Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]#[N:16])=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1.[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[CH:13]=2)[C:9]([C:15]#[N:16])=[C:10]1[CH3:14])[CH3:18]
Reactant: CCI
Reactant: COc1ccc2c(C#N)c(C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) was added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture was poured into ice water and the extracted with CH2Cl2. The organic layer was washed with brine and dried with Na2SO4. The solvent was evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:40]([CH3:43])[C:41]#[N:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[C:36]([CH:40]([CH3:43])[C:41]#[N:42])[CH:37]=[N:38][CH:39]=2)=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C#N)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C#N)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (from example 1, step 4, 0.12 g, 0.5 mmol) in 1,4-dioxane (8 mL) and H2O (0.55 mL) under nitrogen was added 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propanenitrile (0.120 g, 0.4 mmol) and potassium carbonate (0.14 g, 1 mmol). The resulting mixture was degassed with nitrogen for 15 min. After this time, (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.26 mg, 0.036 mmol) was added and the reaction mixture was again degassed with nitrogen for 10 min. At the conclusion of this period, the reaction mixture was stirred at 95° C. for 16 h. The reaction mixture was then allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then transferred to a separation funnel. The aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using 1% methanol in DCM to afford racemic 2-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)propanenitrile (95 mg, 63% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H), 8.80 (d, 1H, J=2 Hz); 8.77 (s, 1H); 8.26 (d, 1H, J=6 Hz); 7.92 (dd, 1H, J=1.2, 6.8 Hz); 7.85 (t, 1H, J=6.8 Hz); 7.73 (dt, 1H, J=1.6, 7.6 Hz); 7.58-7.52 (m, 5H); 7.34-7.32 (m, 2H); 7.24 (t, 1H, 7.2 Hz); 6.86 (t, 1H, J=4 Hz); 4.76 (d, 2H, J=4.4 Hz); 4.59 (q, 1H, J=7.2 Hz); 1.68 (d, 3H, 7.2 Hz). LCMS Method Y: retention time 1.68 min, [M+1]=443.2.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=2)=[CH:7][CH:8]=1)N.[H][H]>CO.[Ni]>[NH2:1][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(NN)nn2)cc1OC(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(-c2ccc(N)nn2)cc1OC(C)C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
10 g (36 mmol) of 3-hydrazino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine are hydrogenated in 100 ml of methanol in the presence of 1 g of Raney nickel with hydrogen under atmospheric pressure at room temperature while stirring efficiently. Starting material is no longer detectable after 4 hours. The solution is filtered to remove catalyst and concentrated in vacuo, and the residue is crystallized from isopropanol/cyclohexane. 4.3 g (46%) of 3-amino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine of m.p. 184° C. are obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Br>C(COC)OC>[C:3]1([CH:9]([CH2:18][CH:17]=[CH:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[CH3:13])[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C=CCBr
Reactant: CC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccccc1C)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (11.76 g., 0.28 mole, oil dispersion) is suspended in glyme (400 ml.) and phenyl acetone (37.57 g., 0.28 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for one hour. The mixture is cooled to room temperature and a solution of crude o-methylcinnamyl bromide (59.10 g., 0.28 mole) in glyme (50 ml.) is added dropwise. When addition is complete, the mixture is heated on a steam bath for 24 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from filtrate, a dark viscous residue is obtained. Trituration of this residue with petroleum ether (30°-60°C., 100ml.) produces tan solid, yield 26.5 g., m.p. 72°-75°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:35][NH2:36]>C(Cl)Cl>[OH:35][NH:36][C:12](=[O:13])[CH2:11][CH:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(CC(=O)NO)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
To a solution of 1 g (3.31 mmol) of 3-(4-methoxyphenylsulfanyl)-4-phenylbutyric acid in 30 mL of CH2Cl2 at 25° C. under argon is added 0.2 mL of DMF followed by 4.1 mL (8.27 mmol) of 2 M solution of oxalyl chloride in CH2Cl2. After stirring at 25° C. for 1.5 hours, 2.1 mL (16.53 mmol) of O-trimethylsilylhydroxylamine is added and this is then stirred at 25° C. for 18 hours. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 0.86 g (82%) of N-hydroxy-3-(4-methoxyphenylsulfanyl)-4-phenylbutyramide as a yellow crystalline solid.
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([O:23][C@@H:24]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:27]([CH3:38])[O:26][C@H:25]1Br)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@@H:27]([CH3:38])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[O:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Br)[C@@H]1OC(C)=O
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@@H]1OC(C)=O
Yield: 56.6 %

Procedure:
Following a procedure similar to that of Example 1 but using 2.88 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 7.77 g of 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl bromide there was obtained 3.32 g of 1-(4-nitrobenzyl)-4-(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl)oxy-1H-imidazole-5-carboxamide.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18][C:19]2[C:20]([F:41])=[N:21][C:22]([N:25](C(OC(C)(C)C)=O)[CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:17][C:15]1[CH:16]=[C:11]2[C:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=4)=[N:21][C:20]=3[F:41])=[CH:9][NH:8][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2cn(C(=O)OC(C)(C)C)c3ncc(Cl)cc23)c(F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)c(F)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To 3-{6-[tert-butoxycarbonyl-(5-fluoro-pyridin-3-ylmethyl)-amino]-2-fluoro-pyridin-3-ylmethyl}-5-chloro-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (144, 0.280 g, 0.478 mmol) in 10.0 mL of dichloromethane, trifluoroacetic acid (1.00 mL, 13.0 mmol) was added and the reaction stirred at room temperature overnight. This was pooled with a separate reaction run similarly and concentrated under vacuum. The resulting material was combined with aqueous potassium carbonate and ethyl acetate and mixed. The aqueous layer was separated and the organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (P-2001, 99 mg). MS (ESI) [M+H+]+=386.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=O)C.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nnc(S)o1
Reactant: CN
Product: CNC(=O)c1nnc(S)o1

Procedure:
This product was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with methylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:13]O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:10][C:9]1[O:11][N:13]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)on1
Yield: 56.2 %

Procedure:
A mixture of ethyl 2,4-dioxovalerate (25 ml, 178 mmol), hydroxylamine hydrochloride (13.7 g, 197 mmol) and sodium bicarbonate (15.4 g, 183 mmol) in ethanol (125 ml) were heated at reflux for 2.5 h, cooled and the solvent removed under reduced pressure. The residue was taken up in chloroform and washed with water, the organic layer separated and dried (MgSO4). Solvent removal and distillation under reduced pressure gave the desired product (15.44 g, 100 mmol, 56%); b.p. 82°-86° C. at 0.5 mm Hg; νmax (film) 3120, 2980, 2930, 1730, 1600, 1450, 1270, 1200, 1100, 1020, 915, 830, 780 cm-1 ; δH (CDCl3) 1.40 (3H, t, J 7 Hz, OCH2CH3), 2.50 (3H, s, CH3 -5), 4.40 (2H, q, J 7 Hz, OCH2CH3), 6.40 (1 H, s, CH-4).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:10]([I:11])=[C:9]([NH2:12])[C:8]([I:13])=[C:7]([NH2:14])[C:6]=1[I:15])[CH2:3][OH:4].C([O:19][CH2:20][C:21](Cl)=[O:22])(=O)C>>[OH:1][CH:2]([C:5]1[C:6]([I:15])=[C:7]([NH:14][C:2](=[O:1])[CH2:3][OH:4])[C:8]([I:13])=[C:9]([NH:12][C:21](=[O:22])[CH2:20][OH:19])[C:10]=1[I:11])[CH2:3][OH:4]
Reactant: Nc1c(I)c(N)c(I)c(C(O)CO)c1I
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)Nc1c(I)c(NC(=O)CO)c(I)c(C(O)CO)c1I

Procedure:
1-(1,2-Dihydroxyethyl)-3,5-diamino-2,4,6-triiodobenzene is acylated with acetoxyacetyl chloride using for example such a procedure as described in Example 4d. The crude product is then hydrolyzed analogous to Example 4e to give the final product. Purification of the crude product is carried out using preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH:20]=C)[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.[O:24]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH:20]=[O:24])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=Cc1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 3-necked flask is charged with 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-vinyl-pyridazin-3-one (418 mg, 1.19 mmol) and dichlormethane (10 mL). The flask was fitted with a thermometer, an inlet tube and an outlet tube connected to two Dreschel bottles, the latter of which contained a 10% aq. KI solution. The inlet tube was connected to the ozone generator (turned off). The airflow was turned on to give a steady bubbling through the reaction flask and out through the KI solution. The flask was cooled to −78° C. and once at this temperature, the ozone generator was turned on and bubbled for 10 min. The KI solution became darker over the course of the reaction. The ozone generator was turned off and the reaction purged with air for 2 min. It was then disconnected from the inlet and outlet tubes and triphenylphosphine (939 mg, 3.58 mmol) was added. The reaction was allowed to stir and gradually warm to RT over 1 h, then stirred at RT for a further 3 h and left to stand overnight. The resulting reaction mixture was concentrated onto silica and the purified by chromatography (combiflash, 0 to 50% EtOAc/ihexane) to give the desired product 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carb aldehyde (262 mg, 0.744 mmol, 63%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1)=O)(C)(C)C.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 48 mg (166 μmol) 3-benzothiazol-2-yl-azetidine-1-carboxylic acid tert-butyl ester was added 5 mL DCM and 5 mL TFA. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the product as the TFA salt which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][CH2:66][CH2:67][NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:65][CH2:66][CH2:67][NH:68][C:69]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:75])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25](=[O:26])[O:27][CH:28]([CH3:29])[CH3:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
To a flask charged with 2-(4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid (for a preparation see Intermediate 50) (85 mg, 0.2 mmol) and HATU (91 mg, 0.240 mmol) was added DMF (2 mL) and the mixture treated with DIPEA (0.105 mL, 0.600 mmol) at room temperature. After 5 min, 1,1-dimethylethyl (2-aminoethyl)carbamate (0.047 mL, 0.300 mmol) was added, the mixture was stirred at room temperature for 3 h and then partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. the residue was purified by chromatography, eluting with a MeOH/DCM gradient, to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-2-oxoethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (56 mg, 0.099 mmol, 49.4% yield) as a pale yellow foam. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1I.F[P-](F)(F)(F)(F)F>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([C:17]([O:16][CH3:15])=[O:29])=[CH:19][C:20]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a solution of 4-fluorophenol (1.25 g, 11.15 mmol) in toluene (50 mL) was added cesium carbonate (6.10 g, 18.7 mmol) and the mixture was stirred for 15 min at rt. 2-Iodoterephthalic acid dimethyl ester (3.0 g, 9.37 mmol) and tetrakisacetonitrilecopper hexafluorophosphate (435 mg) were added, and the mixture was heated to reflux for 18 h. The mixture was allowed to cool to rt and poured into an ice-cold saturated ammonium chloride solution. The organic layer was separated, washed with a saturated potassium carbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified via flash column chromatography (elent gradient 1% to 20% EtOAc in heptane) to yield 1.25 g (43.8%) of title compound 2-(4-fluorophenoxy)-terephthalic acid dimethyl ester, 1e. MS m/z (MH+) 305.0.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][C:13]1[N:14]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:32][C:17]1[C:16]2[N:25]=[C:13]([CH3:12])[N:14]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[C:15]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: [NH4+]
Reactant: Cc1nc2cnc3ccccc3c2n1CCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (3.48 g, 15.1 mmol) was added to a solution of 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (2.20 g, 8.65 mmol) in chloroform (100 mL). The reaction was stirred for two hours at ambient temperature and cooled to 0° C. Ammonium hydroxide (40 mL) was added followed by p-toluenesulfonyl chloride (3.21 g, 16.9 mmol), which was added over a period of five minutes. The reaction was stirred for two hours at ambient temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 80:20). The resulting solid was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven at 60° C. to provide 0.145 g of 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a off-white powder, mp 237-239° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=1[CH2:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>O1CCCC1>[CH2:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]2[CH2:16][C:15]3[C:14](=[CH:34][C:33]([F:35])=[CH:32][CH:31]=3)[NH:13][C:1]2=[O:2])[CH2:19][CH2:20]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)ccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
1,1′-Carbonyldiimidazole (6.92 g, 42.7 mmol) was added to a solution of N-(2-amino-4-fluorobenzyl)-1-benzylpiperidin-4-amine (8.64 g, 30.2 mmol) in dry tetrahydrofuran (150 mL) at 0° C. in one portion. After 5 min, the mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was partitioned between water/diethyl ether (200 mL/200 mL). After separation, the aqueous solution was extracted with diethyl ether (200 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford a light yellow solid which was triturated with diethyl ether (3×10 mL) to give the title compound as a white solid (3.41 g, 36% yield). 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.18 (m, 5H), 6.92-6.82 (m, 1H), 6.75 (dd, J=8.2, 2.6, 1H), 6.66 (dd, J=8.8, 4.8, 1H), 4.48-4.34 (m, 1H), 4.03 (s, 2H), 3.53 (s, 2H), 2.98 (d, J=11.2, 2H), 2.37-2.12 (m, 2H), 1.99-1.82 (m, 2H), 1.67 (d, J=11.2, 2H); Mass spec.: 340.03 (MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:19][C:20]([S@@:23](/[N:25]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:8][N:7]=2)=[CH:10][CH:11]=1)=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: [Ti+4]
Agent: CC[O-]
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Yield: 80.9 %

Procedure:
A three-neck two liter flask equipped with dropping funnel, reflux condenser, and mechanical stirrer was charged with 4-[5-(trifluoromethyl)pyridin-2-yl]benzaldehyde (69.00 g, 274.7 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (33.66 g, 277.7 mmol). The apparatus was purged with dry nitrogen and warmed with a heat gun. The solids were suspended in dichloromethane (1.0 L) whereupon titanium(IV) ethoxide (115 ml, 549 mmol) was added dropwise over 30 minutes during which time the solids dissolved affording a yellow solution. No increase in temperature was observed. The reaction was heated to reflux for 12 hours. The reaction was quenched with a dropwise addition of MeOH (400 mL) followed by saturated aqueous sodium bicarbonate (150 mL). The resulting precipitate was removed by filtration through a pad of 1:1 celite:florisil and the filter cake was washed with ethyl acetate (3×200 ml). The resulting mixture was partially concentrated under vacuum (50% volume) and then dried over magnesium sulfate. The resulting solution was filtered through a Buchner funnel, the salts were washed with ethyl acetate (3×200 ml) and the resulting filtrate was concentrated in vacuo. The crude solid was suspended in heptane (250 ml) and heated to boiling with a heat gun whereupon ethyl acetate was added in aliquots to dissolve the solids. The mixture was then cooled slowly to affect crystallization (slowly to ambient temperature, then with ice). The solids were collected by vacuum filtration, and the process was repeated once more to yield the final product (78.78 g, 81%) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3, δ): 9.01 (s, 1H), 8.67 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.07 (dd, J=8.4, 2.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.2 Hz, 1H), 1.30 (s, 9H). MS (M+1) 355.1.