Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:33])([CH3:32])[C:25](=[O:31])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:29]=[C:28]5[C:23]([C:24]([CH3:33])([CH3:32])[C:25](=[O:31])[NH:26][C:27]5=[O:30])=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Solvent: CC#N
Product: CC1(C)C(=O)NC(=O)c2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Yield: 50.1 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (7.5 mg), 7-amino-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (30 mg) (prepared according to the reference: Snow, R. J. et al, J. Med. Chem. 2002, 45, 3394), and acetonitrile (0.5 mL) was heated with microwave at 180° C. for 60 min. The solvent was removed and the residue was purified by chromatography to give an off-white solid (6 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:5]=1[C:6](=[O:12])[O:7]2>CN1CCCC1=O>[NH2:17][C:14]1[CH:15]=[CH:16][C:4]2[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[OH:1])[O:7][C:6](=[O:12])[C:5]=2[CH:13]=1
Reactant: O=c1oc2cccc(O)c2c2ccc([N+](=O)[O-])cc12
Solvent: CN1CCCC1=O
Product: Nc1ccc2c(c1)c(=O)oc1cccc(O)c12

Procedure:
treating 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one with a second transition metal catalyst under a hydrogen atmosphere at a pressure of about 20 to about 60 psi, preferably about 40 psi, in a third solvent, preferably N-methylpyrrolidin-2-one (NMP) at a concentration of about 0.5M to about 1.0M, preferably 0.7M, to provide 8-amino-1-hydroxy-6H-benzo[c]chromen-6-one in NMP;
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10]([Br:21])=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10]([Br:21])=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 70 °C
Yield: 123.6 %

Procedure:
Step 2 A mixture of 7-(azidomethyl)-4-bromo-9H-carbazole-1-carboxamide (350 mg, 0.814 mmol), triphenylphosphine (427 mg, 1.627 mmol), and water (18 μL, 0.976 mmol) in THF (10 mL) was heated at 70° C. for 3.5 h. The mixture was cooled to rt and partitioned between EtOAc and 1 M hydrochloric acid. The pH of the aqueous phase was raised to 8-9 with sodium hydroxide pellets, and then was extracted with EtOAc. The organic phase was dried and concentrated to provide crude 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide as a yellow glassy foam (320 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 11.61 (1H, br.), 8.47-8.55 (1H, m), 8.19 (1H, br. s.), 7.81-7.84 (1H, m), 7.76 (1H, s), 7.63-7.66 (1H, m), 7.53-7.59 (2H, m), 7.41 (1H, d, J=8.1 Hz), 7.27 (1H, dd, J=8.4, 1.3 Hz), 3.90 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[O:12])[CH3:11].COC(OC)N(C)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[C:10]([C:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH:1]=1)(=[O:12])[CH3:11]
Reactant: COc1ccccc1CC(C)=O
Agent: BrB(Br)Br
Agent: COC(OC)N(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(=O)c1coc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of 2-methoxyphenylacetone (5 g, 30.5 mmol) in N,N-dimethylformamide dimethyl acetal (8.7 ml, 73.1 mmol) was stirred at 80° C. for 4 hours. The mixture was concentrated under vacuum. The resulting residue was dissolved in dichloromethane (40 ml), cooled to 0° C. and treated with a solution of boron tribromide (5 ml, 52.9 mmol) in dichloromethane (10 ml). After stirring at 0° C. for 1 hour, additional boron tribromide (5 ml, 52.9 mmol) was added. The mixture was stirred at 0° C. for 10 more minutes and was poured into a mixture of ice and saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane three times. The combined organic extracts were washed with water once and dried over anhydrous sodium sulfate to give 3-acetylbenzofuran (4.7 g, 96%, 94.5% AUC HPLC): 1H NMR (300 MHz, CDCl3) δ 8.16-8.19 (m, 2H), 7.44-7.48 (m, 1H), 7.29-7.32 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH3:46])[C:8]([NH:10][C:11]2[CH:45]=[CH:44][C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([O:29][Si](C(C)(C)C)(C)C)[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:17]3C(OC(C)(C)C)=O)=[CH:13][CH:12]=2)=[O:9])[N:6]=1.Cl>CO>[F:28][C:24]1[CH:23]=[C:22]([C@@H:21]([OH:29])[C@@H:18]2[NH:17][C@H:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:5]4[N:6]=[CH:2][S:3][CH:4]=4)[CH3:46])=[CH:45][CH:44]=3)[CH2:20][CH2:19]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)N2C(=O)OC(C)(C)C)cc1)c1csc(N)n1
Agent: Cl
Solvent: CO
Product: CC(C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccc(F)c3)N2)cc1)c1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8 mg (0.01 mmol) tert-butyl (2S,5R)-2-(4-{[2-(2-amino-1,3-thiazol-4-yl)propanoyl]amino}benzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(3-fluorophenyl)methyl]pyrrolidine-1-carboxylate (isomer 2) in 0.20 mL methanol from Step A was added 0.20 mL conc. HCl and the reaction mixture stirred at room temperature for 1 h. Azeotrop with toluene (2×) to remove water. The residue was taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 0-50% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (Example 275) (4.3 mg, 79%). m/z (ES) 440 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:13][C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CC(=O)Nc1cccc(OCC(=O)O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of N-(3-hydroxyphenyl)acetamide (300 mg, 2.0 mmol) in MeCN (5 mL) was added ethyl bromoacetate (500 mg, 3 mmol) and K2CO3 (828 mg, 6 mmol). The mixture was stirred at 80° C. for 4 hours, filtered and the filtrate was concentrated. NaOH (80 mg, 2 mmol) and water:EtOH (1:1, 10 mL) was added to the mixture. This mixture was then stirred at 50° C. for 4 hours before being acidified by 1M HCl, extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated with the residue used directly for the next step. LCMS (m/z): 183.0 (M+1).
Reaction SMILES: C(OCC)(=O)C.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH2:23]([N:25]1[C:29]([OH:30])=[CH:28][CH:27]=[N:26]1)[CH3:24].CC(C)(O)C#N.[Cl:37][C:38]1[C:46]([CH:47]([O:50][CH3:51])[O:48][CH3:49])=[C:45]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:23]([N:25]1[C:29]([OH:30])=[C:28]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:45]([S:52]([CH3:55])(=[O:54])=[O:53])=[C:46]([CH:47]([O:50][CH3:51])[O:48][CH3:49])[C:38]=2[Cl:37])[CH:27]=[N:26]1)[CH3:24]
Reactant: CCn1nccc1O
Reactant: COC(OC)c1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(OC)OC)c2Cl)c1O
Temperature: 25 °C

Procedure:
To ethyl acetate in a volume of 50 ml, was dissolved 2-chloro-4-methanesulfonyl-3-dimethoxymethylbenzoic acid in an amount of 3.0 g (9.7 mmol), and to the resulting solution, were added DCC in an amount of 2.2 g (10.7 mmol) and 1-ethyl-5-hydroxypyrazole hydrochloride in an amount of 1.4 g (9.7 mmol) while cooling with ice and the mixture was subsequently stirred for a night at an ambient temperature. Insoluble product precipitated was filtrated, and the filtrate was condensed under reduce pressure. The residue obtained was then dissolved in chloroform in a volume of 30 ml, and the resulting solution was stirred for 6 hours at an ambient temperature following to an addition of acetone cyanohydrin in an amount of 0.25 g (2.9 mmol) and triethylamine in an amount of 2.0 g (20 mmol) thereto. The reacted-mixture was washed with 1-N hydrochloric acid and then with saturated saline solution, dried over anhydrous magnesium sulfate and subjected to distillation for eliminating the solvent therein. The crystals remained were washed with methanol to obtain 1-ethyl-5-hydroxy-4-(2-chloro-4-methanesulfonyl-3-dimethoxymethylbenzoyl)pyrazole in an amount of 1.6 g. The melting point of this compound is in a range of from 168° to 170° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][CH2:39][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][N:33]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1cnccn1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cnccn4)cc3)oc2C)cc1
Yield: 69.2 %

Procedure:
Reaction of oxalyl chloride (74 λL, 0.8 mmol) and benzoic acid 4 (209 mg, 0.6 mmol) with subsequent coupling to 2-pyrazinylmethylamine (90 mg, 0.6 mmol) gave benzamide 13 (192 mg, 74%) as a white powder: mp (EtOAc) 204-206° C.; 1H NMR δ 9.30 (t, J=5.8 Hz, 1H, CONH), 8.66 (d, J=1.5 Hz, 1H, H-3′), 8.59 (dd, J=2.6, 1.5 Hz, 1H, H-5′), 8.54 (d, J=2.6 Hz, 1H, H-6′), 8.02 (d, J=8.6 Hz, 2H, H-2, H-6), 7.90 (d, J=8.6 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 4.62-4.66 (m, 4H, CH2SO2, CH2N), 2.41 (s, 3H, CH3), 2.14 (s, 3H, CH3); 13C NMR δ 165.7, 158.0, 154.1, 149.9, 144.5, 143.9, 143.5, 143.2, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 53.0, 42.9, 21.0, 9.7; MS m/z 433.6 (MH+, 100%). Anal. calcd for C24H22N4O4S: C, 62.32; H, 4.79; N, 12.11. Found: C, 62.36; H, 4.67; N, 12.09%.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH:8]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:4]1[CH:5]=[CH:6][C:2]([CH:25]=[O:26])=[CH:3]1)([CH3:10])[CH3:9]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (2.0 g, 6.61 mmol) in THF (30 mL) was added n-butyllithium (2.5 M in hexanes, 3.4 mL, 8.60 mmol) at −78° C. The mixture was stirred at −78° C. for 10 min then DMF (0.76 mL, 9.92 mmol) was added and the mixture was warmed to 0° C. over 1 hour. The reaction mixture was quenched by saturated NH4Cl and extracted with EtOAc (200 mL). The organic phase was washed with brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% EtOAc in hexanes) to afford the sub-title compound (1.65 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[S:5][C:6]=1[CH2:7][C:8](O)=[O:9]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[S:5][C:6]=1[CH2:7][CH2:8][OH:9]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
A solution of [4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-acetic acid (430 mg, 1.4 mmol) in tetrahydrofuran (6 ml) was treated at 0° C. with a 1 M solution of BH3*THF in tetrahydrofuran (3.6 ml, 3.6 mmol). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 16 h. Careful quenching with MeOH and ice water, twofold extraction with AcOEt, washing with ice water/brine 1/1, drying over magnesium sulfate, and evaporation of the solvent left a crude product which was refluxed for 30 min in MeOH to liberate quantitatively the free alcohol. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 230 mg (0.8 mmol, 56%) of the title compound as yellow oil.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[S-:35][C:36]#[N:37].[K+]>CS(C)=O>[CH3:32][Si:31]([CH3:33])([CH3:34])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][S:35][C:36]#[N:37])[CH2:12][CH2:11]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Reactant: N#C[S-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSC#N)CC4)c3)ncnc21
Temperature: 68 °C

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (prepared as in Example 679A, step 6; 0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL) with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction was heated at 68° C. for 4 days at which time LCMS analysis showed ˜4:1 product/starting material ratio. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+: 469, 1H NMR (CDCl3): δ 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[CH:10][C:11]([O:13]C)=[O:12])[CH2:3]2.Cl>[Pd].C(O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([OH:13])=[O:12])[CH2:3]2
Reactant: COC(=O)C=C1CN2CCC1CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CC1CN2CCC1CC2
Temperature: 60 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
A mixture of methyl quinuclidin-3-ylideneacetate hydrochloride (Example 18, Step 1) (2 g), ethanol (50 ml), 2M hydrochloric acid (5 ml) and 10% Pd/C (1 g) was stirred for 24 hours under H2 at atmospheric pressure, filtered through celite and evaporated to dryness. The residue was dissolved in concentrated hydrochloric acid (10 ml). heated at 60° C. for 18 hours, treated with a further 10 ml of concentrated hydrochloric acid, heated at 80° C. for 6 hours and evaporated to dryness. The residue was kept under vacuum over P2O5 for 3 days to give the title compound as a white solid (1.8 g); MS (+ve ion electrospray) m/z 170 (MH+, 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N+:10]([O-])=[CH:9][C:8]=3[N:18]=[C:5]2[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.[OH-].[NH4+:27].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:27][C:9]1[C:8]2[N:18]=[C:5]3[N:4]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:3][C@H:2]([CH3:1])[N:6]3[C:7]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c(N)nc4ccccc4c3n21

Procedure:
A solution of tert-butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate 5-oxide (1.22 g, 3.58 mmol) in 50 mL of CH2Cl2 was treated with 5 mL of concentrated aqueous ammonium hydroxide and stirred vigorously. p-Toluenesulfonyl chloride (0.68 g, 3.58 mmol) was added in one portion and the reaction became slightly exothermic. The following day the reaction was treated with 5 mL of H2O, and the layers were separated. The organic layer was washed with saturated NaHCO3 solution (2×), then brine. It was dried over Na2SO4, filtered and concentrated to give a crude solid. Chromatography (SiO2, 0-20% CMA/CHCl3) afforded an off white solid, which was recrystallized from ethyl acetate to give tert-butyl (10S)-6-amino-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate (0.26 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1.C(Cl)CCl.[NH2:33][O:34]C1CCCCO1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:33][OH:34])=[O:28])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (133 mg, crude compound from STEP B) was dissolved in DCM (4 ml) and TEA (0.098 ml, 0.704 mmol). EDC (101 mg, 0.53 mmol) HOBT (71 mg, 0.53 mmol) and NH2OTHP (49 mg, 0.42 mmol) were added, the mixture was stirred at RT overnight and then partitioned between water and DCM. The organic phase was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent:DCM/MeOH/NH4OH 96:4:0.2) and the resulting (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with HCl/Et2O for 4 h. The precipitate was filtered and washed with DCM to give (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide as its di-hydrochloride (66 mg, white powder).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]C1C=CC=CC=1C(C1C=CC=CC=1)=O>>[Br:17][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][NH2:9]
Reactant: Cc1ccccc1C(CN)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1Br
Product: NCC(c1ccccc1)c1ccccc1Br

Procedure:
The title material was prepared as described for the synthesis of 2-phenyl-2-o-tolylethanamine (Example FF) in using (2-bromophenyl)(phenyl)methanone. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.15 (2H, dd, J=7.45, 2.65 Hz) 4.36 1H, (t, J=7.45 Hz) 7.12-7.20 (2H, m) 7.22-7.29 (5H, m) 7.38 (1H, td, J=7.52, 1.14 Hz) 7.48 (1H, dd, J=7.71, 1.64 Hz) 7.58 (1H, dd, J=7.83, 1.26 Hz).
Reaction SMILES: C(OC(OC1C=C[C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20](OCCC)=[CH:19][CH:18]=2)=CC=1)=O)(C)(C)C.[CH2:27](OC1C=CC(C#C)=CC=1)[CH2:28]C>>[CH2:16]([C:17]1[CH:18]=[CH:19][C:20]([C:27]#[CH:28])=[CH:21][CH:22]=1)[CH2:15][CH3:12]
Reactant: C#Cc1ccc(OCCC)cc1
Reactant: CCCOc1ccc(C#Cc2ccc(OC(=O)OC(C)(C)C)cc2)cc1
Product: C#Cc1ccc(CCC)cc1

Procedure:
1-[4-(tert-butoxycarbonyloxy)phenyl]-2-(4-n-propyloxyphenyl)acetylene was gained in the same manner as in the step (iii) of the Example 31, except for using 4-(n-propyloxy)phenylacetylene obtained in the step (iii) instead of 4-n-propylphenylacetylene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[CH:2].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[N+:17]=[N-:18].Cl>O.O1CCOCC1.CO>[NH2:30][C@@H:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH:2]=[C:1]([C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:5][CH:4]=3)[N:18]=[N:17]2)=[CH:20][CH:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N=[N+]=[N-])cc1)C(=O)O
Reactant: C#Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: N[C@@H](Cc1ccc(-n2cc(-c3ccc(Oc4ccccc4)cc3)nn2)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A mixture of 1-ethynyl-4-phenoxy-benzene (126 mg, 0.65 mmol) and (S)-3-(4-azido-phenyl)-2-tert-butoxycarbonylamino-propionic acid (200 mg, 0.65 mg) in H2O:dioxane (5:1) was heated at 100° C. in a sealed tube for overnight. After completion of reaction, 3N HCl (5 ml) was added and the mixture was stirred for 2 hr at 50° C. Removal of solvent gave crude product which was dissolved in MeOH and purified by preparative HPLC to give 45 mg of desired product (yield: 29%). 1H-NMR (400 MHz, CD3OD): δ (ppm) 3.2 (m, 1H), 3.4 (m, 1H), 4.3(m, 1H), 6.9(d, 2H), 7.0(d, 2H), 7.2(m, 1H), 7.3(d, 2H), 7.4-7.55 (m, 6H), 8.0(s, 1H).
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=O)[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:20][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:15][C:14]=1[O:20][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]
Reactant: Nc1ccc(Cl)c(OC2CCCC2=O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reaction time: 2.5 h

Procedure:
A mixture of 1.52 g. of cyclohexene-1,2-dicarboxylic anhydride, 2.26 g. of 4-chloro-3-(cyclopentanon-2-yloxy) aniline and 10 ml. of acetic acid was stirred at room temperature for 30 minutes and then was refluxed with stirring for 2.5 hours. The solvent was distilled off under a reduced pressure and then, ethyl acetate was added to the residue to extract the product. The extract was washed with water and dehydrated over sodium sulfate. The solvent was distilled off and the product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:4) to obtain Compound No. 5 shown in Table 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:22])=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1=[O:29]>>[F:22][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:26]4[CH2:27][CH2:28][NH:23][C:24](=[O:29])[CH2:25]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: O=C1CNCCN1
Reactant: Fc1c(Cc2cnc3ccc(Cl)nn23)ccc2ncccc12
Product: O=C1CN(c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)CCN1

Procedure:
The title compound was prepared in analogy to Example 38 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5-fluoro-quinoline (Intermediate N, 100 mg, 0.320 mmol), piperazin-2-one (96 mg, 0.959 mmol) (tR 3.16 min (conditions 5), MH+=377, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.47 (d, 1H); 8.07 (s, 1H); 7.84 (d, 1H); 7.78 (d, 1H); 7.69 (m, 1H); 7.60 (m, 1H); 7.47 (s, 1H); 7.12 (d, 1H); 4.42 (s, 2H); 3.98 (s, 2H); 3.66 (m, 2H); 3.25 (m, 4H)).