Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:40]=[C:39]([C:41]2[CH:45]=[CH:44][NH:43][N:42]=2)[CH:38]=[C:37]([F:46])[C:34]=1[C:35]#[N:36].CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>CCOC(C)=O.C(Cl)Cl.O>[NH2:5][C@@H:3]([CH3:4])[CH2:2][N:43]1[CH:44]=[CH:45][C:41]([C:39]2[CH:38]=[C:37]([F:46])[C:34]([C:35]#[N:36])=[C:33]([Cl:32])[CH:40]=2)=[N:42]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
(S)-tert-Butyl (1-hydroxypropan-2-yl)carbamate (259 mmol, 45.4 g) and triphenylphosphine (259 mmol, 68.0 g) were mixed in dry EtOAc (380 ml) under nitrogen atmosphere. 2-Chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (130 mmol, 35.9 g) was added and the resulting mixture was stirred for 10 min. DIAD (259 mmol, 52.4 g) was added slowly while keeping the temperature between 15-25° C. with an ice bath. After the addition the mixture was allowed to warm to RT and stirred for 4 h. Water and concentrated HCl (1296 mmol, 106 ml) was added to the mixture and stirred for 6 days during which more HCl (107 ml in total) was added. Water and DCM was added and the mixture was stirred for a while before separating the phases. The organic phase was extracted twice with water. The water phases were combined and washed twice with DCM. DCM was added to the water phase and the pH of the water phase was adjusted to 12.5 with 50% NaOH. The phases were separated and the water phase was extracted once more with DCM. The DCM phases were combined and washed once with water. The separated DCM phase was evaporated and dried under vacuum. 24.0 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 0.96 (d, 3H), 1.18 (bs, 2H), 3.19-3.29 (m, 1H), 3.97-4.08 (m, 2H), 7.03 (d, 1H), 7.85-7.92 (m, 2H), 7.98-8.02 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[C:16]([F:23])[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[C:16]([F:23])[CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Fc1cc(Br)ccc1Nc1nc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][CH2:20][NH2:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][CH2:20][NH:21][C:35](=[O:37])[CH3:36])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Product: Cl
Reaction time: 24 h
Yield: 71.9 %

Procedure:
3-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-propylamine (50 mg, 0.139 mmol) and Diisopropylethyl amine (26.9 mg, 0.208 mmol) were taken into dichloromethane (2 ml). Acetic Anhydride (0.016 mL, 0.166 mmol) was then added to the reaction mixture. The reaction was left at room temperature for 24 h. The mixture was then partitioned between sodium bicarbonate (aq) and dichloromethane. The aqueous layer was washed with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude compound was purified by flash silica chromatography (40:1 silica ratio, eluted with 5% methanol in dichloromethane, followed by 10% methanol in dichloromethane). The pure product was then taken into 4M HCl in dioxane and left at room temperature for 3 h. The mixture was concentrated to dryness under vacuum to yield the title product (22 mg, 0.05 mmol, 36%); LCMS; m/z 404 (m+1 of free amine); 1H NMR (400 MHz, DMSO-d6) δ 1.8-2.05 (m, 7H), 2.20-2.27 (m, 1H), 3.07-3.18 (m, 3H), 3.43-3.52 (m, 1H), 3.54-3.57 (m, 1H), 4.28-4.38 (m, 2H), 4.88 (s, 3H), 6.93-6.96 (m, 2H), 7.06 (s, 4H), 7.39-7.41 (m, 2H), 8.06 (m, 1H)
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[NH2:11]>C(#N)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[N+:11]#[N:6]
Reactant: N#[O+]
Reactant: Nc1cc(F)ccc1Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: N#[N+]c1cc(F)ccc1Cl
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate (802 mg, 6.87 mmol) was added to a solution of 2-chloro-5-fluoroaniline (1.00 g, 6.87 mmol) in acetonitrile (50 mL) at 0° C. The resulting mixture was stirred for 1 hour, then diluted with ethyl ether (150 mL). The precipitate was filtered and air-dried to give 2-chloro-5-fluorobenzenediazonium tetrafluoroborate (1-1) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.66 (ddd, 1H, J=6.7, 2.1, 1.0 Hz), 8.16 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.CCCCCC.C[O:20][C:21]([C:23]1[C:28]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=1)=O>O1CCOCC1>[C:33]([O:32][C:30](=[O:31])[NH:29][C:28]1[C:23]([C:21](=[O:20])[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[N:24][C:25]([CH3:37])=[CH:26][CH:27]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Nc1ccnc(Cl)c1
Reactant: COC(=O)c1nc(C)ccc1NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)Nc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 2-chloro-4-aminopyridine (0.97 g, 7.5 mmol, 4.0 equiv.) in dry dioxane (20.0 ml) were added 3.75 ml of a 2M solution of trimethyl aluminium in hexane (7.5 mmol, 4.0 equiv.) and the mixture was stirred for 1 h at r.t.. Then 3-tert-Butoxycarbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester (0.50 g, 1.88 mmol) were added and the reaction was refluxed for 2 h. After allowing the reaction to cool to r.t., the reaction was quenched with water (0.5 ml), stirred for 5 min, dried by addition of magnesium sulfate and filtered over Dicalite which was further washed with methylene chloride. The filtrate was concentrated in vaccuo. The residue was purified by flash chromatography (heptane/ethyl acetate 2:1) to yield the title compound as a white solid (total 0.50 g, 73%), MS (ISP): m/e=363.1, 365.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:6][C@@H:5]2[NH2:17].[O:18]1[CH2:20][C@@H:19]1[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:16])([C:12]([F:14])([F:13])[F:15])[CH2:6][C@@H:5]2[NH:17][CH2:20][C@@H:19]([OH:18])[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:7]([OH:18])([C:12]([F:15])([F:14])[F:13])=[O:8]
Reactant: CC1(C(F)(F)F)C[C@H](N)c2cc(Br)ccc2O1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN[C@H]1CC(C)(C(F)(F)F)Oc2ccc(Br)cc21
Product: O=C(O)C(F)(F)F

Procedure:
A mixture of (4S)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine (179 mg, 577 μmol) and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (198 mg, 750 μmol) in ethanol was heated at reflux for 16 h. At this point, there was still the starting amine left. An additional 1.3 eq of epoxide was added to the reaction, and continued to reflux for 6 h. The resulted mixture was concentrated and purified on Shimadzu HPLC to afford the title compound as a TFA salt. MS m/z: 573, 575.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([O:24][CH2:23][C:22]1[C:17]([N:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:16])=[N:18][CH:19]=[CH:20][C:21]=1[Cl:25])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3CO)ncc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-tert-butyl-2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-8-fluorophthalazin-1(2H)-one 104a (150 mg, 0.42 mmol) and triethylamine, Et3N (0.12 mL, 0.84 mmol) in tetrahydrofuran, THF (2.5 mL) was added acetyl chloride, AcCl (44 μl, 0.62 mmol). The mixture was stirred at rt for 1 h and quenched with water, extracted with ethylacetate, EA. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 104b (160 mg) as a colorless oil. MS-ESI: [M+H]+ 404.1
Reaction SMILES: CN(C=O)C.P(Cl)(Cl)([Cl:8])=O.[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[NH:16][C:17](=O)[S:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([Cl:8])[S:18][C:14]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc2ccc(Br)cc2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
DMF (0.807 mL, 10.4 mmol) was added to phosphorous oxychloride (8.10 mL, 86.9 mmol), and the reaction mixture was stirred for 15 min. 6-bromobenzo[d]thiazol-2(3H)-one (2.00 g, 8.69 mmol) was added and the reaction mixture was heated to 100° C. overnight. Upon cooling to rt, the reaction mixture was slowly added to a solution of K2CO3 (75 g) in water (200 mL) while maintaining the temperature below 35° C. Additional K2CO3 was added in order to maintain the pH above 10. Upon complete addition, the mixture was allowed to stir for 1 h. The solid was collected by filtration, washed with water (2×25 mL), and air dried. Further drying in a vacuum oven gave 2.06 g (95%) of the desired product as a brown solid. The material was used without further purification. LC-MS: RT=9.94 min., compound does not ionize.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1OC1C>C(COC)OC>[Br:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([Cl:12])=[CH:11][C:2]3[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Cl)c2ccc(Br)cc2n1
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g of 2-amino-7-bromo-4-chloroquinoline was suspended in 10 ml of dimethoxyethane and then a solution of 1 g of ethyl bromopyruvate and 300 mg of propylene oxide in 10 ml of dimethoxyethane was added. The mixture was stirred at room temperature for 2 days and 300 mg of ethyl bromopyruvate were then added. Stirring was continued for a further day and the precipitated quaternary salt was filtered off, washed with ether and then was suspended in 20 ml of ethanol. The mixture was heated at reflux for 2 hours and the solvent was removed under vacuum. The residue was partitioned between CHCl3 /Na2CO3 solution and the organic solution was dried over MgSO4 and the solvent was removed to leave a cream solid. This was purified by chromatography over silica with 5% methanol in chloroform as eluent and the product was crystallized from chloroform/ether to obtain pale cream needles of ethyl 8-bromo-5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 206° to 207° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: COC(=O)[C@H]1C[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 85 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (2.10 g, 7.51 mmol), trans-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (1.11 g, 8.53 mmol), and PS-PPh3 (loading 2.21 mmol/g; 6.80 g, 15.0 mmol) in dry THF (80 mL), cooled by ice/water, was added DIAD (2.20 mL, 2.26 g, 11.2 mmol), then the cooling bath was removed, and the mixture was vortexed (150 rpm) overnight. The resin was filtered off and washed thoroughly with THF (≈400 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-16)→5% EtOAc in CH2Cl2 (17-40)]. Fractions 3-32 were combined, concentrated, and suspended in iPrOH (10 mL). The suspension was heated to 85° C. for 20 min and cooled to −20° C. for 2 h, the solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo. One obtained the title compound as white solid. Analytically pure material with cis/trans=50:1 had a melting point of 168-169° C. 1H NMR (CDCl3, 400 MHz): δ=2.66-2.78 (m, 2H), 2.81-2.93 (m, 2H), 3.06 (quint, J=8.7 Hz, 1H), 3.76 (s, 3H), 5.32 (quint, J=8.7 Hz, 1H), 7.68 (s, 1H), 8.60 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=30.93 (+), 34.09 (2C, −), 44.65 (+), 51.58 (Cquart), 52.19 (+), 117.07 (Cquart), 131.87 (+), 150.48 (Cquart), 150.72 (+), 152.69 (Cquart), 174.31 (Cquart). MS (ES+): m/z 391.9/393.9 (100/38) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min). C12H11ClIN3O2 (391.60): C: calc. 36.81. found 36.88/36.78; H: calc. 2.83. found 2.81/2.76; N: calc. 10.73. found 10.59/10.50.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:17]1(=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of triethyl phosphono acetate (35.2 g) in 100 mL THF, at 0° C., was added slowly via a syringe a solution of NaH (6.2 g) in 60 mL THF. The mixture was stirred at 0° C. for 10 minutes, cyclobutanone (10 g) was added by a syringe, and the resulting mixture was stirred at room temperature for 2 hours, followed by addition of distilled water to quench the reaction. The aqueous solution was extracted by ethyl acetate (3×20 mL), the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude residue was eluted by column chromatography (10% ethyl acetate/hexane), to give ethyl 2-cyclobutylideneacetate (20 g). 1HNMR (300 MHz, CDCl3) δ=5.57 (s, 1H), 4.13 (q, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 2.08(m, 2H), 1.26 (t) ppm. MS: m/z 370 (100, M+H)+
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH:8]([OH:9])[CH2:7][C:6]3([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]3)[N:5]2[CH3:16])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH2:2]1[O:3][C:4]2([CH:8]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][C:6]3([CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)[N:5]2[CH3:16])[O:17][CH2:1]1
Reactant: CN1C2(CCC(=O)CC2)CC(O)C12OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2

Procedure:
To a mixture of 3-Hydroxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.0 g), triethylamine (1.73 mL) and methylene chloride (10 mL) was added methanesulfonyl chloride (950 mg) dissolved in methylene chloride (5 mL) in a dropwise fashion at 0° C. After 30 min the reaction mixture was washed with water, the organic layer dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was filtered through silica gel with ethyl acetate as the eluent to afford 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#N)[CH:26]=2)(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.O1CCOCC1.[OH-:39].[Na+].Cl.C[OH:43]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[C:31]([OH:43])=[O:39])(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C#N)c2)c1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)O)c2)c1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 94 %

Procedure:
To a solution of N-(3-{[2-chloro-5-(methoxy)-phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide (6.02 g, 12.95 mmol), prepared using procedures similar to those in Example 115 or Example 423, in methanol (20 mL) and 1,4-dioxane (20 mL) was added 6.0 N aqueous sodium hydroxide (40 mL) at room temperature. The solution was stirred at 90° C. for 3.5 h. The reaction was cooled to room temperature and neutralized slowly by adding 2.0 N hydrochloric acid until the pH of the solution became in the 2-3 range at 0° C. The solution was diluted with ethyl acetate (300 mL). The organic layer was washed with saturated aqueous sodium chloride (50 mL) and dried over magnesium sulfate. Filtration and concentration at reduced pressure afforded 3-{[(3-{[2-chloro-5-(methoxy)-phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoic acid (5.921 g, 94%). MS (EI) m/z for C22H17ClN4O5S: 485.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:33]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:37][CH:36]=2)=[O:34])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCCCC3)cc2)cc1
Yield: 35 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]benzoic acid hydrochloride in 35% yield as an oil following radial chromatography (SiO2; gradient of 1-10% isopropanol in CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=2)[C:5]([C:16]#[N:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g (3.96 mmol) of 2-amino-4-phenyl-6-sulfanylpyridine-3,5-dicarbonitrile (Example 30A), 0.96 g (4.36 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 1.33 g (15.84 mmol) of sodium bicarbonate were dissolved in 20 ml of DMF and the mixture was stirred at RT for 2 h. 500 ml of water were added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:11][C:12]#[N:13].[Na+].C1(N2CC(=O)NN2)C=CC=CC=1.[Cl-].[Na+]>O.C(O)(=O)C.C(O)(C)(C)C>[CH3:10][CH:9]1[NH:13][C:12](=[O:11])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8]1
Reactant: N#C[O-]
Reactant: CC=NNc1ccccc1
Agent: O=C1CN(c2ccccc2)NN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)(C)O
Product: CC1NC(=O)N(c2ccccc2)N1
Temperature: 5 °C

Procedure:
A 500 gallon reactor is charged with 61.1 pounds of tert-butanol (88/12 azeotrope with water) which is stirred and cooled to 5° C. To this is added 22.0 pounds (0.203 lb-mole) of acetaldehyde phenylhydrazone. While maintaining the temperature of the reaction mixture at 0° to 5° C., 15.6 pounds (0.240 lb-mole) of 85% pure sodium cyanate in 44.5 pounds of water is added during a five-minute period. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period. While maintaining the reaction mixture at about 10° C., 14.8 pounds (0.247 lb-mole) of acetic acid is added during about a 30-45 minute period. Upon completion of the addition, the reaction mixture is stirred for three hours at about 10° C. until the reaction is complete. The reaction endpoint and the concentration of the phenyltriazolidinone intermediate are determined by gas chromatograph. At the end of this time, a solution of 12.6 pounds of sodium chloride in 35.8 pounds of water is stirred into the reaction mixture. The aqueous phase is separated when the reaction mixture temperature is about 15° C. After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C. The residue is cooled to 0° C., and a solid is collected by filtration. The solid is dried at 80° C./5 mm Hg for 24 hours to yield 3-methyl-1-phenyl-1,2,4-triazolidin-5-one.