Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:4]=1[CH3:21].CC(O)=O.O>I>[OH:2][C:3]1[C:4]([CH3:21])=[CH:5][C:6]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(-c2cc(=O)c3ccccc3o2)cc1C
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(=O)c3ccccc3o2)cc(C)c1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2-hydroxyacetophenone (1.361 g, 10 mmol) in 20 mL anhydrous pyridine was added 3,5-dimethyl-4-methoxybenzoic acid (2.162 g, 12 mmol). The mixture was cooled to 0° C. and phosphorous oxychloride (1 mL) was added. A white precipitate was formed. The reaction mixture was stirred at rt for 2 h under nitrogen atmosphere. Then the reaction mixture was poured into 100 mL cold 2N HCl and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give a colorless liquid (2.89 g, 97%), which was used in the next step without further purification. The compound (2.88 g, 9.65 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide (1.62 g, 28.95 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (100 mL) was added and the mixture was neutralized to pH 7 with conc. HCl. The yellow solid was filtered off, washed with water and dried under vacuum. Yield: 1.16 g, 40%. To a suspension of the yellow solid (1.14 g, 3.83 mmol) in 8 mL glacial AcOH was added 4 drops of conc. HCl and the reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt and water (50 mL) was added. The solid was isolated by filtration and washed with water and dried under vacuum to give 2-(4-methoxy-3,5-dimethyl phenyl) chromen-4-one (1.05 g, 98%) as a pale green solid. 2-(4-methoxy-3,5-dimethyl phenyl) chromen-4-one was suspended in 20 mL hydroiodic acid and 8 mL glacial AcOH was added. The reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt. Water (100 mL) was added and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and methanol (20 mL) to give 0.763 g of 2-(4-hydroxy-3,5-dimethylphenyl)-4H-chromen-4-one (85%) as a pale yellow solid. MS (ES) m/z: 267.06 (M+1); Mp. 255-256° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].C(N(CC)CC)C.[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]1[O:28][CH2:27]1.O>C(O)C>[CH2:30]([O:29][CH2:25][CH:26]([OH:28])[CH2:27][N:6]1[C:4](=[O:5])[C:3]([CH2:2][CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOCC1CO1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CC)(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of phenobarbital (69.6 g, 0.3 mole) in ethanol (150 ml) containing triethylamine (2.02 g, 0.02 mole) was stirred with butyl glycidyl ether (26.0 g, 0.2 mole) (available from Merck & Co.) for 6 hours at 70° C. The reaction mixture was then poured into water (500 ml) and the precipitated product was extracted with toluene (200 ml) at 70° C. The toluene layer was separated, washed with 3% aqueous sulphuric acid (200 ml) and left overnight at 4° C. The precipitated phenobarbital was filtered off and the filtrate extracted with 5% aqueous sodium carbonate (5×100 ml). The organic layer was then extracted with 1M aqueous sodium hydroxide (2×200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (40.1 g, 55%); purity by HPLC 99% m.p. 92° C.
Reaction SMILES: N[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:3]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:4]=1[C:16]([OH:18])=[O:17].Cl[C:28]1C=CC(CC2N=C(C3C=CN=CC=3)SC=2C2NC=NN=2)=CC=1.CO.C=O.[C:55]([BH3-])#[N:56].[Na+]>O.CCOC(C)=O>[C:8]([C:7]1[C:3]([CH:2]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[N:56]([CH3:55])[CH3:28])=[C:4]([C:16]([OH:18])=[O:17])[S:5][C:6]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)#[N:9]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(N)c1ccc(Cl)c(Cl)c1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(c1ccc(Cl)c(Cl)c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a suspension of 3-[amino(3,4-dichlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid.HCl (186.0 mg, 0.4145 mmol, prepared according to Example 6) in methanol (8.09 mL, 0.101 mol) was added 10 M of formaldehyde in water (74.00 uL, 0.9119 mmol), and sodium cyanoborohydride (130 mg, 2.07 mmol). Stirred at rt under argon for 16 hours. Added 10 M of formaldehyde in water soln (74.00 uL, 0.919 mmol) and sodium cyanoborohydride (0.130 g, 2.07 mmol) and stirred at rt for 72 hours. Quenched reaction with saturated aqueous sodium bicarbonate solution, added EtOAc, separated layers, extracted again w/EtOAc, combined organics, washed organics with saturated sodium bicarbonate, brine, dried over Na2SO4, filtered, added Celite to filtrate, and concentrated in vacuo. Purification of dry load via silica gel column chromatography (gradient elution: 100% DCM to 8% MeOH in DCM) afforded racemic 4-cyano-3-[(3,4-dichlorophenyl)(dimethylamino)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid (134 mg, 68%) as an off-white solid. LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H). Combined with another batch of 134 mg racemate for chiral HPLC to obtain pure enantiomers. Purified on IC 4.6×250 mm with 90/10/0.1 HEX/ETOH/DEA 10 uL Injection at 1.0 mL/min for 70 min. CD AT 254 nm to obtain separated enantiomers as the diethylamine salts. Each compound Peak1 and Peak2 were separately dissolved in water, acidified to pH of 2 with aqueous 1N HCl solution, extracted w/EtOAc, 3×, combined organics and washed w/brine, dried over Na2SO4, filtered, concentrated in vacuo, added water, freeze-dried, lyophilized overnight to recover parent compound. Peak 1 (103 mg, tan solid, overall 27% yield) LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H). Peak 2 (80 mg, beige solid, overall 20% yield) LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2 H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.CCOCC.[CH3:20][C:21](=[O:24])[CH2:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:22]([CH3:23])[C:21](=[O:24])[CH3:20])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CCC(C)=O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.5 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 2.0 ml of butanone was saturated with gaseous hydrogen chloride. After standing over night ether was added to the solution and it was filtered. The product was crystallized from isopropanol, yield 0.2 g (30%), m.p.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(N(CC)CC)C.C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 87.6 %

Procedure:
To a mixture of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06, 0.01 mol), anhydrous sodium acetate (0.98 g, 0.01 mol) and glacial acetic acid (15 ml) was added three drops of triethylamine. The mixture was heated and the resulting solution was stirred at reflux for 6 hours and was left at room temperature over night. The acetic acid was removed in vacuo and the residual gum was diluted with 25 ml of ice water. The product was extracted into 3×50 ml of ether. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2.5 g of yellow solid (88% yield). Recrystallization from chloroform gave material with a m.p. 113°-115° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.Br[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: ClCCCOc1ccccc1Nc1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccccc1Nc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine (3 mmol), bromo-cyclopentane (4.1 mmol) and potassium carbonate (water free, 3.6 mmol) are suspended in DMF (20 ml) and heated up to 50° C. and the mixture is stirred at this temperature for 5 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=20:1) as mobile phase. The product containing fractions are combined and evaporated. The product is cristallized from diethyl ether/pentane, filtered off and dried. A solid powder with mp. 110-112° C., Rf=0.78 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(N(C)C)cc3)c1)C(C)(C)C2
Yield: 89.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (680 mg, 1.67 mmol), 4-dimethylaminophenylboronic acid (358 mg, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (524 mg, 70.0%) as a white solid: LC/MS m/e calcd for C27H29ClN2O2 (M+H)+: 450.01, observed: 449.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13][CH:14]1[O:16][CH2:15]1.O.[OH-].[Li+]>C(OCC)(=O)C>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:15][CH:14]([OH:16])[CH2:13][CH3:12]
Reactant: CCC1CO1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)COc1cccc(C(F)(F)F)c1

Procedure:
40.5 g of 3-hydroxybenzotrifluoride, 18.0 g of α-butylene oxide and 1.0 g of lithium hydroxide monohydrate are heated in a bomb tube (pressure reactor) for 16 hours to 140° C. After cooling the reactor, the reaction mixture is dissolved in 200 ml of ethyl acetate and the organic phase is washed with water and then dried over sodium sulfate and concentrated. The desired product, 1-(3-trifluoromethylphenoxy)-2-butanol, is obtained in a yield of 54.0 g and in high purity. The product can be used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[N:5]=[CH:4][CH:3]=1.[I:12]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[I:12][C:9]1[S:8][C:7]([N:6]2[C:2]([CH3:1])=[CH:3][CH:4]=[N:5]2)=[CH:11][CH:10]=1.[I:12][C:3]1[CH:4]=[N:5][N:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccnn1-c1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(I)cnn1-c1cccs1
Product: Cc1ccnn1-c1ccc(I)s1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
5-methyl-1-(2-thienyl)-1H-pyrazole (64 mg, 0.39 mmol) and N-iodosuccinimide (88 mg, 0.39 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 70° C. After 6 hours, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 1-(5-iodo-2-thienyl)-5-methyl-1H-pyrazole and 4-iodo-5-methyl-1-(2-thienyl)-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>ClCCl>[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5](=[NH:7])[O:6][CH3:19])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cccc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of the title compound of Step A (1.07 g, 5.9 mmol) in dichloromethane (15 mL) was added trimethyloxonium tetrafluoroborate (1.06 g, 7.1 mmol) and the mixture was stirred overnight at ambient temperature. Concentration gave the title compound of Step B as a white solid (1.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13][C:14](=[NH:16])[NH2:15].[OH-:17].[Na+]>>[CH2:1]([O:8][C:9]([NH:16][C:14](=[N:15][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])[S:13][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [OH-]
Reactant: CSC(=N)N
Agent: [Na+]
Product: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 20 h
Yield: 97 %

Procedure:
Benzylchloroformate (161 mL, 1075 mmol, Aldrich, 95%) was added slowly through an addition funnel at room temperature with vigorous stirring to a solution of the sulfate salt of 2-methyl-2-thiopseudourea (74.6 g, 525 mmol) in 1N sodium hydroxide solution (1050 mL, 1050 mmol) in a 5 L three-necked round bottom flask, equipped with a 250 mL addition funnel. After the addition, stirring was continued and the reaction was monitored by TLC. The reaction was finished in ca. 20 hours. After all mono-CBZ (benzyloxy carbonyl) intermediate disappeared, the reaction mixture was transferred to a 4 L separatory funnel. The aqueous layer was separated and extracted with hexanes (1.28 L). The extracts were combined with the methylene chloride layer. The combined organic layer was washed with 553 mL of NaH2PO4 (5.7%, 533 mL, wash pH ~5) and brine (2×533 mL). It was dried over sodium sulfate, filtered and concentrated on a rotovap. The resulting residual oil was dried on a high vacuum pump to a constant weight. The remaining benzyl chloroformate, benzyl chloride and possibly benzyl alcohol were further removed by a lyophilizer. The resulting thick oil crystallized on standing in about six hours. The solid was broken up and the drying was continued to a constant weight in two days. The crude title compound thus obtained (182 g, 97% yield), was pure enough by 1H NMR and TLC to be used for the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH3:35])[CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CNCc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)Cc3cccnc3)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step G (0.125 g, 0.262 mmol), 3-(methylaminomethyl)pyridine (0.038 g, 0.314 mmol), 1-hydroxy benzotriazole (0.039 g, 0.288 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.055 g, 0.288 mmol) were combined in amine-free N,N-dimethylformamide (1.1 mL), followed by addition of N,N-diisopropylethyl amine (0.068 mL, 0.393 mmol). The reaction was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform, and recrystallized from diethyl ether/pentane to afford 0.140 g of the title compound as a white crystalline solid, m.p. 178-179° C., 98.0% pure by analytical HPLC (Primesphere C-18, 2.0×150 mm, 45% acetonitrile/water, 0.2 mL/min.).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][CH2:19][CH2:20][S:21](=[O:23])(=[O:22])[C:13]=3[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Br:31])[CH:25]=3)[C:11]=2[C:10](=[O:32])[CH2:9]1)C1C=CC=CC=1.Cl[C:34]([O:36][CH:37]=[CH2:38])=[O:35]>C1COCC1>[Br:31][C:26]1[CH:25]=[C:24]([CH:12]2[C:11]3[C:10](=[O:32])[CH2:9][N:8]([C:34]([O:36][CH:37]=[CH2:38])=[O:35])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][CH2:19][CH2:20][S:21](=[O:23])(=[O:22])[C:13]2=3)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: O=C1CN(Cc2ccccc2)CC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCS1(=O)=O)N2
Reactant: C=COC(=O)Cl
Solvent: C1CCOC1
Product: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C2c2ccc(F)c(Br)c2)S(=O)(=O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of the product from Example 9A 0.48 g, 0.92 mmol) in THF (5 mL) was treated with vinyl chloroformate (0.10 mL, 0.94 mmol) and stirred at ambient temperature overnight. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (ethyl acetate and then 10% ethanol/methylene chloride) to provide the title compound (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:21].C1(O)C=CC=CC=1.[ClH:34]>CC(C)=O.C(O)C>[ClH:1].[ClH:34].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CN(C)CCCCN
Agent: Cl
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN(C)C)c2n1

Procedure:
A mixture of 4.2 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.6 g. of dimethylaminobutylamine and 10 g. of phenol is stirred and heated on a steam bath for 3 hours. The reaction is cooled, 30 ml. of ethanol is added and this mixture is poured into a mixture of 300 ml. of acetone and 3.75 ml. of concentrated hydrochloric acid. The yellow precipitate is collected, washed with acetone, air-dried and recrystallized from 100 ml. of 95% alcohol giving the desired product as yellow crystals, mp. 237°-238° C. (dec.)
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Reactant: CCC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Cl)C(=O)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol (2.60 g, 15.0 mmol, described in Intermediate 10) and triethylamine (4.19 mL, 30.0 mmol) in CH2Cl2 (150 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.71 mL, 15.0 mmol). After 60 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30 to 0:100, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: C(C1C=C(C)C(CNC)=C(C)C=1O)(C)(C)C.C(C1C=C(C)C(CNCCO)=C(C)C=1O)(C)(C)C.[C:35](Cl)(=O)[C:36]1[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:38]([Cl:40])=[O:39].[C:47](Cl)(=O)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56](Cl)=O>>[C:38]([Cl:40])(=[O:39])[CH2:37][CH2:41][CH2:42][CH2:43][CH2:44][CH2:36][CH2:35][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Agent: CNCc1c(C)cc(C(C)(C)C)c(O)c1C
Agent: Cc1cc(C(C)(C)C)c(O)c(C)c1CNCCO
Product: CCCCCCCCCCCCCCCCCC(=O)Cl

Procedure:
By an analogous procedure to that described in the first part of Example 16 and using 6-tert.-butyl-3-(N-methylaminomethyl)-2,4-xylenol (produced as described in the first part of Example 22) in place of 6-tert.-butyl-3-[N-(2-hydroxyethyl)aminomethyl]-2,4-xylenol and phthalic acid dichloride and sebacic acid dichloride, respectively, in place of stearoyl chloride, the following compounds, respectively, are produced: ##STR69##