatography of the residue on silica gel (cyclohexane/ethyl acetate 70:30) gives the title compound. Yield: 5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:12]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:11][C:10]([Cl:27])=[CH:9][N:8]=2)[CH:6]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C:12]2[C:7]([N:5]3[CH:6]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[CH:3]=[N:4]3)=[N:8][CH:9]=[C:10]([Cl:27])[CH:11]=2)(=[O:15])=[O:16])=[CH:18][CH:19]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(N)cn2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[2-(4-amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (20 mg, 0.049 mmol), acetyl chloride (3.5 μL, 0.049 mmol), and triethylamine (14 μL, 0.099 mmol) were stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, followed by the addition of dichloromethane (1 mL) and tetrabutylammonium fluoride (0.4 mL, 1.0 M in THF). The reaction was stirred for 2 hours at room temperature and then the crude mixture was partitioned with saturated sodium bicarbonate. The aqueous phase was subsequently extracted with dichloromethane and the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% ethyl acetate in hexanes) to afford N-{1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazol-4-yl}-acetamide: MS (ES) M+H expected 448.1, found 448.0.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=1.CN(C)C=O>C(N(CC)CC)C>[C:7]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A mixture comprising 5 g of triphenylchloromethane and 15 ml of dichloromethane was added dropwise at -30° C. to a mixture comprising 3.1 g of ethyl 2-aminothiazole-4-carboxylate, 25 ml of dimethylformamide and 1.8 g of triethylamine. The reaction mixture was maintained at -30° C. for 10 minutes and was then stirred at room temperature for 2 hours. after which it was poured into ice water and extracted with ethyl acetate. The extract was washed successively with 0.1N hydrochloric acid and aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel chromatography, using as eluent a 10:1 by volume mixture of benzene and ethyl acetate. The crystals obtained thereby were washed with n-hexane, to afford the desired compound as a white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.C[O-].[Na+]>[Ni].CO>[NH:6]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][NH:14][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CNc1ncccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNc2ncccc2CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
Raney nickel (3 g) was added to anhydrous methanol (50 mL) under argon and washed with anhydrous methanol (4×50 mL). (3-Cyanopyridin-2-ylamino)-acetic acid ethyl ester (3.35 g, 16.3 mmol) was dissolved in methanol (50 mL) and added to the Raney nickel slurry. The reaction vessel was purged with argon for 10 min. Sodium methoxide solution (16.3 mmol, 3.75 mL) was added and the argon purge was repeated (5 min). The reaction flask was charged with H2 and stirred at room temperature for 48 h. Dilute HCl (16.3 mL of a 1 M solution) was added and the flask was purged with argon for 30 min. The slurry was filtered through celite and the filter cake was washed with 1:1 methanol/water. The filtrate was concentrated and extracted with ethyl acetate (4×100 mL), dried over MgSO4 and concentrated to afford the title compound as a beige solid (850 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (t, J=5.2 Hz, 1H), 7.82 (dd, J=4.9, 1.5 Hz, 1H), 7.21 (dd, J=7.1, 1.6 Hz, 1H), 6.69 (t, J=5.0 Hz, 1H), 6.43 (dd, J=7.2, 5.0 Hz, 1H), 4.24 (d, J=5.9 Hz, 2H), 3.91 (d, J=5.1 Hz, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:32][CH2:33][N:34]([C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=4)[N:16]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(C2(O)CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
DIPEA (1.174 mL, 6.74 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol) and 4-(4-hydroxyphenyl)piperidin-4-ol (0.955 g, 4.94 mmol) in DMF (10 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. The residues were triturated with water and the resulting solid collected by filtration, washed with further water followed by ether, then dried under vacuum to afford 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (1.680 g, 99%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[I-].[Na+]>>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCI
Reactant: O=Cc1cccc(O)c1
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCOc1cccc(C=O)c1
Yield: 92.6 %

Procedure:
The compound was synthesized as in Example 24.1, using 3-hydroxybenzaldehyde (200 mg, 1.64 mmol) in place of 4-hydroxybenzaldehyde and 1-iodo-3-methylbutane (649 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 3-(isopentyloxy)benzaldehyde (292 mg, quant. crude) as a dark yellow oil that was used without further purification or characterization.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>CN(C=O)C>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][C:18](=[O:26])[CH2:19]2)=[O:12])([O-:7])=[O:6]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3 L, 3 necked round bottomed flask equipped with a mechanical stirrer, thermocouple and was charged with AlCl3 (256 g, 1.92 mol). The solids were cooled to 0° C. with an ice-H2O bath. DMF (42 ml) was added dropwise over a period of 35 min. The temperature was stirred at 0° C. for 2 h then was warmed to room temperature. The reaction mixture was treated with 3-Nitrobenzoyl chloride (37.3 g, 0.2 mol) and the resulting slurry was heated to 41° C. Subsequently, oxindole (25 g, 0.19 mol) was added over a period of 10 min. The reaction that ensued was exothermic and caused the internal reaction temperature to rise to 60° C. The reaction was heated at 90° C. for 3.5 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 1:1) indicated completion of reaction. The reaction was cooled and ice-H2O (1.5 L) was added dropwise over a period of 1.5 h. The solids were filtered, washed with saturated NaHCO3(aq) (2×300 mL), H2O (300 mL) and Methyl-t-Butyl Ether (500 mL) to yield 5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one in quantitative yield (53.63 g, 0.19 mol).