Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:26])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]
Reactant: CCN(CC)CCSc1nnc(N)s1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropyloxybenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.4 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[S:38]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)(=[O:39])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 50.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.75 g of (2RS,4SR,5RS)-5-(2-flurophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-4-(phenylsulphonyl)pyrrolidine and 0.32 g of potassium hydroxide in a mixture of 55 cm3 of distilled water and 140 cm3 of methanol. After treatment, there are obtained 1.84 g of (2RS,4SR,5RS)-3-{3-[2-(5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.73; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:13])[N:3]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:13])[N:3]=1)[NH2:16]
Reactant: NN
Reactant: Cc1ccc(C)c2c(C)cc(Cl)nc12
Product: Cc1ccc(C)c2c(C)cc(NN)nc12
Yield: 38 %

Procedure:
A solution of 2-chloro-4,5,8-trimethylquinoline (2.2 g, 10.7 mmoles) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound (830 mg, 38%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.62 (s, 3 H) 2.78 (s, 6 H) 4.13 (br. s., 2 H) 5.74 (br. s., 1 H) 6.52 (s, 1 H) 6.95 (d, J=7.03 Hz, 1 H) 7.28 (d, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH:32]=[O:33])=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C1COCC1.[BH4-].[Na+].[NH4+].[Cl-]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32][OH:33])=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(CCOCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(CCOCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
A crude 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinoline-3-carbaldehyde is dissolved with ethanol-THF (120 mL/20 mL) and treated with sodium borohydride (1.33 g, 36 mmol) at 5° C., and the resulting mixture is stirred at the same temperature for 30 min. After addition of sat. NH4Cl aq. and ethyl acetate, the mixture is partially concentrated to remove ethanol. The mixture is extracted with EtOAc, and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give [2-((R)-2-{-4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-yl]methanol as a yellow syrup.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH2:23])=[CH:20][CH:21]=2)[CH:16]=[N:15]1.Cl[S:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)(=[O:27])=[O:26].O>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])[CH2:32][CH2:33]3)(=[O:26])=[O:27])=[CH:20][CH:21]=2)[CH:16]=[N:15]1
Reactant: Nc1ccc2c(cnn2C2CCCCO2)c1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3c(cnn3C3CCCCO3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Triethylamine (0.789 ml, 5.69 mmol) was added to a solution of 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (1.04 g, 4.79 mmol) and benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (1.5 g, 4.74 mmol) in methylene chloride (50 ml) at 0° C. and stirred at 0° C. for 30 minutes and then at room temperature for 15 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate=3/1) to obtain benzyl 4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate (1.32 g, 56%).
Reaction SMILES: C(OC([N:7]1[CH2:28][CH2:27][C:11]2[C:12]3[C:13]([CH3:26])([CH3:25])[CH2:14][CH2:15][C:16]=3[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:10]=2[CH2:9][CH2:8]1)=O)CC.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH3:25][C:13]1([CH3:26])[C:12]2[C:11]3[CH2:27][CH2:28][NH:7][CH2:8][CH2:9][C:10]=3[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]=2[CH2:15][CH2:14]1
Reactant: CCCOC(=O)N1CCc2cc(-c3ccccc3)c3c(c2CC1)C(C)(C)CC3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2c(-c3ccccc3)cc3c(c21)CCNCC3
Temperature: 60 °C
Yield: 17.4 %

Procedure:
Into a glass vial containing the product from step (b) (71 mg, 0.195 mmol) dissolved in CHCl3 (2 ml), TMSI (266 μL, 1.95 mmol) was added. The reaction mixture was heated to 60° C. for 4 hours. The volatiles were evaporated in vacuo and the residue was dissolved in 2M HCl (3 ml) and water (20 ml). The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo gave the crude product. Purification by preparative reverse phase HPLC gave the title compound as a colorless oil (9.9 mg). 1H NMR (300 MHz, CDCl3) δ 8.66 (bs, 1H); 7.41-7.26 (m, 5H); 7.00 (s, 1H); 3.31-3.15 (m, 8H); 2.84 (t, J=7.5 Hz, 2H); 1.89 (t 7.2 Hz, 2H); 1.33 (s, 6H); MS: ESI (positive): 328 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]2[O:18][CH2:17][CH2:16][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: OCCO
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (4.01 g, 18.10 mmol) in toluene (200 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer under N2 was added ethylene glycol (1.20 mL, 21.52 mmol) followed by p-toluenesulfonic acid monohydrate (348 mg, 1.83 mmol). The mixture was stirred overnight under reflux using a Dean-Stark apparatus. After cooling to RT, the mixture was concentrated at 40° C. under vacuum, then the residue was diluted with saturated aqueous NaHCO3 solution (40 mL) before extraction with CH2Cl2 (100 mL). The organic phase was isolated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 92:8 to 75:25) gave 2-chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44002 as a white solid (4.39 g, 91% yield).
Reaction SMILES: COC1C=C(C=C(OC)C=1)C=O.BrC1C=CC=CC=1.C([Li])CCC.O1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]([C:37]3[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=3)[OH:36])=[CH:34][C:29]=2OCC1>>[CH3:46][O:45][C:39]1[CH:38]=[C:37]([CH:35]([C:33]2[CH:34]=[CH:29][CH:30]=[CH:31][CH:32]=2)[OH:36])[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1
Reactant: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: COc1cc(C=O)cc(OC)c1
Agent: [Li]CCCC
Solvent: Brc1ccccc1
Product: COc1cc(OC)cc(C(O)c2ccccc2)c1
Yield: 85 %

Procedure:
3,5-Dimethoxybenzaldehyde (2.50 g, 15.04 mmol), bromobenzene (2.60 g, 16.55 mmol), and n-butyl lithium (33.10 ml, 13.24 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 20% EtOAc in hexane in about 30 min.) to give (3,5-Dimethoxy-phenyl)-phenyl-methanol as a light yellow oil (3.14 g, 85%). HPLC purity was 83% at 3.01 min. (50/50 ACN/0.1% H3PO4). 1HNMR (CDCl3) δ 7.39-7.25 (m, 4H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.50-6.34(m, 2H, Ar), 5.74 (d, J=3 Hz, 1H, CHOH), 3.75 (s, 6H, 2OCH3), 2.34 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH:35]=[O:36].[CH3:37]Br.[Mg].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[CH:35]([OH:36])[CH3:37]
Reactant: CBr
Reactant: O=Cc1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
16 mg (0.033 mmol, 1 eq.) of 3-(4-chloro-3-formylphenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 63) are dissolved in 0.7 mL of dry THF. Once the solution has been cooled to 0° C., 17 μL (0.049 mmol, 1.5 eq.) of magnesium methyl bromide in solution (3 M in diethyl ether) are added to the medium. After stirring for 20 min. at 0° C., the reaction is neutralised with a saturated ammonium chloride solution at 0° C. The aqueous phase is extracted with dichloromethane, the organic phases are washed with brine, dried over MgSO4, filtered and concentrated. The crude reaction product is subjected to chromatography over silica gel (eluent: 1/1 heptane/AcOEt). 11.4 mg of expected product are obtained (yield=67%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH:6]1([C:9]2[N:14]=[C:13](O)[CH:12]=[CH:11][N:10]=2)[CH2:8][CH2:7]1>>[Cl:3][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([CH:6]2[CH2:8][CH2:7]2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(C2CC2)n1
Product: Clc1ccnc(C2CC2)n1
Temperature: 150 °C

Procedure:
POCl3 (5 mL) was added to 2-cyclopropylpyrimidin-4-ol (100 mg, 0.735 mmol) and refluxed at 150° C. for 2.5 hours. The resulting mixture was concentrated, the concentrate was basified with dilute sodium bicarbonate solution and diluted with DCM. The organic layer was washed with brine, dried over sodium sulphate and concentrated to afford 125 mg of the crude product as a pale brown liquid.
Reaction SMILES: [I-].[Na+].Cl[Si](Cl)(C)C.[F:8][C:9]1([F:38])[CH2:14][CH2:13][CH:12]([CH:15](O)[C:16]2[N:20]3[C:21]([CH3:32])=[CH:22][C:23]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:24][C:19]3=[N:18][C:17]=2[C:33]2([CH3:36])[CH2:35][CH2:34]2)[CH2:11][CH2:10]1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.ClCCl.C(#N)C>[F:38][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([CH2:15][C:16]2[N:20]3[C:21]([CH3:32])=[CH:22][C:23]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:24][C:19]3=[N:18][C:17]=2[C:33]2([CH3:36])[CH2:34][CH2:35]2)[CH2:13][CH2:14]1
Reactant: CCCCOC(=O)c1cc(C)n2c(C(O)C3CCC(F)(F)CC3)c(C3(C)CC3)nc2c1
Agent: C[Si](C)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: ClCCl
Product: CCCCOC(=O)c1cc(C)n2c(CC3CCC(F)(F)CC3)c(C3(C)CC3)nc2c1
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
Sodium iodide (121 mg, 0.805 mmol) was suspended in a dichloromethane-acetonitrile (1:1) mixed solvent (0.8 mL). Under ice-cooled condition, dichlorodimethylsilane (52.0 mg, 0.403 mmol) was added, and the mixture was stirred for 20 minutes. The reaction mixture was stirred at room temperature for 30 minutes after adding a dichloromethane solution (0.4 mL) of butyl 3-{(4,4-difluorocyclohexyl) (hydroxy)methyl}-5-methyl-2-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-7-carboxylate (35.0 mg, 0.0810 mmol) obtained in step 3. Then, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium thiosulfate aqueous solution were added to the reaction mixture, and the mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20→65/35) to give butyl 3-(4,4-difluorocyclohexylmethyl)-5-methyl-2-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-7-carboxylate (24.6 mg, yield 73%).
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(OCC)(=O)C>COC(C)(C)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:9])[CH2:4][CH:5]([CH3:6])[CH3:7].[ClH:1]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Gaseous HCl (10.2 g, 279 mmol) was infused into a mixture of Boc-Leu-Leu-OMe (17.9 g, 50.0 mmol) and ethyl acetate (71.4 g) at 20 to 25° C. After 30 min, t-butyl methyl ether (142.9) was added to the resulting solution followed by a seed crystal. The resulting solid crystalline product was filtered at 0 to 5° C. and dried in vacuo to give H-Leu-Leu-OMe·HCl (14.1 g, 95.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])=[N:24][CH:25]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1Nc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
tert-butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (60 mg), 2,5-dibromopyridine (48.6 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.12 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.37 mg) were then added. The reaction mixture was then capped and stirred at 80° C. for 1 hour. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate (40 mg, 44%) as a colourless amorphous solid. MS (ISP): 450.2 ([{81Br}M+H]+), 448.1 ([{79Br}M+H]+), 394.3 ([{81Br}M+H—C4H8]+), 392.1 ([{79Br}M+H—C4H8]+).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34].[OH-].[NH4+]>C(O)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[N:16]([CH3:17])[C:12]3[C:11]4[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=4[CH:28]=[CH:27][C:13]=3[N:14]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
To a glass scintillation vial equipped with a magnetic stir bar was added 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.204 g, 0.483 mmol). A freshly prepared mixture of H2O (3.3 mL), glacial acetic acid (3.3 mL), and concentrated sulfuric acid (3.3 mL) at 60° C. was added to the vial. The vial was sealed with a screw cap and heated to 100° C. in a heating block. After 2.5 hours, the vial was allowed to cool to room temperature and stirred for an additional 12 h. The reaction mixture was then poured onto ice and neutralized by addition of concentrated ammonium hydroxide. The resulting precipitate was recovered by filtration and further purified by trituration with methanol to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.1188 g, 70%) as a light gray solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.43 (br s, 11H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37 (dd, 11H, J1=3.1 Hz, J2=9.8 Hz), 7.27 (td, 1H, J1=3.1 Hz, J2=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): found, 351.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1[C:27]2N=CC=[CH:31][C:26]=2[N:25]=N1.C(N(CC)C(C)C)(C)C.CC(N)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:26]([CH3:31])[CH3:27])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(Br)cc1F
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (1.50 g, 6.85 mmol, Combi-Blocks: Cat. # CA-4096), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.86 g, 7.53 mmol), and N,N-diisopropylethylamine (2.4 mL, 14 mmol) in methylene chloride (20. mL) was stirred for 10 minutes. 2-Propanamine (2.3 mL, 27 mmol) was then added and stirring was continued for 1.5 hours LC/MS data indicated that the major reaction component was the desired product. The reaction mixture was diluted with methylene chloride (40 mL) and H2O (3 mL). The layers were separated and the organic layer was washed with water (3×3 mL) and 1N HCl (3×3 mL). The combined aqueous phases were extracted with methylene chloride (5 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated in-vacuo. The crude product was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS (M+H)+: m/z=260.0/262.0.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl.[CH3:35][OH:36]>>[CH:35]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:26][CH2:27][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)=[O:36]
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Reactant: CO
Agent: Cl
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCOC=O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]-N,N-dimethylcyclohexan-1-amine (110 mg, 0.22 mmol, 1.00 equiv) in methanol (5 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. The resulting solution was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.1% HCOOH) and CH3CN (6.0% CH3CN up to 53.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to remove water and CH3CN. The residue was lyophilized overnight to give the 2-[(12S)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol formate (46 mg, 55%) as an off-white semi-solid. MS (ES): m/z 376 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.49 (d, 2H), 5.22 (s, 1H), 3.82 (t, 2H), 3.16 (m, 2H), 2.88 (s, 2H), 2.66 (s, 6H), 2.48 (t, 3H), 2.19 (s, 2H), 2.05 (d, 2H), 1.70 (m, 7H).
Reaction SMILES: [O-]CC.[Na+].ClCC1OC([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[C:22]([F:25])[CH:21]=[C:20]([C:26]([NH:28]C4CC4)=[O:27])[CH:19]=3)=[CH:14][CH:13]=2)=NN=1>C(O)C>[F:25][C:22]1[CH:21]=[C:20]([C:26]([NH2:28])=[O:27])[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[C:23]=1[CH3:24]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cc(C(N)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Freshly prepared sodium ethoxide in ethanol (0.2M, 0.8 ml) was added to a solution of (4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (50 mg) in ethanol (1 ml) and the reaction stirred at room temperature for 18 hours. The reaction was reduced to dryness under vacuum and the residue partitioned between ethyl acetate and water. The organic phase dried (magnesium sulphate) and reduced to dryness under vacuum. The residue was purified by HPLC to give N-cyclopropyl-4′-[5-ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.