Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C)C=O>[N:12]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCOCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)-imidazole hydrochloride (14.7 g.) sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate, was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted withh isopropyl alcohol (3 × 50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48g.). A sample of the monopicrate monohydrochloride had m.p. 139°-140° (from nitromethane). (Found: C, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15CIN6O8 requires: C, 35.4; H, 3.7; N, 20.7; Cl, 8.7).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][CH2:12][OH:13]>[OH-].[Na+]>[I:1][C:2]1[C:7]([O:8][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: OCCBr
Reactant: Cc1ccc(O)c(I)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCCO)c(I)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was stirred in a 1M solution of sodium hydroxide (30 ml). To this was added 1-bromoethan-2-ol (3.91 ml, 55.20 mmol) dropwise at room temperature. The resulting solution was then heated to 100° C. and stirred for 2 hours. The reaction mixture was cooled and then extracted into chloroform (2×100 ml). The organic phases were combined and extracted with a solution of 1M sodium hydroxide (25 ml). The organic phase was then dried over magnesium sulfate and concentrated in vacuo. This provided the desired product which was used without further purification (5.26 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[C:16]2=[N:21][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Reactant: O=S(=O)(Cl)CCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (208.2 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-(3-fluorobiphenyl-4-yl)pyridin-2-amine (149.5 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and THF (3 mL), and dried in vacuo at 60° C. to give the title compound (143 mg) as an off-white powder.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](N)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:18]>>[F:18][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: F[B-](F)(F)F
Reactant: Nc1cccc2ncccc12
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Fc1cccc2ncccc12
Reaction time: 1 h

Procedure:
To a solution of quinolin-5-amine (2 g, 13.9 mmol) in 10 mL of 48% HBF4 at 0° C. was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1:1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N HCl (50 mL). After neutralization with NaHCO3, the mixture was extracted with ethyl acetate (3×50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3% EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[ClH:11].[Cl:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.O.Cl>C1(C)C(C)=CC=CC=1.CO>[ClH:12].[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(F)ccc1N1CCNCC1
Yield: 51.5 %

Procedure:
To a solution of 4-fluoro-2-methoxyaniline (3.0 g) in orthoxylene (50 ml) was added bis(2-chloroethyl)amine hydrochloride (3.8 g) and the mixture was refluxed under heating for 13 hr. The reaction mixture was poured into water and washed with isopropyl ether. To the aqueous layer was added an aqueous sodium hydroxide solution to make it alkaline (pH 12) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a black oil. The oil was dissolved in methanol and conc. hydrochloric acid was added and the mixture was concentrated. To this concentrated solution added tetrahydrofuran to give the title compound (3.1 g) as pale-purple crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](C)(C)N[Si](C)(C)C.[Cl-].[NH4+].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CO.C(N(CC)CC)C>[C:19]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then hexamethyldisilazane (134.15 ml) was added to the suspension in 10-15 minutes at ambient temperature. Catalytic amount of ammonium chloride (1 gm) was added. The reaction mixture was refluxed at 35° C. to 40° C. for 3 hours and then it was cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25° C. to 30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for overnight under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40° C. to 45° C. Toluene (400 ml) and 5% citric acid solution (750 ml) was added to the recovered solid and filtered. The solid product obtained was washed with water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with toluene (200 ml) and dried to obtain the titled product. Yield=100 gm; Mass: (−EI): 346 (M−1); 242.9 (−Tr).
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH:22]=[O:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (321 mL, 4.5 mol) and triethylamine (941 mL, 6.75 mol) were added to a solution of 3-tert-butoxycarbonylamino-1-propanol (262.6 g, 1.5 mol) in dichloromethane (1.2 L) at 0° C. Sulfur trioxide pyridine complex (286.4 g, 1.8 mol) was added in 6 portions. The reaction mixture was then stirred for 30 min at 0° C. and for 30 min at room temperature. The reaction was cooled down to 0° C., quenched with 1N hydrochloric acid, washed with brine (2×500 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 3-(tert-butoxycarbonylamino)propionaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:26])[O:23][C@H:22]([CH2:24]O)[CH2:21][O:20]1.Cl[CH2:28]Cl>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@@:22]1([CH3:24])[CH2:21][O:20][C:19]([CH3:18])([CH3:26])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 33.5 g, 0.145 mol) and ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-l-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent evaporated under reduced temperature. The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (2:8) to give the title compound (35.8 g, 92% yield) as a white solid. Mp 79-80° C. 1H NMR (CDCl3) δ 7.76 (d, J=9.1 Hz, 2H), 7.46 (dd, J=8.7, 1.8 Hz, 1H), 7.19 (m, 2H), 7.0 (s, 1H), 4.28 (m, 1H), 4.18 (m, 2H), 4.0 (m, 2H), 3.94 (s, 3H), 3.68 (m, 1H), 1.65 (d, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.9, 127.1, 126.1, 126.0, 119.0, 109.6, 105.5, 73.4, 66.1, 64.4, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 345 (MH)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:23])[NH:10]2)=[O:4].C1(C)C=CC=CC=1.B.CSC>C1COCC1>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([C@@H:3]([OH:4])[CH2:2][Br:1])=[C:6]2[C:11]=1[NH:10][C:9](=[O:23])[CH:8]=[CH:7]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 1 °C
Reaction time: 0.29 h

Procedure:
A dry 5 liter flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 5-Bromoacetyl-8-benzyloxycarbostyril (100 gms/0.268 moles) and dry THF (1.2 liter) under argon. A solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborolidine catalyst in toluene (43 ml/0.388 moles) was added and reaction mass was chilled to 0-2° C. Then, 1M solution of borane-methyl sulfide (32.42 ml/0.3417 moles) in THF (342 ml) was added in 3 hours while maintaining temperature at 0-2° C. The reaction was stirred for another 15-20 minutes at same temperature. The reaction mass was quenched by addition of methanol (171 ml) in 15-20 minutes. The temperature of resulting solution was raised to 25-30° C. and concentrated to a volume of 500 ml under vacuum at 50° C. To this concentrate was added a mixture of water (1.45 liters) and concentrated HCl (74 ml) in 10-15 minutes. The resulting suspension was stirred for 30 minutes at 25° C. The solid 8-benzyloxy-5-[(R)-(2-bromo-1-hydroxyethyl)]-carbostyril obtained was isolated by filtration and washed with water till neutral pH, dried under vacuum at 60-65° C. for 12-14 hours. Yield-70-73 gms.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: BrBr
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (19.3 mL, 171 mmol) in CH2Cl2 (100 mL) was added iron (3.15 g, 56 mmol). To this stirred suspension was added a solution of bromine (11 mL, 214 mmol) in CH2Cl2 (25 mL) drop wise over 30 min. The resulting mixture was stirred at rt overnight. The reaction mixture was slowly poured into saturated aqueous Na2S2O3 (200 mL), and the resulting mixture was stirred at rt for 30 min. This was extracted with CH2Cl2 (3×80 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1,5-dibromo-2,4-difluorobenzene (40 g, 86% yield) as a brown oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.79 (t, J=7.0 Hz, 1H), 7.00 (t, J=8.2 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.CN(C)C.C(OP(Cl)(OCC)=O)C.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)C
Solvent: C1CCOC1
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
5-Carboxyoxindol (0.93 g) and 0.8 ml of trimethylamine were suspended in 10 ml of tetrahydrofuran (THF), and a solution of 1.0 g of diethylchlorophosphate in 10 ml of THF was added dropwise thereto at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. To the mixture was added dropwise a solution of 1.1 g of benzylpiperazine in 10 ml of THF and was further stirred for 10 hours at room temperature. After completion of reaction, crystals which precipitated were filtered off and the filtrate was concentrated. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with chloroform. Organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. Recrystallization of the residue from isopropyl alcohol gave 1.01 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:21][CH2:22][C:23]([OH:25])=[O:24]>FC(F)(F)C(O)=O>[C:7]([S:21][CH2:22][C:23]([OH:25])=[O:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CS
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 94.4 %

Procedure:
This compound was synthesized by the condensation of triphenylmethanol (2.84 g, 10.8 mmoles) with mercaptoacetic acid (0.75 ml, 10.8 mmoles) in 19 ml trifluoracetic acid. The TFA was removed in vacuo, giving an orange oil, which was purified by dissolution in ether and extraction with 1 N NaOH. The aqueous phase was acidified with 6N HCl, and extracted with two 30 ml portions of ether. The ethereal phase was dried over MgSO4 and evaporated to give 3.41 g (93%) of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To 1-bromo-4-trifluoromethyl-benzene (1 g), rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g), in toluene (10 mL) was added sodium tert-butylate (0.6 g), 2-(dicyclohexylphosphino)biphenyl (31 mg), and tris(dibenzylideneacetone)Pd-CHCl3 (23 mg). The reaction mixture was then stirred at 80° C. overnight. Ethyl acetate was then added to the reaction mixture. Solids were filtered off. The filtrate was then concentrated in vacuo, and the residue was purified by column chromatography to yield 0.46 g of the title compound. MS (m/e): 345.2 (M+H+, 100%)
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:9][CH:10]([O:19][C:20](=[O:22])C)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3]C(OCC)=O.[OH-].[Na+].C(OCC)(=O)C>CO>[OH:1][C:2]1([CH3:3])[CH2:9][CH:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:19][C:20](=[O:22])[CH2:23]1
Reactant: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrocholoric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.). solution of 4-(hydroxymethyl)cyclohexanecarboxylic acid (40 g) in methanol (632 mL) was added thionyl chloride (22.15 mL) dropwise via an addition funnel. The reaction was slowly warmed to room temperature, stirred for 1 hour, concentrated by rotary evaporation, and the residue was purified by regular phase flash column chromatography (Analogix, 0-100% hexanes/ethyl acetate).
Reaction SMILES: C(OCCOCCO)C.[BH4-].[Na+].[O:12](C)[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:13]([OH:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOCCOCCO
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 97 %

Procedure:
11.2 g (0.083 mole) of diethylene glycol monoethyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 90° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 2.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 97% yield.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([O:42]CC4C=CC=CC=4)=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.C(Cl)Cl.CO>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6](=[O:50])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:9][CH2:10][CH2:11]3)=[CH:13][CH:14]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
Atmosphere of tert-butyl[1-(4-{2-[4-(benzyloxy)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (430 mg, 0.650 mmol) and 10% Pd—C(dry) (43 mg) in THF (7 mL) and MeOH (7 mL) was exchanged to H2 and stirred at 50° C. for 24 hours. The mixture was diluted with CH2Cl2+MeOH and filtrated through Celite pad. The filtrate was concentrated and the reaction was repeated again. Atmosphere of the residue and 10% Pd—C(dry) (43 mg) in THF (21 mL) and MeOH (21 mL) was exchanged to H2 and stirred at 50° C. for 25 hours. The mixture was diluted with CH2Cl2 and filtrated through Celite pad. The filtrate was concentrated and the residue was purified by column chromatography (CH2Cl2/MeOH=5:1) to afford the desired product (362 mg, 97%) as a pale brown solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.42 (s, 1H), 8.51 (s, 1H), 8.04 (d, J=3.4 Hz, 1H), 7.93 (dd, J=7.4, 1.4 Hz, 1H), 7.36-7.26 (m, 5H), 7.14-7.08 (m, 3H), 6.88-6.81 (m, 2H), 6.64 (d, J=8.6 Hz, 2H), 2.42-2.33 (m, 4H), 2.02-1.97 (m, 1H), 1.81-1.74 (m, 1H), 1.34 (br s, 5H), 1.17 (br s, 4H). LCMS: 572 [M+H].