Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C[Al](C)C.[CH2:28]([N:30]([C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][N:44]=2)[S:39][C:38]=1[C:46]([O-])=[O:47])C(=O)C(F)(F)F)[CH3:29]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([NH:2][C:46]([C:38]2[S:39][C:40]3=[N:41][CH:42]=[CH:43][N:44]=[C:45]3[C:37]=2[NH:30][CH2:28][CH3:29])=[O:47])[CH:4]=1)=[O:23])([CH3:20])[CH3:19])#[N:22]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCN(C(=O)C(F)(F)F)c1c(C(=O)[O-])sc2nccnc12
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCNc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Temperature: 25 °C
Yield: 5 %

Procedure:
To a suspension of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (40 mg, 0.121 mmol) in toluene (1 mL) was added trimethylaluminum (0.243 mL, 0.485 mmol) and stirred for 15 at rt. 7-(N-ethyl-2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 45 (42.1 mg, 0.121 mmol) in toluene (1 mL) was added and the reaction was stirred overnight at 70° C. Diluted with EtOAc and washed with seignette salt solution. Organic layer was washed with brine, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 46 (3 mg, 4.96%). NMR (400 MHz, DMSO-d6) 1.20 (t, J=7.4 Hz, 3H), 1.75 (s, 6H), 2.22 (s, 1H), 3.98 (q, J=14.0 and 6.5 Hz, 12H), 7.26 (d, J=8.2 Hz, 1H), 7.58-7.64 (m, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.04-8.11 (m, 2H), 8.74 (d, J=2.3 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 9.53 (s, 1H), 10.32 (s, 1H). (m/z)=499 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[CH2:25]([O:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1)[CH:24]=[CH2:23]
Reactant: CCOC(=O)c1cc2c(ccn2O)nc1C(=O)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOn1ccc2nc(C(=O)OCC)c(C(=O)OCC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Diethyl 1-hydroxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (6.2 g, 0.022 mol)is dissolved in (200 mL) dry tetrahydrofuran and cooled to 0° C. under nitrogen. Sodium hydride (0.77 g, 0.033 mol) is added in portions over ten minutes and the reaction is stirred for 30 minutes at 0° C. Allyl bromide (2.01 mL, 0.024 mol) is added all at once to the suspension and the mixture allowed to warm to room temperature and then stirred for 16 hours. The mixture is filtered and the filtrate concentrated in vacuo. The resulting oil is chromatographed using 4:1 hexanes/ethyl acetate and then increasing the polarity to 2:1 hexanes/ethyl acetate to give the product as a yellow oil in 89% yield.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution containing (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid methyl ester (1.50 g, 4.7 mmol) in tetrahydrofuran (30 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 20 mL, 10.0 mmol). The mixture was stirred at 20° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1.30 g, 91%) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>O>[OH:12][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[N:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc(C(F)(F)F)nc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)nc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of 0.80 g of 3-amino-2-hydroxy-6-trifluoromethylpyridine, 1.14 g of triethylamine and 10 ml of DMF, 0.88 g of isonicotinic acid chloride hydrochloride was added while ice-cooling. The reaction mixture was stirred at room temperature for one hour and further stirred while heating at 50° C. for one hour. To the reaction mixture, 0.88 g of isonicotinic acid chloride hydrochloride and 1.1 g of triethylamine were added, and the reaction mixture was stirred while heating at 50° C. for further 1.5 hours. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture. Precipitated crystals were collected by filtration. The resultant solid was dissolved in ethyl acetate, then washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.91 g of N-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-isonicotinamide.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:15])=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]nnc2c1
Yield: 99.6 %

Procedure:
To a solution of 1H-1,2,3-benzotriazole-5-carboxylic acid (2 g), EDCl/HCl (2.82 g), and HOBt in DMF (70 ml) was added an aqueous NH3 solution (5.1 ml), followed by reaction at room temperature for 2 hours. It was concentrated, and the residue was washed with a saturated NaHCO3 solution, collected by filtration, and dried to obtain 1H-1,2,3-benzotriazole-5-carboxamide (1.98 g) as a black solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].Br.Br[CH2:14][CH2:15][NH2:16].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]1[O:5][CH2:14][CH2:15][N:16]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCBr
Agent: Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1cccc(F)c1C1=NCCO1
Temperature: 0 °C
Yield: 50 %

Procedure:
2,6-Difluorobenzoyl chloride (100 g, 566 mmol) was added dropwise over 2 h to a vigorously stirred and ice water cooled mixture of 2-bromoethyl amine hydrobromide (116.05 g, 566 mmol), benzyltriethylammonium chloride (5 g, 22.0 mmol), 10% aq NaOH (680 mL, 1.7 mol), and CH2Cl2 (1.5 L). The resulting mixture was stirred at RT overnight, than was washed with water (3×200 mL), dried (MgSO4), concentrated, and kugelrohr distilled to afford 51.8 g of 2-(2,6-difluorophenyl)-2-oxazoline as a colorless oil, a 50% yield.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O.CC(C(OC(=O)C[N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])C)(C)C>O1CCCC1>[CH3:7][C:6]([CH3:9])([O:5][C:3](=[O:4])[CH2:2][N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])[CH3:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(OC(=O)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)(C)C
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (32.16 g., 72 mmole), tert-butyl bromoacetate (14.2 g., 72 mmole), triethylamine (20.1 ml., 144 mmole), and tetrahydrofuran (290 ml.) are stirred at room temperature for 72 hours. Benzyl chloroformate (12.4 ml., 87.8 mmole) and triethylamine (12.5 ml., 87.8 mmole) are added and the mixture stirred overnight. The reaction product is evaporated, and partitioned between water and ethyl acetate. The ethyl acetate solubles are washed with dilute hydrochloric acid and then water. The ethyl acetate solution is then evaporated and chromatographed over silica gel (mesh 230-400) using the solvent system ethyl acetate/hexane (1:1) (10 psi pressure) to give 19.5 g. of 1-[N-[2-(1,1-dimethylethylethoxy)-2-oxoethyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.C(ON1C(=O)CCC1=O)(=O)CCCCCCCCCCCCCCC([O-])=O.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(O)(C(F)(F)F)=O>>[NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[OH:11]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
This compound was prepared in analogy with example 4, via reaction of L-Glu(OtBu)-OtBu with succinimidyl hexadecandioate followed by activation with TSTU, coupling with Des(B30) human insulin and deprotection by TFA. LCMS 6130.8, calculated 6132.2.
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[C:39]1([N:28]([CH2:27][O:19][C:18]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:20])[S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCl)c2ccccc2)cc1
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(COC(=O)c2[nH]c3ccccc3c2Nc2ccncc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 10.1 %

Procedure:
Under N2, at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.2 g, 7.5 mmol) in a mixture of anhydrous THF and DMF (90:10 mL). Cool to 0° C. and add a solution of N-chloromethyl-N-phenyl-4-methylbenzenesulfonamide (2.6 g, 8.80 mmol) in anhydrous THF (5 mL) dropwise. After 20 min add water (100 mL) and then extract with ethyl acetate (4×50 mL). Combine the organic layers, wash with NaHCO3 (sat), water, brine, dry with Na2SO4 and then concentrate. Purify the residue on an ISCO RediSep 35 gram silicagel cartridge, eluting with ethyl acetate and then 30% methanol/ethyl acetate. Combine product containing fractions and concentrate to a solid. Dissolve the solid in methanol and precipitate with ether to give the title compound as a yellow solid (390 mg): ESI/MS 313 (M+H, 1H NMR (CD3OD) δ 8.05 (2H, 2br d, J=6.5 Hz, J=6.8 Hz), 7.38 (14H, m), 6.61 (2H, br d, J=7.0 Hz), 5.93 (2H, s), 2.44 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1I.[C:38]([N:42]1[C:46](=[O:47])[CH:45]=[CH:44][S:43]1(=[O:49])=[O:48])([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C.CN(C)C=O>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[C:44]1[S:43](=[O:48])(=[O:49])[N:42]([C:38]([CH3:40])([CH3:39])[CH3:41])[C:46](=[O:47])[CH:45]=1
Reactant: CC(C)(C)N1C(=O)C=CS1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A solution of tert-butyl [(1S)-2-(3-bromo-4-iodophenyl)-1-(5-phenyl-1-[2-(trimethylsilyl)ethoxy]methyl-1H-imidazol-2-yl)ethyl]carbamate (130 mg, 112 μmol), 2-tert-butylisothiazol-3(2H)-one 1,1-dioxide (42.3 mg, 223 μmol), triethylamine (46.7 mL, 335 μmol), palladium acetate (25.1 mg, 112 μmol), N,N-dimethylformamide (3.0 mL) and tetra-N-butylammonium chloride (31.0 mg, 112 μmol) was degassed and stirred at 70° C. for 2 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (20.0 mg, 24%). MF=C35H47BrN4O6SSi; LCMS found for C35H48BrN4O6SSi (M+H)+: m/z=759.
Reaction SMILES: CC(OC(=O)[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)C.[ClH:52].C(O)(C)C.CCOCC>CO>[ClH:52].[ClH:52].[ClH:52].[ClH:52].[NH2:36][CH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([C:19]3[CH:18]=[N:17][CH:16]=[C:15]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)[CH:20]=3)=[O:22])[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4cccnc4)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)O
Product: NCc1cccc(C2CCN(C(=O)c3cncc(NCc4cccnc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
{5-[1-(4-{3-[N,N-Bis-(tert-butoxycarbonyl)amino-methyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-pyridin-3-ylmethyl-carbamic acid dimethyl-ethyl ester (0.0250 g, 0.0356 mmol) was treated with 5-6 M HCl in isopropanol (1.0 mL, 8.0 mmol) and stirred at ambient temperature. After 90 minutes the reaction mixture was diluted with methyl alcohol (0.5 mL) and stirring was continued for an additional 75 minutes. Dripping the reaction solution into ether (40 mL) with vigorous stirring afforded a white precipitate which was collected by filtration, washed with fresh ether (3.0 mL), and dried to afford 1-[4-(3-aminomethyl-phenyl)-piperidin-1-yl]-1-{5-[(pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-methanone tetrahydrochloride (0.0160 g): 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.95 (m, 2H), 8.39 (br s, 2H), 8.29 (d, J=8.0 Hz, 1H), 7.97-8.25 (m, 2H), 7.65-7.85 (m, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.20-7.38 (m, 3H), 4.63 (s, 2H), 4.43-4.61 (m partially obscured, 1H), 4.00 (AB q, J=5.8 Hz, 2H), 3.05-3.25 (m partially obscured, 1H), 2.72-2.95 (m, 2H), 1.80-1.88 (m, 1H), 1.47-1.77 (m, 3H); MS (CI) m/z 402 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[OH:27].C(N(CC)CC)C>O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([OH:27])=[C:17]([NH:16][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][N:9]=[CH:10][C:2]=2[F:1])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccncc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(O)c(NC(=O)c2ccncc2F)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionyl chloride and 50 mg of DMF was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-fluoroisonicotinic acid chloride. A mixture of the resultant 3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise to a mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g of triethylamine and 10 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added. Precipitated crystals were collected by filtration. The resultant crystals were dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 2.41 g of N-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].CN1CCCC1=O.Cl>O.[Br-].[Zn+2].[Br-]>[F:25][CH:16]([C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([C:20]2[NH:32][N:31]=[N:30][N:21]=2)[CH:18]=1)[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:7]2[CH:26]=[CH:27][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:29])[C:6]=2[CH3:28])=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)c(C)c1O
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)c(C)c1O
Temperature: 140 °C
Yield: 22.5 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile (400 mg, 1.03 mmol), zinc (II) bromide (280 mg, 1.24 mmol), sodium azide (160 mg, 2.48 mmol) and N-methylpyrrolidinone (10 mL) is stirred at 140° C. 1 hr. The reaction mixture is cooled, diluted with water, and the pH is adjusted to 2 with aqueous hydrochloric acid. The product is extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated. The residue is purified via reversed phase C-18 chromatography eluting with 4:6 acetonitrile:(0.1% trifluoroacetic acid) water to acetonitrile to give the title compound (100 mg, 22%) as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.6107.70 (m, 2H), 7.48-7.55 (m, 4H), 6.78-6.94 (d, 1H), 6.73 (d, 1H), 5.29 (s, 2H), 2.59 (s, 3H), 2.05 (s, 3H). LCMS M−1 431.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:42][O:41][CH2:40]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@@:17]([S:27]([CH3:30])(=[O:29])=[O:28])([NH:19][O:20]C2CCCCO2)[CH3:18])[CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:40][O:41][CH2:42]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@:17]([NH:19][OH:20])([S:27]([CH3:30])(=[O:29])=[O:28])[CH3:18])[CH:14]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NOC1CCCCO1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 5-fluoro-1-{(3R)-3-(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one (164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir at rt overnight and then concentrated under vacuum. The residue was re-dissolved in dichloromethane and n-heptane and concentrated again to afford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3 H) 2.35 (ddd, J=13.66, 10.63, 5.17 Hz, 1 H) 2.53-2.67 (m, 1 H) 3.09 (s, 3 H) 3.91 (ddd, J=12.98, 10.63, 5.27 Hz, 1 H) 4.16-4.30 (m, 1 H) 4.69 (dd, J=7.51, 4.78 Hz, 2 H) 5.02 (t, J=6.73 Hz, 2 H) 5.33 (t, J=5.46 Hz, 1 H) 6.58 (d, J=7.42 Hz, 1 H) 6.85-6.91 (m, 2 H) 7.55 (dd, J=8.68, 1.85 Hz, 2 H) 7.80 (d, J=6.24 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Reaction time: 1 h
Yield: 129.6 %

Procedure:
1,1-Dimethylethyl 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 66) (320 mg, 0.658 mmol) was dissolved in 1,4-dioxane (1 ml) and treated with HCl (2 ml, 8.00 mmol) in 1,4-dioxane. The reaction mixture was left at RT for 1 hr, evaporated and then triturated with ether to give the title compound (180 mg) as a white solid. MS (ES): C20H2035ClN3O3 requires 385; found 386 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[Br:16][CH2:17][CH2:18]Br.C(Cl)CCl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[Br:16][CH2:17][CH2:18][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(=O)oc2cc(OCCBr)ccc12
Yield: 70 %

Procedure:
17.62 g. (0.1 mole) 7-hydroxy-4-methyl-coumarin (4-methyl-umbelliferon) are dissolved in a 8% aqueous solution of 0.2 mole sodium hydroxide and a solution of 4 g. benzyl-tributyl-ammonium-chloride phase transfer catalyst and 37.5 g. (0.2 mole) 1,2-dibromo-ethane in 200 ml. ethylene-chloride is added. The mixture is heated for 14 hours under stirring and allowed to cool. 60 ml. dichloromethane are added, the mixture is filtered and the organic layer is separated from the filtrate and washed with distilled water, dried and evaporated. 19.82 g. (0.07 mole) 7-(2'-bromo-ethyl-oxy)-4-methyl-coumarin are obtained, melting point: 94°-97° C.