Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]2([CH3:33])[CH3:32])=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:33])([CH3:32])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 189.5 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) in ethanol (3 mL) and tetrahydrofuran (5 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.29 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=414.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CC([O-])(C)C.[K+].[SiH:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:3]1
Reactant: CC[SiH](CC)CC
Reactant: Cn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cn(C)c2ccccc12
Yield: 83.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating N-methylindole (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (56 mg, 0.5 mmol, 1 equiv.) and Et3SiH (88 microliters, 0.55 mmol, 1.1 equiv.) in 1 mL of tetrahydrofuran for 312 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with 95:5 hexanes:NEt3 (isochratic) to obtain 103 mg (84%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.63 (dt, J=7.9, 1.0 Hz, 1H), 7.32 (dt, J=8.2, 0.9 Hz, 1H), 7.15 (s, 1H), 7.12 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.01 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 3.78 (s, 3H), 1.06-0.95 (m, 9H), 0.95-0.83 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 138.63, 135.94, 133.37, 121.44, 120.88, 118.79, 108.96, 104.39, 31.61, 7.04, 4.11. The HSQC spectrum of this reaction product as provided in FIG. 9.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]12.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[C:17]([N:6]1[CH2:5][CH2:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]2[CH2:1]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1cc2n(c1)CCNC2
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCn2cccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 12.2 g of 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine and 22.2 g of triethylamine in 50 ml of anhydrous benzene, 15.4 g of benzoyl chloride was added in small portions at 10°-15° C. The reaction mass was stirred for 3 hours at room temperature and then poured into water. The organic phase was separated, and washed with a 5% solution of sodium carbonate and then water. The solvent was removed by distillation, the residue was distilled under vacuum, and the fraction with a boiling point of 189°-191° C. at 1 mm Hg was collected. The yield of the title compound was 15 g (66.5%). Nmr (CDCl3): δ3.7-3.9 (m) (4H, 3,4-CH2); 4.58 (s) (2H, 1-CH2); 5.6-5.8 (m) (1H, 7-H); 5.8-6.0 (m) (1H, 8-H); 6.2-6.4 (m) (1H, 6 -H); 7.2-7.4 (m) (5H-C6H5). Anal. calculated for C14H14N2O: C 74.31%; H 6.24%; N 12.38% and found: C 74.21%; H 6.24%; N 12.45%.
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].O1CCOCC1.Cl>O.O1CCOCC1>[CH3:12][S:13]([O-:16])(=[O:15])=[O:14].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CS(=O)(=O)O
Agent: CCCC[n+]1ccn(C)c1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)[O-]

Procedure:
Analogously to Example 1, 26.5 g (0.152 mol) of 1-butyl-3-methylimidazolium chloride are reacted with 21.4 g of approx. 70% aqueous methanesulfonic acid, CH3SO3H. 100 ml of 1,4-dioxane are subsequently added, and 107 ml of HCl-containing water/dioxane azeotrope are distilled off at atmospheric pressure (85-101° C.). After 18 additional azeotropic distillations with 100 ml of 1,4-dioxane each time and drying of the distillation residue under reduced pressure at 1.3 Pa and 80° C., 1-butyl-3-methylimidazolium methylsulfonate is obtained. The yield is approximately quantitative.
Reaction SMILES: C(O)(=O)C.[NH2:5][NH2:6].[CH3:7][O:8][C:9](=[O:21])[C:10](=O)[CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)(=O)C>[CH3:7][O:8][C:9]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:6][N:5]=1)=[O:21]
Reactant: NN
Reactant: COC(=O)C(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2)[nH]n1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
983 mg hydrazine acetate was added to 2 g 2,4-Dioxo-4-phenyl-butyric acid methyl ester in 10 mL concentrated acetic acid. The mixture was stirred over night at RT. Then water was added. The precipitate was filtered, stirred with diisopropylether and again filtered to give 1.3 g desired product. Rt: 1.39 min (method O), (M+H)+: 203
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C(=O)(O)[O-].[Na+].[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25]C(C)(C)C)=[O:24]>C(Cl)Cl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]([OH:25])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 59.9 %

Procedure:
To a vigorously stirred solution of 4-formylbenzenesulfonyl chloride (1 g, 5 mmol) in DCM (10 mL), was added saturated aqueous sodium bicarbonate solution (10 mL), followed by tert-butyl(2S)-pyrrolidine-2-carboxylate (856 mg, 5 mmol). The organic phase was passed through a hydrophobic frit, and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in isohexane, to afford the title compound as a colourless gum (849 mg, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzamide as a white powder, m.p. 90.5-91.5° C. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (t, J=5.7 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.21 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.61 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.25 (m, 2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 451.2008 (451.2008 calcd for C27H25N5O2).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:10][CH:9]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:19]([Li])CCC.CCCCCC.CI>O1CCCC1>[CH3:19][C:1]1([S:4]([N:7]2[CH2:10][CH:9]([O:11][Si:12]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH2:13][CH3:14])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2CC2)C1
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2(C)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cyclopropylsulfonyl)-3-[(triethylsilyl)oxy]azetidine (1.0 g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added 2.50 M of n-butyllithium in hexane (1.37 mL, 3.43 mmol) dropwise. After stirring at this temperature for 1 hour, methyl iodide (0.224 mL, 3.60 mmol) was added. After 30 minutes, the reaction temperature was raised to 0° C. and stirred for 50 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate, followed by brine and the product was extracted with ethyl acetate. The extracts were dried over sodium sulfate, decanted and concentrated. Flash column chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes afforded product (890 mg, 85%).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].[CH3:15][CH:16]([OH:18])[CH3:17].O>O1CCCC1>[CH:16]([O:18][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10])([CH3:17])[CH3:15]
Reactant: FC(F)(F)c1cnccc1Cl
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccncc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-chloro-3-trifluoromethylpyridine hydrochloride salt (2.0 g) in tetrahydrofuran (5 mL) were added sodium hydride (60%, 2.8 g) and propan-2-ol (2.8 g), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 4-isopropoxy-3-trifluoromethylpyridine (1.5 g). To a solution of the obtained compound (1.5 g) in ethyl acetate (20 mL) was added 4-bromomethylbenzoic acid methyl ester (2.0 g) at room temperature, and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was removed to give 4-isopropoxy-1-(4-methoxycarbonylbenzyl)-3-trifluoromethyl-pyridinium bromide (2.1 g). To a solution of the obtained compound (2.1 g) in dimethoxyethane (10 mL) were added acrylonitrile (1.3 g), manganese dioxide (2.1 g) and triethylamine (1.5 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was filtered through a Celite pad, and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.04 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:3]=1[F:28].Cl.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[F:28][C:3]1[C:2]2[N:1]=[N:30][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (2.07 g, 5.17 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO2 (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO3 (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.57 (s, 1H), 7.08 (m, 4H), 4.03 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:6]=[CH:7][C:8]=2[NH:12]C(=O)OC(C)(C)C)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C:8]1[CH:7]=[CH:6][C:5]([CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:4]2[C:9]=1[C:10](=[O:11])[N:2]([CH3:1])[CH2:3]2
Reactant: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(CN3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl [2-methyl-3-oxo-7-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 109B) was added DCM (0.5 mL) and TFA (0.5 mL, 6 mmol). The solution was stirred at room temperature for 20 minutes. The crude product was dried in vacuo and used directly in next step without further purification. MS (ES+): m/z 246.31 (100) [MH+]; HPLC: tR=0.29 min (UPLC, Analytical).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:40].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 79.7 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(3-ethoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (165 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (261 mg, 79%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.17 (t, 3H), 1.96 (quintet, 2H), 2.39 (m, 4H), 2.46 (t, 2H), 3.60 (m, 6H), 3.93 (s, 3H), 4.19 (t, 2H), 4.40 (s, 2H), 6.17 (s, 2H), 7.17 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.33 (s, 1H), 9.54 (s, 1H); Mass Spectrum: M+H+ 555/557.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][OH:16])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25]>CCOC(C)=O>[Cl:29][C:28]([Cl:31])([Cl:30])[CH2:27][O:26][C:24](=[O:25])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][OH:16])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccnc(OCCO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a stirred solution of Intermediate 67c (139 mg, 0.50 mmol) in EtOAc (5 mL) and 1M NaOH solution (1.26 mL, 1.26 mmol) was added 2,2,2-trichloroethyl chloroformate (117 mg, 76 μL, 0.55 mmol) and the reaction was stirred at RT. After 1 h, a further 1.1 eq of 2,2,2-trichloroethyl chloroformate was added, stirred for an additional 1 h, then a further 2.2 eq. of 2,2,2-trichloroethyl chloroformate added. After stirring for an additional 2 h, the reaction was partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous layer extracted with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-50% EtOAc/cyclohexane, and triturated with Et2O to afford the title compound (74 mg, 33%). LCMS (Method 3) Rt 3.93 min, 451.1, 453 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[O:3]1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:13])([CH3:1])[O:3][C:4]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: CC1(C)OC(c2cscn2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2cscn2)=C(Br)C1=O
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (90 mg, 0.46 mmol) in CHCl3 (1.8 mL) was added NBS (0.12 g, 0.69 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water (5 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (40 mg, 71%) as an off white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)C.[OH-].[K+].Cl>CO.O>[CH2:14]([C:9]1[CH:8]=[C:7]([CH2:6][CH:5]([O:21][CH2:22][CH3:23])[C:4]([OH:24])=[O:3])[CH:12]=[CH:11][C:10]=1[OH:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester (0.38 g, 1.16 mmol) in MeOH (5 mL), a solution of KOH (1.62 g, 29 mmol) in H2O (5 mL) was added. The mixture was stirred for 2 h at room temperature then acidified with aq. HCl (10%) and extracted with dichloromethane. The combined organic layers were dried and evaporated and the remaining crude product was purified by column chormatography to yield the title compound as an oil (0.35 g, 74.8%). Mass Spectrum: M+H+ 300.94, M−H+ 298.99.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=O.[CH3:34][CH:35]([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:35]([S:38]([NH:41][C:25](=[O:27])[C:24]1[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:23]=1[F:22])(=[O:40])=[O:39])([CH2:36][CH3:37])[CH3:34]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: CCC(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reaction time: 18 h
Yield: 46 %

Procedure:
N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.41 g, 2.1 mmol), 4-dimethylaminopyridine (0.26 g, 2.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.9 mL, 4.2 mmol) were added to a solution of 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) in DCM. After 10 minutes butane-2-sulfonamide (Preparation 29, 0.29 g, 2.1 mmol) was added and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to yield the title compound as a white solid (0.19 g, 31% yield):
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]5[S:35][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=5)=[O:37])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)s1

Procedure:
The title compound, light yellow solid (107 mg, 83%), MS (ISP) m/z=517.2 [(M+H)+], mp 255° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([OH:30])[CH:27]([CH3:29])[CH3:28].[H-].[Na+]>O1CCOCC1>[CH2:26]([O:30][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(F)c3)CC2)cc1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(OCC(C)C)c3)CC2)cc1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To a mixture of 34 mg (0.10 mmol) (S)—N-{1-[4-(2′-fluoro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-phenyl]-ethyl}-acetamide (XIX.1) and 74 mg (1.0 mmol) isobutyl alcohol in 2 mL dioxane is added 20 mg (0.50 mmol) NaH (60% in mineral oil). The mixture is stirred at 130° C. for 12 h. The solvent is removed in vacuo and the residue is purified by HPLC (RP X-Bridge; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38].C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:37]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:15][C:16]4[C:17]5[CH:25]=[C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[N:23]=[CH:22][C:18]=5[N:19]=[CH:20][N:21]=4)=[CH:3][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:38])[CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: COc1cccc(C(=O)N2CCC(Oc3ccc(Nc4ncnc5cnc(N6CCOCC6)cc45)cc3C)CC2)c1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and 3-methoxy benzoylchloride by a procedure analogous to the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone. LRMS: 555.2 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.57 (s, 1H), δ 8.79 (s, 1H), δ 8.32 (s, 1H), δ 7.47-7.53 (m, 3H), δ 7.32 (t, J=7.68, 1H), δ 7.31 (d, J=8.72, 1H), δ 6.93-6.99 (m, 3H), δ 4.62 (br. s, 1H), δ 3.76 (br. s, 1H), δ 3.52-3.54 (m, 6H), δ 3.75 (m, 6H), 3.302 (s, 3H), δ 2.18 (s, 3H), δ 1.97 (br. s, 1H), δ 1.90 (br. s, 1H), δ 1.66 (br. s, 1H).