Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[I:23]N1C(=O)CCC1=O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([I:23])=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2I)CC1
Temperature: 25 °C

Procedure:
A solution of 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (160.0 g, 444.4 mmol) in methylene chloride (2.5 L) was purged under an atmosphere of argon. N-iodosuccinimide (202.1 g, 888.8 mmol) and zirconium tetrachloride (20.4 g, 88.9 mmol) was added and the reaction was stirred at room temperature under an atmosphere of argon. The reaction was monitored by 1H NMR and showed complete conversion to product after 30 minutes. The mixture was then concentrated under reduced pressure to give ˜250 g crude as a brown solid. The crude material was purified by silica gel chromatography with hexanes to give 200 g of desired product as a brown solid (yield: 92.6%). EDI-MS: 487.1 (M+H)+.
Reaction SMILES: [CH2:1](S)[CH3:2].[H-].[Na+].OC([C:9]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[S:11][C:10]=1[S:25]([NH2:28])(=[O:27])=[O:26])C.Cl.CN(C)C=[O:33]>>[OH:33][CH:1]([C:13]1[CH:9]=[C:10]([S:25]([NH2:28])(=[O:27])=[O:26])[S:11][C:12]=1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CCS
Reactant: CN(C)C=O
Reactant: COc1ccc(S(=O)(=O)c2cc(C(C)O)c(S(N)(=O)=O)s2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(O)c1cc(S(N)(=O)=O)sc1S(=O)(=O)c1ccc(O)cc1
Temperature: 80 °C
Yield: 87 %

Procedure:
Ethanethiol (2.1 ml, 0.028 mol) was added dropwise over a 10 minute period to a stirred suspension of 60% NaH in mineral oil (1.4 g, 0.035 mol) in dimethylformamide (50 ml) at ice bath temperature under a nitrogen atmosphere. After the sodium hydride had reacted, 4-(1-hydroxyethyl-5-(4-methoxyphenylsulfonyl)thiophene-2-sulfonamide (2.64 g, 0.007 mol) was added to the solution and the solution was heated in an oil bath at 80° C. for 31/2 hours. The solution was cooled to ice bath temperature and 3N HCl was added (20 ml). The acidic mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl, dried, filtered and concentrated in vacuo. The crude amber oil obtained was washed with pet. ether several times to remove mineral oil and was solidified by trituration in nitromethane. A white solid was obtained, 2.2 g. Recrystallization from nitromethane gave material of mp 173°-175° C. Yield 87%. Purity and structure were confirmed by HPLC, C, H, N analyses and NMR.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]1=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:20][CH:21]=1)[NH:19][C:3]1[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C1CCCCC(Br)C1=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Yield: 53.4 %

Procedure:
Methyl 3-bromo-2-oxocycloheptanecarboxylate (16.8 g, 67.4 mmol) and 4-chloroaniline (18.4 g, 98%, 2.13 eq, 143.6 mmol) were added to flask with thermometer, nitrogen inlet and mechanical stirring machine. As the temperature of the mixture passed 140° C. a relatively rapid exotherm and vigorous evolution of gas occurred. The reaction was cooled with water immediately. The reaction mixture was dissolved in DCM (200 mL). The material was transferred into a separatory funnel and washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine, dried over Na2SO4, and the solvent was removed by vacuo. The crude residue was applied to a Biotage and eluted with 9/1 heptane/ethyl acetate to afford product 10 g (53%) as an off white solid, which was used for next reaction without further purification.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=1)(=O)=O.C1COCC1.CC(C)=O.[Na+].[I-:34]>O>[Cl:15][C:10]1[CH:9]=[C:8]([C@H:7]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][I:34])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccc(F)c(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CI)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 224 (1.5 g, 4.1 mmol) and THF/acetone (24 mL, 5:1) was added NaI (3.1 g, 20 mmol) and the reaction was stirred at RT overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo to afford 1.6 g (98%) of (S)-tert-butyl 1-(3-chloro-4-fluorophenyl)-2-iodoethylcarbamate which was used without additional purification.
Reaction SMILES: [Cl-].[Mg+2:2].[Cl-].[C:4]([OH:10])(=[O:9])[CH2:5][C:6]([OH:8])=[O:7].[CH2:11]([K])[CH3:12]>C(O)(C)C>[C:4]([O-:10])(=[O:9])[CH2:5][C:6]([O-:8])=[O:7].[CH2:11]([Mg+2:2])[CH3:12]
Reactant: [Mg+2]
Reactant: CC[K]
Reactant: O=C(O)CC(=O)O
Agent: [Cl-]
Solvent: CC(C)O
Product: CC[Mg+2]
Product: O=C([O-])CC(=O)[O-]

Procedure:
To a stirred aqueous solution of 1.5 M magnesium chloride and 3 M ethyl potassium malonate was added five volumes of isopropanol. After filtration, ethyl magnesium malonate was dried in vacuo.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:21])([F:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:7])[CH3:6].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:22][C:23]1[S:27][C:26]([S:28]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]([OH:7])([CH3:6])[C:4]([F:3])([F:20])[F:21])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: CC(O)(c1ccc(N2CCNCC2)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)CC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A 250-mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (2.66 g, 7.65 mmol), 5-bromothiophenesulfonyl chloride (2.00 g, 7.65 mmol, Sigma-Aldrich, St. Louis, Mo.), 25 mL of CH2Cl2, and triethylamine (3.73 mL, 26.8 mmol). After stirring at room temperature for 15 min, the mixture was diluted with CH2Cl2 (50 mL) and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.10 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(O)C>Cl.O>[Br:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[N:22]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]3=[N:1]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Temperature: 0 °C

Procedure:
A solution of methyl 2-amino-4-bromo-benzoate (460 mg; 2 mmol), 2-chloronicotinic acid (315 mg; 2 mmol), concentrated hydrochloric acid (5 drops), ethanol (5 ml) and water (25 ml) was heated at reflux for 18 hours, cooled to 0° C. and filtered. The solid filter cake obtained was dried in vacuo and used directly in the next example.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[CH3:23]I>COCCOCCOC>[CH3:19][C:17]1[CH:18]=[C:13]2[N:12]([CH3:23])[C:11](=[O:20])[C:10]3[CH:9]=[N:8][C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=4[C:15]=3[N:14]2[N:16]=1
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3cc(C)nn3c12
Reaction time: 10 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) are added to a suspension of 0.03 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at reflux temperature. The temperature is maintained for one hour and then lowered to 120°. 2.8 g. of methyl iodide are added and heating is continued for 10 hours. The precipitated sodium iodide is filtered off, the solution evaporated to dryness and the residue recrystallized from ethyl-acetate, yield 1.9 g. (68%); m.p. 206°-207°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.CO.[C:72]([O:75][CH2:76]C)(=[O:74])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[CH3:76][O:75][C:72]([C:13]1[C:14]2[C:5]([CH:6]3[CH:11]([C:12]=1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)=[O:74]
Reactant: COc1ccc(C2=C(OS(=O)(=O)C(F)(F)F)c3ccc(OC)cc3C3CCCCC23)cc1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1=C(c2ccc(OC)cc2)C2CCCCC2c2cc(OC)ccc21
Reaction time: 18 h
Yield: 63 %

Procedure:
Combine trifluoro-methanesulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthren-9-yl ester (19.83 g, 42.3 mmol), palladium acetate (1.93 g), dppb (4.58 g), Et3N (60.0 mL), methanol (265 mL), and DMSO (400.0 mL), and stir under 100 psi of CO atmosphere at 80° C. After 18 hours, add ethyl acetate and wash the ethyl acetate 5× with brine, then dry the organic phase with anhydrous sodium sulfate and concentrate. Flash chromatograph using 5% to 30% ethyl acetate/hexanes to yield the titled compound (10.06 g, 63%) as a pinkish-white solid. TLC Rf=0.25 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.31 (m, 2H), 7.25 (d, 1H, J=8.4 Hz), 6.92 (m, 3H), 6.76 (dd, 1H, J=8.6, 2.4 Hz), 3.86 (m, 6H), 3.60 (s, 3H), 3.25 (d, 1H, J=4.4 Hz), 2.70 (m, 1H), 2.40 (m, 1H), 1.75 (m, 1H), 1.53 (m, 4H), 1.31 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:8]1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2
Reactant: O=Cc1cccc(Cl)c1
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from (S)-(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-3-phenylurea, prepared as described in Example 41A, and 3-chlorobenzaldehyde by procedures analogous to those described in Example 3A. HPLC (method B): retention time 7.2 min. MS (ES): m/z 417 [M+H]+. Chiral HPLC 100% e.e.; retention time=27.3 min; Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in hexanes for 60 min at 1 mL/min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[OH:13][CH2:14][Sn](CCCC)(CCCC)CCCC>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>[OH:13][CH2:14][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1cc(CO)cc2ccoc12
Reaction time: 4 h
Yield: 60.1 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (2.02 g), hydroxymethyltributyltin (4.29 g) and tetrakis(triphenylphosphine palladium (O) (1.03 g) in dry 1,4-dioxan (8 ml) was heated at reflux for 18 h. A further portion of catalyst (203 mg) was added and heating continued for 4 h. The reaction mixture was allowed to cool, and the solution was purified by FCC eluted with hexane:ethyl acetate (1:1) to give the title compound as yellow oil (0.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:16][CH:17]([CH3:21])[CH2:18][C:19]#[N:20].Cl.O>O1CCOCC1>[CH2:18]([C:19]1[NH:20][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1)[CH:17]([CH3:21])[CH3:16]
Reactant: CC(C)CC#N
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(CC(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (3.0 g, 14.4 mmol), 3-methylbutanenitrile (1.2 g, 14.4 mmol), and saturated HCl solution in dioxane (20 mL) in sealed tube was stirred at 100° C. overnight. After it was cooled to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated and the residue was purified by silica gel chromatography give the desired product. MS (ESI): 260 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:26]=2[NH2:34])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:24](=[O:35])[C:25]3[C:26](=[CH:27][CH:28]=[C:29]([N:31]([CH3:32])[CH3:33])[CH:30]=3)[NH:34][C:37]2=[O:38])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(N(C)C)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(N(C)C)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
There was suspended, in 480 mL of acetonitrile, 47.1 g of 4-{2-amino-5-di-methylamino-benzoylamino}-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester synthesized in the foregoing step 1, then 15.9 g of 1,1′-carbonyl-diimidazole (CDI) was added to the suspension and then the mixture was heated at a temperature ranging from 55 to 60° C. for 2.5 hours with stirring. After the completion of the reaction, the mixture was cooled to 5° C. and the resulting crystals were filtered off to thus give 35.6 g of primary crystals. The filtrate and the wash liquid were concentrated to half, then 200 mL of water was added thereto to thus separate out crystals, the resulting slurry was filtered and the resulting crystals were dried to thus give 6.35 g of secondary crystals. The physical properties of the resulting compound were found to be in good agreement with those observed for the same compound prepared in the foregoing synthesis Example.
Reaction SMILES: [N:1]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[C:18]=[O:19].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:18]([NH:17][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]4)=[O:19])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCCCC2)cc1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azocanyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.53 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.50 (t, 1H, J=7.5 Hz), 7.15 (m, 2H), 6.83 (t, 1H, J=5.4 Hz), 6.63 (m, 2H), 4.20 (d, 2H, J=5.4 Hz), 3.43 (m, 4H), 2.63 (s, 3H), 1.67 (m, 4H), 1.48 (m, 6H); MS (ESI) 403 (M+H)+; Anal. Calcd for C25H30N4O: C, 74.60; H, 7.51; N, 13.92. Found: C, 74.26; H, 7.48; N, 13.64.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([F:14])[CH:8]=1.N1C=CC=C[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CI>ClCCl.CN(C)C=O>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([N:11]([CH3:16])[S:2]([CH3:1])(=[O:4])=[O:3])=[C:9]([F:14])[CH:8]=1
Reactant: c1ccncc1
Reactant: Nc1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: CN(c1ccc(Br)cc1F)S(C)(=O)=O
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Methane sulfonyl chloride (2.03 ml, 26 mmol) was added to a solution of 4-bromo-2-fluoroaniline (5.0 g, 26 mmol) and pyridine (2.12 ml, 26 mmol) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude oil was dissolved in dimethylformamide (50 mL) and treated with potassium carbonate (5.1 g, 37.5 mmol) followed by methyl iodide (2.33 ml, 37.4 mmol). The reaction mixture was stirred for 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a brown oil (6.9 g). 1H NMR (CDCl3): δ 2.94 (s, 3H), 3.10 (s, 3H), 6.77 (t, J=4.96 Hz, 1H), 6.95 (d, J=4.96 Hz, 1H), 7.05 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=Cc1cccc(C)c1[N+](=O)[O-])C(=O)OCC
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
To a solution of this aldehyde (10.0 g, 60.6 mmol) in 20 mL of acetic anhydride was added diethyl malonate (9.7 g, 60.6 mmol) and sodium bicarbonate (7.6 g, 91 mmol). The reaction mixture was stirred at 100° C. for 24 h. The reaction was allowed to cool and then was partitioned between ethyl acetate and water. The organics were washed sequentially with water, aq sat'd NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford 16.9 g (90%) of the title compound.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].CCCCC.[C:10]([N:14]=[N:15][C:16](Cl)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].O>C(O)(C)C>[C:10]([N:14]=[N:15][C:16]([N:3]=[C:2]=[O:1])([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: N#C[O-]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCC
Solvent: O
Product: CC(C)(C)N=NC(C)(C)N=C=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 40.5 grams (0.5 moles) of potassium cyanate in 250 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added the above pentane solution of 2-t-butylazo-2-chloropropane over 15 minutes, holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 2 hours at room temperature, 500 ml of water added and the reaction stirred until the salts dissolved. The pentane layer was separated, washed with 250 ml water, 250 ml 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 59.6 grams (70% overall crude yield) of a yellow liquid. The product had a strong broad band at 2225 cm-1 in its infrared spectrum.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].C(Cl)Cl>>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:36][C:34]([OH:40])=[O:35])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)O)C3)ccc1-2

Procedure:
Following a similar procedure to 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 using {3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid tent-butyl ester and TFA:DCM (1:2), {3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid TFA salt was isolated as a white solid (75 mg, 90%). 1H NMR δ (ppm) (DMSO-d6): 8.35 (1 H, d, J=8.20 Hz), 8.11 (1 H, d, J=0.75 Hz), 7.29 (1 H, d, J=8.33 Hz), 7.21 (1 H, s), 5.85-5.77 (1 H, m), 4.48-4.39 (2 H, m), 4.41-4.35 (2 H, m), 4.36-4.22 (3 H, m), 3.48-3.42 (2H, m), 1.55 (6 H, d, J=6.59 Hz) plus 2 protons obscured by the water peak and 2 exchangeable protons not observed.
Reaction SMILES: N1CCOCC1.C(OC([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25]([O:27][CH3:28])=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])=[CH:31][CH:30]=3)[C:23]2=[O:48])=[CH:18][CH:17]=1)=[NH:15])=O)C=C>O1CCCC1>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:26][C:25]([O:27][CH3:28])=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])=[O:38])=[CH:31][CH:30]=3)[C:23]2=[O:48])=[CH:20][CH:21]=1)(=[NH:13])[NH2:15]
Reactant: C=CCOC(=O)NC(=N)c1ccc(N2CC(OC)=C(c3ccc(CCC(=O)OCOC(=O)C(C)(C)C)cc3)C2=O)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COC1=C(c2ccc(CCC(=O)OCOC(=O)C(C)(C)C)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared by dropwise addition of 1 equivalent of morpholine to 1-[4-(allyloxycarbonyl-amidino)-phenyl]-4-methoxy-3-[4-[2-[(pivaloyloxymethyl)-oxycarbonyl]ethyl]-phenyl]-3-pyrrolin-2-one and 0.1 equivalents of tetrakis-(triphenyl-phosphine)-palladium(O) in tetrahydrofuran under inert gas followed by 1 hours' stirring at ambient temperature.