Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:30])[CH2:5]1)=[O:3].[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]>CC(=O)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:30])[CH2:5]1)=[O:3]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: Cc1cccc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Solvent: CC(C)=O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A solution of 3 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide in 80 parts of 2-propanone was added to a solution of 1.9 parts of (Z)-2-butenedioate in 40 parts of 2-propanone: slowly crystallization. The product was filtered off and recrystallized twice from 2-propanol and once from 2-propanone, yielding 1.56 parts (39%) of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (Z)-2-butenedioate (1:2) monohydrate; mp. 119.6° C. (compound 174).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[CH:18]=[O:19].[CH2:20]=[N:21][CH:22](S(C1C=CC(C)=CC=1)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[C:23]1([C:22]2[N:21]=[CH:20][O:19][C:18]=2[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=NC(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ocnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
To a solution of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbaldehyde (52.8 mg, 0.197 mmol) in MeCN (0.4 mL) were added N-methylidene-1-[(4-methylphenyl)sulfonyl]-1-phenylmethanamine (53.8 mg, 0.197 mmol) and K2CO3 (35.4 mg, 0.256 mmol) at room temperature. The suspension was stirred at room temperature for 1 day. The suspension was diluted with water, extracted with AcOEt, washed with brine, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=90/10 to 0/100) and crystallized with AcOEt/hexane to yield the title compound (18.6 mg, 25% yield) as a solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.75 (1H, d, J=8.5 Hz), 7.33-7.43 (3H, m), 7.64-7.70 (2H, m), 7.72-7.83 (2H, m), 7.92-8.01 (2H, m), 8.65 (1H, s), 9.02 (1H, d, J=7.7 Hz). Anal. Calcd for C20H12F3N3O2.0.2H2O: C, 62.08; H, 3.23; N, 10.86. Found: C, 62.08; H, 3.38; N, 10.67.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[CH2:4][C:5]#[N:6].[H-].[Na+].I[CH3:12].O>CN(C)C=O>[CH3:12][O:1][CH2:2][C:3]([CH3:8])([CH3:7])[CH2:4][C:5]#[N:6]
Reactant: CC(C)(CO)CC#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)(C)CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
Step C To the solution of 4-hydroxy-3,3-dimethyl-butyronitrile (0.8 g, 7 mmol) in anhydrous dimethylformamide (5 mL) was added NaH (60%, 0.42 g, 11 mmol). The mixture was stirred at room temperature for 15 min, then iodomethane (0.88 mL, 14 mmol) was added. The mixture was stirred at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 4-methoxy-3,3-dimethyl-butyronitrile as a yellow oil (0.85 g, 94%).
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1>[CH2:1]([Sn:5]1([CH2:6][CH2:7][CH2:8][CH3:9])[O:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: OCCO
Solvent: c1ccccc1
Product: CCCC[Sn]1(CCCC)OCCO1
Reaction time: 4 h
Yield: 94.2 %

Procedure:
24.98 g (0.1 mol) of dibutyltin oxide and 6.21 g (0.1 mol) of ethylene glycol were introduced into a 500 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 250 ml of benzene was added, and the mixture was dehydrated by azeotropic distillation at 93° C. and stirred for 4 hours during which it became an uniform solution. Then, the solution was filtered while it was hot. The benzene was distilled off under reduced pressure, and the resulting white solids were dried at 60° C. for 3 hours in vaccuo to give 1,1-dibutylstanna-2,5-dioxacyclopentane, 27.6 g (94.2% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])cn1

Procedure:
To a suspension of 36.9 g of 2-chloro-5-nitropyridin-4-amine (example E6) in 500 ml methanol were added 250 ml of a freshly prepared solution of sodium methoxide in methanol (5.7 g sodium) and the reaction mixture was refluxed for 12 h. About 500 ml methanol were distilled off and 500 ml of water were added. The resulting precipitate was filtered, washed with ice water and dried under vacuum to the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]4[C:18]([C:21]([CH3:30])([O:23]C5CCCCO5)[CH3:22])=[N:19][N:20]=[C:14]4[CH:13]=3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]4[C:18]([C:21]([OH:23])([CH3:30])[CH3:22])=[N:19][N:20]=[C:14]4[CH:13]=3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccn2c(C(C)(C)OC3CCCCO3)nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccn2c(C(C)(C)O)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of N-cyclopropyl-3-fluoro-4-methyl-5-{3-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl][1,2,4]triazolo[4,3-a]pyridin-7-yl}benzamide (0.065 g, 0.14 mmol) in methanol (1 mL) was added 4-methylbenzenesulfonic acid hydrate (0.010 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 5 hours, the solvent was concentrated under reduced pressure and the oil obtained was dissolved in ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulphate and concentrated. The crude was treated with diethyl ether to obtain the title compound (78%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:18][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccccc1-c1cc2c(O)ncnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccccc1-c1cc2c(Cl)ncnc2[nH]1
Temperature: 0 °C

Procedure:
Under argon, 6.2 g (25.7 mmol) of 6-(2-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 62 ml of phosphorus oxychloride are heated at 125° C. for 1.5 hours. The reaction mixture is poured into ice-water and extracted three times with ethyl acetate. The organic phases are washed with water, NaHCO3 solution and brine, dried with MgSO4 and concentrated by evaporation. Filtering through a silica gel column with ethyl acetate yields the title compound; TLC-Rf =0.8 (hexane/ethyl acetate [1:1]).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[N+:19]([O-])=O)=[S:7])=[O:4]>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH2:19])=[S:7])=[O:4]
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Yield: 82.4 %

Procedure:
1-Methoxycarbonyl-3-(4n-butyl-2-nitrophenyl)-thiourea (69.0 g; 0.22 mole) and ferrous chloride tetrahydrate (9.2 g) were finely powdered together and suspended in a mixture of methanol (350 ml) and water (70 ml). The vigorously stirred suspension was then heated to reflux and reduced iron powder (42.0 g; 0.78 mole) was added in portions during forty-five minutes. When the addition was complete, the reaction mixture was refluxed for a further thirty minutes and filtered. On cooling a crystalline solid separated from the filtrate. The dark brown filter cake was extracted with boiling methanol (3 × 200 ml) and the combined methanol extracts were evaporated to dryness to give a solid residue. This was combined with the solid obtained from the cold filtrate and the combined solids were crystallised from methanol to give 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea (51.0 g), m.p. 157°-159° C. (with decomposition).
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][O:5][C:6]1[C:11]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([O:31]C)=O)[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)=[CH:10][CH:9]=[C:8]([O:34][CH3:35])[N:7]=1>>[CH3:4][O:5][C:6]1[C:11]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([NH:3][CH3:2])=[O:31])[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)=[CH:10][CH:9]=[C:8]([O:34][CH3:35])[N:7]=1
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1
Reactant: CN
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N4-(2,6-dimethoxypyridin-3-yl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine gave (±)-N4-(2,6-dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.98 (d, 1H, J=8.1 Hz), 7.81 (d, 1H, J=3.6 Hz), 7.39 (bd, 1H, J=2.4 Hz), 7.06 (dd, 1H, J=2.4 and 8.7 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.31 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.3 Hz), 3.96 (s, 3H), 3.93 (s, 3H), 3.46 (dd, 1H, J=7.8 and 10.5 Hz), 3.19 (dd, 1H, J=5.7 and 6.3 Hz), 2.77 (d, 3H, J=4.8 Hz); LCMS: purity: 98%; MS (m/e): 441 (MH+).
Reaction SMILES: C[Si](CC[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(C)C.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[CH:27]([CH3:29])[CH3:28].O.S(=O)(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:28][CH:27]([CH3:29])[CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: CCOC(=O)CCC[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)C(C)C
Reaction time: 0.33 h
Yield: 5.9 %

Procedure:
Under a nitrogen atmosphere, ethyl trimethylsilylethylacetate (5.19 g) was added at −78° C. to a solution of a lithium diisopropylamide/tetrahydrofuran solution (1.5 M, 21.6 mL) added to tetrahydrofuran solution (100 mL). After 20 minutes, a tetrahydrofuran solution (10 ml) of isobutyrophenone (4.0 g) was added thereto, and the temperature of the mixture was naturally returned to room temperature. After stirring 18 hours, sodium bisulfate monohydrate (0.6 g) was added and the mixture was stirred. Further, after 10 minutes, the organic layer was separated by adding a 0.2N hydrochloric acid solution (250 mL) and ethyl acetate (200 mL) thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. 756 Mg among the resulting crude product (7.9 g) was dissolved in methanol (5 mL), a catalytic amount of 10% palladium carbon (9.5 mg) was added, and the mixture was stirred under hydrogen atmosphere. After 4 hours, the catalyst was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a colorless oil (350 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([OH:15])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)OC(C)(C)C)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 59.1 %

Procedure:
(R)-tert-Butyl 2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate was stirred in DCM/TFA (50%, 10 mL) for 1 h, concentrated and dried in vacuo to afford the title compound as a beige solid (0.32 g, 59.1%). 1H NMR (400 MHz, DMSO-d6) δ 0.84 (d, J=6.30 Hz, 3 H) 1.04 (d, J=6.32 Hz, 3 H) 2.39 (dt, J=10.61, 6.57 Hz, 1 H) 4.83 (d, J=10.61 Hz, 1 H) 5.04 (d, J=9.60 Hz, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 12.39 (br. s., 1 H). [M+H] calc'd for C14H14FN3O3, 292; found, 292.5.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:22]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: C=C(F)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
27.5 g (0.169 mol) of 3-trifluoromethylphenol were dissolved in 100 ml of anhydrous methylene dichloride, and 17.1 g (0.169 mol) of triethylamine were added in portions to the solution; 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 30 ml of methylene dichloride. The mixture of filtrate and wash solution was distilled, after adding 0.01 g of hydroquinone monomethyl ether. 27 g (68% of theory) of 3-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 78° to 79° C. (under 4 mbar).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>CN(C)C=O>[NH2:12][C:11]1[N:3]=[CH:4][N:5]=[C:6]2[C:10]=1[N:9]=[CH:8][N:7]2[CH:14]=[CH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2C=CCCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
3.4 g of sodium hydride were added to 9.6 g of adenine in 270 ml of dimethylformamide and the mixture was stirred for 2 hours and 30 minutes. 20 g of N-(4-bromobutyl)-phthalimide were added and the mixture was stirred at ambient temperature for 74 hours, followed by filtering. The solvent of the filtrate was evaporated and the precipitate was washed with ether, with water, with ethanol, then again with ether and dried. The residue was dissolved in methanol at 65° C. and chilled to obtain 15.00 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][CH2:48][OH:49]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:48][OH:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Reactant: OCCBr
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCO)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(a), the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] was alkylated with 2-bromo-1-ethanol to yield the (3R,4R)-3-[1-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 661 (M+H)+.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1.O>CN(C=O)C>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reaction time: 16 h

Procedure:
1-Hydroxy-7-azabenzotriazole (0.844 g, 6.21 mmol, 0.05 eq), EDCxHCl (26.09 g, 136.64 mmol, 1.1 eq) and morpholine (12.9 g, 149.06 mmol, 1.2 eq) were added to a stirred solution of 1H-indole-6-carboxylic acid (20.0 g, 124.22 mmol, 1.0 eq) in DMF (150 mL). Stirring was continued for 16 h at room temperature and water (200 mL) was then poured into the reaction mixture. The mixture was extracted with dichloromethane (2×150 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulphate and evaporated. White solid. Yield: 16.0 g (56% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5](F)[CH:4]=1)#[N:2].Cl.[CH2:18]([NH2:20])[CH3:19].CN(C=O)C>O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([NH:20][CH2:18][CH3:19])[CH:4]=1)#[N:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc(C#N)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
The product from Example 140 Part A (0.30 g, 1.36 mmol) and ethylamine hydrochloride (0.22 g, 2.72 mmol) were added together with 5 mL of DMF. The mixture was heated at 50° C. under N2 for 2 h. Water was added, and the mixture was extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (silica, EtOAc/hexane) to give 50 mg of the desired product. MS: 247.3 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:32].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([F:32])[N:15]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [F-]
Reactant: CC(C)(C)c1ccc(CCOc2nc(OS(=O)(=O)C(F)(F)F)nc3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2nc(F)nc3ccccc23)cc1

Procedure:
A 15 ml round bottom flask is charged with 4-(2-(4-tert-butylphenyl)-ethoxy)-2-(trifluoromethanesulfonyloxy)-quinazoline (0.3 g, 0.66 mmol). Tetrabutylammonium fluoride solution (1M in THF, 3.3 ml, 3.3 mmol) is then added to it and the solution refluxed for 60 minutes. The mixture is then cooled and water is added to it. It is then extracted with dichloromethane, washed with water and dried. The crude obtained after concentration is purified by silica gel flash chromatography (ethyl acetate/hexanes) to obtain the desired compound.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]4[OH:30])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A stirred mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (165 mg, 0.53 mmol) from Step 5 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (122 mg, 1.06 mmol), and DIEA (137 mg, 1.06 mmol) in anhydrous DMA (3 mL) was sealed and heated at 100° C. for 15 h. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (44 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.39 (dd, J=1.1, 4.7 Hz, 1H), 8.08 (dd, J=1.2, 8.0 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.10-7.19 (m, 2H), 5.50 (s, 2H), 4.70 (br s, 1H), 3.25-3.45 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.14-1.32 (m, 4H). LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]N3C4C(=CC=CC=4)CC3=O)[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([O:34]C(C)(C)C)=[O:33].[O:45]1[CH2:50][CH2:49]OCC1>Cl>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:50](=[O:45])[C:49]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@@H:31]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:32]([OH:34])=[O:33]
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Reactant: C1COCCO1
Agent: Cl
Product: O=C(CCCN1CCC2(CC1)C(=O)N([C@H](C(=O)O)c1ccccc1)CN2c1ccccc1)c1ccccc1
Yield: 28 %

Procedure:
A solution of (R)-tert-butyl 2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (257 mg, 0.453 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The pure extract was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as a cream powder (100 mg, 28%); 1H NMR (400 MHz, DMSO-d6): δ 1.88 (m, 2H); 2.05-2.09 (m, 2H); 2.85 (m, 2H); 3.15-3.24 (m, 2H); 3.56-3.59 (m, 4H); 4.19 (d, 1H, J=4.4 Hz); 4.89 (d, 1H, J=4.8 Hz); 5.81 (s, 1H); 6.84 (m, 1H); 6.99 (d, 2H, J=8.4 Hz); 7.23 (t, 2H, J=7.6 and 8.4 Hz); 7.45-7.47 (m, 5H); 7.55 (t, 2H, J=7.6 and 8 Hz); 7.64-7.68 (m, 1H); 7.98-8.01 (m, 2H); 10.4 (bs, 1H); 13.5 (bs, 1H); MS for C31H33N3O4 m/z 512.4 (M+H)+.