Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21](S(C)(=O)=O)=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH3:29][NH2:30].O1CCCC1>CN1CCCC1=O>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([NH:30][CH3:29])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Yield: 67 %

Procedure:
In the same manner as in Example 433 and using 1-[4-(difluoromethoxy)phenyl]-6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(OCl)(C)(C)C.[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:5]([C:4]1[CH:13]=[CH:14][CH:15]=[C:2]2[C:3]=1[CH:24]([S:23][CH3:22])[C:25](=[O:26])[NH:1]2)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2cccc(C(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 30.6 (0.152 mole) of 3-aminobenzophenone in 160 ml. of methylene chloride was cooled to -78° C. in a dry ice/acetone bath and treated dropwise under a nitrogen atmosphere with a solution of 16.5 g. (0.152 mole) of t-butylhypochlorite in 60 ml. of methylene chloride. After stirring for 1 hr. after addition was complete, thin layer chromatography showed no starting material. A solution of 20.2 g. (0.152 mole) of ethyl α-(methylthio)acetate in 60 ml. of methylene chloride was added dropwise and stirring continued at -78° C. for 2.5 hr. A solution of 15.4 g. (0.152 mole) of triethylamine in 60 ml. of methylene chloride was added dropwise at -78° C. and the reaction mixture allowed to warm to room temperature while stirring for 16 hr. (overnight). The dark brown solution was treated with 100 ml. of 3 N hydrochloric acid and stirred for 3 hrs. at room temperature. Precipitation of a tan solid began after 15-30 minutes. Filtration gave 18.5 g. of solid, m.p. 224°-228° C. (dec.) The layers of the filtrate were separated, the organic phase dried over magnesium sulfate, evaporated under reduced pressure, and the residue triturated in isopropyl ether (25 g.). The gummy solid was triturated in cold methanol to give 8.3 g. of product, m.p. 222°-225° C. (dec.). The total yield was 26.8 g. (62%). A 7.0 g. sample recrystallized from methanol weighed 5.6 g. and melted at 235°-237° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2[nH]c(C(=O)O)cc2c1)OCc1ccccc1

Procedure:
Ethyl 5-Benzyloxycarbonylaminoindole-2-carboxylate, (PREPARATION 56, 0.76 g) is dissolved in 1,4-dioxane (5.6 ml) and water (0.56 ml). Crushed potassium hydroxide (0.23 g) is added and the reaction is heated to 50° for 5 hr. The reaction is neutralized by adding 4.05 ml of 1N aqueous hydrochloric acid. The reaction is extracted with THF/chloroform (10/90, 3×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title acid, NMR (300 MHz, d4-CD3OD) 7.64, 7.34-7.15, 6.98 and 5.09δ.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2].[CH2:14]([OH:17])[CH:15]=[CH2:16].[Na]>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:17][CH2:14][CH:15]=[CH2:16])=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2]
Reactant: C=CCO
Reactant: CCc1nc(C#N)c(C#N)nc1Cl
Agent: [Na]
Solvent: CC(C)=O
Product: C=CCOc1nc(C#N)c(C#N)nc1CC
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2,3-Dicyano-5-chloro-6-ethylpyrazine (1.35 g; 0.007 mole) was dissolved in 30 ml of acetone, and while the solution was cooled to -5° C., a solution prepared from 20 ml of allylalcohol and 0.16 g (0.007 mole) of sodium was added dropwise. Then, the mixture was stirred for 30 minutes. The reaction mixture was poured into 200 ml of ice water, and the separated oily product was extracted with toluene. The toluene layer was concentrated under reduced pressure to afford a crude product. The resulting crude product was chromatographed on a column containing silica gel using toluene as an eluent to afford 1.00 g (yield 67%) of 2,3-dicyano-5-allyloxy-6-ethylpyrazine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:22][C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:22][C:23]4[N:24]=[CH:25][C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=5)[C@@H:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: Clc1ccc2cc(CBr)ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1Cc1cc2ccc(Cl)cc2cn1
Reaction time: 16 h

Procedure:
To a solution of 1-(4-amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, (0.06 g, 0.2 mmol) in 2 mL of DMF is added 3-bromomethyl-7-chloroisoquinoline, EXAMPLE 11, 0.052 g, 0.20 mmol), and K2CO3 (0.08 g, 0.06 mmol). After 16 h, the reaction mixture is concentrated to dryness The crude product is purified by RP-HPLC eluting with a gradient of 5% CH3CN/H2O (0.1% TFA) to 50% CH3CN/H2O (0.1% TFA). The product fractions are lyophilized to give the title compound as a tristrisfluoroacetic acid salt (0.06 g, 0.08 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.79 (bs, 2H), 9.40 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H), 7.79 (d, 1H), 7.60 (m, 2H), 4.80 (AB, 2H), 4.72 (AB, 2H), 4.28 (m, 1H), 3.54 (m, 4H), 1.96 (d, 3H). MS (ion spray) 447, 449, (Cl pattern). Elemental analysis C28H25ClF6N6O6.3CF3CO2H.0.28H2O, cal C=45.38%, H=3.35%, N=10.58%; found C=45.38, H=3.35%, N=10.63%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>C(O)C.C(OCC)(=O)C.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(N2CCOCC2)c1

Procedure:
Meta-morpholino nitrobenzene (2a) (2 g, 9.6 mmol) is hydrogenated in a mixture of ethanol and ethyl acetate (50 ml/10 ml), over 10% Pd on carbon (200 mg) for 1 hour. The catalyst is removed by filtration and the solvent removed by evaporation to yield a solid, which is dried under vacuum; ES+ (M+1) 179.35; mp 125.4-127.6° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:13])=[CH:7][CH:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NC1CC1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(OCc2ccccc2)cc1

Procedure:
N-Cyclopropyl-4-hydroxybenzamide was stirred with benzyl bromide and potassium carbonate in DMF at room temperature to obtain 4-(benzyloxy)-N-cyclopropylbenzamide.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[CH:3]=1
Reactant: CCC(=O)CBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCC(=O)COc1cc(N)c(Cl)cc1C(=O)NCCN(CC)CC
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.3 g, 10 mmoles) in acetonitrile (100 ml) was treated with 1-bromo-2-butanone (1.5 g, 10 mmoles) and stirred at 20° for 2 hours. The residue after concentration was treated with water and extracted with ethyl acetate and methylene chloride-2-propanol (5:1). The insoluble solid material was collected and combined with the organic extracts. Concentration of this mixture gave sticky crystalline material which was recrystallized from acetonitrile-water (4:1) to give the title product (3.1 g, 86%), mp. 103.0°-104.5°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:27][CH:28]([CH3:32])[CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:31][CH2:30][CH2:29][CH:28]([CH3:32])[CH3:27])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(C)CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)CCN=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.3 %

Procedure:
A solution of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg), 3-methylbutylamine (1.15 mmol,100 mg) and triethylamine (1.5 mmol, 150 mg) in acetonitrile (2 ml) was stirred for 24 h at 60° C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 1:1) to give the title compound (100 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([I:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>C(Cl)Cl>[I:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(I)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(I)cc(OC)n1
Reaction time: 20 h
Yield: 20.4 %

Procedure:
To a solution of 0.25 g of 2-amino-4-iodo-6-methoxypyrimidine in 5 mL of dry methylene chloride was added 0.30 g 2-carbomethoxybenzenesulfonyl isocyanate. The resulting solution was allowed to stand for 20 hours at ambient temperature. The solution was cooled in an ice bath and crystallization induced with scratching. The crystals were collected, washed with n-butylchloride and dried to afford 0.10 g of the title compound, m.p. b 194°-196° C. (dec).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#N)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].C([Al+]CC(C)C)C(C)C.C[OH:59].[H-]>C1C=CC=CC=1.O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:59])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C=O)c1)OCCCCCCCCCCCCCCCC
Yield: 40 %

Procedure:
A solution of 1,2-di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (5.0 g., 7.6 mmoles) and diisobutylaluminum hydride (1.17 g., 8.2 mmoles) in benzene (25 ml.) was stirred for 16 hours at ambient temperature. The reaction mixture was treated with methanol (4.22 ml.) and water (2.5 ml.) and stirred to decompose unreacted hydride, and then filtered and extracted with benzene (3×25 ml.). The combined benzene extract was dried (Na2SO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [2.0 g., 40% yield, oil, ir (CHCl3) 1700 cm-1, n.m.r. (CDCl3) δ10.1 (s, 1, --ArCHO)].
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:16][CH:17]=1
Reactant: Oc1nccc2ccc(Br)nc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3ccc(Br)nc3c2=O)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). The solid is crystallized from hexanes/ethyl acetate 2:1, the white crystals collected by filtration and dried to give the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-8-azaisoquinolin-2-ylmethyl]benzoic acid methyl ester
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1ccc2nc(-c3ccc(F)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 2.0 g of 4-chloro-2-(4-fluorophenyl)-6-methylquinoline, 1.88 g (10 mmol) of isonipecotamide, and 4 g of phenol was stirred and heated in an oil bath at 165°-170° for 2 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 1.9 g of crude product, mp 264°-271° dec. Recrystallization from pyridine gave the titled product as off-white prisms, mp 275°-277° dec.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:8]([CH2:7][C:6]([CH3:32])([CH3:5])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31])=[O:10]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Reactant: CN(C)CCN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCNC(=O)CC(C)(C)CC(=O)Nc1ccc(OC(=O)N(C)c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added N,N-dimethylethylenediamine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (74 mg, 39% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][S:33]([C:30]4[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=4)(=[O:35])=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.35 g, 1.08 mmol) and 4-methoxybenzenesulfonyl chloride (0.25 g, 1.19 mmol) in chloroform (5 ml) was added triethylamine (0.16 ml, 1.19 mmol) and the mixture was stirred at room temperature for 14 hours. The solvent was concentrated under reduced pressure. Water (20 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 0.18 g (34% yield) of the title compound. Melting point: 206-208° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH2:21].Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].CN1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CN
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)NCC1CN=C(c2ccccc2F)c2ccccc2N1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
According to the method of Example 1, 1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg, 0.88 mmole) and isobutyl chloroformate (114 μl, 0.88 mmole) were combined with 4 ml of dry methylene chloride, and 97 μl of N-methylmorpholine (0.88 mmole) at -5° C. was added to the mixture. The resulting reaction mixture was allowed to warm to room temperature over 2 hours, and after dilution and washing, rotoevaporation of the dried extracts of the reaction afforded 230 mg of an oil which was purified by silica gel chromatography (ethyl acetate-hexane elution, 7:3 v/v) to give the analytical sample (120 mg) which was 98% pure by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH:13]1[CH2:15][CH2:14]1)[CH2:6][C@H:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].Cl[C:24]([O:26][CH2:27][CH2:28]Cl)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH:13]1[CH2:15][CH2:14]1)[CH2:6][C@H:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:28][CH2:27][O:26][C:24]1=[O:25]
Reactant: Nc1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Reactant: O=C(Cl)OCCCl
Solvent: C1CCOC1
Product: O=C1OCCN1c1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Reaction time: 8 h
Yield: 132.1 %

Procedure:
2-((R)-6,8-Dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (400 mg) was dissolved in absolute THF (25 ml), and 2-chloroethyl chloroformate (102 mg) was added with stirring. After stirring at room temperature for 3 h, the mixture was left to stand overnight. The solvent was then removed and the residue purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. 380 mg of the desired product were obtained.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:38]([O:40][C:41](=[O:53])[CH2:42][C@H:43]1[C:51]2[C:46](=[CH:47][C:48]([OH:52])=[CH:49][CH:50]=2)[CH2:45][CH2:44]1)[CH3:39].[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61]O>C1COCC1.C(Cl)Cl>[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61][O:52][C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[C@H:43]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:53])[CH2:44][CH2:45]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1nc(-c2ccccc2)oc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3oc(-c4ccccc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
ADDP (0.205 g, 0.81 mmol) was added to a mixture of PPh3 (0.212 g, 0.81 mmol), ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (0.107 g, 0.49 mmol), and 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethanol (step 4, Example 51, 0.110 g, 0.54 mmol) in THF (5 mL). The reaction was stirred overnight at rt, and additional ADDP (0.136 g, 0.54 mmol) and PPh3 (0.141 g, 0.54 mmol) were added with CH2Cl2 (5 mL). The solution was stirred for 24 hours at rt and filtered. The filtrate was evaporated and the resulting mixture was purified by Biotage using a gradient 0 to 50%. EtOAc/hexane. Gave ethyl {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.145 g, 66% yield) as yellowish oil. ES-MS m/z 406.2 ((MH)+); HPLC RT (min.) 3.89; 1H NMR (Acetone-d6) δ 7.85-7.82 (m, 2H), 7.36-7.30 (m, 3H), 6.94 (d, 1H), 6.65 (s, 1H), 6.60-6.55 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.31-3.27 (m, 1H), 3.03 (t, 2H), 3.27-2.51 (m, 3H), 2.24-2.14 (m, 2H), 2.18 (s, 3H), 1.58-1.53 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]=[CH:13]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>ClC1C=CC=CC=1Cl>[CH2:21]([O:20][C:18]([C:15]1[N:14]=[C:13]2[C:23](=[O:24])[NH:1][C:2]3[C:3](=[CH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=3)[N:12]2[C:16]=1[CH3:17])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ncn(-c2ccc(C(F)(F)F)cc2N)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Temperature: 180 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A mixture of 1-(2-amino-4-trifluoromethylphenyl)-4-ethoxycarbonyl-5-methyl-1H-imidazole (12.3 g, 39.3 mmol), 1,1'-carbonyldiimidazole (7.0 g, 43.2 mmol) in 1,2-dichlorobenzene (250 ml) was stirred at 180° C. for 6 h under N2. The reaction mixture was cooled to room temperature. The precipitate was filtered off and washed with acetone to give 10.2 g (77%) of the title compound. M.p. >250° C.