Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:19](C)=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([NH:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:12]([CH3:13])[N:11]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1COCC1CC1
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.06 g) and 3-chloro-6-methyl-benzenesulfonyl chloride (0.072 g) as a light yellow solid (0.07 g). MS (ESI−): 364.9 ([M−H] )
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O[C:5](=O)[C:4]=1[C:15]([O:17][CH3:18])=[O:16].[C:19]1([N:25]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30]C3=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)[C:5]=2[C:4]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1c(SC)cc(-c2cccs2)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2cccs2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(thiophen-2-yl)-2H-pyran-3-carboxylate (282 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 6 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 211 mg of (49%) of methyl 8-(methylthio)-2-phenyl-6-(thiophen-2-yl)-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CI.[C:40](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:40][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (205 mg) was dissolved in dimethylformamide (5 ml), methyl iodide (75 μl) and cesium carbonate (391 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (184 mg).
Reaction SMILES: C(O[C:6]([N:8]1CC[CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][N:19]([CH2:25][C:26]([OH:28])=[O:27])[C:18]3=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>O1CCOCC1>[ClH:30].[O:29]=[C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:11]3[CH2:10][CH2:9][NH:8][CH2:6][CH2:12]3)[CH:16]=2)[N:21]=[CH:20][N:19]1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3ncn(CC(=O)O)c(=O)c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cn1cnc2ccc(N3CCNCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(3-Carboxymethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (9.8 g) was suspended in 20 mL of dioxane. To this suspension was added 4N HCl/dioxane solution (100 mL) and 20 mL of dioxane; the mixture was stirred at room temperature for 3 hours. At this time, the solvent was removed by concentration of the reaction mixture in vacuo, and to the residue was added tetrahydofuran. The mixture was again concentrated in vacuo. The residue was triturated with dry diethyl ether, filtered and washed with dry diethyl ether. In this manner, 14.74 g of a solid was obtained. This solid was used without further purification.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH3:30])[CH:24]=[C:23]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:22]=1[C:41](=[O:43])[CH3:42]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH3:30])[CH:24]=[C:23]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:22]=1[C:41](=[O:43])[CH2:42][C:8](=[O:10])[C:7]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1c(OCOC)cc(OCOC)cc1Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of sodium tert-butoxide (31.5 g, 328 mmol) and diethyl oxalate (60.5 mL, 3 eq.) in THF (250 mL) was slowly added dropwise a solution of 1-[2,4-bis(methoxymethoxy)-6-(4-nitrophenoxy)phenyl]ethanone (56 g, 149 mmol) in THF (350 mL) at −5° C. After stirring for 1 hour at this temperature, the resulting solution was stirred for further 3 hours at room temperature. The solution was then taken up in 10% citric acid solution (2000 mL) and thoroughly extracted with ethyl acetate. After washing with brine and drying over Na2SO4, the solvent was removed to provide a yellowish residue that was taken up in light petrol ether to remove the excess of diethyl oxalate to afford the quite pure title compound (58 g, 81% yield).
Reaction SMILES: Cl[C:2]1[C:3]([CH:16]=O)=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]2[S:20][C:19]([C:18]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1c(Cl)cncc1OCc1ccccc1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(OCc3ccccc3)cncc2s1
Temperature: 25 °C
Yield: 55 %

Procedure:
To an ice cold solution of Example 236B (4.2 g, 17 mmol) in anhydrous tetrahydrofuran (42 mL) under nitrogen atmosphere was added methyl thioglycolate (1.83 mL, 20.4 mmol) followed by powdered cesium carbonate (6.65 g, 20.4 mmol). Then the reaction mixture was allowed to warm to room temperature with stirring under nitrogen. After 30 minutes the reaction was refluxed for 15 minutes and cooled to room temperature. The reaction mixture was quenched with ice (50 mL) and partitioned with ethyl acetate (250 mL). The organic layer separated was washed with an ice cold solution of saturated NaCl (3×60 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the crude product which was recrystallized from methanol. The mother liquor was purified by flash chromatography on silica gel eluting with 7% acetone-hexane. The combined fractions gave the title compound in 55% yield (3.07 g). MS (APCI) m/e: 300 (M+H)+; 1H NMR (300 MHz, DMSO-d6) d: 3.92 (s, 3H), 5.42 (s, 2H), 7.35-7.47 (m, 3H), 7.52-7.57 (m, 2H, Ar—CH), 8.12 (s, 1H,), 8.36 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH:18]([CH3:21])[CH:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:20])[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: CC(C=O)c1ccccc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(=O)N(O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (30 mg, 0.2 mmol) was added under argon to a solution of 2-phenylpropanal (134 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (72.8 mg, 0.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:34][C:35]([NH2:37])=[O:36].[I-].[Na+]>C(#N)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]([N:27]5[CH2:32][CH2:31][N:30]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:29][CH2:28]5)[CH:24]=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: NC(=O)CCl
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCNCC5)c4)nc23)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCN(CC(N)=O)CC5)c4)nc23)cc1
Temperature: 70 °C

Procedure:
A suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine (100.0 mg, 0.2229 mmol), 2-chloroacetamide (23.0 mg, 0.246 mmol) and sodium iodide (3.0 mg, 0.020 mmol) in acetonitrile (2 mL) was stirred and heated at 70° C. for 6 hours. The suspension was cooled to room temperature, diluted with water (30 mL). The precipitate was filtered and rinsed with water. The recovered yellow solid was triturated with methanol (5 mL), filtered and placed under high vacuum overnight. 2-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-acetamide and was isolated as a yellow solid (0.075 g, 67%). MP=271-275° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.86 (d, J=6.5 Hz, 1H), 8.43 (d, J=7.5 Hz, 2H), 8.06 (d, J=7.6 Hz, 2H), 7.96 (d, J=7.5 Hz, 1H), 7.53 (s, 1H), 7.26-7.06 (m, 5H), 6.50 (d, J=6.5 Hz, 1H), 3.29 (s, 3H), 3.20-3.15 (m, 4H), 2.93 (s, 2H), 2.64-2.58 (m, 4H). MS=506 (MH)+.
Reaction SMILES: COC1C=CC(CN[C@H](CC(C)C)C(N)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>CO.[Pd]>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]([C@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C)CC(C(N)=O)N(Cc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(2R)-(2-[N-(4-Chlorobenzenesulfonyl)-N-(4-nitrobenzyl)amino]-4-methylpentanoic acid amide (Compound of Example 24; prepared as described in Reaction Scheme 1; 2.8 g, 6.6 mmol) was suspended with 10% Pd/C (1 g) and conc. HCl (1 mL) in MeOH (100 mL) and placed under a hydrogen atmosphere at 40 psi for 1 h. The suspension was filtered through Celite and then concentrated to give the title compound as a tan solid (2.4 g, 88% yield). MS (ESI), (M+H)+ 410.1; 1H NMR (CDCl3) δ 7.80 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.5), 7.52 (br s, 1H), 7.46 (d, 1H, J=8.0), 7.26 (d, 1H, J=8.0), 7.02 (br s, 1H), 4.70 (dd, 2H, J=50, 18), 4.30-4.41 (m, 1H), 3.67 (br s, 2H), 1.28-1.33 (m, 3H), 0.86 (d, 3H, J=7.0), 0.57 (d, 3H, J=7.0).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([N:32]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.6 g) was dissolved in 4 mL dry THF and 1247 mg triphenylphosphine and 650 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 933 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 1.8 g desired product after drying. 1H NMR (400 MHz, acetone-d6): 8.35 (m, 2H), 7.96 (m, 2H), 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.42 (m, 3H), 7.29 (m, 5H), 7.10 (m, 2H), 6.88-6.80 (m, 3H), 5.21 (s, 2H), 5.11 (m, 1H), 4.82 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.49 (m, 1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 0.77 (t, 3H).
Reaction SMILES: Cl.[CH:2]1([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH2:6])[CH2:4][CH2:3]1.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].C(N=C=NCCCN(C)C)C>ClCCl>[CH:2]1([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:6][C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]2=[O:13])[CH2:3][CH2:4]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC(c1ccccc1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC(c1ccccc1)C1CC1
Reaction time: 8 h

Procedure:
A solution of cyclopropyl(phenyl)methanamine hydrogen chloride (0.050 g, 0.272 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.073 g, 0.247 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.066 mL, 0.371 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.39 (m, 13H), 7.14-7.18 (m, 2H), 6.44 (d, J=8.1 Hz, 1H), 4.32 (t, J=8.6 Hz, 1H), 4.05 (d, J=15.3 Hz, 1H), 4.03 (d, J=15.6 Hz, 1H), 3.42-3.56 (m, 2H), 2.73-2.88 (m, 2H), 0.81-0.97 (m, 1H), 0.39-0.56 (m, 2H), 0.21-0.37 (m, 2H); MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:27](O)([CH3:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([O:18][CH:27]([CH3:29])[CH3:28])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-benzyloxy-2-nitrophenylacetic acid (4.0 g) and conc. sulphuric acid (0.6 ml) in isopropyl alcohol (40 ml) was stirred under reflux for 1 day. After removal of solvent by evaporation, the resulting residue was dissolved with ethyl acetate. The ethyl acetate extract was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure to give isopropyl 5-benzyloxy-2-nitrophenylacetate (4.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (639 mg, 2.00 mmol, Eq: 1.00) and oxetan-3-one (288 mg, 4.00 mmol, Eq: 2.0) in THF (10 ml) was added acetic acid (360 mg, 343 μl, 5.99 mmol, Eq: 3.0). The reaction mixture stirred under N2, at 55° C. for 1 h. Then sodium triacetoxyborohydride (847 mg, 4.00 mmol, Eq: 2.0) was added and the mixture was stirred at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and saturated NaHCO3. The layers were separated and the organic layer was washed with water. The organic layer was then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 40% (60:10:1 DCM:MeOH:NH4OH)/DCM) gradient) to give 6-chloro-2-methyl-4-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-2H-pyridazin-3-one (453 mg, 60%). LC/MS-ESI observed [M+H]+ 376. 1H NMR in CDCl3 is consistent with desired product.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[N:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:6]=1[F:20]>C1COCC1>[Br:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]([NH:10][S:11]([C:14]([CH3:16])([CH3:17])[CH3:15])(=[O:13])=[O:12])[CH3:1])=[CH:7][C:6]=1[F:20]
Reactant: CC(C)(C)S(=O)(=O)N=Cc1ccc(Br)c(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(NS(=O)(=O)C(C)(C)C)c1ccc(Br)c(F)c1
Reaction time: 2 h

Procedure:
Under inert gas atmosphere 37.2 mL (112 mmol) of a 3N solution of methyl magnesium bromide in THF are added dropwise to 17.1 g (55.8 mmol) 2-methyl-propane-2-sulfonic acid 4-bromo-3-fluoro-benzylideneamide (IX.1) in 170 mL THF at −78° C. The cooling bath is removed and stirring is continued for 2 h. After that time, the mixture is poured into sat. NH4Cl-solution (300 mL) and extracted with EtOAc. The organic layer is separated, washed with brine and dried over sodium sulphate. The solvent is removed by evaporation to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]#[C:12][Si](C)(C)C)=[C:9]([NH:17]C(=O)C)[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[C:22]=2[F:30])[N:6]=1)=[O:4].C(Cl)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]#[CH:12])=[C:9]([NH2:17])[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[C:22]=2[F:30])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C#C[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)Cl
Product: C#Cc1c(N)cc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-trimethylsilanylethynylpyridine-2-carboxylic acid methyl ester (0.196 g, 0.437 mmol) was suspended in methanol (4.36 mL) and acetyl chloride (0.310 mL, 4.37 mmol) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated to dryness. The residue was dissolved in methanol (4.36 mL) and potassium carbonate (0.121 g, 0.873 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h, acidified with 2N HCl, and concentrated but not to dryness. The residue was partitioned between ethyl acetate and sodium bicarbonate; and the organic phase was dried and concentrated. The resulting product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.109 g, 74.6% yield) as a yellow solid, mp 167-169° C.: 1H NMR (CDCl3) δ 7.7 (m, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 5.08 (br s, 2H), 3.99 (s, 3H), 3.97 (d, 3H), 3.84 (s, 1H).