Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH2:40][CH2:39][CH2:38]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[C:42]4[C:37](=[CH:36][C:35]([CH3:34])=[CH:44][CH:43]=4)[CH2:38][CH2:39][CH2:40]3)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:9][CH2:10]1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)CCCN2C(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
DMAP (51 mg, 0.42 mmol) and WSCD (161 mg, 0.84 mmol) were added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (150 mg, 0.42 mmol) in dichloromethane (10 ml) and triethylamine (0.176 ml, 1.26 mmol) and the mixture was stirred for 30 min at room temperature. 6-Methyl-1,2,3,4-tetrahydro-quinoline (67 mg, 0.46 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (12 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([N:9]=[C:10]=[O:11])[S:8][C:4]=2[CH:3]=1.[CH2:14]([NH:17][CH2:18][CH:19]=[O:20])[CH:15]=[CH2:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH:19]=[O:20])[C:10]([NH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=2[N:6]=1)=[O:11])[CH:15]=[CH2:16]
Reactant: C=CCNCC=O
Reactant: O=C=Nc1nc2ccc(Cl)cc2s1
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nc2ccc(Cl)cc2s1
Reaction time: 1 h

Procedure:
6-Chlorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(6-chlorobenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: C([O:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([O:25]C(=O)C)[CH3:24])[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.[OH-:33].[Na+].Cl>CO.O>[OH:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([OH:25])[CH3:24])[C:19]=1[I:20])[CH2:12][OH:33])=[O:7]
Reactant: [OH-]
Reactant: CC(=O)OC(C)C(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C(C)OC(C)=O)c1I
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)Nc1c(I)c(CO)c(I)c(NC(=O)C(C)O)c1I
Reaction time: 15 h
Yield: 46 %

Procedure:
N,N'-Bis(2-acetoxypropionyl)-3,5-diamino-2,4,6-triiodobenzylacetate (0.16 g, 0.2 mmol) was dissolved in a mixture of methanol (5 ml) and water (5 ml) and the pH was adjusted to 12 using a 1M aqueous solution of NaOH. After stirring for 15 h, the solution was neutralized with 1M HCl and the solvents were removed by evaporation. Purification by preparative HPLC gave 61 mg (46%) of the pure product.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.O>[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A suspension of 60% sodium hydride (54 mg, washed with n-hexane) in N,N-dimethylformamide (1 ml) was added slowly to a stirred solution of (2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (512 mg) in N,N-dimethylformamide (5 ml) under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. A solution of ethyl bromoacetate (225 mg) in N,N-dimethylformamide (1 ml) was added dropwise therein at the same temperature and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo to afford (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.59 g) as a crude oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C(OCC)C.CCCCCC>[CH2:1]([O:9][C:10]1[N:11]=[CH:12][C:13]([B:26]([OH:27])[OH:25])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(B(O)O)cn1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2.75 g (10 mmol) of 2-octyloxy-5-bromopyridine are dissolved in 60 ml of absolute diethyl ether, and the solution is cooled to -75° C. under inert gas. 16 mmol of 1.6M butyllithium solution in hexane are added, and the mixture is additionally stirred at -75° C. for 15 minutes. 4.5 g of triisopropylborate in 50 ml of absolute diethyl ether are then added dropwise. The cooling device is then removed. After the batch has warmed to room temperature, 50 ml of 10% HCl are added, and the mixture is additionally stirred at room temperature for 30 minutes. The phases are separated, and the organic phase is washed twice with saturated NaCl solution. The solvent is distilled off in vacuo, and the residue is recrystallized from acetonitrile, giving 6-octyloxypyridine-3-boronic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[CH:18][CH:19]=1
Reactant: C[C@@H]1CCCN1
Reactant: ClCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 78 %

Procedure:
To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Oc1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Oc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-3-pyridinol (156 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (280 mg, 62%). MS (ISP) 449.2[(M+H)+]; mp 258-260° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=[O:25])=[O:12].Cl>O.CC(C)=O>[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]([CH3:27])([CH3:26])[CH2:23][C:24]([OH:2])=[O:25])=[O:12]
Reactant: Cc1cc(C)c(C(C)(C)CC=O)c(OC(=O)CCCBr)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(C(C)(C)CC(=O)O)c(OC(=O)CCCBr)c1
Reaction time: 24 h
Yield: 114.9 %

Procedure:
A solution of 1 g of potassium permanganate in a mixture of 46 cm3 of distilled water and 30 cm3 of acetone is added dropwise, at 20° C., to 2.3 g of 3-[2-(4-bromobutyryloxy)4,6-dimethylphenyl]-3,3-dimethylpropanal in solution in 200 cm3 of acetone. After stirring for 24 hours, the reaction mixture is supplemented with 100 cm3 of distilled water, acidified to pH 1–2 by addition of a 1 N aqeuous hydrochloric acid solution, and then extracted with five times 100 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 2.7 g of 3-[2-(4-bromobutyryloxy)4,6-dimethylphenyl]-3,3-dimethylpropionic acid are obtained in the form of a colorless oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24].C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(O)c1ccc(C(=O)OC)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(Br)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of PPh3 (42.2 g. 320 mmol) in DCM (200 mL) was added dropwise to a solution of methyl 4-(1-hydroxybutyl)benzoate (33.5 g, 160 mmol) and CBr4 (53.1 g, 320 mmol) in DCM (1200 mL) at 0° C. Once the addition was complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated, then the resulting residue was purified by silica gel chromatography eluting with 5% EtOAc/petroleum ether to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=6 Hz, 2 H); 7.45 (d, J=6 Hz, 2 H); 4.95 (t, J=7 Hz, 1 H); 3.91 (s, 3 H); 2.19-2.32 (m, 1 H); 2.02-2.14 (m, 1 H); 1.43-1.55 (m, 1 H); 1.24-1.38 (m, 1 H); 0.93 (t, J=7 Hz, 3 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5]>CO.O>[CH3:3][S:4]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
3.6 g (90 mmol) of NaOH was added to the solution of methyl 4-[(methylsulfonyl)amino]benzoate in 40 mL methanol and 20 mL water and stirred overnight at room temperature. Solvents were then removed and the product purified by ethyl acetate extraction from 1N aqueous hydrochloric acid, providing 1.2 g (yield 74.6%) of the 4-[(methylsulfonyl)amino]benzoic acid. 1H NMR in d-chloroform: 8.03 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 3.09 (3H, s). 13C NMR in d-chloroform: 131.2, 117.9, 38.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2ccnn2C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)sc1-c1ccnn1C
Reaction time: 1 h

Procedure:
A solution of methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude from part a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h, the solution was poured onto H2O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated affording the title compound as a white solid which was used directly without further purification: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 5-chloro-3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (210 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 139 mg) and 2-chloroethanesulfonyl chloride (339 mg) in THF (dry) (10.0 mL) at room temperature. The mixture was stirred at room temperature overnight. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and IPE to give the title compound (232 mg) as a pale yellow solid. The solid was crystallized from EtOAc-hexane to give a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[N+:13]([O-:25])[CH:14]=[CH:15][CH:16]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(Cc1cccnc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN(Cc1ccc[n+]([O-])c1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a stirred solution of tert-butyl methyl(pyridin-3-ylmethyl)carbamate of Step A (0.50 g, 2.25 mmol) in dichloromethane (15 mL) was added 90% m-chloroperbenzoic acid (1.3 g, 6.8 mmol). After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.38 g of product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[C:9]([Br:11])=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1c(Br)cc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chlorobenzaldehyde (2.1 g, 13.5 mmol) was dissolved in chloroform (20 mL) and treated with N-bromosuccinimide (2.6 g, 14.9 mmol). The reaction was stirred for 30 min at ambient temperature. The reaction was diluted with methylene chloride and washed with sodium thiosulfate (2×), 5% sodium bicarbonate (2×), water (2×), brine, dried over sodium sulfate, and concentrated to afford 3.0 g (95%) as a pale yellow powder. 1H-NMR (CDCl3, 500 MHz) δ 9.75 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H). Mass spec.: 236.01 (MH)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (2.05 g, 10 mmol) were mixed in 1,2-dchloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 12) (356 mg, 0.85 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (288 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[OH:37][CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1.O>CN(C)C=O>[OH:37][CH:38]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:29][CH3:30])[CH2:39]1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCCC(O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (46 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (45 mg) and 3-hydroxypiperidine (33 mg) were added to the solution, and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (37 mg, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(COc2ccc(F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cnc1N1CC(COc2ccc(F)cc2)C1
Temperature: 140 °C
Yield: 111.2 %

Procedure:
To a solution of methyl 5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinate (D82) (52.1 mg, 0.148 mmol) in a mixture (3:1) 1,4-dioxane/water (1.6 ml), lithium hydroxide monohydrate (9.3 mg, 0.22 mmol) was added and the resulting mixture was heated under microwave irradiation 6 min at 140° C. After solvent evaporation the residue was taken in a mixture water/1M HCl (20 ml/5 ml) and extracted with ethylacetate (3×20 ml). Collected organics after solvent evaporation afforded the title compound (D113) (55.4 mg).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCN(C)C1=O>C(Cl)Cl>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CN1CCCN(C)C1=O
Solvent: ClCCl
Product: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 20 h
Yield: 106.8 %

Procedure:
A stirred suspension of 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of methylene chloride is added 0.44 g of morpholine followed by 1 ml of 1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirring continued for 20 hours. The methylene chloride is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The brown solid is dissolved in 15 ml of ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to give 0.23 g of a colorless gum which is stirred with ethyl acetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9](Cl)[CH3:10].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])[CH3:10]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1ccc(C)c(C(C)Cl)c1
Agent: [Na]
Product: Cc1ccc(C)c(C(C)Sc2cccc[n+]2[O-])c1
Yield: 83 %

Procedure:
The intermediate 2-(1-[2,5-dimethylphenyl]-ethylthio)pyridine N-oxide is prepared from 1-(2,5-dimethylphenyl)ethyl chloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 118° - 120°C. Structure confirmed by IR and NMR.