Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1cc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (180 mg. 0.267 mmol) was alkylated using (S)-2-methyloxirane (47 mg, 0.802 mmol), DIPEA (207 mg, 1.604 mmol) and ethanol (5 mL) to get 120 mg (crude) of the titled compound. MS: m/z=695.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1ccccc1N
Product: COc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and o-anisidine (187 mg, 1.52 mmol) in a similar manner as described above and recrystallized from acetonitrile to give 30 mg (11%) as yellow crystals; 1H-NMR (DMSO-d6): δ 11.07 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 7.13 (dd, 1H), 6.84-6.73 (m, 3H), 6.60-6.56 (m, 1H), 4.85-4.80 (m, 1H), 4.72 (d, 1H), 3.73 (s, 3H), 2.70-2.53 (m, 2H), 2.00-1.75 (m, 4H); MS m/z (M−1) 369, 371.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: NCCCCCCN
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCCCCCCNCc1ccccc1O

Procedure:
122.1 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of hexamethylenediamine and having a melting point of 72°-73° C. are hydrogenated in 550 ml of isopropanol in an autoclave in the presence of 8 g of Raney nickel at 75° C. and under a pressure of 90 atmospheres. The product crystallises out at room temperature and is dissolved by boiling with the addition of a further 650 ml of isopropanol. The catalyst is filtered off, and N,N'-bis-(2-hydroxybenzyl)hexamethylenediamine crystallises out on cooling.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)#[CH:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([CH2:2][CH2:1][C:3]2[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C#Cc1cccc(CO)n1
Reactant: C1COCCN1
Solvent: CCO
Product: OCc1cccc(CCN2CCOCC2)n1
Yield: 22.8 %

Procedure:
(6-Ethynylpyridin-2-yl)methanol (320 mg) and morpholine (1 g) were dissolved in 3 mL of ethanol, and the solution was heated to reflux under argon atmosphere for 24 hours. After allowing the reaction to cool, the ethanol was removed under reduced pressure, and the residue was basified with aqueous sodium hydroxide, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (chloroform-methanol-aqueous ammonia=200:10:1) to give 122 mg of [6-(2-morpholin-4-ylethyl)pyridin-2-yl]methanol as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:23])[N:4]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole (0.300 g, 0.99 mmol) and sodium acetate (0.162 g, 1.976 mmol) in acetic acid (5 ml) is refluxed for 48 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (2 ml) and 5M potassium hydroxide (KOH) (5 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 200 mg (71%).
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17](C(C)C)=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:38][S:39](O)(=[O:41])=[O:40].[OH-].[Na+:44]>CO>[CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([S:39]([O-:41])(=[O:40])=[O:38])=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:44]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (476 mg, 1.00 mmol) and CH2Cl2 (1.0 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (1.00 mL) and fuming sulfuric acid (3.0 mL, 20% SO3) were added dropwise. The solution was allowed to warm to room temperature and stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜10 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜20.0 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×50 mL) and concentrated under reduced pressure to give a beige solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (4) as a beige solid (503 mg, 94%). Mp=>250° C. 1H NMR (400 MHz, CD3OD) δ: 7.52 (s, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 6.90 (m, 1H), 2.24 (m, 1H), 0.71-1.83 (34H). 13C NMR (125 MHz, CD3OD) δ: 148.4, 147.9, 147.8, 147.5, 145.6, 142.8, 137.4, 137.2, 133.92, 133.91, 132.43, 132.42, 129.3, 128.1, 121.3, 121.0, 40.1, 39.9, 39.7, 39.5, 39.3, 38.8, 35.8, 35.7, 32.5, 32.3, 31.9, 30.8, 30.6, 28.7, 28.6, 28.4, 28.3, 27.7, 26.0, 25.9, 23.3, 23.1. 31P NMR (162 MHz, CD3OD) δ: −10.7. IR (neat, cm−1): 3459, 2927, 2851, 1634, 1463, 1447, 1184, 1078, 1040. Anal. Calcd for C30H42NaO3PS: C, 67.14; H, 7.89. Found: C, 66.93; H, 7.77.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1ccc(C(O)C(=O)c2ccccc2)cc1C

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and o-xylene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 20 minutes. Using the same procedure as in Example 1, 3',4'-dimethylbenzoin was obtained as crystal (258.7 mg, 54.0% yield).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH:28]=[CH2:29])=[CH:22][CH:21]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:7]2([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:29][CH:28]([CH2:27][S:26][C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[O:10][N:8]2[CH3:9])[CH:16]=[CH:15][CH:14]=1
Reactant: C=CCSc1ccc(C)cc1
Reactant: COc1cccc(C(Cn2ccnc2)=[N+](C)[O-])c1
Product: COc1cccc(C2(Cn3ccnc3)CC(CSc3ccc(C)cc3)ON2C)c1

Procedure:
The title compound was prepared by a procedure similar to that described in Example 1 by reacting 2-(1H-imidazol-1-yl)-1-(3-methoxyphenyl)-N-methylethanimine N-oxide (1, R1 =3--OCH3) with allyl 4-methyphenyl sulfide (2: R2 =4--CH3). The resulting cis- and trans-diastereomeric mixture of compound 3 (R1 =3--OCH3, R2 =4--CH3, n=0) was flash-chromatographed on neutral silica gel using ethyl acetate as eluent.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[Cl:18])([CH3:10])([CH3:9])[CH3:8].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:13][C:12]=1[Cl:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Temperature: 60 °C
Yield: 126.8 %

Procedure:
To a suspension of potassium carbonate (994 mg, 7.2 mmol) and 4-tert-butyl-3-chlorophenol (440 mg, 2.4 mmol) in acetone (5 ml) was added t-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 60° C. for 14 hours. Filtrating of potassium carbonate, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 10:1) to furnish the tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 100%). The mixture of tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 2.4 mmol), TFA (2.0 ml), DCM (2.0 ml) was stirred for 5 hours at room temperature. After being concentrated in vacuo, the residue was triturated with hexane to furnish the title compound (582 mg, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.45 (9H, s), 4.67 (2H, s), 6.76 (1H, dd, J=2.6, 8.6 Hz), 6.96 (1H, d, J=2.6 Hz), 7.35 (1H, d, J=8.6 Hz).
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:16][C:4]2([CH2:7][CH:6]([NH:8]C(=O)OC(C)(C)C)[CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:6]1[CH2:7][C:4]2([CH2:16][C:2]([CH3:17])([OH:1])[CH2:3]2)[CH2:5]1
Reactant: CC1(O)CC2(CC(NC(=O)OC(C)(C)C)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CC2(CC(N)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
To a solution of tert-butyl (6-hydroxy-6-methylspiro[3.3]heptan-2-yl)carbamate (760 mg, crude) in DCM (7 mL) was added TFA (3.5 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product (500 mg, crude) as a brown oil, which was used in the next step without further purification. MS (ESI) m/z 142.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN1C(=O)CCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:20]([O:25][CH3:26])[CH:19]=1
Reactant: COc1cc(F)ccc1O
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27 mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs2CO3 (826.3 mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, the pH was adjusted to pH 6 with 1N HCl and the mixture was extracted with ethyl acetate (3×). The organics were combined, washed with brine, dried with Na2SO4, filtered and evaporated to dryness. Purification by column chromatography using a gradient of 0-10% MeOH in dichloromethane gave 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg, 90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+; Retention time: 1.35 minutes (3 minutes run).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]1[O:41][CH:21]1[CH:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C1OC1C(Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
A mixture of 39.2 g (71.2 mmol) of 2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 atmosphere with 13 g (0.36 mol) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h at ambient temperature, the resulting mixture was quenched with 1N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered. washed with water, and dried to provide 22.85 g (58%) of the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: Cc1ccc(C(=O)Cl)s1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)s1
Yield: 85.9 %

Procedure:
Beginning with 0.40 gm (1.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.34 gm (2.08 mMol) 5-methyl-2-thiophenecarbonyl chloride, 0.53 gm (86%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:15]=[CH:16][C:3]=12.S(=O)(=O)(O)[OH:27].N([O-])=O.[Na+]>O1CCOCC1.O>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][N:14]1[C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([OH:27])=[C:3]2[CH:16]=[CH:15]1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To solution of ethyl 4-amino-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6 g, 14.8 mmol) in 1,4-dioxane (16 mL) at 0° C. was added dropwise a cold solution of sulfuric acid (16 mL, 300 mmol) in water (24 mL) followed by dropwise addition of a solution of sodium nitrite (4.2 g, 60.5 mmol) in water (12 mL) in 10 min. After stirring for 1 h at 0° C. and 3 h at RT for 3 h the mixture was cooled to 0° C. and more sodium nitrite (1.3 g) in water (3 mL) was added. After 2 h at RT cold water was added and the mixture was filtered washing with water. The solid was dissolved in MeOH and solid NaHCO3 was added. The mixture was stirred for 10 min then filtered and concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3/water and the organic phase was dried (Na2SO4), concentrated and dried in vacuo to provide ethyl 1-(3,4-difluorobenzyl)-4-hydroxy-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.02 g, 13.8 mmol, 93% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (t, J=7 Hz, 3 H), 2.86 (s, 3 H) 4.49 (q, J=7 Hz, 2 H), 5.40 (br s, 2 H), 6.66 (d, J=3.51 Hz, 1 H), 6.91-7.15 (m, 4 H), 12.82 (br s, 1 H); LCMS (m/z) ES+=347 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[CH2:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C(=O)C>[CH2:21]([O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
In a 1 liter flask were charged 1-fluoro-2,4-dinitrobenzene (40.94 g, 0.22 mol), triethylamine (24.29 g, 0.24 mol), 1-decanol (34.82 g, 0.22 mol), 220 g of N,N-dimethylacetamide and stirred at room temperature for 24 hours under a nitrogen atmosphere. The resultant etherified product was extracted with 1 liter of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain crude product. Isolation and purification of the target product by silica gel chromatography afforded 57.80 g (yield: 81%) of 4-decyloxy-1,3-dinitrobenzene as yellow crystals.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Yield: 106.2 %

Procedure:
A mixture of 4-nitro-phthalonitrile (4.00 g), 4-methoxy-phenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) was heated to reflux for 2 h. Reaction mixture was cooled and filtered. Filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1 N, 50 ml), water, and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product (6.14 g). 1H NMR (200 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1 H), 7.21 (m, 2 H), 6.96 (m, 4 H), 3.84 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1>ClCCl>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[O:25])[CH:19]=1
Reactant: Cc1cc(O)ccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 4-amino-m-cresol (Fluka, 4.17 g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyrimidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:18][NH2:19]>C(O)C>[S:5]1[CH:4]=[CH:3][C:2]([C:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:19][N:18]=2)=[CH:1]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccsc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccsc2)c2ccccc12
Yield: 51.4 %

Procedure:
1.8 g of o-(3-thenoyl)benzoic acid and 580 mg of hydrazine hydrate were dissolved in 20 ml of ethanol, and the solution was refluxed for 4 hours. After cooling the solution, it was crystallized by adding ether, thereby obtaining 910 mg of 4-(3-thienyl)-1-phthalazinone.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])=[CH:37][CH:36]=1>FC(F)(F)C(O)=O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH2:43][S:44]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)(=[O:46])=[O:45])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=S(=O)(Cl)CCCc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(S(=O)(=O)CCCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (3 ml, 21.52 mmol) was added followed by stirring at room temperature for 10 minutes, and then 3-(4-chlorophenyl)propane-1-sulfonyl chloride (300 mg, 1.19 mmol) was added followed by stirring at room temperature for 3 days. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[3-(4-chlorophenyl)propane-1-sulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (330 mg, yield 84%) as a white powder.