Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:31]=1[CH:32]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[CH2:5][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7][C@H:2]([NH:1][CH2:32][C:31]2[CH:34]=[C:35]([O:38][C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Yield: 114.1 %

Procedure:
To a stirred solution of (2S*,3S*,5R*)-3-amino-1-benzyloxycarbonyl-5-methoxycarbonyl-2-phenylpiperidine (0.84 g, 2.28 mmol) and 2-methoxy-5-trifluoromethoxybenzaldehyde (0.63 g, 2.85 mmol) in CH2Cl2 (18.0 ml) was added NaB(OAc)3H (0.73 g, 3.42 mmol) potionwise at room temperature. After the turbid reactin mixture was stirred vigorously at room temperature for 4 hours, sat. Na2CO3 aq. solution (15.0 ml) was added to make the mixture to be basic (pH10-11). The CH2Cl2 layer was separated from the mixture, and the aqueous layer was extracted with CH2Cl2 (×4). The combined CH2Cl layer and extracts were dried (Na2SO4), and concentrated in vacuo to give a viscous pale yellow oil (1.49 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 30.0 g). Elution with CH2Cl2 --MeOH (300:1/250:1) gave title compound (1.26 g, 96.2%) as a viscous colorless oil. IR νmax (film): 3450(w), 3330(w), 1740(shoulder, s), 1735(s), 1703(s), 1700(s), 1687(s), 1610(w), 1497(s), 1160(br., s), 1030(s), 815(m), 765(s), 740(s), 700(s) cm-1 ; 1H-NMR δ: 7.65-7.50(m, 1H), 7.52-7.38(m, 1H), 7.40-7.11(m, 8H), 7.2-6.96(m, 2H), 6.74(br.d, J=8.8 Hz, 1H), 5.45-5.34(m, 0.5H), 5.20-5.00(m, 2H), 5.17-5.05(m, 0.5H), 4.49-4.33(m, 0.5H), 4.35-4.17(m, 0.5H), 3.90-3.53(m, 2H), 3.69(br.s, 6H), 3.20(br.dd, J=13.2, 13.2 Hz, 1H), 3.20-3.00(m, 1H), 2.83-2.60(m, 1H), 2.26-1.99(m,2H), 1.52(br.s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (300 mg, 0.79 mmole), para-cyanophenylboronic acid (233 mg, 1.59 mmole), cesium carbonate (776 mg, 2.38 mmole) and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmole) in dioxane (4 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (136 mg). MS: (+) m/z 402.32 (M+H+)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+].Cl>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C=O)c3)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(CO)c3)c2)cc1
Yield: 101.2 %

Procedure:
A solution of methyl 4-[(3′-formyl-[1,1′-biphenyl]-3-yl) methoxy]benzenepropanoate (0.80 g, 2.1 mmol) in methanol (5 mL) and tetrahydrofuran (2 mL) was ice-cooled, and sodium borohydride (81 mg, 2.1 mmol) was added. The mixture was stirred under ice-cooling for 30 min. The reaction mixture was added to 0.2N hydrochloric acid (11 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to give the title compound 0.80 g (quantitative). oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)CCNS(=O)(=O)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC(C)CCNS(=O)(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-hydroxy-N-(3-methyl-butyl)-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (11%, light yellow oil). HPLC-MS m/z=377.2 (M+1), Rt: 4.32 min.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl.ClCC1[N:37]=[CH:38][S:39][CH:40]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]4[N:37]=[CH:38][S:39][CH:40]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: ClCc1cscn1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCc4cscn4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), tetrabutylammonium bromide (322 mg, 1.0 mmol), and DMF (15 mL) was stirred at 75° C. for 10 minutes. 4-(Chloromethyl)thiazole hydrochloride (187 mg, 1.1 mmol) was added. Additional 4-(chloromethyl)thiazole hydrochloride (1 eq. total) was added in small portions over a period of 3 hours. The reaction mixture was poured into water (100 mL). A solid was isolated by filtration, allowed to dry, dissolved in dichloromethane, and then purified by HPFC eluting with a gradient of 0-25% CMA in chloroform over 1400 mL and then 25% CMA in chloroform over 600 mL. The resulting solid was recrystallized from acetonitrile to provide 200 mg of 2-propyl-7-[(thiazol-4-yl)methoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 218.0-220.0° C. MS (APCI) m/z 357 (M+H)+; Anal. calcd for C17H16N4OS2.0.2H2O: C, 56.71; H, 4.59; N, 15.56. Found C, 56.66; H, 4.29; N, 15.45.
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=O>>[C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C=O
Product: CCOC(=O)CNCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The reductive alkylation of N-[N2 (1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline and ethyl glyoxylate was carried out in accordance with the procedures described in Example 1 to give N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -ethoxycarbonylmethyl-L-lysyl]-L-proline. The product was then treated with ammonia at 100° C. followed by absorption on strong acid ion exchange resin and eluting with 2% pyridine in water. Freeze drying of product-rich cuts afforded N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -carbamoylmethyl-L-lysyl]-L-proline. The nmr spectrum was consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Li+].[Cl-].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1.C([Cu])#N>C1COCC1>[CH:21]1([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[O:8][C:7]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: BrC1C=CCCC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1oc([N+](=O)[O-])cc1C1C=CCCC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Methyl 5-nitrofuran-2-carboxylate (24) (171 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −50° C., 3-bromocyclohexene (209 mg, 1.3 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added and the resulting mixture was stirred for 1 h at this temperature. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 26 (179 mg, 72%) as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[ClH:50]>ClCCl.CO>[ClH:50].[CH3:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:6]=2[CH:17]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Reaction time: 6.5 h

Procedure:
A solution of 6-methyl-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (D94) (μmol, 256 mg) in dichloromethane (10 mL) was treated with tetrahydro-4H-pyran-4-one (10 mmol, 1.0 g, 10 eq) and triethylamine (3 mmol, 303.6 mg, 3 eq) at room temperature under argon, then sodium triacetoxyborohydride (10 mmol, 2.12 g, 10 eq) was added and the mixture was allowed to stir for 6.5 h and to stand overnight. The mixture was diluted with dichloromethane and treated with aqueous sodium hydroxide so that the pH was maintained around 12. The aqueous phase was extracted with dichloromethane and the organics were combined, washed with an aqueous sodium hydroxide solution (pH ˜12), dried and concentrated under reduced pressure. The residue was purified by chromatography (methanol/dichloromethane) to give a gum which was dissolved in dichloromethane and methanol, treated with hydrogen chloride (in ether, 2M) then concentrated under reduced pressure to give the title compound as its hydrochloride salt-beige solid (0.22 mmol, 83 mg, 22% yield). M+H 341.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=1[Cl:39]>>[Cl:39][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][C:24]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1)[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(Cl)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (0.060 g, 0.18 mmol) and diethyl (4-amino-3-chlorobenzyl)phosphonate (Compound 104A, 0.101 g, 0.363 mmol). 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 9.40 (s, 1H), 8.70 (d, J=4.55 Hz, 1H), 8.38 (s, 1H), 7.66 (dd, J=1.39, 7.96 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.46 (t, J=2.27 Hz, 1H), 7.29-7.34 (m, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=7.20 Hz, 1H), 3.94-4.05 (m, 4H), 2.77 (d, J=4.55 Hz, 3H), 1.19 (t, J=6.95 Hz, 6H); MS (ES+): m/z: 572.08 [MH+]. HPLC: tR=3.42 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11](=[O:17])[NH:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24]1([O:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([O:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]4[CH:14]=[CH:15][CH:16]=[C:12]4[C:11](=[O:17])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 50 mg 4-(4-aminophenyl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (0.22 mmol) in 1 ml tetrahydrofuran at room temperature a solution of 0.03 ml pyridine (0.3 mmol) in 0.5 ml of tetrahydrofuran was added over 5 minutes. Subsequently, 0.03 ml phenylchlorformate (0.23 mmol) dissolved in 3 ml of tetrahydrofuran was added over 30 minutes and the reaction was stirred at room temperature overnight. The solvent was evaporated on vacuo and the mixture was directly incorporated on silica by dichloromethane. The mixture was purified by silica gel chromatography (4 g, cyclohexane:ethylacetate gradient) to afford crude material which was purified by column chromatography (cyclohexane:ethylacetate gradient) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:15][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.CN1CCCC1=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH3:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: Clc1ccc(CN2CCOCC2)cn1
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCOCC2)cn1
Temperature: -5 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-(6-Chloro-pyridin-3-ylmethyl)-morpholine (212 g, 1 mol) in tetrahydrofuran (1.5 L) and N-methylpyrollidinone (318 ml) was added iron (III) 2,4-pentanedionate (35.2 g, 0.01 mol) and the mixture cooled to −5° C. under nitrogen. A solution of methylmagnesium chloride in tetrahydrofuran (498 ml, 3.0M, 1.5 mol) was added dropwise over 40 mins and after an additional 30 mins the reaction mixture was poured into a saturated aqueous ammonium chloride solution (1.7 L) at 0° C. The resulting biphasic solution was filtered through a Celite® plug. The filtrate was separated and the aqueous layer extracted with ethylacetate (600 ml). The combined organic layer was concentrated and diluted with ethylacetate (200 ml) then extracted with aqueous hydrochloric acid (10%, 200 ml). The acidic layer was separated and washed with ethylacetate, then cooled in an ice bath and basified to pH 11 with sodium carbonate (solid). Sodium chloride (125 g) was added to the aqueous layer which was then extracted twice with ethylacetate (300 ml). The combined organic layer was concentrated to a solid, which was dissolved in hexane (600 ml) at 50° C. then placed in the fridge at −5° C. overnight. Two crops were obtained, which gave a total of 126.6 g, 68% yield of 4-(6-Methyl-pyridin-3-ylmethyl)-morpholine as beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Methane sulphonyl chloride (0.11 ml, 1.4 mmol) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.25 g, 1.24 mmol) and 4-(dimethylamino)pyridine (0.167 g, 1.4 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour and then 4-(dimethylamino)pyridine (0.051 g, 0.42 mmol) and methane sulphonyl chloride (0.033 ml, 0.42 mmol) were added and the mixture stirred at room temperature for a further 1 hour. The mixture was purified directly by silica gel chromatography, eluting with a 3:1 to 1:1 mixture of iso-hexane:ethyl acetate to yield tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 94% yield):
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[CH2:12]([O:14][CH2:15][CH2:16]Cl)[CH3:13]>>[CH2:12]([O:14][CH2:15][CH2:16][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])[CH3:13]
Reactant: CCOCCCl
Reactant: CCc1nc2ccccc2[nH]1
Product: CCOCCn1c(CC)nc2ccccc21
Yield: 80 %

Procedure:
1-(2-Ethoxyethyl)-2-ethyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-ethylbenzimidazole was used instead of benzimidazole, and an equimolar amount of 2-chloroethyl ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 80%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15][C:16]([CH3:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:20])=[CH:10][C:9]=1[O:15][C:16]([CH3:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1cc(C)ccc1CC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of 2-(2-acetoxyl-4-methylphenyl)acetic acid tert-butyl ester (4.9 g, 18.5 mmol) in CCl4 (50 ml) was added N-bromosuccinimide (3.29 g, 18.5 mmol, 1 equivalents) and benzoyl peroxide (100 mg), the reaction mixture was refluxed under argon for 3 hr. The reaction mixture was then cooled to room temperature. The solid precipitate was filtered off, and washed with hexanes, the combined organic was taken to dryness, and the residue obtained was purified by chromatography (Hexanes—EtOAc, 50:1 to 40:1) to give (2-acetoxyl-4-bromomethylphenyl)acetic acid tert-butyl ester 2.467 g (38.8% yield) as an oil. 1H NMR (CDCl3) δ: 7.290 (1H, d, J=7.81 Hz), 7.230 (1H, dd, J=1.71, 7.81 Hz), 7.158 (1H, d, J=1.71 Hz), 4.467 (2H, s), 3.462 (2H, S), 2.320 (3H, s), 1.430 (9H, s) ppm. FABMS (+Ve), m/z 345 [MH+, 81Br], 343 [MH+, 79Br], 389 [MH+—C4H8, 81Br], 387 [MH+—C4H8, 79Br]. Anal. calcd. for C15H19BrO4: C, 52.5; H, 5.6; Br, 23.3. Found: C, 52.30; H, 5.50; Br, 23.44.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[NH2:36][C:34](=[O:35])[CH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:28][CH2:29]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Reactant: NC(=O)CC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(N3CCC(CC(N)=O)CC3)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
An orange solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide (14A, 69 mg, 0.186 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (40 mg, 0.279 mmol), and N,N-diisopropylethylamine (96 mg, 0.745 mmol) in DMF (1.8 mL) was stirred at 100° C. for 2 h, cooled to 80° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, filtered, and then purified by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (13.1 mg, 15%). 1H NMR (DMSO-d6) δ: 10.96 (s, 1H), 8.02-8.14 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.26 (br. s., 1H), 7.23 (s, 1H), 6.74 (br. s., 1H), 6.08 (s, 1H), 4.36 (d, J=12.4 Hz, 2H), 2.90-3.03 (m, 2H), 2.31 (s, 3H), 1.97-2.01 (m, 2H), 1.89-1.97 (m, 1H), 1.74 (d, J=11.6 Hz, 2H), 1.24-1.38 (m, 2H); ESI-MS: m/z 477.4 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.C(O)C.Cl>C(O)C>[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)CCc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)C[C@@H](N)CC2
Yield: 100.3 %

Procedure:
Ethyl (S)-3-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]propionate (1.47 g) was dissolved in ethanol (21 ml), and 3 M hydrogen chloride ethanol solution (4 ml) was added to the solution at room temperature with stirring. After reaction for 20 hours, the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution (50 ml) and dichloromethane (10 ml) were added to the residue, and the resulting mixture was stirred for an hour at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl (S)-3-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)propionate (1.05 g) as an oil.