Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:32])[C:10]([O:12][CH2:13][C@@H:14]1[C:18]([OH:20])([CH3:19])[C@:17]([F:22])([CH3:21])[CH:16]([N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[O:15]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][CH:9]([CH3:32])[C:10]([O:12][CH2:13][C@@H:14]1[C:18]([OH:20])([CH3:19])[C@:17]([F:22])([CH3:21])[CH:16]([N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[O:15]1)=[O:11]
Reactant: Cc1cn(C2O[C@H](COC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(C2O[C@H](COC(=O)C(C)N)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 556.6 %

Procedure:
To a stirred solution of (2S)-((2R,4R)-4-fluoro-3-hydroxy-3,4-dimethyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl 2-(tert-butoxycarbonylamino)propanoate (Example 47, about 0.005 g, 0.01 mmol) in dichloromethane was added trifluoroacetic acid (about 0.01 ml, 0.10 mmol) at about 0° C. and stirred at room temperature for about 1 hour. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was added to saturated sodium bicarbonate and extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulphate, Concentrated under reduced pressure to afford (0.02 g) crude compound. ES Mass: [M+1] 360 (100%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].Br[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][CH:21]=2)[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:12]
Reactant: Brc1cccc2ccccc12
Reactant: CCNC(=O)c1ccccc1Cl
Product: CCNC(=O)c1c(Cl)cccc1-c1cccc2ccccc12
Yield: 28 %

Procedure:
The title compound was prepared from the compound of Example f and 1-bromonaphthalene (0.76 g, 3.65 mmol) according to General Method D. It was obtained as 0.28 g of a white solid, a 28% yield. m.p. 181-182° C.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[CH3:44].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[CH3:44]
Reactant: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(C)c2)cc1
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (125 mg, 0.40 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetic acid (146 mg, 0.40 mmol) and N,N-dimethylaminopyridine (49.0 mg, 0.40 mmol) in DMF (10 ml) was added EDC.HCl (84.1 mg, 0.44 mmol) at rt, and the resulting mixture was stirred for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (238 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 1.92 (s, 3 H), 2.09–2.27 (m, 3 H), 2.42–2.50 (m, 1 H), 3.22–3.41 (m, 2 H), 3.88 (s, 3 H), 4.39 (d, J=4.4 Hz, 1 H), 4.64 (br s, 1 H), 5.00 (t, J=6.8 Hz, 1 H), 6.72 (s, H), 6.81–6.93 (series of m, 8 H), 7.22–7.42 (series of m, 6 H), 8.01 (d, J=8.4 Hz, 2 H), 8.13 (d, J=8.0 Hz, 1H); MS (FAB) m/z, 656 (M+), 658 (M++2).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:18]=[S:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccc1C1CCCC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a biphasic solution of 2-cyclopentylaniline (0.46 g, 2.9 mmol) in dichloromethane (10 mL) and water (4.8 mL) in a 100 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet was added sodium hydrogencarbonate (0.73 g, 8.6 mmol) followed by thiophosgene (0.21 mL, 2.8 mmol). The reaction was stirred at room temperature for 1 hour, filtered through a phase separator cartridge, and concentrated providing the 1-cyclopentyl-2-isothiocyanatobenzene as a red oil which was used without further purification. To a solution of the isothiocyanate in ethanol (5.5 mL) in a 100 mL roundbottom flask was added hydrazine hydrate (0.15 mL, 3.1 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with hexanes and the resulting solid was collected by filtration, washed with hexanes, and dried under house vacuum to provide the title compound (0.41 g, 1.7 mmol, 63% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.02 (bs, 1H), 7.52 (bs, 1H), 7.41-7.18 (m, 4H), 4.06 (bs, 2H), 3.21-3.06 (m, 1H), 2.04 (s, 2H), 1.90-1.74 (m, 2H), 1.74-1.58 (m, 4H); ESIMS m/z 236 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]OC(OC)OC.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:17]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:25]=[N:16][C:14]2=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: NC(=O)C1(NCC2CCCCC2)CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1N=CN(CC2CCCCC2)C12CCN(Cc1ccccc1)CC2
Yield: 76.5 %

Procedure:
A stirred mixture of 1-benzyl-4-(cyclohexylmethylamino)piperidine-4-carboxamide (8 g, 24.32 mmol), 8 ml of trimethoxymethane, 2 ml of acetic acid and 65 ml of toluene was refluxed for 48 hours. The mixture was concentrated. The residue was dissolved in water, made alkaline with aqueous ammonia, and the mixture was extracted with chloroform. The extracts were dried (MgSO4) and concentrated. Recrystallization of the residue from ethyl acetate gave 6.3 g (76.5%) of crystals, mp 117°-118° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:17][I:18]>>[I-:18].[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][N+:14]([CH3:17])=[CH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2ccncc2)CCC2(C1)OCCO2
Reactant: CI
Product: C[n+]1ccc(C2=CCC3(CC2)OCCO3)cc1
Product: [I-]

Procedure:
4-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-pyridine (as prepared in the previous step, 1.5 g, 6.91 mmol) in MeI (˜10 mL) was heated to reflux until the precipitate was completely dissolved. The reaction was cooled and filtered to collect the brown solid as the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:21])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26].O>CN(C)C=O>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][S:21][C:10]1[CH2:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11.4 g of 1,3-dihydro-5-phenyl-7-nitro-2H-1,4-benzodiazepin-2-thione in 140 ml of anhydrous dimethylformamide is added under ice cooling with stirring 3.6 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 15 minutes. To this mixture is added dropwise at room temperature with stirring 13.2 g of N,N-dimethyl-2-chloroethylamine over a period of about 1 hour, followed by stirring for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is washed with water and dried over magnesium sulfate, and the solvent is then distilled off under reduced pressure. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with a benzene-chloroform (5:1) eluant. The eluate is concentrated under reduced pressure to obtain an oily 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous ethanol-acetone mixture to obtain 9.0 g of 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine maleate, m.p. 131°-134° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8]Cl>C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8][NH:2][NH2:3]
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(CNN)ccc1[N+](=O)[O-]
Yield: 96.6 %

Procedure:
To an ethanol solution (60 ml) of hydrazine monohydrate (5.00 g), an ethanol solution (20 ml) of 3-methyl-4-nitrobenzyl chloride (3.71 g) was added dropwise while refluxing it, and the mixture was continuously refluxed for 6 hours. After finishing the reaction, the solvent was distilled off and (3-methyl-4-nitrobenzyl)-hydrazine (3.50 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[C:26]([OH:39])(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([O:37][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)(=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)=[O:39]
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Product: O=C(CCCCCCCCC(=O)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 13 or Example 17, the title compound is prepared by reacting an equivalent amount of the alcohol compound of Example 7 with a half equivalent amount of sebacic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24](=[O:36])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:38])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24](=[O:36])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)C(=O)Nc3cccc(C(F)(F)F)c3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)C(=O)Nc3cccc(C(F)(F)F)c3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.6 %

Procedure:
To methyl 3-methyl-2-(3-(4-(2-oxo-2-(3-(trifluoromethyl)phenylamino)acetamido) phenyl)isoxazole-5-carboxamido)butanoate (100 mg) in THF (2 ml) 1 M aqueous solution of Lithium hydroxide monohydrate (0.375 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to yield 22 mg (22%) of the title compound as white solid. MS (ES+): m/z 519 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 11.24 (s, 1H), 11.13 (s, 1H), 9.01 (d, 1H), 8.35 (dd, 1H), 8.16 (dd, 1H), 8.06 (d, 2H), 7.96 (d, 2H), 7.73 (s, 1H), 7.64 (m, 1H), 7.54 (dd, 1H), 4.28 (m, 1H), 2.23 (m, 1H), 0.98 (d, 6H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3](O)=O.O.[NH3:33].[C:34]([O:37]C(=O)C)(=O)[CH3:35]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[CH2:3][NH:33][C:34](=[O:37])[CH3:35]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: N
Solvent: O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CNC(C)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid; ammonia water (28% ammonia water); and acetic anhydride.
Reaction SMILES: C(O[CH:5]([N+:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=O)C.C(O[CH:18]([CH2:34][CH2:35][C:36]([C:50]#[N:51])([CH:47]([CH3:49])[CH3:48])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[CH:19]([N+:31]([O-:33])=[O:32])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=O)C.[B].[BH4-].[Na+]>>[N+:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([O-:13])=[O:12].[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH2:20][CH:19]([N+:31]([O-:33])=[O:32])[CH2:18][CH2:34][CH2:35][C:36]([C:50]#[N:51])([CH:47]([CH3:49])[CH3:48])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CCCCCC(OC(C)=O)[N+](=O)[O-]
Reactant: COc1ccc(CC(C(CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)OC(C)=O)[N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [B]
Agent: [Na+]
Product: CCCCCC[N+](=O)[O-]
Product: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC

Procedure:
The resulting nitrohexanol acetate of formula 9 is then reduced using a boron-based reducing agent, e.g., sodium borohydride, in a 2° or 3° alkanol at 25°-80° C. for 3-15 hours to produce a nitrohexane derivative of formula 10 (step 8). For example, O-acetyl-1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol (9) is heated with NaBH4 in 2-propanol at reflux for 3-15 hours to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyphenyl)hexane (10).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14](OC1C=CC(C)=CC=1)=[O:15].O>CC1CCCO1>[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:15]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 65 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of sodium hydride (7.39 g, 184.66 mmol) in 2-methyltetrahydrofuran (400 mL) at 0-5° C. was added methanesulphonamide (16.47 g, 173.12 mmol) and the mixture stirred for 1 hour and allowed to reach room temperature. 4-Methylphenyl 5-chloro-4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-fluorobenzoate (Preparation 163, 53 g, 115.41 mmol) in 2-methyltetrahydrofuran (100 mL) was added and the reaction mixture heated at 65° C. for 6 hours and cooled. Water (250 mL) was charged to the stirred reaction mixture and the layers separated. The organic layer was further washed with 1M citric acid solution (200 mL) and concentrated under reduced pressure at 45° C. The resulting solid was stirred in tert butyl methyl ether (250 mL) at 50° C. for 1 hour, cooled to 0-5° C., filtered and dried to give the title compound as an off-white solid (27.5 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2.S(O)(O)(=O)=O.[CH2:21]([N:23]([CH2:31][CH3:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1N)[CH3:22].CC[N:35](CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([N:23]([CH2:31][CH3:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:35][C:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:15])=[CH:26][CH:25]=1)[CH3:22]
Reactant: CCN(CC)c1ccccc1N
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(OC)c3C2)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
To 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (206 mg, 1.0 mmol) in DMF (1.5 mL) was added N,N-diethylphenylene diamine sulfate (262 mg, 1.0 mmol), Et3N (606 mg, 6.0 mmol), and TBTU (321 mg, 1.0 mmol) at 0° C. After stirred overnight, ice chips and 20 mL ethyl acetate were added. Organic layer was washed with water (3×10 mL), dried over MgSO4, and then concentrated. Purification by column chromatography provided the titled compound (170 m g, 48%). 1H NMR (300 MHz, DMSO-D6) δ 9.59 (s, 1H), 7.39 (d, J=9.3 Hz, 2H), 7.08 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.61 (d, J=9.0 Hz, 2H), 3.76 (s, 3H), 3.29 (q, J=6.9 Hz, 4H), 2.91–2.56 (m, 5H), 2.00 (m, 1H), 1.69 (m, 1H), and 1.06 (t, J=6.9 Hz, 6H). MS (ESI) positive ion 353 (M+H)+; negative ion 351 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24].N>C(Cl)Cl.O>[CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH:17][C:23]([NH2:25])=[O:24])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: ClCCl
Product: CCC(C(c1ccc2nc(NC(N)=O)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (50 mg, 0.151 mmol) and carbonyldiimidazole (50 mg, 30 mmol) in DCM was stirred at RT for 5 h. Aqueous ammonia was added and the reaction was stirred over night. The reaction was diluted with water and extracted with DCM. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to afford 1-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea. MS ESI: m/z 359.27 [M+1+].
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH3:8])[CH3:17]
Reactant: CC[SiH](CC)CC
Reactant: COc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1ccccc1OC
Yield: 53.1 %

Procedure:
The reaction was conducted according to the General Procedure by heating anisole (54 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 59 mg (54%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.40-7.17 (m, 2H), 7.01-6.81 (m, 2H), 3.77 (s, 3H), 1.02-0.85 (m, 9H), 0.87-0.74 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 164.58, 135.52, 130.42, 123.92, 120.08, 109.23, 54.09, 6.93, 3.22.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=3[O:49][CH2:50][C@@H:51]3[CH2:55][CH2:54][CH2:53][NH:52]3)[N:42]=[CH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[F:37].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=2[O:49][CH2:50][C@@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:1](=[O:5])[CH2:2][OH:3])[N:42]=[CH:41][N:40]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Glycolic acid (20 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 109 mg) were added sequentially, each in one portion, to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) and N,N-diisopropylethylamine (83 μl) in DCM (3 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 hours 30 minutes and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 0-10% methanol in dichloromethane as eluent to give the title compound as a white solid (55 mg, 50%); NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.70-7.60 (m, 1H), 7.40 (t, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.65-4.53 (m, 2H), 4.40 (dd, 1H), 4.17 (dd, 1H), 4.03 (d, 1H), 3.90 (s, 3H), 3.45-3.35 (m, 3H), 2.10-1.82 (m, 4H); Mass spectrum MH+ 461.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[C:59]([CH3:64])=NOC=1C)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH2:58]([NH:55][C:56]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:57])[C:59]1[CH:64]=[CH:3][CH:2]=[CH:17][CH:16]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1noc(C)c1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NCc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as starting materials in 30% yield. LCMS for C30H33ClN9O3 (M+H)+: m/z=602.2.