Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([N:10]([CH3:44])[CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=O)(=[O:4])=[O:3].CSC>C1COCC1>[NH2:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][N:10]([CH3:44])[CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)CCCS(N)(=O)=O)COc1ccccc1-3
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)CCCCS(N)(=O)=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl(7R)-7-[{2-[[4-(aminosulfonyl)butanoyl](methyl)amino]ethyl}-(methyl)amino]-14-cyclohexyl-7,8-dihydro -6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.03 M) in THF was treated with BH3.DMS complex (2 M in THF; 15 eq.). The resulting solution was stirred at RT for 1 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution heated at 80° C. until all volatiles had evaporated to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 611 (M+H)+.
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].[NH4+].[Cl-]>C1COCC1>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: ClCCCCBr
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) was added drop wise to a solution of iPr2NH (12.3 mL, 88 mmol, distilled from NaOH) in dry THF (150 mL) in 10 min. The reaction mixture was stirred for 20 min, cooled to −70° C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem., 1937, 43, 282-285, 12.5 g, 88 mmol) was added drop wise in 20 min. After 3 min, 1-bromo-4-chlorobutane (13.7 mL, 20.1 g, 117 mmol) was added drop wise in 15 min. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (1×200 mL, 1×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The remaining oil, was purified by fractional distillation to give tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.73 g, 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR (CDCl3): δ=3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-:12].[K+]>COCCOC.O>[Br:1][C:2]1[N:6]2[NH:7][C:8](=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: [OH-]
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=c1ccc2ncc(Br)n2[nH]1

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine [13526-66-4] (425.7 mg, 1.8 mmol) in 1,2-dimethoxyethane (9 mL) was added a solution of potassium hydroxide [1310-58-3] (185.4 mg, 2.8 mmol) in water (9.0 mL) and the stirred resultant solution heated to reflux under N2 for 3d, cooled and partitioned between ethyl acetate and water. The water phase was evaporated to dryness, taken up in methanol, filtered, and evaporated to yield 3-bromo-imidazo[1,2-b]pyridazin-6-one as 340 mg of yellow solid. LRMS (ESI) m/z 214.0/216.0 [(M+H)]+, calc'd for C6H4BrN3O3: 214.02.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
2,6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([Br:11])[C:5]=1[NH2:12].[OH-].[Na+].C(OCC)C.O>CO>[NH2:12][C:5]1[C:6]([Br:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: Nc1c(C(=O)O)cc(Cl)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-2-bromo-6-chloroisonicotinic acid methyl ester (260 mg) (example 3, step 5) was dissolved in methanol (2 mL), 2N aqueous sodium hydroxide solution (2 mL) was added and the reaction mixture was stirred for 2 hours at reflux. After cooling to room temperature, diethyl ether and water were added and the layers were separated. The aqueous layer was washed with diethyl ether and acidified by addition of 2N hydrochloric acid. The formed precipitate was extracted with MTB-ether (3×), the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 246 mg of
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[CH:15](=[N:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:28][CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Cl-:7].[CH:15](=[N:22][N+:23]1[CH:27]=[CH:26][N:25]([CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[C:24]=1[CH2:28][CH3:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCc1nccn1N=Cc1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: CC#N
Product: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccccc1
Product: [Cl-]

Procedure:
2.16 g (10 mmol) of 3,4,5-trimethoxybenzyl chloride are added to a solution of 1.99 g (10 mmol) of 1-benzylideneamino-2-ethylimidazole in 10 ml of acetonitrile and the mixture is heated under reflux for 28 hours. The crystallized-out product is filtered off and washed with ether. There is obtained 1-benzylideneamino-2-ethyl-3-(3,4,5-trimethoxybenzyl)imidazolium chloride of melting point 205°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:37])[NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)[CH2:25][CH2:24]4)=[C:17]3[N:16]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:37])[CH2:27][CH2:28]4)=[C:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 1 h
Yield: 109 %

Procedure:
To (3-{6-Bromo-7-[4-(thiazol-2-ylcarbamoylmethyl)-piperazin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}-benzyl)-carbamic acid tert-butyl ester (0.027 g, 0.04 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (0.5 mL) at 0° C. trifluoroacetic acid (0.25 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was run trough a 2 g SCX cartridge and eluted with 0.1M NH3 in methanol to give the title compound as a pale yellow solid (0.023 g, 100%);
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: CN(C)c1ccncc1
Product: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Yield: 19 %

Procedure:
2,6-Dichloroquinoline (15.2 mmoles, 3.0 g), 4-aminothiophenol (15.2 mmoles, 1.9 g), and DMAP 15.2 mmoles, 1.85 g) were stirred at room temperature for 3 days. The solvent was removed, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-6-chloroquinoline 830 mg, 19%. Mass spec (FD) 286. Calculated. for C15H11ClN2S: C, 62.82H, 3.87; N, 9.77. Found: C, 63.09; H, 3.94; N, 9.61.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.[CH:30]1[CH:31]=[CH:32][C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:36]([C:16](=[O:18])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH:14]=1)[C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(CC(=O)Nc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl]acetic acid (0.2 g, 0.757 mmol), EDCI (0.22 g, 1.15 mmol) and HOBt (0.16 g, 1.18 mmol) were stirred in DMF (6 mL) for 10 minutes before adding aniline (85 mg, 0.913 mmol). The solution was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue partitioned between H2O-EtOAc. The aqueous phase was extracted with further portions of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Et2O was added and the resulting beige solid collected by filtration to give 0.17 g of product (66%). 1H NMR (DMSO-d6) δ 10.21 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.01 (t, J=7.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:13]([CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4])=[N+:14]=[N-:15]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To the solution of 4-chloroacetylcatechol (25 g) in DMF (200 ml) was added sodium azide (10.5 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the solids thus obtained was washed with a solution of n-hexane:ether=5:1 to give 23.2 g of 4-azidoacetylcatechol (yield, 90%).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[C:16]1([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(Sc2ccccc2)C(C)=O)cc1
Yield: 84.7 %

Procedure:
The reaction of 392 mg of 1-chloro-1-[(4-methoxyphenyl) hydrazono]-2-propanone, 220 mg of thiophenol and 280 ul of triethylamine in 6 ml of ethanol as in Example 11 yielded 440 mg of 1-[(phenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 120°-123° C.
Reaction SMILES: [CH2:1]([N:8]([CH:28]1[CH2:31][N:30]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:29]1)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)N(C)CCC1.O>[CH3:51][O:50][C:48](=[O:49])[CH2:47][N:41]([C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:30]2[CH2:29][CH:28]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[CH2:31]2)(=[O:34])=[O:33])=[CH:40][CH:39]=1)[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCCCN(CC(=O)OC)c1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To a solution of 1-{benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.10 g, 0.15 mmol) in N,N′-dimethylpropyleneurea (1 ml) was added methyl bromoacetate (46 mg, 0.3 mmol) and potassium carbonate (28 mg, 0.2 mmol), and the mixture was stirred at 50° C. for 2 days. It was then cooled to room temperature and diluted with water (20 ml). The aqueous phase was removed, and the residue dissolved in ethyl acetate (20 ml). The organic solution was washed with brine, and dried over anhydrous sodium sulfate. It was then filtered and evaporated, and the residue was chromatographed on silica gel (ethyl acetate-hexanes/1:1) to give 50 mg of a colorless gum; MS (ES) m/z 702.2 (MH+); HRMS (FAB) Calcd. for C39H48N3O7S (MH+): 702.3213, Found: 702.3231.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 55 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), 3-phenylpropionyl chloride (60.3 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (74.4 mg, yield 55%).
Reaction SMILES: Cl[CH:2]([O:8][CH3:9])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:21])[F:20])[NH:16][C:15]=2[CH:22]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH:19]([F:20])[F:21])[N:16]([CH2:9][O:8][CH2:2][CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[C:15]=2[CH:22]=1
Reactant: COC(Cl)C[Si](C)(C)C
Reactant: FC(F)c1nc2ccc(Br)cc2[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C(F)F)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-Chloro-methoxy-ethyl)-trimethyl-silane (1.1 ml, 6.4 mmol, 1.5 eq.) was added to an anhydrous dichloromethane solution (22 ml) of 6-bromo-2-difluoromethyl-1H-benzimidazol (1.0 g, 4.27 mmol) and N,N-diisopropyl ethyl amine (1.9 ml, 10.6 mmol, 2.5 eq.). This was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6-bromo-2-difluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole was obtained as a yellow solid (1.37 g, 85%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].I[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: Cc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 89.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.2 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of 4-iodotoluene, 1.49 g (45%) of the expected compound was recovered, after chromatography on a silica column eluted with dichloromethane, in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH:12][C:13]=2[C:14](O)=[O:15])=[CH:5][CH:4]=1.O.OC1C2N=N[NH:30]C=2C=CC=1.N.O1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH:12][C:13]=2[C:14]([NH2:30])=[O:15])=[CH:5][CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc(-c2nc(-c3ccncc3)[nH]c2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(-c3ccncc3)[nH]c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxylic acid (0.090 g, 0.3 mmol) and hydroxybenzotriazole monohydrate (0.047 g, 0.3 mmol) in DMF (2.5 ml) was added 0.5M ammonia in dioxane (2 m, 1.0 mmol) and the resulting solution stirred at room temperature for 10 minutes. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.064 g, 0.33 mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxamide (0.025 g, 0.08 mmol, 67%). 1H NMR (DMSO) 3.83 (3H, s), 7.03 (2H, d), 7.20 (1H, br. s), 7.50 (1H, br. s), 7.84 (2H, d), 8.03 (2H, dd), 8.68 (2H, dd), 13.12 (1H, br. s). LCMS (2) Rt 1.68 min; m/z (ES+) 295.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1cccnc1Br
Product: COc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (3.97 g) and 2-bromo-3-methoxypyridine (1.50 g) were heated with stirring at 100° C. for 48 hours. The cooled residue was partitioned between chloroform and water. The aqueous layer was further extracted with chloroform and the combined chloroform layers were washed with water, dried and evaporated to dryness. The brown residue was dissolved in aqueous acetic acid to pH 4 and extracted with ether to remove unreacted 2-bromo-3-methoxypyridine. The aqueous solution was basified with potassium carbonate to pH 9-10 and then extracted with chloroform. The combined chloroform extracts were washed, dried and evaporated to dryness. The residue was subjected to column chromatography on silica with chloroform as eluant to afford the title compound as an oil. This was treated with maleic acid in isopropanol to give as a white solid, 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-methoxypyridine dimaleate (0.82 g), m.p. 111°-112° C. (recrystallised from acetone-ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[S:36][C:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:34][C:33]=3[CH:45]=2)O1>>[NH2:37][C:35]1[S:36][C:32]2[CH:31]=[CH:30][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:45][C:33]=2[N:34]=1.[C:40]([O:39][C:38]([NH:37][C:35]1[S:36][C:32]2[CH:31]=[CH:30][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:45][C:33]=2[N:34]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2s1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4sc(N)nc4c3)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4sc(NC(=O)OC(C)(C)C)nc4c3)ccn2c1=O
Yield: 20 %
Yield: 38 %

Procedure:
The title compounds were prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and a mixture of tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate and di-tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl-di-carbamate (195.7 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded methyl 8-(2-aminobenzo[d]thiazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (58 mg, 38%) and yellow solid methyl 8-(2-(tert-butoxycarbonylamino)benzo[d]thiazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (42 mg, 20%).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:36]([CH3:38])[CH3:37])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (45%).