Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:28](=[O:29])[N:14]2[C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[CH2:19]([C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:28](=[O:29])[N:14]2[C:15]=1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:20]
Reactant: [H][H]
Reactant: C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: CCOC(C)=O
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 86 %

Procedure:
Hydrogen was bubbled through a suspension of 10%-palladium on carbon (3 g, 0.00282 g atoms) in dry ethyl acetate (100 ml.) for 30 minutes. A solution of t-butyl 7β-phenoxyacetamido-3-vinylceph-3-em-4-carboxylate (1.4 g., 3.36 mmole) in dry ethyl acetate (50 ml.) was added and the mixture was stirred for 21/2 hours in a hydrogen stream and filtered through a bed of kieselguhr. The filtrate was evaporated in vacuo to give the title ester as a white foam (1.21 g, 86.5%), [α]D23 + 55.4° (c 0.85; CHCl3), λmax. (EtOH) 263 nm(ε 8,100) and 268 nm (ε 8,450), inflexion at 273 nm (ε 7,600), νmax. (CHBr3) 3420(NH), 1782 (azetidin-2-one), 1715 (CO2R), and 1695 and 1525 cm.-1 (CONH), τ (CDCl3) 2.66 and 3.03 (2H and 3H, two m; C6H5O) 4.15 (1H, dd, J 9.5 and 5 Hz; C7 --H), 5.00 (1H, d, J 5 Hz; C6 --H) 5.45 (2H, s; C6H5OCH2), 6.51 and 6.73 (2H, AB-q, J 18 Hz; C2 --H2), 7.37 and 7.80 (2H, AB-part of ABX3 -system, JAX, JBX 7 Hz, JAB 13 Hz; C3 --CH2CH3), 8.47 (9 H, s; CO2C(CH3)3), 8.87 (3 H, t, J 7 Hz; CH2CH3) (Found: C, 60.1; H, 6.3; N, 6.7; S, 7.2. C21H26N2O5S (418.5) requires C, 60.25; H, 6.2; N, 6.8; S, 7.7%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.O[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxyphenyl)ethanone are treated as described in Example 76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=O)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>CCO>[CH3:38][C:28]1[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:13]([C:11]1[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][N:10]=1)=[O:15])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1ncc(-c2cccc(Cl)c2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ncc(-c2cccc(Cl)c2)o1
Reaction time: 64 h
Yield: 70.9 %

Procedure:
A mixture of the product from Step 79c (0.419 g, 1.66 mmol, 1.0 eq), (R)-(+)-3-aminoquinuclidine (0.221 g, 1.75 mmol, 1.05 eq) and EtOH (4.0 mL) is heated under reflux. After 64 h, the mixture is cooled and the contents are filtered through glass wool into p-toluenesulfonic acid monohydrate (0.315 g, 1.65 mmol, 1.0 eq). The resulting solid is filtered and dried in vacuity to afford the title compound (0.59 g, 65%). HRMS (FAB) calculated for C17H18ClN3O2+H1 332.1165, found 332.1180.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[CH2:20](O)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:20][CH3:21])=[O:17])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCO
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.18 mgs, 0.67 mmol) was dissolved in dry THF (7 mls). To this solution was added ethanol (0.037 mls, 0.81 mmol) and resin bound triphenylphosphine (0.93 g, 2.014 mmol, 2.16 mmol/g). This mixture was gentyl stirred at room temperature for 20 minutes. Diisopropylazidodicarboxylate (0.34 mls, 1.68 mmol) was then added and the mixture was stirred at room temperature for one hour, then filtered, and the resin rinsed several times with EtOAc. The filtrate was concentrated and the resulting material was purified by Flash 40 Biotage (40M cartridge, 30% EtOAc/Hexanes) to give 137 mgs (70%) of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as an orange oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[S:30])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[C:12](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:29]1=[S:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccccc1C(=O)NCc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-[2-(N-benzylcarbamoyl)-anilino]acetate (1.5 g) and N,N'-thiocarbonyldiimidazole (2.85 g) was stirred at 120° C. for 30 minutes. After cooling, the reaction mixture was diluted with chloroform and chromatographed on silica gel. Elution with chloroform gave ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate. A mixture of ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate and 1N sodium hydroxide (2 ml) in methanol (10 ml) was stirred for 4 hours at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The extract was washed with brine and dried. Removal of the solvent gave 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetic acid (280 mg).
Reaction SMILES: [F:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Cl)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([CH2:13][CH2:14][CH2:15][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[F:1])=[O:17])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CCCCl
Reactant: Fc1ncc[nH]1
Product: CC(C)(C)OC(=O)CCCn1ccnc1F

Procedure:
2-Fluoroimidazole was alkylated with t-butyl-4-chlorobutyrate, using the same procedure as that for the starting material of Example 74, to give 1-(3-t-butoxycarbonylpropyl)-2-fluoroimidazole.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][C:14]#[N:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:13][C:14]#[N:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCl
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1nnc(-c2ccccc2)n1

Procedure:
To 146 mg (1 mmol) of 5-phenyltetrazole and 75 mg (1 mmol) of chloroacetonitrile was added three mL of dimethyl formamide. The resulting solution was stirred, then 158 mg (1 mmol) of potassium carbonate was added and the mixture was further stirred at room temperature for 18 hours. Twenty-five mL of water was then added and the mixture was extracted twice with 25 mL of ethyl acetate. Evaporation of the extracts left the crude product, which was purified by silica gel chromatography, leaving an oil that was pure by NMR.
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH2:4][CH2:3]1)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:24].[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:15][C:11]1[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9](=[O:24])[C:8]2[C:13](=[CH:14][C:5]3[CH2:4][CH2:3][CH:2]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:46][CH:47]=4)[C:6]=3[CH:7]=2)[N:12]=1
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1)C(=O)OCC
Temperature: 110 °C

Procedure:
A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (21 g), prepared as described in section (6) of Example 1, diethyl p-aminobenzoyl-L-glutamate (52.5 g), prepared as described in the Journal of Medicinal Chemistry, 1985, 28, 1428, calcium carbonate (27.5 g) and DMA (200 ml) was stirred and heated to 110° C. for 30 minutes. The mixture was cooled to ambient temperature. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially a 1:1 mixture of hexane and ethyl acetate as eluant and then a 1:3 mixture of hexane and ethyl acetate as eluant. There was thus obtained a gum which on trituration under diethyl ether gave diethyl N-{(p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoyl}-L-glutamate (13.5 g), m.p. 156° C.;
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([OH:17])[C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26]OC(=NC(C)C)NC(C)C)=[CH:24][CH:23]=1>ClCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([O:17][CH2:26][C:25]4[CH:37]=[CH:38][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: O=C1c2c(O)cncc2C(=O)c2c(Cl)ccc(F)c21
Reactant: COc1ccc(COC(=NC(C)C)NC(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1

Procedure:
A solution of 9-chloro-6-fluoro-4-hydroxybenzo[g]isoquinoline-5,10-dione of Preparative Example 28 (0.050 g) and O-p-methoxybenzyl-N,N'-diisopropylisourea prepared in Step a (0.095 gs) in dichloromethane (1 mL) is stirred at room temperature for 3.5 h under a nitrogen blanket. The dark reddish-brown mixture is purified by flash chromatography over silica gel using gradient elution commencing with 100:2 (300 mL) followed by 100:4 (300 mL) mixtures of chloroform: tert-butyl methyl ether. Removal of the eluent yields 9-chloro-6-fluoro-4-(p-methoxy benzyloxy)benzo[g]isoquinoline-5,10-dione as a yellow-brown solid (0.032 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([C:19](=[N:21][O:22]C3CCCCO3)[CH3:20])=[C:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.Cl.[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([C:19](=[N:21][OH:22])[CH3:20])=[C:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C(C)=NOC1CCCCO1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C(C)=NO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-[1-[[(tetrahydro-2H-pyran-2-yl)oxy]imino]ethyl]-1H-indole (5.0 g, 11.3 mmol) in tetrahydrofuran (115 ml) is added 10 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 21/2 hours, at which time it is neutralized with concentrated ammonium hydroxide. It is concentrated to near dryness, diluted with ethyl acetate and washed twice with water and once with a saturated solution of sodium chloride. The organic phase is further dried over magnesium sulfate, filtered, and concentrated slowly in vacuo to 50 ml. The powdery crystals are collected to give 2.8 g (70.4%) of pure 1-(4-chlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-5-methoxy-2-methyl-1H-indole; mp darkens (chars) at 170°-197° C. (dec).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH2:10])[CH2:5][CH:4]1[CH:11]=[CH2:12])=[CH2:2].[CH2:13]([O:15][SiH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14]>[Pt]>[CH2:13]([O:15][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:2][CH2:1][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[CH2:5][CH:4]1[CH:11]=[CH2:12])[CH3:14]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CC1CCC(C=C)C(C=C)C1
Agent: [Pt]
Product: C=CC1CC(CC[Si](OCC)(OCC)OCC)CCC1CC[Si](OCC)(OCC)OCC
Temperature: 110 °C

Procedure:
Into a 5 liter round-bottom flask, equipped with an addition funnel, thermocouple, condenser and a magnetic stir were charged 1,2,4-trivinylcyclohexane (1390 g rams, 8.6 moles) and platinum catalyst (25 ppm of platinum (0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylenes from Aldrich). The mixture was heated to 110° C. and triethoxysilane (1132 grams, 6.9 mole, from Momentive Performance Materials, Inc.) was added drop wise while sparging dry air through the flask. The reaction was exothermic during the addition. The reaction temperature was maintained at approximately 110° C. using a stream of cool air along the side of the flask. After the addition, the reaction was stirred an additional few hours at 110° C. The reaction was monitored using gas chromatography. The products were vacuum distilled at a pressure below 1 torr, to separate out dihydrosilation product, 1,4-bis-[2-(triethoxy-silanyl)-ethyl]-2-vinyl-cyclohexane and its stereoisomers from unreacted trivinylcyclohexane and monohydrosilation product.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1(C(OC(C)(C)C)=O)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:35])[N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:54])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 177.4 %

Procedure:
To a mixture of 16-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (292 mg, 0.36 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated. The resulting oil was dissolved in DCM (2 mL) and TFA (2 mL) was added dropwise. After 30 minutes, the solvents were removed under vacuum. The residue was dissolved in 50% ACN/water (30 mL) and freeze dried to give the title compound (560 mg) as a TFA salt.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72]O)[CH2:68][CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:72][CH:69]4[CH2:70][CH2:71][N:66]([C:64]([O:63][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:65])[CH2:67][CH2:68]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (139 μl, 0.71 mmol) was added to a mixture of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), triphenylphosphine (186 mg, 0.71 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate), (152 mg, 0.71 mmol) in methylene chloride (3 ml), cooled in an ice/water bath. The mixture was allowed to warm to ambient temperature and was stirred overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography, eluting with 1% methanol/methylene chloride and 0.1% triethylamine to give tert-butyl 4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxylate (293 mg containing 13.5 mol % triphenylphospine oxide, 86%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[NH:17][N:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[CH3:22][O:21][CH2:20][C:18]1[NH:17][N:16]=[C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:19]=1
Reactant: COCc1cc([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)n[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc([C@H]2CC[C@H](N)CC2)n[nH]1
Reaction time: 8 h

Procedure:
To a Parr shaker bottle containing 13F (110 mg, 0.282 mmol) and EtOH (10 mL), was added palladium hydroxide on carbon (39.7 mg, 0.282 mmol). The mixture was purged with H2, and the bottle was shaken overnight under H2 (45 psi). The catalyst was removed by filtration and the filtrate was concentrated to provide 13G (57 mg, 96% yield) as a colorless gummy solid. MS (ES): m/z=210.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][CH2:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH:10]=C.FC(F)(CCOCCCCC1C=CC=CC=1)CCC=[O:26]>>[F:1][C:2]([F:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][CH2:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH:10]=[O:26]
Reactant: O=CCCC(F)(F)CCOCCCCc1ccccc1
Reactant: C=CCCC(F)(F)CCOCC(F)(F)c1ccccc1
Product: O=CCCC(F)(F)CCOCC(F)(F)c1ccccc1
Yield: 60 %

Procedure:
Obtained from Intermediate 85 (0.80 g, 2.7 mmol) by the procedure described in Intermediate 17. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (1:5) gave the title compound (0.48 g, 60%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CNCC(F)(F)F)cc1Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNCC(F)(F)F)cc1Cl

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.