Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[Cl:15]C1C=CC(O)=CC=1N.Cl.ClCCN(CCCl)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Reactant: Nc1cc(O)ccc1Cl
Agent: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: CN1CCN(c2cc(O)ccc2Cl)CC1

Procedure:
4-chloro-3-(4-methylpiperazin-1-yl)phenol Compound 14B is prepared according to the same procedure as 13A, using the following reactants: 14A (1.1 g, 10.1 mmol); 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.96 g, 10.1 mmol); sodium carbonate (535 mg, 5.05 mmol) in 1-butanol (40 ml).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[CH2:6][N:7]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH3:8].O.Cl>C1COCC1.CO.O>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([C:9]([N:7]([CH2:6][C:5]([OH:23])=[O:4])[CH3:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)CN(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
LiOH (293 mg, 6.9 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid methyl ester (330 mg, 1.1 mmol) in THF:MeOH:H2O (2:2:1, 10 mL), and the resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 250 mg (79.7% yield) of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid.
Reaction SMILES: [NH2:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH3-]C#N.[Na+].Cl>O.CO>[CH2:11]([NH:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCC(N)(CO)COC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(CO)(COC)NCc1ccccc1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
A mixture of crude 4-aza-3,3-bis-(methoxymethyl)-1-oxaspiro[4.5]decane (66A, 40.0 g, 0.174 mol) and 6N HCl (100 mL) was refluxed for 1 h. The mixture was cooled and washed with Et2O (3×100 mL). The volume of the aqueous layer was reduced to 25 mL by rotary evaporation, basified with excess 50% NaOH solution and extracted with a mixture of Et2O/CH2Cl2 (3:1, 2×200 mL). The organic layers were combined, the solvent removed and the resulting crude oil distilled to give 16.4 g (63.2%) of 2-amino-2,2-bis-(methoxymethyl)ethanol, (bp 109°-110°/15 mm). This material also contains some of the --NCH3 compound. This material was further purified by conversion to the --NCH2Ph derivative. Thus, a mixture of crude 2-amino-2,2-bis-(methoxymethyl)ethanol (15.0 g, ~0.10 mol), benzaldehyde (Aldrich, 7.42 g, 0.07 mol), NaBH3CN (Aldrich, 4.4 g, 0.07 mol) and CH3OH (100 mL) was stirred at 5° for 15 min then at RT for 2 h. H2O (50 mL) then excess 12N HCl was then added to the flask. The volume of the mixture was reduced to 50 mL by rotary evaporation. The mixture was washed with Et2O (100 mL), basified with 50% NaOH solution and extracted with Et2O (200 mL). After removal of the solvent the crude oil (15.54 g) was distilled to give 11.64 g of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol, bp 118°-119°/0.10 mm, shown to 99.7% pure by GLC (10% OV-17 on Chromasorb W at 250°), (C,H,N). A mixture of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol (8.25 g, 0.0345 mol), 5% Pd/C (Aldrich, 1.0 g), abs. EtOH (250 mL) and glacial HOAc (25 mL) was hydrogenated in a Parr apparatus at 40 psi for 15 min. The catalyst was removed by filtration through a pad of Celite® and the solvent removed to give the crude product which after crystallization from abs. EtOH gave a 48.6% yield of 2-amino-2,2-bis-(methoxymethyl)ethanol acetate, mp 119.5°-120.5°, (C,H,N).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1)[CH3:10]>C(Cl)Cl>[Br:8][C:16]1[C:11]([CH2:9][CH3:10])=[CH:12][C:13]([NH2:17])=[N:14][CH:15]=1
Reactant: CCc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NBS (231 mg, 1.30 mmol) was added to a solution of 4-ethylpyridin-2-amine (144 mg, 1.18 mmol) in DCM (5 ml) at room temperature. After stirring for 5 minutes at room temperature the reaction mixture was partitioned between aqueous Na2S2O3 and DCM, extracted with DCM (2×), the combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.61; ESI-MS 200.9 and 202.9 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N=C2CCCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>C(O)(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCCC2)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCC3
Yield: 146.3 %

Procedure:
Following method A, potassium t-butoxide (37 g, 320 mmol) was added in portions to a cooled (2° C.) solution of cyclohexanone oxime (35 g, 300 mmol) in DMF (350 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-chloro-4-nitrobenzene (50 g, 320 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from isopropanol and column chromatography provided cyclohexanone O-(4-nitro-phenyl)-oxime (48 g). Cyclohexanone O-(4-nitro-phenyl)-oxime (48 g, 205 mmol) was dissolved in warm isopropanol (350 mL) and 12 N hydrochloric acid (94 mL) was added. The reaction mixture was heated to reflux for 3.5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (33 g, 150 mmol). A mixture of 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (11 g, 50 mmol) and Raney nickel (˜11 g wet weight) in ethanol (200 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was recrystallized from hexane to give 6,7,8,9-tetrahydro-dibenzofuran-2-YLAMINE (7.6 g). Mp 71-72° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(O)c1ccc[nH]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc[nH]3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1H-pyrrol-2-yl)-1-propyne (212 mg, 1.75 mmol) (from Example 30 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (125 mg, 0.39 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (42 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1H-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][C:8]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]3[CH:29]=[CH:30][C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[CH:4][C:5]=3[N:9]=2)[C:12]1=[O:23])([CH3:21])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CN)ccc21
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of 1-[5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (20 mg, 0.05 mmol) and TEA (10 mg, 0.10 mmol) in THF (2 ml) was added acetyl chloride (5 mg, 0.06 mmol) at room temperature and the reaction mixture was stirred for 12 h. After evaporation, the residue was purified by prep-HPLC (gradient 10%-100% B) to afford 18 mg (80%) of N-[2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-acetamide as a colorless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1cc(Br)c2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1cc(Br)c2[nH]ccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 7-bromo-5-hydroxy-1H-indole and 0.2 N NaOH (1.1 eq.) in THF. Cool to about 0° C. before adding benzenesulfonyl chloride (1.10 eq.). Allow the reaction mixture to warm to ambient temperature. After 8 hours, pour into ethyl acetate, wash with water, dry the organic layer over Na2SO4 and concentrate. Purify to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1.[NH2:30][C@H:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34]>>[CH2:33]([C:32]([OH:37])([CH2:35][CH3:36])[C@H:31]([NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:34]
Reactant: CCC(O)(CC)[C@H](N)c1ccccc1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12)C(F)(F)F
Product: CCC(O)(CC)[C@H](Nc1nnc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccccc23)c2ccccc12)c1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-naphthalen-2-yl ester (600 mg, 1.37 mmol) was added 3-((R)-aminophenyl-methyl)pentan-3-ol (1.06 g, 5.49 mmol). The resulting suspension was stirred for 24 hrs at 120° C. The mixture was purified by flash chromatography on silica gel (toluene/EtOAc 10:0→5:1) followed by crystallization from diethyl ether to give 451 mg of the title compound as a white powder as a mixture of diastereomers. (yield: 55%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Br[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 4-bromomethyl-5-methyl-2-phenyl-thiazole [PCT Int. Appl. (2001), WO 01/9805 A1] in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[C:5]([OH:16])=[CH:6][C:7]=1[S:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])=[O:9].C([O:20][C:21](=[O:25])[CH:22](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.O>[CH3:1][C:2]1[C:7]([S:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][C:5]2[O:16][CH:22]([C:21]([OH:25])=[O:20])[O:17][C:4]=2[CH:3]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1cccs1
Reactant: CCOC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2c(cc1S(=O)(=O)c1cccs1)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a manner analogous to that described in Example 4, 30.0 g (111 mmol) of 4-methyl-5-(2-thienylsulphonyl)-1,2-benzenediol, 17.4 g (111 mmol) of dichloroacetic acid ethyl ester and 76.7 g (555 mmol) of potassium carbonate in 300 ml of 1,2-dimethoxyethane are boiled under reflux. After 18 hours, the reaction mixture is poured into water, stirred for one hour at room temperature and then adjusted to pH 1-2 by means of hydrochloric acid. Some of the 1,2-dimethoxyethane is distilled off in vacuo and the mixture remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The resulting dark-red oil is chromatographed over silica gel. As eluant, a mixture of chloroform/methanol/concentrated ammonia in a ratio of 40:10:1 is used until elution of the starting diol, then an analogous mixture in a ratio of 12:5:1 is used. The uniform fractions are combined and concentrated almost completely by evaporation. Ice/water is added to the residue and the pH is adjusted to 1-2 with concentrated hydrochloric acid. The acidic solution is extracted with ethyl acetate. The combined organic phases are washed, dried and concentrated by evaporation. The residue is boiled in diisopropyl ether and the black sludge formed is removed by decanting. The clear solution is concentrated to a large extent and the substance which has crystallised out is filtered off with suction. The crystals are recrystallised from 1,2-dichloroethane, yielding 5-methyl-6-(2-thienylsulphonyl)-1,3-benzodioxole-2-carboxylic acid in the form of white crystals having a melting point of 162.5°-164.5°.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[C:7]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:23]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Br:23][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[C:7]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:9]=1
Reactant: CC(C)[Si](Oc1cccc2c1C(C)(C)CO2)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 24, 7.4 g, 23.19 mmol) was dissolved in THF (70.0 mL). N-Bromosuccinimide (4.2 g, 23.88 mmol) was added dissolving in few minutes. This mixture was stirred at room temperature for 3 hrs. More NBS (0.64 g, 3.48 mmol) was added and the reaction mixture was stirred at room temperature for a further hour. CCl4 (50 mL) was added to the reaction mixture and the solution was evaporated to dryness. The residue was re-suspended in CCl4 and stirred at room temperature for 15 min. The white solid was removed by filtration and the wet cake was washed with more CCl4. The CCl4 was swapped with ethyl acetate and the organic solution was washed three times with 2.5% w/w aqueous NaHCO3 and finally with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness to give the title compound (8.6 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=1
Reactant: Cc1cc(C=O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(CO)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To the solution of 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (3.0 g, 10.8 mmol) in MeOH (20 ml) is added NaBH4 (410 mg, 10.8 mmol). The mixture is stirred at room temperature for about 2 h, diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated to afford 2.5 g of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10]>CS(C)=O>[N+:1]([CH2:6][CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CCCC(CBr)CCC
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(CCC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of sodium nitrite (30.6 g, 0.43 mol) in DMSO (700 ml) was added 1-bromo-2-propylpentane (49 g, 0.254 mol). The mixture was stirred overnight at room temperature and poured into ice water (700 g). The mixture was extracted with ether (4×250 ml), the organic layers were combined, washed with water (2×500 ml), brine (500 ml), dried and concentrated in vacuo to furnish 37.4 g (93%) of 1-nitro-2-propylpentane which was 85% pure based on 1H NMR data.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>C(O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)=[O:11]
Reactant: NCCc1c[nH]cn1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCc1c[nH]cn1
Yield: 14.3 %

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 6A using 5.55 g (0.05 mol) of 4-(2-aminoethyl)imidazole in 40 ml ethanol and 8.31 g (0.05 mol) of isatoic anhydride with the exception that after removing ethanol from the reaction solution the product was purified using column chromatography (500 ml dichloromethane; 2000 ml 9% methanol in dichloromethane, isocratic eluent). The fractions containing the desired product were combined and reduced to dryness under reduced pressure to provide a solid. This solid was recrystallized from diethyl ether to provide 1.65 g of the desired subtitled compound (m.p. 85°-87° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].C(NC(C)C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:12]#[C:11][C:10]([OH:14])=[O:13]
Reactant: C#CC(=O)O
Reactant: Fc1ccc(I)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(O)C#Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4.95 ml (41.4 mmol) of 2,4-difluoroiodobenzene and 2.56 ml (41.4 mmol) of propiolic acid were dissolved in DMF (16 ml). Following cooling of the reaction medium to 0° C. (ice-water bath), 578 mg (0.83 mmol) of Pd(PPh3)2Cl2 and 308 mg (1.66 mmol) of Cul were added. The reaction solution was then cooled to −10° C. (ice methanol bath) and 14.5 ml (103.4 mmol) of diisopropylamine were added dropwise at this temperature. The cooling bath was then removed and the reaction mixture was stirred a further 16 h after RT had been re-established. The reaction solution was then diluted with EA and washed successively with a 2N HCl solution and a satd aq. NaCl solution. Following drying over MgSO4, filtration, and removal of solvent in vacuo, the residue was boiled with hexane and filtered after cooling to RT. The residue was dissolved in diethyl ether at 30° C. and filtered at this temperature. By removal of solvent in vacuo there were obtained from the filtrate 6.43 g (35.3 mmol, 85%) of (2,4-difluorophenyl)propiolic acid.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:9]3=[N:10][C:6]=2[CH:5]=1.I[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[ClH:3].[ClH:1].[CH2:19]([N:13]1[CH2:12][CH2:11][C:9]2=[N:10][C:6]3[CH:5]=[C:4]([Cl:3])[CH:17]=[CH:16][C:7]=3[N:8]2[CH2:15][CH2:14]1)[CH2:20][CH3:21]
Reactant: Clc1ccc2c(c1)nc1n2CCNCC1
Reactant: CCCI
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCN1CCc2nc3cc(Cl)ccc3n2CC1

Procedure:
A solution of 1.1 g. (5 mmole) of 8-chloro-2,3,4,5-tetrahydro-1H-1,4-diazepino[17-a]benzimidazole prepared in Example 1 above, 0.85 g. (5 mmole) 1-iodopropane, and 0.75 g. (7.5 mmole) of sodium carbonate in 100 ml. of 95% ethanol is refluxed 72 hours. After removing the solvent in vacuo, the residue is chromatographed over silica gel, eluting with hexane/chloroform saturated with ammonia (1:4). The product obtained is dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. The crystals which separate are filtered and dried to afford 0.41 g. (25%) of the dihydrochloride salt: m.p. 271°-274° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:7][S:8][CH2:9][C@@H:10]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:6])[CH3:2].[C:30]([O:34][C:35](=[O:39])[CH:36](Br)[CH3:37])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:30]([O:34][C:35](=[O:39])[C@H:36]([CH3:37])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH2:7][S:8][CH2:9][C@@H:10]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)[C@@H](N)CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 46 g quantity of S-[(S)-2-benzyloxycarbonylamino-3-phenylpropyl]-L-cysteine ethyl ester and 27 g of 2-bromopropionic acid t-butyl ester were dissolved in 150 ml of HMPA. To the solution was added 18 ml of triethylamine and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was separated and purified by silica gel column chromatography (a 5:4 mixture of ether and n-hexane as an eluent), giving the α-isomer of the title compound as a colorless oil from the first eluate. Yield 10.6 g.