Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>O>[OH2:29].[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH2:27][CH2:28][OH:29])[CH3:25])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH3:25])[CH2:27][CH2:28][OH:29])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CNCCO
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: Cl
Solvent: O
Product: CN(CCO)Cc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 130 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 1.4 g of the alcohol) was added to N-methylethanolamine (20 mL). The mixture was heated in an oil bath for 3 hr at about 130° C. The solution was diluted with water and the mixture extracted with diethyl ether (7×200 mL). The combined extracts were washed with saturated sodium chloride solution and evaporated to dryness to yield an orange solid. The crude product was recrystallized from methanol/dichloromethane. m.p. 188-195° C. Analysis: Calculated: C, 68.1; H, 6.5; N, 18.9. Found: C, 68.4; H, 6.5: N, 18.7.
Reaction SMILES: [N+](=[CH2:3])=[N-].CCOCC.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[C:12]([CH3:23])=[C:13]([C:20]([OH:22])=[O:21])[NH:14]2>CCOCC>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[C:12]([CH3:23])=[C:13]([C:20]([O:22][CH3:3])=[O:21])[NH:14]2
Reactant: Cc1ccc(Cl)c2c(C)c(C(=O)O)[nH]c12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1[nH]c2c(C)ccc(Cl)c2c1C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
An excess diazomethane ether solution was added to an ether solution of 0.50 g (2.24 mmol) of 4-chloro-3,7-dimethylindole-2-carboxylic acid under ice-cooling. The reaction mixture was allowed to stand for 30 minutes and then washed with 1N HCl aqueous solution and aqueous saturated sodium chloride solution. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide white crystals. The crude crystals were purified by silica gel column chromatography to provide 0.41 g of white crystals. Yield: 77%
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCO.C1(C)C=CC=CC=1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of 46 (375 mg, 0.711 mmol) in a mixture of EtOH (5 mL) and toluene (5 mL) at RT was added phenylacetyl isothiocyanate (189 mg, 1.066 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47 (400 mg, 80%) as a red solid. MS (m/z): 705.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C1CCN2C(=NCCC2)CC1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(O)C>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=2)[NH:7]1
Reactant: CCOC(=O)CBr
Reactant: O=C1Cc2cc(O)ccc2N1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccc2c(c1)CC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of 5-hydroxyindolin-2-one (1 g, 6.70 mmol) in 2-Propanol (10 mL) was added DBU (1.52 mL, 10.06 mmol) and ethyl bromoacetate (1.12 mL, 10.06 mmol) at room temperature. The reaction mixture was refluxed at 80° C. for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated and water (100 mL) was added. The solid which precipitated was filtered and dried to yield ethyl 2-((2-oxoindolin-5-yl)oxy)acetate as an off white solid (0.75 g, 47.6%) LCMS: RT 0.67 min. LCMS (ES-API), m/z 236.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:12]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH3:24])[C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:32]1[CH:37]=[CH:36][C:35]([Se:38]Br)=[CH:34][CH:33]=1.CN(C)C=O>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:12]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH3:24])[C:13](=[O:22])[CH:14]([Se:38][C:35]3[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=3)[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N(C(=O)C=Cc1ccccc1)[C@H](C(N)=O)c1ccc(Cl)cc1
Reactant: Br[Se]c1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C([Se]c2ccccc2)C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
Silver triflate (1.69 g, 6.6 mmol) was added to a stirred solution of (S)-α-(4-chlorophenyl)-α-[(R)-N-[1-(4-chlorophenyl)ethyl]-N-(cinnamoyl)amino]acetamide (1.5 g, 3.3 mmol), in acetonitrile (120 mL). To the resulting solution was successively added benzeneselenyl bromide (1.54 g, 6.53 mmol) and dimethylformamide (5.2 mL). After 6 h, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and 1N sodium hydrogenocarbonate (70 mL), dried (Na2SO4), and evaporated. Purification by column chromatography (AcOEt/hexanes, 1:3) afforded the title compound, which was recrystallized from Et2O to give colorless prisms (855 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 1.68 (d, J=7.0 Hz, 3H, CH3), 4.29 (d, J=12.2 Hz, 1H, CH), 4.79 (d, J=12.2 Hz, 1H, CH), 5.28 (s, 1H, CH), 6.21–6.25 (m, 3H, ArH), 6.31 (q, J=7.0 Hz, 1H, CH), 6.71–6.76 (m, 4H, ArH), 6.93–7.11 (m, 6H, NH+5ArH), 7.34–7.40 (m, 4H, ArH), 7.50 (d, J=8.4 Hz, 2H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C31H26Cl2N2O2Se: 608.0; found: 609.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:27][CH2:28][S:29][CH3:30])[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:27][CH2:28][S:29][CH3:30])[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a mixture of (2S,6R,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-isobutoxy-6-(2-(methylthio)ethyl)nonanoate (326 mg, 0.725 mmol) in THF (2.4 ml) and H2O (1.2 ml) was added LiO.H2O (91 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 3 h, quenched with 2N HCl (3 mL), diluted with H2O (20 mL), and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to provide the title compound as a sticky colorless oil (307 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 5.05 (d, J=7.3 Hz, 1H), 4.31 (s, 1H), 3.88 (p, J=6.3 Hz, 1H), 3.36 (dd, J=8.5, 6.3 Hz, 1H), 3.23 (dd, J=8.6, 6.6 Hz, 1H), 3.07 (dd, J=5.7, 3.9 Hz, 1H), 2.59 (ddd, J=13.9, 8.6, 5.3 Hz, 1H), 2.48 (dt, J=12.8, 7.5 Hz, 1H), 2.10 (s, 3H), 1.84 (tt, J=13.2, 7.1 Hz, 3H), 1.78-1.62 (m, 2H), 1.55 (dd, J=13.6, 5.8 Hz, 1H), 1.46 (s, 12H), 1.22 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.7, 2.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 155.81, 99.99, 84.81, 79.35, 68.26, 38.01, 32.80, 30.94, 29.22, 28.80, 28.32, 22.88, 19.51, 19.46, 19.13, 15.44; ESIMS m/z 436.3 ([M+H]+), 458.3 ([M+Na]+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:18](=[O:19])[CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)COC(C)=O
Temperature: 20 °C

Procedure:
To a 0° C. solution of diethylamine (1819 mL) and triethylamine (25.5 mL) in 500 mL of methylene chloride was added dropwise, with stirring, 25 g of acetoxyacetyl chloride. The ice bath was removed, and the mixture allowed to warm to 20° C. while stirring for an additional 2 hr. After filtration to remove amine hydrochloride salts, the methylene chloride solution was evaporated under reduced pressure to provide 29.1 g of crude, N,N-diethylacetoxyacetamide, as a yellow oil. The yellow oil was dissolved in 125 mL of methanol and 168 mL of 1N sodium hydroxide added with stirring. A slight exotherm was noted, and the mixture was allowed to stir for 2 hr. without further warming. Solvents were removed under reduced pressure to 1/4 volume, and the remaining aqueous solution extracted with ethyl acetate (200 ml). The ethyl acetate extract was dried over anh. sodium sulfate, and evaporated under reduced pressure to provide 14.0 g of N,N-diethylglycolamide as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Br:33])[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:32]([Br:33])=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(Br)c(Br)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)c(Br)c2)[nH]1
Reaction time: 8 h

Procedure:
12.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 1 g of p-toluenesulphonic acid were dissolved in 200 ml of ethanol. A solution of 21.6 g of 3,4-dibromobenzylhydrazine in 50 ml of ethanol was added dropwise thereto, under nitrogen. After stirring overnight, the solvent was concentrated in vacuo and the compound identified above, which has separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 182°, 11 g (41%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[C:30]([NH:29][S:26]([CH3:25])(=[O:27])=[O:28])[CH:31]=[CH:32][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(NS(C)(=O)=O)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 3.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylsulfonamido)phenylboronic acid (22 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)phenyl)methanesulfonamide (0.91 mg, 4%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.62 (m, 1H), 2.97 (s, 3H), 3.29 (s, 3H), 5.86 (m, 1H), 6.94 (m, 2H), 7.13 (m, 1H), 7.18 (m, 1H), 7.41 (m, 6H), 7.62 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH:16]([CH3:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[CH:10]2)=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Product: COC(=O)c1cc(Br)cc2cnn(C(C)C)c12
Yield: 65 %

Procedure:
Compound 14 was prepared following general method 1, using 5-bromo-1H-indazole-7-carboxylic acid methyl ester as a starting material and 2-iodopropane as alkylating agent. Yield: 65%.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[S:22])[C:17]([F:29])=[CH:16][C:15]=2[Cl:30])[CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:14]([S:13][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:12][CH2:11][CH2:10]2)=[CH:19][C:18]([N:20]=[C:21]2[N:23]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:1](=[O:2])[S:22]2)=[C:17]([F:29])[CH:16]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
While stirring at a temperature of +10° C., 12.5 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 10.4 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclobutanecarboxylic acid methyl ester and 10 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 6 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 4.6 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclobutylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7one, ηD22 1.6010.
Reaction SMILES: [CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:18](Cl)(=[O:20])[CH3:19]>>[CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Product: CCCCS(=O)(=O)NC1Cc2ccc(C(C)=O)cc2C1

Procedure:
2-n-Butylsulfonylaminoindane and acetyl chloride were treated in the same manner as in Example 31-(2) to obtain 2-n-butylsulfonylamino-5-acetylindane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.Cl.[CH2:38](Cl)Cl>CO.O1CCOCC1>[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:34]=[CH:35][C:14]([C@H:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[OH:36])=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][C:29]([CH3:38])=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCNC[C@H]4O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of cis-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6 mL) was added 4M HCl in dioxane (1.5 mL) slowly and the reaction mixture stirred at RT for 2.5 h before being concentrated in vacuo. The resultant residue was triturated in diethyl ether to give racemic cis-4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol which was resolved as the (3R,4S) enantiomer 328 as a white solid (10 mg, 67%). MS RT 2.47, [M+H]+=409. 1H NMR (DMSO-d6) δ: 8.92 (1H, br, d), 8.33 (1H, d, J=8.30 Hz), 7.97 (1H, s), 7.08 (1H, d, J=8.36 Hz), 6.96 (1H, d, J=1.66 Hz), 5.79 (1H, t, J=6.59 Hz), 4.50 (4H, d, J=7.99 Hz), 4.06 (1H, s), 3.27 (2H, m), 3.17 (2H, m), 2.97 (2H, d, J=14.58 Hz), 2.32-2.27 (1H, m), 2.29 (3H, s), 1.74 (1H, d, J=13.43 Hz), 1.46 (6H, d, J=6.59 Hz)
Reaction SMILES: [N:1]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[CH:19][N:18]2[C:21]([C:24]([NH:26][C:27]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:28]=3[C:29]([CH:44]3[CH2:46][CH2:45]3)=[N:30][N:31]4[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=3)=[O:25])=[CH:22][N:23]=[C:17]2[CH:16]=1>C(O)(C)(C)C>[N:1]1([CH2:5][CH2:6][O:7][C:15]2[CH:20]=[CH:19][N:18]3[C:21]([C:24]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:28]=4[C:29]([CH:44]4[CH2:45][CH2:46]4)=[N:30][N:31]5[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=4)=[O:25])=[CH:22][N:23]=[C:17]3[CH:16]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Reactant: OCCN1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCC6)ccn45)cccc32)n1
Temperature: 88 °C
Reaction time: 0.08 h

Procedure:
2-(Azetidin-1-yl)ethanol (52 mg, 0.51 mmol) was dissolved in tert-butanol (0.3 mL) and treated with potassium tert-butoxide (51 mg, 0.45 mmol). The mixture was stirred at 88° C. for 5 minutes before adding 7-fluoro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide in one portion. The mixture was stirred at 88° C. for 16 hours. The mixture was cooled to ambient temperature and quenched with water (2 mL) followed by vigorous stirring for 2 hours at ambient temperature. The precipitate was isolated by filtration and dried under vacuum to give a pale yellow residue which was triturated with diethyl ether 3 times to give a solid. Purification by Preparative Thin Layer Chromatography (Silica, 20×20, 0.5 mm thickness) eluting with 10% MeOH/DCM with 0.6% ammonium hydroxide gave 7-(2-(azetidin-1-yl)ethoxy)-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (18 mg). MS (APCI), positive scan, m/z=522.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 14, 13 g, 51.73 mmol) in dry tetrahydrofuran (150 ml) at −70° C. under argon atmosphere was added 1 M lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide in tetrahydrofuran (56.9 ml, 56.9 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. It was again cooled to −70° C. and a tetrahydrofuran (50 ml) solution of 2,4,5-trifluorobenzenesulfonyl chloride (11.9 g, 51.73 mmol) was added dropwise to it at this temperature. After complete addition, reaction mixture was gradually allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. Crude product was purified over 100-200 silica gel using 5-15% v/v ethyl acetate in hexane to give 17 g (75%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH:19]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:11])[C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)Oc1ccc(C[C@@H](N)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyloxycarbonyloxysuccinimide (5.75 g) was added to a suspension of D-Tyr(tBu)-OH (5.0 g) in N,N-dimethyl formamide (40 ml). The pH of the solution was adjusted to 8 using triethylamine. The reaction mixture was stirred overnight at room temperature and then evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and diluted with ice water. The pH of the water layer was adjusted to pH 2.5 with 2 N hydrogen chloride. The organic layer was seperated and the aqueous phase was extracted with dichloromethane. The organic layers were combined and washed with water, dried over sodium sulfate and concentrated. Yield: 9.95 g. TLC: Rf=0.31, heptane/ethyl acetate 1/1.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][C:11]1[S:12][C:8]([C:3]2([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]2)=[CH:9][CH:10]=1)(=[O:25])=[O:24]
Reactant: CCC1(c2ccc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(c2ccc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.25 g (43.2 mmol) of [5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]methanol are dissolved in 500 mL of dichloromethane and cooled to 0° C. 9.0 mL (64.7 mmol) of triethylamine are added, followed by 3.5 mL of methylsulphonyl chloride (45.3 mmol). After stirring for 1 hour, the reaction medium is treated with ammonium chloride solution and extracted with dichloromethane. The organic phases are combined, dried and concentrated under reduced pressure. A brown oil is obtained (m=9.28 g; Y=75%).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1([NH2:8])[CH2:7][CH2:6]1.C[O-].[Na+].[N:12]#[C:13][Br:14]>CO>[BrH:14].[CH2:7]1[C:5]2([CH2:4][CH2:3][N:2]=[C:13]([NH2:12])[NH:8]2)[CH2:6]1
Reactant: NCCC1(N)CC1
Reactant: N#CBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC1=NCCC2(CC2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 2.65 g (10.11 mmol) of 1-(2-aminoethyl)cyclopropanamine hydrobromide in 21 ml of methanol was added 3.83 ml (21.24 mmol) of a solution of sodium methoxide in methanol (5.55 N). The mixture was stirred at room temperature for 2 h. The precipitate was filtered and the filtrate was evaporated. The crude was dissolved in 9 ml of water and 1.07 g (10.11 mmol) of cyanogen bromide was added portion wise. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness to give 2.08 g of pure compound as an orange oil.