Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16](=O)[CH3:17])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21].[CH3:26][O:27][NH2:28]>CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:16][CH:17]=[N:28][O:27][CH3:26])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CON
Reactant: CC=C(C(=O)OC)c1ccc(C(C)=O)c(COc2ccccc2)c1C
Solvent: CO
Product: CC=C(C(=O)OC)c1ccc(CC=NOC)c(COc2ccccc2)c1C
Temperature: 25 °C
Yield: 72.7 %

Procedure:
22 g (67.4 mmol) of methyl α-[2-methyl-4-acetylphenyloxymethylphenyl]-β-methylacrylate and 11.3 g (0.135 mol) of O-methylhydroxylamine hydrochloric were refluxed in 600 ml of methanol for 6 hours. The mixture was allowed to cool to about 25° C., was hydrolyzed and extracted with ice water. The organic phases were washed with water, dried and evaporated down. There was obtained 18 g of the title compound in the form of pale yellow crystals (mp.: 55°-60° C.).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3].C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:35](=[O:34])[CH2:36][OH:37])[CH2:29][CH2:30]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Agent: Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CO)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f17) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2ccccc2)CC1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A solution of aniline (2.0 g, 1.95 mL, 21.475 mmol), N-methyl-4-piperidone (2.64 mL, 21.475 mmol) and AcOH (1.21 mL, 21.475 mmol) in dry 1,2-dichloroethane (20 mL) was treated with NaBH(OAc)3 (6.82 g, 32.213 mmol) at 0° C. The reaction was brought to room temperature and stirred for over night (16 h). The reaction was basified with 1 N NaOH solution (40 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 1-methyl-N-phenylpiperidin-4-amine (4.0 g, 98%) as a solid. 1H NMR (DMSO-d6) δ: 1.29-1.42 (m, 2H), 1.82-1.88 (m, 2H), 1.93-2.02 (m, 2H), 2.15 (s, 3H), 2.68-2.74 (m, 2H), 3.08-3.18 (m, 1H), 5.36 (d, 1H, J=8.1 Hz), 6.47 (t, 1H, J=7.2 Hz), 6.54 (d, 2H, J=7.8 Hz), 7.03 (t, 2H, J=7.2 Hz); ESI-MS (m/z, %) 191 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)[CH:10]=1)[C:5]([OH:7])=O.Cl.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1>O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=3[CH:30]=2)[CH:8]=[C:4]([C:5](=[O:7])[NH:42][C:39]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[CH2:41][CH2:40]2)[CH:3]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(F)cc(C(=O)O)c3)cc12
Agent: Cl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(F)cc(C(=O)NC4(c5ccccn5)CC4)c3)cc12

Procedure:
The product precipitated from the reaction mixture during the coupling of 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (0.068 mmol scale) with 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (TBTU, iPr2NET, DMF, r.t.). The mixture was diluted with 4 ml H2O, the off white solid filtered and washed with 3×2 ml H2O. The solid was further washed with 3×1 ml MeOH and dried. 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.52 (d, J=4.58, 1H), 8.47 (d, J=3.97, 1H), 8.17 (s, 1H), 8.03-8.00 (overlapping m, 3H), 7.83 (overlapping m, 3H), 7.73 (d, 1H), 7.70 (dt overlapping with d, 1H), 7.43-7.40 (overlapping m, 3H), 7.17 (dd, J=6.87, 5.34, 1H), 2.88 (d, J=4.27, 3H), 1.59 (m, 2H), 1.32 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=524.25, HPLC Rt=1.512 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.CN(C)C1C=CN=CC=1>[C:37]([NH:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1)(=[O:39])[CH3:38]
Reactant: C[C@H](NC(=O)c1cnc(N)s1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C(=O)N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (2) (100 mg, 0.24 mmol) and triethylamine (0.07 mL, 0.48 mmol) in anhydrous THF (5 mL), acetyl chloride (0.025 mL, 0.35 mmol) and 4-(dimethylamino)pyridine (2.5 mg, 0.02 mmol) were added and the resulting mixture was stirred at RT for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-acetamido-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (compound 50). ESI-MS m/z: 467.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C@H:15]([CH3:18])[CH2:16][OH:17]>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: C[C@@H](N)CO
Solvent: O
Product: C[C@H](CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and (R)-(-)-2-amino-1-propanol by a procedure analogous to the procedure described in example 1Bb; mp 203°-204° C. (water), 1H-NMR (DMSO-d6): δ 1.11 (d, 3H), 3.4 (d, 2H), 3.78 (m, 1H), 4.95 (br. s, 1H), 7.05 (br. s, 1H), 7.09 (s, 1H), 10.8 (br. s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[CH:10]=1
Reactant: Brc1ccccn1
Reactant: Cc1cc(C)cc(O)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2ccccn2)c1

Procedure:
General procedure A (110° C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 292 μl of 2-bromopyridine (3 mmoles), 244 mg of 3,5-dimethylphenol (2 mmoles), 600 mg of ground and activated 3 Å molecular sieve and 1.2 ml of DMF.
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[O:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1.C(Cl)Cl>[C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([O:21][C:44](=[O:46])[CH3:45])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[NH2:19]
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide (1.01 g, 2.14 mmol) in pyridine (4 mL) was added dimethylaminopyridine (DMAP) (65 mg, 0.533 mmol) and acetic anhydride (0.400 mL, 4.23 mmol). The resulting solution was stirred for 2 hours, then diluted with methylene chloride and washed with 1 M hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (1.16 g, >100%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:13].CCOCC>ClCCl>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[CH3:13]
Reactant: CCOC(=O)CCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To a solution of pyridinium chlorochromate (2.0 g) in dichloromethane (15 ml) was added a solution of 6-hydroxyhexanoic acid ethyl ester (1.0 g) in dichloromethane (1.5 ml) in one portion and stirred for 1.5 hours at ambient temperature. Ether (15 ml) was added to the reaction mixture, and the insoluble material removed by filtration and discarded. The filtrate was purified by silica gel chromatography (diethyl ether) to give 6-oxohexanoic acid ethyl ester (884.6 mg), as a pale green oil.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.O.[NH2:29][NH2:30]>ClCCl>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=[C:2]([NH:29][NH2:30])[C:11]1=[O:12]
Reactant: NN
Reactant: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 3-chloro-1-(2,4-dimethoxybenzyl)benzo[f]quinoxalin-2(1H)-one (900 mg, 2.4 mmol) and hydrazine hydrate (250 μl, 5.1 mmol) in dichloromethane (70 ml) was stirred at room temperature. After 48 h the mixture was evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 800 mg (85%) of the title compound. M.p. 182°-183° C., 1H-NMR (CDCl3): δ 3.80 (s, 3H), 3.85 (s, 3H), 4,15 (br. s, 2H), 5.58 (s, 2H), 6.45 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H), 7.40 (m, 3H), 7.70 (s, 2H), 7.85 (dd, 1H), 8.10 (d, 1H).
Reaction SMILES: [CH:1]1(/[C:7](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8]/[CH:9]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:9]/[CH:8]=[C:7](/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(=C\C=O)C2CCCCC2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C1CCCCC1
Yield: 63.5 %

Procedure:
As in Example 99, (Z)-3-cyclohexyl-3-(4-methoxyphenyl)-2-propenal (7.3 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (11 g) in carbon tetrachloride (40 mL) and dichloromethane (4 mL) overnight at room temperature. The crude ester, isolated in the normal fashion, was purified by HPLC (ether-hexane; 1:7) to yield 5.7 g of (2E,4Z)-5-cylcohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester. A portion was crystallized from hexane to give the analytical specimen, mp 70.5°-72° C.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)CCC.O1CCOCC1>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.[Cu](I)I.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cncs1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.24 g, 1.05 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), copper iodide (0.028 g, 0.15 mmol) and then purged with N2 (g) inlet prior to addition of 5-(tributylstannyl)thiazole (0.63 g, 1.67 mmol), dioxane (2.3 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile (153 mgs, 61%) Retention time (min)=1.715, method [4], MS (ESI) 238.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19]([N:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[S:8]2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6y (84% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and cyclohexyl isocyanate as a white solid. IR(CHCl3) 3289, 1711, 1533 cm−1; 1H-NMR (CDCl3) δ1.20-1.48 (m, 5H), 1.58-1.68 (m, 1H), 1.70-1.80 (m, 2H), 1.92-2.05 (m, 2H), 3.80-3.92 (m, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.92 (d, J=8.3 Hz, 1H), 8.75 (d, J=7.8 Hz, 1H); ESIMS m/e 311 and 313 (M++1, 35Cl and 37Cl).
Reaction SMILES: [CH:1]([O-])([O-])OCC.[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][Si:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>C(O)C>[CH2:19]([O:18][Si:14]([O:21][CH2:22][CH3:23])([O:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][N:7]=[CH:1]1)[CH3:20]
Reactant: CCO[Si](CCCNCCN)(OCC)OCC
Reactant: CCOC([O-])[O-]
Solvent: CCO
Product: CCO[Si](CCCN1C=NCC1)(OCC)OCC

Procedure:
53.2 g of ethyl orthoformate (0.36 mol) is added at +20° C. to 80 g of N-(2-aminoethyl)-3-aminopropyltriethoxysilane (0.3 mol). The temperature of the mixture is brought up to reflux until formation of ethanol is no longer observed. The reaction mixture is then distilled under partial vacuum (2-5 mbar) and the desired product (69.1 g) is recovered (temperature: 130-135° C.)
Reaction SMILES: [CH3:1][C:2]1[C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH2:35][O:36][Si](C)(C)C(C)(C)C)[CH2:26][O:27][Si](C)(C)C(C)(C)C)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:48])[O:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:27][CH2:26][CH:25]([C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][O:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:48])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:24][CH:23]=1)[CH2:35][OH:36]
Reactant: Cc1noc(C)c1OCc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1noc(C)c1OCc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(CO)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 4-(((3,5-dimethylisoxazol-4-yl)oxy)methyl)-N-isobutyl-N-(4-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)phenyl)benzenesulfonamide (214.7 mg, 0.299 mmol) in tetrahydrofuran (THF) (10 mL) was added TBAF (1 M in THF, 0.748 mL, 0.748 mmol), and this was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and extracted to the organic phase of an aqueous workup between ethyl acetate and water/brine. The organic phase was separated (hydrophobic frit), then concentrated in vacuo and purified by flash silica (Si) chromatography (using a 0-100% ethyl acetate-cyclohexane gradient). The product containing fractions were combined and condensed, then freeze-dried to provide 76.4 mg of desired product. LCMS (M+1) 489, RT 1.02 mins.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>CN(C=O)C.O>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
To a mixture of (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.300 g, 0.952 mmol, Example #6, Step C) in DMF (9 mL) was added TEA (0.462 mL, 3.33 mmol) and cyclopropanesulfonyl chloride (0.097 mL, 0.95 mmol). After about 1.5 h at ambient temperature, the reaction was diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the crude material was added MeOH (˜50 mL) and a small amount of insoluble material (<0.01 g) was removed by filtration. Silica gel (2 g) was added to the filtrate and the mixture was concentrated under reduced pressure. The mixture was purified by silica gel chromatography eluting with a step-wise gradient of DCM/MeOH/NH4OH 990:9:1 to 980:18:2 to give an off-white solid that was dried in a vacuum oven at about 70° C. The solid was dissolved in hot MeOH, filtered while hot to remove particulates and then the filtrate was sonicated while cooling to provide a fine suspension which was concentrated under reduced pressure and dried in a vacuum oven at about 100° C. to give N-((1S, 3R)-3-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.21 g, 64%): LC/MS (Table 2, Method a) Rt=1.51 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:35][CH2:36][CH2:37][CH3:38]>>[NH:2]=[C:1]([N:42]1[CH2:43][CH2:44][N:39]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:40][CH2:41]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of n-pentylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=O)=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=[N:34][OH:35])=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=NO)c1ccccc1C
Yield: 47.3 %

Procedure:
A mixture of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (0.49 g), hydroxylamine hydrochloride (0.1 g) and pyridine (0.1 g) in ethanol (10 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×50 mL) and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and filtered and the solvent is removed in vacuo, to give a yellow oil. Flash chromatography on silica gel, eluting with a mixture of petroleum ether (b.p.40-60° C.) and ethyl acetate (7:1 v/v), gives ethyl (RS)-4-(5-benzyloxy-2-hydroxyiminomethylphenoxy)-4-(2-methylphenyl)butanoate (E:Z ratio 4:1), (0.24 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:4]([C:3]1[N:10]=[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:21][CH2:22]3)=[N:15][N:16]2[CH:2]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCCC(=O)CBr
Product: CCCCCc1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to 1-bromoheptan-2-one in place of 1-bromobutan-2-one to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid in 62% yield. 1H NMR (300 MHz, CDCl3) δ 7.71-7.69 (m, 1H), 7.64-7.49 (m, 3H), 7.42 (s, 1H), 7.34-7.32 (m, 1H), 6.7 (d, J=9.9 Hz, 1H), 4.01-3.83 (m, 2H), 3.57-3.48 (m, 2H), 3.37-3.27 (m, 4H), 2.73-2.68 (m, 2H), 1.75-1.65 (m, 2H), 1.4-1.25 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 154.3, 146.8, 135.7, 134.4, 132.3, 129.4, 127.1, 126.8, 126.7, 126.6, 125.4, 125.3, 121.8, 113.6, 109.3, 46.5, 46.4, 46.2, 41.1, 31.5, 29.1, 29.07, 22.5, 14.0. MS (ES+) m/z 446.2 (M+1).