Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>>[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CCN(CCC2CNCCO2)CC1
Agent: Cl
Product: O=C1Nc2cccnc2N(C(=O)N2CCOC(CCN3CCCCC3)C2)c2ccccc21
Yield: 79 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-(1-piperidinyl)ethyl]morpholine (Rf 0.4 [Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/15/15/2, v/v/v/v/v]) in a yield of 79% of theory. The colourless hydrochloride melted at 274°-275° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide (64 mg, 0.12 mmol) was dissolved in dichloromethane (0.6 ml) and trifluoroacetic acid (0.4 ml, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.6 ml) and ethylenediamine (0.5 ml, 7.3 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 33 mg (65%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.51 (s, 1H), 8.47 (dd, J=8.9, 5.5 Hz, 1H), 8.11 (s, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.25 (s, 1H), 7.07 (td, J=9.2, 2.1 Hz, 1H), 5.48-5.61 (m, 1H), 4.15 (s, 3H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([N:23]3[C@@H:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[C:27]([C:37]([O:39][CH3:40])=[O:38])=[C:26]([CH2:41][O:42][CH3:43])[NH:25][C:24]3=[O:44])=[O:22])[CH2:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([N:23]3[C@@H:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[C:27]([C:37]([O:39][CH3:40])=[O:38])=[C:26]([CH2:41][O:42][CH3:43])[NH:25][C:24]3=[O:44])=[O:22])[CH2:15][CH2:16]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CC=C(c3cccc(NC(C)=O)c3)CC2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(NC(C)=O)c3)CC2)C(=O)N1

Procedure:
Methyl (4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidine carboxylate was tritiated (Amersham) using the described cold method (H2, balloon method, Methanol, Pd/C, overnight) to give the tritiated methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ((+)−isomer), which in turn, was used as a radioligand in the MCH pharmacological assays.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Fc1ccc(-c2[nH]c(C3CCN(Cc4ccccc4)CC3)nc2-c2ccncc2)cc1
Yield: 35.2 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine (0.51 mmol, 0.20 g) in acetonitrile (4.0 mL) and methanol (2.0 mL) was added sodium bicarbonate (1.8 mmol, 0.15 g) and benzyl chloride (0.51 mmol, 64.0 mg). The reaction was heated to reflux overnight, cooled, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 2.5% to 10% MeOH:CH2Cl2. The product containing fractions were evaporated under reduce pressure and crystallized from diethyl ether to give 74 mg of the title compound as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Cl:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:23][CH:1]([C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:20])[F:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(CC)nc2c(C(F)(F)F)cccc2c1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(C)Cl)nc2c(C(F)(F)F)cccc2c1O
Temperature: 65 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
A mixture of 9.3 g of ethyl 2-ethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate, 200 ml of carbon tetrachloride, 4.2 g of N-chlorosuccinimide and 0.45 g of azobis-isobutyronitrile was stirred at 65° C. maximum for 5 hours under a lamp and was then cooled to 20° C. and was filtered. The filtrate was evaporated to dryness and the residue was taken up in methylene chloride. The mixture was washed with water, dried and evaporated to dryness. The residue was empasted with petroleum ether and dried to obtain 9 g of ethyl 2-(1-chloroethyl)-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate melting at 104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[C:16]([CH3:22])[N:15]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:17]=[C:16]([CH3:22])[N:15]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (4.00 g, 0.0237 mol) and 2,6-dimethyl-pyridine-4-carbaldehyde (3.20 g, 0.0237 mol) in N,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 5.05 g, 0.0284 mol) and p-toluenesulfonic acid monohydrate (0.90 g, 4.74 mmol) were added and the reaction mixture was stirred at 130° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered to give 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purifications. Yield: 3.70 g (42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O:36]CC)=[O:35].C1COCC1.C(O)C.[OH-].[Na+].Cl>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(OC)cc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCNC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)c(OC)c1
Reaction time: 3 h
Yield: 101.5 %

Procedure:
Ethyl 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (1.25 g, 2.31 mmol) in 2:1 THF-Ethanol (25 mL) was treated with sodium hydroxide (9.26 ml, 9.26 mmol) at ambient temperature. After 3 hours, HPLC showed complete and clean conversion to a more polar peak. The reaction was diluted with ethyl acetate and acidified with hydrogen chloride (9.72 ml, 9.72 mmol). Brine was added and the reaction transferred to separatory funnel. The mixture was extracted with ethyl acetate. The organic layer showed a single spot (10% MeOH in CHCl3 with a few drops of AcOH). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.2 g of 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as a white solid. MS (apci, pos) m/z=512.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:27][N:16]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:15]2[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.CO.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[NH2:11][C@@H:12]1[CH2:27][N:16]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=3)=[O:23])[N:20]=[C:15]2[CH2:14][CH2:13]1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2n(c(=O)c1O)C[C@@H](NC(=O)OCc1ccccc1)CC2
Solvent: CO
Product: N[C@H]1CCc2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C1

Procedure:
The product from Step 2 was dissolved in MeOH (6 mmol), p-fluorobenzylamine (2.0 eq) was added and the mixture was stirred at reflux for 6 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated to dryness under vacuum. To the resulting crude MeOH was added (20 ml/mmol) and the mixture was hydrogenated at atm pressure on 10% (w/w) Pd/C over night. After filtration of the catalyst, solvent was evaporated to give a crude that was purified by preparative RP-HPLC (Symmetry Column C18, 5 μm, 19×100 mm, gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>ClC1C=CC=CC=1>[F:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Solvent: Clc1ccccc1
Product: CCOC(=O)c1ccc(F)c(NC(=O)COC)c1

Procedure:
A solution of 2.8 g (15.3 mMol) of ethyl 3-amino-4-fluoro-benzoate (cf. L. S. Fosdick, A. F. Dodds in J. Amer. Chem. Soc. 65, 2305 (1943)) and 1.56 ml (1.85 g=17.0 mMol) of methoxyacetylchloride in 50 ml chlorobenzene was stirred for 1 hour at 50° C. and then refluxed for 15 minutes. Then the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane/ethanol=100:1). The desired compound, initially oily, solidified within a few days. Yield: 3.8 g (98% of theory), Rf value: 0.38 (silica gel; dichloromethane/ethanol=19:1)
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:32])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([N+:29]([O-])=O)[CH:20]=2)/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[C:18](/[N:17]=[C:7]1/[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:9]([CH3:10])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6]/1)=[O:32]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)n1C[C@H]1CCCO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(N)cc(C(F)(F)F)c2)n1C[C@H]1CCCO1
Yield: 78 %

Procedure:
A mixture of Example 106 (740 mg, 1.63 mmol) and palladium hydroxide (50 mg) in ethyl alcohol (10 mL) was stirred under an atmosphere of hydrogen (balloon) at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified on Analogix® Intelliflash280™ (SiO2, 15-100% gradient of solvent A in hexanes, solvent A=10:1:0.5 ethyl acetate:methanol:triethylamine) to provide the title compound (540 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 1.73-1.83 (m, 3H) 1.89-1.97 (m, 1H) 3.60-3.68 (m, 1H) 3.73-3.81 (m, 1H) 3.89 (s, 3H) 4.18-4.25 (m, 1H) 4.35-4.48 (m, 2H) 5.50 (s, 2H) 6.83-6.86 (m, 2H) 7.56 (d, J=1.70 Hz, 2H); MS (DCI/NH3) m/z 425 (M+H)+. Anal. calcd C21H27F3N4O2.0.5H2O: C, 58.19; H, 6.51; N, 12.33. Found: C, 57.88; H, 6.56; N, 12.63.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: NC1CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.414 g, 0.88 mmol) in nBuOH (1.5 mL) was added cyclopropylamine (0.0674 mL, 1.06 mmol) and DIPEA (0.188 mL, 1.06 mmol). After stirring at ambient temperature for 15 h, the resulting precipitate was collected by filtration to give 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1)=[O:11]>>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][C:14]=1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: COc1cncc(Br)c1
Product: COc1cncc(-c2cc(C=O)ccc2OC)c1
Yield: 88.6 %

Procedure:
The title compound (2.5 g, white solid) was prepared from 3-Bromo-5-methoxypyridine (2.17 g, 0.0116 mol) and (5-formyl-2-methoxyphenyl)boronic acid (2.5 g, 0.014 mol, Matrix Scientific) analogously to Example 69, step 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:42][CH3:43])=[C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH:20][CH2:21][C:22]3[C:23]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:24]4[CH:32]=[N:31][N:30]([CH2:33][CH3:34])[C:25]4=[N:26][C:27]=3[CH2:28][CH3:29])=[O:19])[CH:13]=2)=[O:11])[CH:7]=1.[CH3:44][C@H:45]1[CH2:50][N:49]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl.O>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:6]4[CH:7]=[C:2]([C:54]5[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][N:49]6[CH2:48][CH2:47][NH:46][C@@H:45]([CH3:44])[CH2:50]6)[CH:53]=5)[CH:3]=[CH:4][C:5]=4[O:42][CH3:43])=[O:11])[CH:13]=3)=[O:19])[C:23]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Br)ccc2OC)c1
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCN[C@@H](C)C4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 14.4 %

Procedure:
N-{[5-Bromo-2-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (97 mg, 0.00015 mol) in dioxane (4 mL) and 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (81.2 mg, 0.000195 mol) were treated with Na2CO3 (48 mg, 0.00045 mol) and 0.75 mL H2O. The mixture was degassed for 15 min with N2, and then treated with tetrakistriphenylphosphine palladium (0) (17.3 mg, 0.000015 mol). The reaction was microwaved at 150° C. for 30 min. The reaction was quenched with H2O, then diluted and extracted with EtOAc (2×). Combined organic extracts were washed with H2O, sat. aq. NaCl and dried (Na2SO4) and concentrated to give 206.6 mg crude t-BOC product. The crude product was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a beige colored solid (16.4 mg, 14%). LC-MS m/z 759.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:20](=[O:21])[C:4]=2[CH:3]=1)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3.[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][C:13]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][C:4]=3[C:20]2=[O:21])[CH2:14][CH2:15]1)#[N:24]
Reactant: CN1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 2-fluoro-10,11-dihydro-1'-methyl-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], free base of Example 26, in 10 ml of methylene chloride is added portionwise to a mixture of 1.3 g of cyanogen bromide and 6.4 g of potassium carbonate in 17 ml of methylene chloride. After total addition, the mixture is stirred at reflux for 2 hours and then permitted to cool to ambient temperature. Thereafter, the mixture is filtered and then evaporated to dryness and the residue is taken up in methyl alcohol. The alcoholic solution is refluxed before the addition of acetone and ether, effecting a precipitate. The mixture is filtered and the supernatant liquid is evaporated. The residue is chromatographed through a silica gel column and eluted with an ether-methylene chloride (1:1) mixture, to provide 1'-cyano-2-fluoro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[Cl:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][C:5]=1[Cl:11]
Reactant: Oc1ccc(CCBr)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-(2-bromoethyl)-3-chlorophenol (158 mg) in acetone (7 ml) were added potassium carbonate (139 mg) and ethyl bromoacetate (89 μl) at room temperature. After the mixture was stirred for 20 hours at room temperature, the insoluble material was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate 7/1) gave ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]acetate (193 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][CH:39]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 85 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.57 g, 10 mmol) was suspended in dichloromethane (20 mL). Oxalyl chloride (2M in dichloromethane, 10 mL) was added followed by DMF (0.028 mL). The mixture was stirred for 1 hr and solvents were evaporated. The residue was treated with benzene (20 mL) and solvents were evaporated. The residue was dissolved in dichloromethane (30 mL) and treated with a mixture of (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.78 g, 10 mmol) and triethylamine (3.6 mL, 25 mmol) under ice bath. The mixture was stirred for 30 minutes and ice bath was removed. The solution was further stirred for 2 hrs. Solvents were evaporated and the residue was extracted with 0.1N hydrochloric acid and ethyl acetate. The organic layer was washed with water, concentrated sodium bicarbonate solution and brine. Solvents were evaporated and the residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexanes, 10% to 80% linear gradient) to give (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester (4.4 g, 85.1% yield). LC-MS for C26H26F3N3O5 (m/e) calcd 517, obsd 516 (M−H).