Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][C:10]3[C:15]4[C:20]([NH:21][C:9]=3[C:8]=2[CH:26]=1)=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=4)[CH:2]=[CH2:3].[OH2:27]>CN(C=O)C.Cl[Pd]Cl>[O:27]=[C:2]([CH3:3])[CH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][C:10]3[C:15]4[C:20]([NH:21][C:9]=3[C:8]=2[CH:26]=1)=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=4
Reactant: O
Reactant: C=CCc1ccc2c(c1)-c1[nH]c3ccc(C(F)(F)F)cc3c1CC(=O)N2
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc2c(c1)-c1[nH]c3ccc(C(F)(F)F)cc3c1CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-(2-propenyl)-9-trifluoromethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (108 mg, 0.3 mmol) in DMF (6 ml) and H20 (1 ml) was added PdCl2 (6 mg, 0.03 mmol) and CuC12 (48 mg, 0.36 mmol). After stirring the mixture overnight at room temperature it was poured into 30 ml of water and extracted with ethyl acetate (50 ml X 3). The organic layers were combined, washed with water (10 ml×3) and dried over NaSO4. Evaporation of the solution yielded a residue, which was purified by flash chromatography (ethyl acetate: petrol ether=70:30) to yield 78 mg of 2-(2-oxopropyl)-9-trifluoromethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (69%), mp295-297° C. (ethanol); IR 3310, 1710, 1650, 1310, 800 cm−1; 1H NMR (400 MHz) 2.20 (s 3 H), 3.58 (s, 2 H), 3.78 (s, 2 H), 7.18-7.30 (m, 2 H), 7.46 (d, J=8.6 Hz, 1 H), 7.57 (s, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 8.13 (s, 1 H), 10.14 (s, 1 H), 12.07 (s, 1 H); 13C NMR (100 MHz) 29.5, 31.2, 49.9, 108.4, 112.1, 115.8, (q, J. 3 Hz), 118.3 (q 3 Hz), 120.0 (q, J=37 Hz), 122.0, 122.3, 125.5 (q, J=270 Hz), 125.8, 127.8, 130.0, 130.3, 134.3, 134.5, 138.7, 171.3, 205.9; Anal. (C2OH15N2O2F3, 372.346): calcd. C, 64.51; H 4.06; N, 7.52; found C 64.30; H, 4.23; N, 7.50
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>CO.O>[CH:14]([C:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1)=[O:23]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCOC(=O)CNc1ccc(C)cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)CNc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
To a solution of ethyl 2-(p-tolylamino)acetate (1.69 mmol) in methanol/water (20 ml/20 ml) was added the 2,3 dichloro-5,6-dicyanobenzoquinone (2.87 mmol) and the mixture was stirred for 4 hours at room temperature. The residue was chromatographed on a silica gel column (dichloromethane/ethyl acetate 8/2 as eluent) to give 88 mg of ethyl 2-(4-formylphenylamino)acetate. (yield 25%). MS (ESI): m/z 208.0 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (6.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (8.96 g), potassium carbonate (7.20 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 60° C. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylate (13.15 g, yield 95%). The crystals were recrystallized from acetone-hexane. melting point: 160-161° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:15][C:10]=1[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. IL) using 10% ethyl acetate-hexanes (˜4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d,J=2.4 Hz, 1H), 7.29 (dd,J=8.5, 2.4 Hz, 1H), 7.06 (d,J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5](OC)=[O:6].[CH3:16][NH2:17].C(Cl)Cl.CCOC(C)=O>C1COCC1.CCOC(C)=O>[CH3:16][N:17]1[CH2:2][C:3]2[C:4](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[C:5]1=[O:6]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CN
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O

Procedure:
At room temperature, a solution of methyl 2-bromomethyl-6-nitrobenzoate (1.26 g, 4.63 mmol) in THF (13 mL) is treated with 2M soln. of methylamine in THF (14 mL), stirred for 5 h, diluted with EtOAc (100 mL), washed with sat. aqueous solution of NaHCO3 (15 mL) and brine (15 mL), dried (MgSO4), and evaporated. A flash chromatography (30 g of silica gel; CH2Cl2/EtOAc 1:1) gives N-Methyl-7-nitro-2,3-dihydroisoindole-1-one (0.561 g, 2.92 mmol) in 63%. Yellow solid. Rf (CH2Cl2/EtOAC 1:1) 0.46. 1H-NMR (400 MHz, CDCl3) 3.21 (s), 4.44 (s), 7.63-7.69 (m, 2H), 7.70-7.75 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=[O:5].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[CH2:19]([O:18][C:16]([NH:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=[O:5])=[O:17])[CH3:20]
Reactant: Cc1nc2sccn2c1C(=O)CN
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)NCC(=O)c1c(C)nc2sccn12
Yield: 43.3 %

Procedure:
To a solution of 4 g of 5-aminoacetyl-6-methylimidazo[2,1-b]thiazole hydrochloride in 50 ml of water is added a mixed solution of 3.2 g of ethyl chloroformate and 50 ml of ethyl acetate under stirring, and then 7.6 g of sodium bicarbonate is added. After the mixture is stirred at room temperature for 4 hours, chloroform and water are added to the resulting mixture. The chloroform layer is separated, washed with water and dried over magnesium sulfate, and then the chloroform is distilled off under reduced pressure. The residual oil is purified with a column chromatography using chloroform as a eluent to give 2 g of 5-ethoxycarbonylaminoacetyl-6-methylimidazo[2,1-b]thiazole.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[N:20]\[OH:21])/[C:16]([NH:18][CH3:19])=[O:17])=[CH:3][CH:2]=1.[C:28](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[N:20]\[O:21][CH3:28])/[C:16]([NH:18][CH3:19])=[O:17])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)/C(=N/O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To (E)-2-[2- (biphenyl-4-yloxymethyl)phenyl]-2-hydroxyimino-N-methylacetamide (9.73 g, 0.027 mol), added were dry acetone (100 ml), potassium carbonate (11.20 g, 0.081 mol) and dimethylsulfate (6.81 g, 0.054 mol), and the reaction mixture was stirred overnight at room temperature. Then, undissolved materials were removed therefrom and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(biphenyl-4-yloxymethyl)-phenyl]-2-methoxyimino-N-methylacetamide (9.85 g; yield, 97.4%) as colorless crystals.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.Cl.[N:15]1([C:22]2[CH:23]=[C:24]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:33][N:32]1[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=[C:28]1[C:24]1[CH:23]=[C:22]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:5]([N:51]3[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]3)=[O:11])[CH2:17][CH2:16]2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(-c2cccc(N3CCCNCC3)c2)nc2ccccc21
Reactant: CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)N2CCCN(c3cccc(-c4nc5ccccc5n4C)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
To a solution of triphosgene (0.41 g, 0.13 mmol) in dichloromethane (2 mL), was added 2-(3-[1,4]Diazepan-1-ylphenyl)-1-methyl-1H-benzoimidazole dihydrochloride salt (0.14 g, 0.37 mmol) and DIPEA (0.11 mL, 0.66 mmol) in dichloromethane (2 mL). After 15 minutes stirring at room temperature was added a solution of N-methyl-piperazine (0.04 mL, 0.44 mmol) and DIPEA (0.04 mL, 0.22 mmol) in dichloromethane (1.5 mL). The resulting suspension was stirred at room temperature for 10 min. The mixture was poured onto a mixture of saturated NaHCO3 solution (25 mL) and dichloromethane (25 mL), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue that was purified by Preparative HPLC, to obtain 20 mg (13%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([OH:16])[CH:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.O>C(O)(=O)C>[OH:16][C:4]1[CH:3]=[C:2]([N:1]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.50 g (18.0 mmol) of the compound of Step A and 2.81 g (19.0 mmol) of phthalic anhydride in 40 mL of glacial acetic acid was refluxed for 4 hours and stirred overnight at room temperature. About two volumes of water were added dropwise and the resulting solid was filtered and washed with water. The damp solid was taken up in a little ethanol, filtered and washed with a little ethanol and ether, and air dried to give the title compound, 5.11 g (69%), m.p. 295-298° C.(dec). Anal. Calcd. for C17H8O3N3Cl3 : C, 49.97; H, 1.97; N, 10.28. Found: C, 49.28; H, 1.95; N, 10.06.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[CH2:37][C@H:36]3[C:42]([OH:44])=O)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:76][C:71]2[CH:72]=[CH:73][CH:74]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:42](=[O:44])[NH:76][CH:71]3[CH2:72][CH2:73][CH2:74]3)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 100 mg 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 5 ml DMF were added 24 μl DIPEA, 53 mg HATU and 12 μl cyclobutylamine. After stirring for 4 h the mixture was dissolved in ethyl acetate and washed with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The solvent was evaporated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 34 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 43 mg MS (ES+): m/e=718.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37](OCC1SC=CN=1)=[O:38])([CH3:27])[CH3:26]>C1COCC1>[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[O:38])([CH3:27])[CH3:26]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Reactant: OCCOCC(F)(F)F
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCCOCC(F)(F)F
Reaction time: 0.17 h
Yield: 0.5 %

Procedure:
2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue is dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(N)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
Add a solution of {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g, 3.66 mmol) in dichloromethane (25 mL) dropwise to a solution of acetyl chloride (0.35 g, 4.50 mmol) in dichloromethane (125 mL) at room temperature. Upon complete addition of the amine, add triethylamine (0.74 g, 7.32 mmol) and a crystal of DMAP to the reaction and stirred at room temperature for 18 hours. Add an additional 65 uL of acetyl chloride to the reaction and stir an additional 2 hours. Pour the reaction into saturated aqueous sodium bicarbonate then extract with dichloromethane (3×100 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 1.3 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g): 1H NMR (CDCl3, 300.00 MHz): 8.00 (s, 1H), 7.49 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.98-6.89 (m, 4H), 4.69 (s, 1H), 3.37 (d, 2H, J=6.2 Hz), 2.77 (t, 2H, J=7.0 Hz), 2.18 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=CC=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.Cl.[CH3:29][N:30]1[CH2:36][C:35]2[CH:37]=[C:38](/[CH:41]=[CH:42]/[C:43](O)=O)C=N[C:34]=2[NH:33][C:32](=O)[CH2:31]1.CN[CH2:49][C:50]1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:33]([CH3:34])[CH2:32][C:31]2[N:30]([CH3:29])[C:36]3[C:42]([CH:43]=2)=[CH:41][CH:38]=[CH:37][CH:35]=3)=[O:12])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:50]=[CH:49][CH:27]=2)[CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCC(Cc2ccccc2)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CN2CCC(Cc3ccccc3)CC2)c1
Yield: 30 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-benzyl-piperidin-1-ylmethyl)-pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (156 mg, 30%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.36-8.25 (m, 2H), 7.52-6.98 (m, 14H), 6.40-6.15 (m, 1H), 5.05-4.84 (m, 2H), 4.20 (s, 2H), 3.74-3.67 (m, 3H), 3.58-5.30 (m, 8H), 3.10-2.73 (m, 6H); MS (ESI) m/e 508 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][C:15]3=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1>[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][CH2:15]3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CC2(CCC3(CC2)OCCO3)CN1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a suspension of LiAlH4 (21 g, 558.56 mmol) in anhydrous THF (500 mL) was added a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (59 g, 279.28 mmol) in anhydrous THF (400 mL) dropwise at 0° C. in 1 h. The reaction mixture was heated to reflux and stirred for 2 h, then quenched with water at 0° C. until no bubble escaped and filtered. The filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the product as a yellow solid (52 g, 94%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 96.7 %

Procedure:
A mixture of tert-butyl 3-[3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate (22.5 mg, 0.0627 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (24 mg, 0.085 mmol, from Example 108, Step 1) and DIPEA (33 μL, 0.19 mmol) in ethanol (1.0 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl 3-[3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate (34 mg). LCMS calculated for C27H35ClFN6O4 (M+H)+: m/z=561.2. found: 561.2. The coupling product made above was treated with 4.0 M HCl in dioxane (0.5 mL, 2 mmol) in methylene chloride (0.2 mL) at room temperature for 1 hour. The reaction mixture was then evaporated to dryness to give N-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9H-purin-6-amine dihydrochloride. The resultant HCl salt was dissolved in methanol (0.2 mL)/acetonitrile (0.2 mL)/THF (0.2 mL) and treated with DIPEA (0.1 mL, 0.6 mmol) until the solid dissolved. Acetone (0.05 mL, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (0.066 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 4 h and then purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C23H25ClFN6O (M+11)+: m/z=419.2. found: 419.1. 1H NMR (300 MHz, DMSO-d6) δ 9.96 (1H, m), 8.41 (1H, m), 8.23 (1H, s), 8.20 (1H, s), 7.53 (1H, s), 5.69 (1H, m), 4.52 (2H, m), 4.26 (1H, m), 4.12 (2H, m), 3.77 (3H, s), 2.08 (3H, m), 1.46 (3H, d, J=6.9 Hz), 1.11 (6H, m) ppm.