Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)=CCCCCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)=CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
1-Bromo-12-methyl-11-tridecene (4.4 g, 16 mmoles) and triphenylphosphine (4.65 g, 17 mmoles) dissolved in acetonitrile (80 ml) were heated to reflux for 4 days, cooled and concentrated in vacuo. The residue was chromatographed on silica gel eluted with chloroform and then with methanol-chloroform (2:3). Fractions containing the product were concentrated in vacuo, triturated with ether, filtered and dried in vacuo to afford the desired phosphonium salt.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][C:52](O)=[O:53])[CH:48]=[CH:49][CH:50]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][C:52]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:53])[CH:48]=[CH:49][CH:50]=1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(3-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (42.3 mg) as a yellow solid. LC/MS (ES) m/z=420.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (s, 2H) 3.93 (s, 2H) 4.26 (s, 2H) 5.41 (br. s., 2H) 7.20-7.30 (m, 3H) 7.32-7.36 (m, 2H) 7.37-7.40 (m, 2H) 7.42 (s, 1H) 7.82 (d, J=5.56 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H).
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:18]([O:20]CC)=[O:19])([F:17])[F:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCOCC1.[OH-].[Na+:36]>O>[C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([F:16])([F:17])[C:18]([O-:20])=[O:19])=[O:12])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[Na+:36]
Reactant: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OC(c1ccccc1)C(F)(F)C(=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
A mixture of 6.6 g of 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate, prepared in Synthesis Example 1-5, 20 g of 1,4-dioxane, and 2.5 g of 25 wt % sodium hydroxide was stirred for 2 hours. Water, 30 g, was added to the reaction solution, which was washed with n-hexane, obtaining an aqueous solution of sodium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate. To this solution, 95 g of an aqueous solution of 4-tert-butylphenyldiphenylsulfonium methylsulfate and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 5.4 g of the target compound, 4-tert-butylphenyldiphenylsulfonium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate as white crystals (yield 52%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24](O)=[O:25])[CH3:22])[C@@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24]([Cl:44])=[O:25])[CH3:22])[C@@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)Cl)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The residue from Step B was taken up in methylene chloride and a trace of DMF was added followed by 0.21 mL of oxalyl chloride. The reaction was stirred at room temperature for 1 h and then evaporated and used in Step D.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([O:23]CC)=O)=[N:4][C:5]([NH:17][CH2:18][CH2:19][OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].OCC[NH:29]C1N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[CH2:53]([OH:55])C>[Pd]>[OH:20][CH2:19][CH2:18][NH:17][C:5]1[N:6]=[C:7]2[C:2]([NH:1][C:53](=[O:55])[N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:3]([C:21]([NH2:29])=[O:23])[N:4]=1
Reactant: CCO
Reactant: CCOC(=O)c1nc(NCCO)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(NCCO)nc(Nc2ccccc2OC)c1N
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NCCO)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
Ethyl 5-amino-2-(2-hydroxyethylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(2-hydroxyethylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate r. (0.250 g, 0.663 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.050 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using Biotage chromatography (5% methanol in ethyl acetate) to afford the title compound (0.200 g, 87%). MS (ESI) m/z 348.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][OH:16])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:19])([F:21])[F:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
3-(4-Chloro-3-trifluoromethyl-phenyl)-5-hydroxymethyl-5-methyl-imidazolidine-2,4-dione from Example 10 (1.01 g, 3.14 mmoL) in DCM (10 mL) was treated with TEA (0.66 mL, 4.70 mmoL) followed by MsCl (360 mg, 3.14 mmoL) at 0° C. The reaction was slowly warmed to room temperature and stirring for another 2 hrs. The crude product was partitioned between DCM and water. The organic layer was washed with sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated, then purified by silica gel column chromatography using heptane and ethyl acetate as eluent to afford the title compound as a white solid (1.05 g, yield 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14]>C1COCC1.Cl>[CH3:12][N:13]([CH3:14])[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)Cc1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3-nitrobenzyl bromide (10, 1.67 g, 7.73 mmol) and N,N-dimethylamine (4.25 mL, 2M in THF) in anhydrous THF (30 mL) was heated at 40° C. overnight. The reaction mixture was diluted with 1N HCl (30 mL, aq.), the aqueous layer separated, and extracted with EtOAc (30 mL). The pH of the aqueous layer was then adjusted to 9 using saturated Na2CO3 (aq.) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with water (40 mL), brine (40 mL), and dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 11 (1.2 g).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].BrCC1C=CC=CC=1[Cl:26]>>[ClH:26].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:1])[C:4]1=[O:17]
Reactant: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Reactant: Clc1ccccc1CBr
Agent: Cl
Product: N[C@H]1CCCCN(Cc2ccccc2Cl)C1=O

Procedure:
(S)-3-Amino-1-(2-chlorobenzyl)azepan-2-one hydrochloride (270 mg, 0.934 mmol) was synthesized as described for the preparation of Intermediate 42 using 1-(bromomethyl)-2-chlorobenzene in step A. Anal. Calcd. for C18H25ClN2O3 m/z 352.8. found: 353.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:25]([CH3:26])=[CH:24][C:8]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].C([O-])(O)=[O:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].C(OC)=O>C(Cl)Cl.O>[C:1]([C:5]1[C:25]([CH3:26])=[CH:24][C:8]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[O:28])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: COC=O
Product: COC(=O)c1cc2nc(S(=O)Cc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
5--Carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.46 g, 0.0055 mol) in H2O (10 ml) was added and the mixture was cooled to +2° C. m-chloroperbenzoic acid 69.5% (0.62 g, 0.0025 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirring was continued at +2° C. for 15 min. After separation the organic layer was extracted with an aqueous 0.2M NaOH solution (3×15 ml, 0.009 mol). After separation the aqueous solutions were combined and neutralized with methyl formate (0.56 ml, 0.009 mol) in the presence of CH2Cl2 (25 ml). After separation the organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN (10 ml) giving the title compound (0.68 g, 70%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH2:11][NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]([CH3:22])[CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
2,2,2-Trifluoroacetic acid (1.88 mL, 24.39 mmol) was added to a solution of tert-butyl 4-(4-(3-(cyclopropylmethyl)ureido)-N-methylbenzamido)piperidine-1-carboxylate (420 mg, 0.975 mmol) in dichloromethane (10 mL). The mixture was stirred at ambient temperature for 4 hours and then treated with strong cation exchange column chromatography to afford the title compound (300 mg). MS (ESI) m/z 331.1 [M+H]+
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C@@H:8]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])SC)#[N:2].[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([C@@H:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=1>CN(C=O)C.CCN(CC)CC.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([C@@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([C:4](=[N:3][C:1]#[N:2])[NH:7][C@H:8]([CH2:9][N:10]([CH3:18])[C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:43]2)[O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CSC(=NC#N)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 105 °C
Yield: 2.3 %

Procedure:
To a solution of (S)-tert-butyl 2-((cyanoimino)(methylthio)methylamino)-3-cyclohexylpropyl(methyl)carbamate (200 mg, 0.543 mmol) in DMF (8 mL) and Et3N (0.5 mL) was added methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (178 mg, 0.543 mmol). The mixture was heated at 100-110° C. for 48 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL×4), dried over Na2SO4 and concentrated to give the residue, which was purified by column to give methyl 2-((R)-(3-chlorophenyl)((R)-1-(N′-cyano-N—((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-yl)carbamimidoyl)piperidin-3-yl)methoxy)ethylcarbamate (8 mg, 2%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:28])[O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:20]=2)[N:17]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:20]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[N:18][N:16]2[C:15]=1[CH:14]=[CH:13][C:12]([O:11][CH:10]([F:9])[F:28])=[N:17]2
Reactant: Fc1cccc(-c2cc3ccc(OC(F)F)nn3n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Reaction time: 18 h
Yield: 91 %

Procedure:
N-bromo succinimide (195 mg) was added to a solution of 6-difluoromethoxy-2-(3fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (251 mg) and sodium bicarbonate (185 mg) in anhydrous DMF (10 ml) and stirred for 18 h. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (10×20 ml), brine (20 ml), dried (Na2SO4) and concentrated to give the title compound as a solid (293 mg, 91%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=C[CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16].[Cl:17]Cl.[CH2:19]([Cl:21])Cl>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:12]([Cl:17])=[C:19]([Cl:21])[CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16]
Reactant: ClCCl
Reactant: ClCl
Reactant: COc1cccc(CCCCCBr)c1OC
Product: COc1cc(Cl)c(Cl)c(CCCCCBr)c1OC
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To 4.0 g of 1-(5-bromopentyl)-2,3-dimethoxy benzene in 50 mL of methylene chloride cooled in an ice bath was added 18 mL of 0.8M chlorine in methylene chloride. After 15 minutes, 17 mL of 0.88M chlorine in methylene chloride was added. The reaction mixture was kept at 0° for 3 hours and then was concentrated under reduced pressure to yield an oil. Purification by HPLC using 30% toluene-hexane gave 2.03 g (41% yield) of 1-(5-bromopentyl)-5,6-dichloro-2,3-dimethoxybenzene. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 354 (C13H17BrCl2O2).
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20](=[O:24])[N:21]([CH3:23])[N:22]=1)(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:23][N:21]1[C:20](=[O:24])[O:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])=[N:22]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1-c1nn(C)c(=O)o1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: Cn1nc(-c2ccccc2S(=O)(=O)N=C=O)oc1=O
Temperature: 25 °C
Yield: 108.7 %

Procedure:
A suspension of 8 g of the product of Example 7 and 0.4 g of DABCO in 90 ml of xylenes were heated under N2 at 130°-135° C. while 1.8 ml of phosgene was added portionwise at a rate to maintain a reflux temperature of about 130°-135° C. The mixture was refluxed an additional two hours, cooled under N2 to room temperature, filtered, and the filtrate was concentrated in vacuo to yield 6.9 g of the subject compound as a crude oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[O:30])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[Li].O>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Nc3ccc(C)c(C)c3)ccn2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of methyl 3-(3-((2-(4-(3,4-dimethylphenylamino)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate (440 mg, 0.72 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), and a solution of LiOH H2O (300 mg, 7.14 mmol, 9.89 equiv) in water (2 mL). The resulting solution was stirred for 18 h at room temperature. The reaction was then quenched with 30 mL of water. The solution was adjusted to pH 6-7 with hydrochloric acid (1 N). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 237.2 mg (55%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 13.76 (s, 1H), 10.22 (s, 1H), 10.11 (s, 1H), 8.21 (d, J=6 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.42 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 7.08 (s, 2H), 6.94 (m, 3H), 6.81 (s, 1H), 3.80 (s, 2H), 3.24 (s, 4H), 2.55 (m, 3H), 2.17 (d, 6H), 1.63 (s, 6H). MS (ES, m/z): 595 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:4][CH:3]=1.[CH3:22][C:23](O)(C#C)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[CH:23])=[CH:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: Brc1ccc(OCCCCCCOC2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OCCCCCCOC2CCCCO2)cc1
Yield: 72.5 %

Procedure:
A degassed mixture of 4-bromo-1-[6-(tetrahydropyran-2-yloxy)hexyloxy]benzene (20 g), 2-methyl-3-butyn-2-ol (18.85 g), triphenylphosphine (TPP, 0.59 g), copper (I) iodide (0.11 g) and bis(triphenylphosphine)palladium dichloride (0.40 g) in 200 ml of triethylamine was refluxed for 4 hours under an atmosphere of argon. After being cooled the reaction mixture was filtered over celite to give a yellowish solution which was evaporated to dryness. The resulting yellow oil was dissolved in 200 ml of a toluene/triethylamine mixture (1:1) to which 14.45 g of KOH was then added. The resulting mixture was heated at reflux for 12 h, cooled and filtered over 260 g of silica gel using diethylether as eluent. This yields a dark oil which was purified by chromatography using a silica gel clolumn and cyclohexane/ethyl acetate (9:1) as eluent to give 12.28 g of 4-[6-(tetrahydropyran-2-yloxy)hexyloxy]phenylacetylene as a red oil.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:33][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: NC1CCC1
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC2CCC2)C1(C)C

Procedure:
The product from Example 173 and cyclobutylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.00 (s, 3H), 0.44 (t, J=7.3 Hz, 3H), 0.74 (s, 3H), 0.77 (s, 3H), 0.80-0.98 (m, 3H), 1.11 (s, 9H), 1.11-1.21 (m, 5H), 1.32-1.57 (m, 3H), 1.62-1.72 (m, 2H), 2.13-2.21 (m, 3H), 2.26-2.36 (m, 1H), 3.67-3.80 (m, 1H), 7.32 (d, J=7.7 Hz, 1H), 8.04 (s, 1H). (ESI+) m/z 448 (M+H)+. Anal. calcd. for C25H41N3O2S: C, 67.07; H, 9.23; N, 9.39. Found: C, 66.48; H, 9.40; N, 9.24.