Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl.C(OCC)C>CN1CCCC1=O.CO>[ClH:15].[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)(=[O:24])=[O:23])=[CH:20][N:21]=1)=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[CH:7]=2
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(-c3ccc(S(=O)(=O)N4CCNCC4)cn3)c(O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
To a suspension of sodium hydride (97%, 0.024 g, 1.0 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added 2-oxoindoline-6-carbonitrile (0.119 g, 0.75 mmol). The formed mixture was stirred for 5 min at room temperature and tert-butyl 4-[(6-chloropyridin-3-yl)sulfonyl]piperazine-1-carboxylate (0.181 g, 0.5 mmol) was added. The resulting reaction mixture was set under an N2 atmosphere and stirred for 1 h at 90° C. Methanol (0.5 mL) was added to the mixture and the solvents were removed in vacuo. The crude product was dissolved in methanol (5 mL) and HCl in diethyl ether (4 M, 2.5 mL, 10 mmol) was added followed by reflux for 3 h. From the cooled solution the formed yellow precipitate was collected by filtration and dried to give 0.209 g (92% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 11.08 (s, 1H), 9.10 (br s, 2H), 8.67 (s, 1H), 7.89 (s, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.0, 1.2 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H) 3.31 (br s, 4H), 3.25 (br s, 4H); MS (EI) m/z 384 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[C:9](OCC)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CCOC(=O)c1ccc(F)c(OCc2c(C)cccc2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cc(CO)ccc1F
Reaction time: 3 h

Procedure:
The solution of Ethyl 3-(2,6-dimethylbenzyloxy)-4-fluorobenzoate (Step A, 4.2 g, 13.9 mmol) in dry THF (20 ml) was added slowly to a suspension of LiAlH4 (0.72 g) in dry THF (20 ml) at −78° C. under argon. The cold bath was replaced by ice bath and the reaction mixture was left to stir for 3 hours or until reaction is complete, quenched very slowly with ice and diluted with ethyl acetate. The organic layer was washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 5:1) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](OC)=[O:7])=[O:4]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:10]1([CH:5]([CH2:3][OH:4])[CH2:6][OH:7])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Product: OCC(CO)c1ccccc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A one liter three-neck flask fitted with mechanical stirrer, thermometer, nitrogen inlet and addition funnel was charged with water (200 mL), tetrabutylammonium chloride (1.0 g) and 98% sodium borohydride (4.83 g, 0.125 mole). The solution was purged with nitrogen, then stirred and cooled to 4° C. in an ice bath. Crude methyl α-formylphenylacetate (90.6 g, 0.5 mole), prepared according to Example 9, was charged to the addition funnel, and rinsed in with t-butyl methyl ether (25 mL), and added to the above solution at 3°-8° C. The addition took a total of 100 minutes. After 20 minutes into the addition of formylacetate, a second charge of sodium borohydride (4.83 g) was added and rinsed in with water (20 mL). After an additional 1 hour and then again at 1.5 hours, sodium borohydride (4.83 g) in water (20 mL) was added to the batch. The slurry was held at 3° C. for an additional 6 hours, and then allowed to warm to room temperature overnight. The batch was cooled to 15° C., and concentrated hydrochloric acid (46 mL) was added. Methyl isobutyl ketone (MIBK, 100 mL) was added and the batch was stirred vigorously for 15 minutes. The pH of the batch was 1.0. Solid sodium carbonate (45 g) was added and the batch was stirred vigorously for 5 hours. The solids were separated by filtration and washed with MIBK. The solids were dried in vacuo at 65° C. (50.16 g). The aqueous layer from the main filtrate was extracted twice with the MIBK washes. The combined MIBK layers were washed with citric acid solution (10 mL, 5.6 g/15 mL water) and then with saturated sodium chloride solution (20 mL). The solution was filtered through Solka Floc and concentrated in vacuo to 75° C. The pale yellow oil (71.60 g) was crystallized from toluene (80 mL) to give 2-phenyl-1,3-propanediol (53.3 g, 70.05%) m.p. 52°-53.5° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=4[O:23][CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([OH:27])=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[N:36]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=4[O:23][CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([NH2:36])=[O:27])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=O
Yield: 102.2 %

Procedure:
To a solution of 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanoic acid (500 mg) and 1-hydroxybenzotriazole (141 mg) in dimethylformamide (5 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg) at room temperature. The solution was stirred for an hour at the same temperature and was ice-cooled. Then concentrated solution of ammonia (0.3 ml) was added into the solution and the resulting mixture was stirred further for an hour. The mixture was diluted with water and was extracted with ethyl acetate. The organic layer was separated and was washed successively with sodium hydrogen carbonate solution and brine, and was dried over magnesium sulfate. Concentration gave 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanamide (510 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:18]([NH2:29])[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:18][C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A mixture of 1 g of the compound obtained in Step 1.1, 0.646 g of veratrylamine, 1.152 g of DIEA and 1.69 g of HBTU in 50 ml of DMF is stirred for 2 days at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 1.2 g of a solid, which is used without purification in the following step.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH2:64]O)[CH2:63][O:62][CH2:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:59][C:60]2([CH3:64])[CH2:63][O:62][CH2:61]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(CO)COC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CC2(C)COC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.44 g), tributylphosphine (1.78 mL), (3-methyloxetan-3-yl)methanol (0.44 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 62%).
Reaction SMILES: [BH4-].[Na+].ClC(Cl)(Cl)C(O)=O.C(#N)C.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=O)[CH2:26][CH2:27]1)[CH2:22][CH2:21]3>C(Cl)Cl>[CH3:16][C@:15]12[CH2:32][CH2:31][C@H:30]3[C@@H:20]([CH2:21][CH2:22][C:23]4[C@:28]3([CH3:29])[CH2:27][CH2:26][CH2:25][CH:24]=4)[C@@H:17]1[CH2:18][CH2:19][C@@H:14]2[OH:13]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
370 mg of anhydrous sodium borohydride is added in portions with ice/water cooling to 5 ml of trichloroacetic acid and 5 ml of acetonitrile. Then, 500 mg of 17beta-hydroxy-4-androsten-3-one in 9 ml of methylene chloride is instilled. It is stirred at room temperature and is worked up after 30 minutes, as described in example 1. 400 mg of 4-androsten-17beta-ol with melting point 144°-147° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.COC(=O)C1C=CC(OCC2CC2)=C(Cl)C=1.CO[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1>>[F:35][CH:33]([F:34])[O:32][C:28]1[CH:27]=[C:26]([C:25](=[O:36])[CH2:6][C:2]#[N:1])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(OC(F)F)c1
Reactant: Nc1cc[nH]n1
Agent: COC(=O)c1ccc(OCC2CC2)c(Cl)c1
Product: N#CCC(=O)c1cccc(OC(F)F)c1

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1 bis) from 3-difluoromethoxy-benzoic acid methyl ester (1.5 g, 7.4 mmol, 1.0 eq). The crude was precipitated by addition of aqueous HCl to give the product which was used directly for the next step.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[O:7][C:6]([CH2:17][F:18])([CH2:15][F:16])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][C:6]([CH2:15][F:16])([CH2:17][F:18])[CH2:5][C@H:4]2[NH2:1]
Reactant: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of Example 65B (54.1 mmol) in THF (190 mL) was cooled to <5° C. To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (12.1 mL, 81.0 mmol) followed by diphenylphosphoryl azide (15.2 mL, 70.3 mmol), keeping the temperature≦5° C. (no exotherm). After stirring for 2 hours at ≦5° C., the reaction mixture was warmed to ambient temperature and stirred for 14 hours. The reaction mixture was diluted with MTBE (250 mL), washed with 2N NaOH (2×125 mL), brine (50 mL), 2N HCl (2×125 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, giving (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman (14.6 g, >100%) as a dark oil. The crude (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman in MeOH (300 mL) was added to 5% Pd—C (4.38 g) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 3 hours at 50° C. and 30 psi H2. Upon cooling, the reaction mixture was filtered through a nylon membrane and concentrated. The resulting residue was used without further purification. MS (DCI) m/z 232 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33].C1N2CCN(CC2)C1>CC#N>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][C:2]1[C:7]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a suspension of the crude 4-chloro-6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine in MeCN (5 mL) were added 2-fluoro-4-nitrophenol (59 mg, 0.37 mmol) and DABCO (45 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the desired compound (54 mg, 33% yield in two steps). MS(ESI) m/z 437.2 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH2:10][OH:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1.Cl>N1C=CC=CC=1>[C:28]([O:11][CH2:10][C:9](=[O:12])[C@@H:8]1[C@:13]2([CH3:26])[C@H:5]([C@H:4]3[C@H:16]([C@@H:15]([OH:25])[CH2:14]2)[C@:17]2([CH3:24])[C:22](=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]2)[C@@H:2]([F:1])[CH2:3]3)[CH2:6][C@H:7]1[CH3:27])(=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)COC(=O)CCC(=O)O
Temperature: 20 °C

Procedure:
Five grams of 6α-fluoro-11β,21 -dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is refluxed in 25 ml. of pyridine with 5 g. of succinic acid anhydride for 2 hours. After cooling to 20°C., the solution is stirred into ice water, acidified with hydrochloric acid, and the thus-precipitated product is vacuumfiltered, washed with water, and dried. By recrystallization from ethyl acetate, 4.85 g. of (6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-yl) hydrogen succinate is obtained, m.p. 212°-214° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[C:1]([C:5]1[N:6]=[CH:7][N:8]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][N:15]=2)[C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(C)(C)C)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (3.6 m mol) of 4-tert-butyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 150 mg (3.7 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.71 g (3.6 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reacton mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 4-tert-butyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methylimidazole.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:21])=[C:6]([F:20])[C:7]([N:12]2[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]2)=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CC(O)C>[C:1]([C:4]1[CH:11]=[C:8]2[C:7](=[C:6]([F:20])[C:5]=1[F:21])[N:12]1[CH2:17][C@@H:16]([CH3:18])[O:15][C@@H:14]([CH3:19])[C@@H:13]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC(=O)c1cc(C=O)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Solvent: CC(C)O
Product: CC(=O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Temperature: 85 °C

Procedure:
To a solution of 5-acetyl-2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (Intermediate 11, 3.0 g, 9.17 mmol) in IPA was added barbituric acid (1.4 g, 11.00 mmol), and the mixture was heated at 85° C. for 12 hours. Solvents were evaporated and the residue was purified over neutral alumina using a gradient of methanol in CH2Cl2 to give the title compound as a racemic mixture in the form of an off-white solid. Yield: 3.0 g (75%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18](=[O:23])[C:17]3[NH:24][CH:25]=[CH:26][C:16]=3[C:15]=2[CH:14]=1.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28].O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18](=[O:23])[C:17]3[NH:24][CH:25]=[CH:26][C:16]=3[C:15]=2[CH:14]=1)(=[O:4])=[O:3].[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
24 μL (0.3 mmol) of methanesulfonyl chloride is added to a solution of 70 mg (0.2 mmol) of 8-(2-aminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 0.3 mL of anhydrous pyridine. The solution is stirred at room temperature for 4 hours then water is added. The compound is extracted with ethyl acetate. The organic phases are washed with an aqueous solution of copper sulfate, dried over magnesium sulfate, filtered and evaporated to give 22 mg (25%) of 8-(2-methanesulfonylaminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.CCCCCC.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>O1CCCC1.CCOCC>[O:4]=[C:3]([CH2:5][CH2:24][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
Ethyl acetoacetate (16.0 g; 0.123 mole) was added dropwise with stirring under nitrogen to 50% sodium hydride (6.5 g; 0.135 mole) in dry tetrahydrofuran (300 ml) at 0°. The resulting solution was stirred for 10 minutes at 0° before adding a solution of n-butyl lithium in hexane (95 ml, 1.6 M; 0.152 mole) dropwise. The resulting yellowish orange dianion solution was stirred for 10 minutes at 0° before adding α-bromo-m-xylene (34 g, 0.189 mole) in ether (20 ml) and allowed to warm to room temperature 30 minutes after completing the addition. The reaction mixture was quenched by addition of conc. HCl (25 ml) in H2O (60 ml) followed by ether (180 ml). The layers were separated and the aqueous further extracted with ether (3×125 ml). The combined organic layers were washed with water until the wash was neutral, then dried (anhydrous MgSO4) and evaporated to dryness. The resulting yellow oil was distilled under vacuum to give a pale yellow oil (22.0 g, 76%), b.p. 132°-139° at 0.19 mmHg, n.m.r. δ(CDCl3) 7.07 (4H, m), 4.25 (2H, q, J=7 Hz), 3.47 (2H, s), 2.95 (4H, s), 2.40 (3H, s) and 1.35 (3H, t, J=7 Hz).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 10 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give desired product as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16].B(Cl)(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:15]([C:4]1[CH:5]=[C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][C:3]=1[OH:2])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(O)c(C(C)=O)c1
Reaction time: 0.17 h

Procedure:
Titanium tetrachloride (82.3 mls) was added dropwise to a stirred solution of methyl 2-(4-methoxyphenyl)propionate (25 g) in dry dichloromethane (250 mls), cooled in an ice/salt-bath, at a rate sufficient to maintain the temperature between -10° C. and -5° C. The mixture was stirred for 10 minutes and acetyl chloride (10 g) was added dropwise at a rate sufficient to maintain the temperature below 0° C. The solution was stirred at -5° C. for 11/2 hours when boron trichloride (15 mls) was added. Stirring was continued for 1/2 hour at +3° C. before pouring on to crushed ice/concentrated hydrochloric acid and separating the two phases. The aqueous phase was extracted with ether (3x) and the combined organic extracts were washed with saturated sodium bicarbonate solution, saturated brine solution, and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the crude product as a pale yellow oil. Vacuum distillation furnished a pale yellow oil bp 120°-125° C./0.15 mm (16.2 g; 59%)