Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl.CS(C)=O>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(NC4CCNCC4)ncc3Cl)n2)c1
Reactant: CCS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 5′-chloro-N6-(3-fluorobenzyl)-N2′-(piperidin-4-yl)-2,4′-bipyridine-2′,6-diamine (Example 6, 16 mg, 0.039 mmol), dichloromethane (0.5 ml), and TEA (0.022 ml, 0.155 mmol) was cooled to 0° C. This cooled mixture was then diluted with a solution of 0.03 ml of dichlormethane with ethanesulfonyl chloride (6.99 mg, 0.054 mmol). The reaction mixture then was warmed to ambient temperature and stirred for 1 hour, followed by LCMS. The reaction mixture solvent was removed under reduced pressure, to yield a residue which was dissolved in 0.75 ml DMSO, filtered, purified by prep LC and then lyapholized to yield 9.9 mg of the title compound, as a TFA salt. LCMS (m/z): 504.2 (MH+), retention time=0.77 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32 (t, J=7.33 Hz, 3H) 1.47-1.67 (m, 2H) 2.08 (d, J=10.84 Hz, 2H) 2.96-3.12 (m, 4H) 3.75 (d, J=12.89 Hz, 2H) 3.80-3.92 (m, 1H) 4.65 (s, 2H) 6.83 (s, 1H) 6.92 (d, J=9.08 Hz, 1H) 6.95 (d, J=7.62 Hz, 1H) 7.01 (t, J=8.64 Hz, 1H) 7.11 (d, J=9.96 Hz, 1H) 7.19 (d, J=7.62 Hz, 1H) 7.30-7.41 (m, 1H) 7.75-7.85 (m, 1H) 8.06 (s, 1H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Br:13]N1C(=O)CCC1=O>>[Br:13][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Product: O=C(O)c1ccc2c(Br)c[nH]c2c1
Yield: 74.5 %

Procedure:
Using the procedure described in Example 34, Part A, indole-6-carboxylic acid (2.6 g, 16.1 mmol) and N-bromosuccinimide (2.9 g, 16.1 mmol) yielded 2.88 g (75%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.F[C:22]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(O)c1ccnc(F)c1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2

Procedure:
6.0 g (22 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 1.5 g (11 mmol) 2-fluoropyridine-4-carboxylic acid in 20 mL NMP were stirred overnight at 110° C. The reaction mixture was cooled and the precipitate formed was suction filtered. This was stirred with water, additionally combined with 15% potassium carbonate solution and extracted several times with DCM. The aqueous phase was acidified, the precipitate formed was suction filtered and dried.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=4)=[CH:14][N:13]3[CH:25]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[O:22][C:21]([CH2:23][OH:24])=[CH:20][CH:19]=4)=[CH:14][N:13]3[CH:25]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
122 mg of sodium borohydride are added, in small portions, to 104 mg of 5-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]furan-2-carbaldehyde dissolved in 20 ml of methanol. The mixture is subsequently stirred at ambient temperature for 2 hours, and the solvent is then evaporated off under reduced pressure. The residue is taken up between dichloromethane and water. The organic phase is separated, dried over sodium sulphate and concentrated under reduced pressure. 39 mg of compound are obtained.
Reaction SMILES: [O:1]=[CH:2]C(Cl)(Cl)Cl.[NH2:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl>[CH:2]([NH:7][CH2:8][C:9]1([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:1]
Reactant: NCC1(N2CCCCC2)CCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=CNCC1(N2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
Chloral (4.65 g.) was added dropwise to a cooled solution of 1-[1-(aminomethyl)cyclohexyl]piperidine (5.9 g) in dry chloroform (30 ml). The mixture was stirred at room temperature for 16 hrs. and then heated under reflux for 30 mins. The solution was evaporated to dryness and the oily residue re-evaporated with ether. This residual brown oil (7.9 g) was distilled under high vacuum to give a viscous pale yellow oil of 1-[1-(formamidomethyl)cyclohexyl]piperidine (5.1 g.) b.p. 170°-2°C at 1.7 mm.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.O[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([F:7])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (10 mL) was added to a cold (−78° C.; dry ice/acetone bath) solution of tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate (8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at −78° C. for ˜1 hour. The reaction was removed from the bath and warmed to ambient temperature then stirred another 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with brine (˜50 mL). Then 3-chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction and stirred at ambient temperature for 30 minutes. This step was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with saturated aqueous NaHCO3 (1×100 mL), water (1×100 mL), and brine (1×100 mL), dried (MgSO4), tested for peroxide (3-10 ppm) and concentrated to light yellow oil. The oil was dried under vacuum to afford 8.27 g (100%) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd, J=5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J=12.0, 2H), 7.33 (d, J=7.1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m/z 280 (M+H+, 60%), 297 (M+NH4+, 100%).
Reaction SMILES: C[C@@:2]1(O[C@H:10]([CH2:12]Br)[C@@:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:9])[C@:6]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:7])[C@:4]1([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:5])[OH:3]>C(O)(C)C.O.[Zn]>[C:32]1([CH2:31][O:30][C@@:4]([C@:6]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C@@:8]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH:10]=[CH2:12])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@]1(O)O[C@H](CBr)[C@](O)(OCc2ccccc2)[C@@](O)(OCc2ccccc2)[C@@]1(O)OCc1ccccc1
Agent: [Zn]
Solvent: O
Solvent: CC(C)O
Product: C=C[C@](O)(OCc1ccccc1)[C@@](O)(OCc1ccccc1)[C@](O)(C=O)OCc1ccccc1

Procedure:
Mix methyl-2,3,4-tris(phenylmethoxy)-6-bromo-6-desoxy-α-D-mannopyranose (20.968 g, 39.75 mmol) and activated zinc dust (20.50 g, 314 mmol) in isopropanol (300 mL) and water (55 mL). Heat at reflux for 38 minutes, cool and filter. Rinse the zinc dust with a mixture of ethyl acetate/water, filter and dilute the filtrate with water. Extract with a mixture of ethyl acetate/cyclohexane (3×) and wash the combined organic extracts with water. Evaporate the solvent in vacuo to give 2,3,4-tris(phenylmethoxy)-5,6-dideoxy-D-lyxo-hex-5-enose.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)COc2ccc(Cl)cc2)CC1
Yield: 63.7 %

Procedure:
Prepared following the method of Example 94 using (4-chlorophenoxy)acetic acid (0.50 g), 1,1-carbonyldiimidazole (0.50 g) and tert-butyl 4-amino-1-piperidinecarboxylate (0.46 g) to give the subtitle compound (0.54 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=[O:22].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=3)[C:21]([OH:23])=[O:22])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(C(=O)O)cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 80 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (3.5 g; 14.54 mmol) and 3-amino-5-(trifluoromethyl)-benzoic acid (2.98 g; 14.54 mmol) were diluted in 15 ml of water and 15 ml of 1,4-dioxane, 2 ml of HCl 37% were added. The reaction mixture was refluxed 24 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, it was filtered, washed with water and dried in vacuo. 4.77 g (0.012 mol; 80% yield) were obtained as white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O=C1CCC(=O)N1[O:28][C:29](=O)[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(#N)C>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@H:2]([NH:1][C:29](=[O:28])[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(CCCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
(Method J15B) A suspension of L-tryptophan (2.040 g, 10 mmol) and NaHCO3 in water (15 ml) was treated with 4-phenyl-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (15/95) (2.610 g, 10 mmol) followed by the addition of acetonitrile (ca. 15 ml) to get a clear solution. The reaction mixture was stirred at ambient temperature for 12 hours and acetonitrile was removed under reduced pressure. The residue was acidified with citric acid to pH 2 and extracted with ethyl acetate (100 ml). The organic layer was washed with water (2×20 ml), brine (20 ml), and dried (MgSO4). The solvents were evaporated to give the crude product 16/95 (3.160 g, 95%). 1H NMR (DMSO-d6, HMDSO) δ: 1.51-1.82 (2H, m); 1.96-2.24 (2H, m); 2.33-2.64 (2H, m); 2.80-3.38 (2H, m); 4.38-4.68 (1H, m); 6.82-7.66 (14H, m); 8.11 (1H, d, J=8.0 Hz); 10.87 (1H, m).
Reaction SMILES: C(O[C:4]1[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][N:9]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([NH:27][NH2:28])=O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:32]([O:31][C:30]([NH:29][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:25]1[N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:5][C:4]2=[N:28][N:27]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(c1ccc(Cl)cc1)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
A solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (0.762 g, 3.34 mmol) and tert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate (1.00 g, 3.34 mmol) in toluene (6.67 mL, 3.34 mmol) was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated to give a residue that was purified by reverse phase chromatography (Biotage SP4, 40+M, C18, 10% to 100% ACN/H2O) to afford tert-butyl 3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.92 g, 60%). LCMS (APCI+) M+H+: 463 (25%), 464 (90%), 466 (25%), 467 (5%); rt=3.56 minutes. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 5.87 (d, J=7.8 Hz, 1H), 4.84 (d, J=17.6 Hz, 1H), 4.75 (d, J=17.6 Hz, 1H), 3.93 (m, 1H), 3.80 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 1.47 (s, 9H), 1.41 (s, 9H).
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C1COCC1>[CH2:8]([CH:5]1[CH2:6][CH2:7][SiH:2]([SiH:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:3][CH2:4]1)[CH2:9][CH3:10]
Reactant: FC(F)(F)c1ccc(C2CC[SiH](Cl)CC2)cc1
Solvent: C1CCOC1
Product: CCCC1CC[SiH]([SiH]2CCC(c3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 85 %

Procedure:
4.4 g (20 mmol) of 4-n-propylsilacyclohexyl bromide was dropped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard reagent. This solution was then dropped into a 50 ml THF solution of 5.6 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethylbenzene to obtain 4-(4-(4-n-propylsilacyclohexyl)-4-silacyclohexyl)-1-trifluoromethylbenzene. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.5 g of the trans-trans isomer (yield 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7].CNC.C=O>O>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccccc1CC(C(=O)O)C(=O)O
Agent: C=O
Agent: CNC
Solvent: O
Product: C=C(Cc1ccccc1C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the acid of Step 2 (12.0 g, 0.11 mol) in H2O (25 ml) at 0° C., add 40% dimethylamine (12.9 ml, 0.115 mol), then another 12.0 g acid. Stir 10 min., add H2O (50 ml), then 38% formaldehyde (25 ml, 0.31 mol). Allow to warm to room temperature over 18 hr., filter the solid, slurry in H2O (200 ml), and heat at 90° for 2.5 hr. Extract with diethyl ether, acidify the aqueous layer, allow the oil to crystallize, and filter the solid. Dissolve in Et2O, filter and concentrate to obtain the product as a waxy solid. Recrystallize from Et2O:hexane to obtain the title compound, m.p. 82°-3° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCN(c2cccc(-c3ccnc(Cl)n3)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(c2cccc(-c3ccnc(Cl)n3)c2)CC1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 1-(3-(2-chloropyrimidin-4-yl)phenyl)piperidin-4-one (200 mg, 0.7 mmol) in methanol (5 mL) was added NaBH4 (53 mg, 1.4 mmol). The reaction mixture was warmed to room temperature and monitored by TLC analysis. When the starting material had been consumed, the reaction was quenched with water and diluted with EtOAc. The layers were separated, and the organics were dried (MgSO4) and concentrated to give 1-(3-(2-chloropyrimidin-4-yl)phenyl)piperidin-4-ol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])=[C:2]=[O:3].[CH3:18][O:19][Si](C)(C)C>>[CH3:18][O:19][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3]
Reactant: O=C=NCCCCCCCCCCCC(=O)Cl
Reactant: CO[Si](C)(C)C
Product: COC(=O)CCCCCCCCCCCN=C=O

Procedure:
0.1 mole 12-isocyanatododecanoic acid chloride was reacted as in Example 1 with 0.11 mole methoxytrimethyl silane at 75° C. until the acid chloride band at 1800 cm-1 had disappeared. The desired product was obtained after distillation.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:34])([F:33])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:33])([F:34])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.092 mmol) in dichloromethane (10 mL) at room temperature was added TFA (0.035 mL, 0.458 mmol) and stirred overnight. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in MeOH. The purification afforded (2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (15 mg, 0.033 mmol, 36% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.64 (m, 1H), 8.54 (m, 1H), 8.23 (m, 1H), 7.88 (s, 1H), 6.91 (s, 1H), 6.10 (m, 1H), 4.3 (m, 1H), 4.12 (m, 1H), 3.52 (m, 1H), 1.85 (m, 1H), 1.72-1.69 (m, 1H), 1.61-1.56 (m, 1H), 1.05 (m, 6H). LCMS (ESI) m/e 445.2 [(M+H)+, calcd for C19H21BrF3N2O2 445.1]; LC/MS retention time (Method C): tR=1.74 min; HPLC retention time (method A): tR=5.66 min, 5.75 min (diastereomeric mixture); HPLC retention time (method B): tR=6.27 min, 6.34 min (diastereomeric mixture).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]([OH:5])=[O:4].[CH3:38]N(C=O)C.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:37][C:2]([CH3:1])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[C:3]([O:5][CH3:38])=[O:4]
Reactant: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.81 g of 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoic acid and 50 mL of DMF were added 2.59 g of methyl iodide and 3.16 g of potassium carbonate, followed by stirring for 1 hour at room temperature. Water was added to a reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol, thereby obtaining 3.24 g of methyl 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoate as a yellowish white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Product: CCc1ccc(-c2cc(NC(=O)c3cccnn3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 98.9%, 403.1386 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:20][C:21]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([NH:34][NH2:35])=O)=[C:27]2[C:22]=1[CH2:23][CH2:24][CH2:25][O:26]2>>[Cl:31][C:30]1[C:21]([NH2:20])=[C:22]2[C:27](=[C:28]([C:32]3[O:14][C:12]([CH2:11][CH:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[N:35][N:34]=3)[CH:29]=1)[O:26][CH2:25][CH2:24][CH2:23]2
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Reactant: O=C(O)CC1CCN(C2CCC2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(CC3CCN(C4CCC4)CC3)o2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To the (1-cyclobutyl piperidin-4-yl) acetic acid (725 mg, 3.52 mmol, obtained in preparation 4) was added phosphoryl chloride (4 mL). The mixture was stirred for 15 minutes and 5-Amino-6-chloro-chroman-8-carboxylic acid hydrazide (500 mg, 2.0 mmol) was added. The reaction mixture was gradually heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure and was purified by silica gel column to obtain 6-chloro-8-[5-(1-cyclobutyl piperidin-4-ylmethyl)-[1,3,4]oxadiazol-2-yl]chroman-5-yl amine (250 mg). Yield: 30%.