Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O)([CH3:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:21]([NH:20][CH2:15][C:14]2[CH:17]=[C:10]([C:2]([CH3:9])([CH3:1])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6])[CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C@@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1C=O
Product: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 58 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][NH:16][C:2]2[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=23)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NCCN1CCOCC1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: Cc1nnc(NCCN2CCOCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 4-(2-aminoethyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt (MeOH/ethereal HCl/diethyl ether), mp 310° C. (dec).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(Cl)Cl.[F:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]3[CH2:25][N:26]([CH2:28][CH2:29][CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[OH:32])[CH2:27][C:12]=3[C:11]=2[CH:10]=1>N1C=CC=CC=1>[F:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]3[CH2:25][N:26]([CH2:28][CH2:29][CH2:30][CH:31]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[O:32][C:1](=[O:3])[CH3:2])[CH2:27][C:12]=3[C:11]=2[CH:10]=1
Reactant: OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (260 mg., 3.3 m moles) in 10 ml. of methylene chloride is added dropwise to a cold solution of 959 mg. (2.2m moles) of 7-fluoro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole in 30 ml. of methylene chloride containing 350 mg. (4.4 m mols) of pyridine. Following the addition, the reaction mixture is allowed to warm to room temperature and stir overnight. The mixture is decanted into a cold saturated aqueous sodium bicarbonate solution, and the crude product is extracted (3 × 50 ml.) with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated to an oil, which on chromatographing on a silica gel column, using 1:1 benzene-ethyl acetate as an eluate, provides the purified product.
Reaction SMILES: [NH2:1][C:2](=[N:44][OH:45])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10].CN(C=O)C.N1C=CC=CC=1.Cl[C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59]>C(OCC)(=O)C>[NH2:1][C:2](=[N:44][O:45][C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(N)=NO)c2)C1c1ccc(Cl)cc1Cl
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)ON=C(N)c1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1

Procedure:
To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N:11]=O)[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:11][C:9]1[C:8]([CH3:13])=[CH:7][C:6]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: Cc1cc(O)c(C(C)(C)C)cc1N=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(O)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
To a solution of 2-(tert-butyl)4-nitroso-5-methylphenol (47.0 g, 243 mmol) in ethanol (500 ml) was slowly added dropwise hydrazine hydrate (29.5 ml, 608 mmol) at 0° C. After completing the dropwise addition, the mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. The residue was combined with water (500 ml), and the crystals were filtered. The crystals were dissolved in ethyl acetate, washed with saturated brine, dried over sodium sulfate and purified by silica gel column chromatography on a small amount of silica gel which was eluted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was suspended in hexane and the crystals were collected by filtration to obtain 39.3 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:22]([O-])=O)=[C:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:22][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Temperature: 80 °C
Reaction time: 1.2 h
Yield: 102.2 %

Procedure:
A mixture of isopropyl 5-benzyloxy-2-nitrophenylacetate (4.2 g), ammonium chloride (0.42 g) and iron powder (4.2 g) in a mixed solvent of ethanol (20 ml) and water (10 ml) was stirred at 80° C. for 1.2 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give isopropyl 2-amino-5-benzyloxyphenylacetate (3.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[N:14]=[CH:15][O:16][CH:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cocn1
Reactant: C1COCCN1
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1Cn1nc(-c2cc(N3CCOCC3)ccn2)nc1-c1cocn1
Temperature: 100 °C
Yield: 10.3 %

Procedure:
To a stirring suspension of 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole (I-54, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube was added morpholine (30 eq). The resultant reaction mixture was heated at 100° C. for 12 hr and then cooled to room temperature, treated with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (methylene chloride/acetonitrile/methanol) to afford 4-(2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholine in 10.3% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]=[C:7]=[O:8])=[O:5].[C:9]([OH:13])([CH3:12])([CH3:11])[CH3:10]>ClC(Cl)C>[Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7](=[O:8])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: O=C=NC(=O)CCCl
Reactant: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(=O)CCCl

Procedure:
To beta-chloropropionyl isocyanate (13.3 g; 100 mmol) in dichloroethane (20 g), a solution of t-butanol (7.4 g; 100 mmol) in dichloroethane (20 g) was dropwise added under ice-cooling in 5 minutes, whereby t-butyl beta-chloropropionylcarbamate was produced. Triethylamine (9.8 g; 100 mmol) was added to the reaction mixture, and the resultant mixture was stirred for 60 minutes. Precipitated salts were eliminated by filtration, and the filtrate was concentrated under reduced pressure to give t-butyl acryloylcarbamate as crude crystals, which were recrystallized from chloroform to give colorless needles. M.P., 131°-132° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([OH:19])=O)[CH:6]=1.[O:20]=[C:21]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[NH:37][O:38][C:39](=[O:41])[N:40]=3)[CH:34]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][C:21](=[O:20])[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)[CH:34]=4)[O:29]3)[CH2:24][CH2:25]2)=[O:19])[CH:6]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nc(=O)o[nH]3)cc21
Reactant: COc1cccc2c(OCCO)cc(C(=O)O)cc12
Product: COc1cccc2c(OCCO)cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5noc(=O)[nH]5)ccc3O4)cc12

Procedure:
The compound was prepared according to the procedure described in the Example 1, using 4-(2-hydroxyethoxy)-8-methoxy-2-naphthoic acid instead of 4,8-dimethoxyquinoline-2-carboxylic acid, and 3-[4-oxospiro(chroman-2,4′-piperidin)-6-yl]-5-oxo-1,2,4-oxadiazole instead of 4-oxospiro(chroman-2,4′-piperidin)-6-yl acetamide. 1H-NMR (400 MHz, DMSO-d6) δ: 8.24 (1H, d, J=4.0 Hz), 8.04 (1H, dd, J=4.0, 8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 7.75 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.34 (1H, d, J=8 Hz), 7.09 (1H, d, J=8 Hz), 7.00 (1H, s), 4.40-4.22 (1H, m), 4.20 (2H, t, J=4.0 Hz), 4.01 (3H, s), 3.92-3.89 (2H, m), 3.75-3.30 (3H, m), 3.03 (2H, s), 2.12-1.75 (4H, m). MS [M+H]+=546.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: Fc1ccc2[nH]cc(C3CCNCC3)c2c1

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 0.7 g (5.5 mmol) of 5-fluoroindol and 2.1 g (13.6 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 0.8 g (67% of yield) of the desired product were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[C:29]=[O:30]>O1CCOCC1>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:17][C:29]([NH:28][C:22]3[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])=[O:30])[CH:16]=2)=[CH:8][CH:9]=1)[CH3:19]
Reactant: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Reactant: O=C=Nc1c(F)cccc1F
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(Nc2cc(NC(=O)Nc3c(F)cccc3F)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine (257.4 mg, 1 mmol), 2,6-difluorophenyl isocyanate (170.6 mg, 1.1 mmol) in dry dioxane (4 mL) is shaken for 1.5 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between CH2Cl2 and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=[CH:12][C:13]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(O)[O-:28].[Na+].[OH2:32]>N1C=CC=CC=1.[Os](=O)(=O)(=O)=O>[C:19]([C:10]1[C:11](=[O:28])[C:12](=[O:32])[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:14]2[C:9]=1[C:8]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:7][CH:6]=[C:5]2[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=S([O-])O
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c2c(C(C)(C)C)ccc(C(C)(C)C)c12
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)C1=c2c(C(C)(C)C)ccc(C(C)(C)C)c2=C(C(C)(C)C)C(=O)C1=O
Temperature: 90 °C

Procedure:
One stoichiometric equivalent of 1,4,5,8-tetra-t-butyl-naphthalene and one equivalent of osmium tetraoxide (OsO4) in pyridine are stirred for several hours at room temperature (about 20°-25° C). A solution of excess sodium bisulfite (NaHSO3) in pyridine and water is added with stirring. The resulting crude product is extracted with methylene chloride (H2CCL2) and is purified by chromatography on alumina. A resulting 1,4,5,8-tetra-t-butyl-2,3-dihydronaphthalene-2,3-diol is treated with excess copper sulfate (CuSO4) in pyridine and water, is heated to 90° C for several hours, and then is cooled. The mixture is diluted with water and is extracted with an organic solvent (e.g., diethylether, chloroform, or methylene chloride). The solvent is evaporated and the crude product purified by chromatography on alumina to obtain 1,4,5,8-tetra-t-butyl-2,3-dihydronaphthalene-2,3-dione (1,4,5,8-tetra-t-butyl-2,3-naphthoquinone).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[NH2:31])[CH2:20][CH:19]3[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[F:35][C:36]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>>[F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[NH:31][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:43]([F:46])=[C:44]([F:45])[C:36]=4[F:35])[CH2:20][C:19]3=[O:32])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(O)C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3NC(=O)c3ccc(F)c(F)c3F)CC2=O)CCCCC1)c1ccc(F)cc1

Procedure:
In accordance with the same procedure as in Example 87, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol and 2,3,4-trifluorobenzoyl chloride was used instead of methoxyacetyl chloride in Step 3 thereof, 321 mg of the titled compound was prepared.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1
Reactant: COCCCNc1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCCNc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-propylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(3-methoxy-propyl)-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](OCC)=[O:14].[H-].[Na+].O>C(COC)OC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([CH:13]=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccco1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of ethyl 3-(2-furanyl)propionate (33.77 g) and ethyl formate (22.22 g) was added dropwise with stirring to a pre-cooled (0° C.) suspension of sodium hydride (50% in oil; 8.45 g) in dimethoxyethane (70 ml) maintaining the temperature below 0° C. throughout the addition. The reaction mixture was allowed to warm to room temperature then poured on to ice and water and extracted with ethyl acetate. The aqueous layer was acidified to pH 4 and re-extracted with ethyl acetate. These second ethyl acetate extracts were combined dried (MgSO4) and evaporated at reduced pressure to yield ethyl 3-(2-furanyl)-2-formylpropionate (19.0 g).
Reaction SMILES: F.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: OB(O)c1ccco1
Reactant: Nc1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Agent: F
Product: Nc1ncc(-c2cccc(Nc3ccc(-c4ccco4)cc3[N+](=O)[O-])c2)cn1

Procedure:
N-(3-(2-Aminopyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline (7p) was prepared analogously from 6l (Example 10) and 2-furanylboronic acid in quantitative yield. Mp 178-180° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH:11]([OH:24])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH:11]([O:24][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(O)CNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1

Procedure:
4-Benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester was prepared by an analogous procedure as described in example 26i) starting from 6.7 g (19.6 mmol) 4-benzyloxycarbonylamino-3-hydroxy-butyric acid benzyl ester and 1.84 ml (1.2 equiv.) methanesulfonyl chloride. 4-Benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester was obtained in crude form as yellow oil. Yield: 8.5 g.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([OH:11])=O)=[C:7]([C:12]3[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:6]=[C:5]2C2C=CC(OC(F)(F)F)=CC=2)[CH2:3][CH2:2]1.C(OC(=O)CN(C1CC1)C(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]([F:47])([F:46])[F:45])[CH:38]=1)C.[N:53]1([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH:1]1([N:4]2[C:8]([C:9]([N:61]3[CH2:62][CH2:63][CH:58]([N:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH2:59][CH2:60]3)=[O:11])=[C:7]([C:12]3[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:6]=[C:5]2[C:41]2[CH:42]=[CH:37][CH:38]=[C:39]([O:43][C:44]([F:45])([F:46])[F:47])[CH:40]=2)[CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOC(=O)CN(C(=O)c1cccc(OC(F)(F)F)c1)C1CC1
Reactant: O=C(O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Product: O=C(c1c(-c2ccc(O)nc2)nc(-c2cccc(OC(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, the title compound has been obtained by coupling of 3-cyclopropyl-5-(6-hydroxy-pyridin-3-yl)-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (prepared in analogy to the sequence described for the preparation of intermediate 9, using [cyclopropyl-(3-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester instead of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in step 9A) with 4-pyrrolidin-1-yl-piperidine to give the title compound as a colorless amorphous solid. MS: 542.4 (MH+).
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CC(N(C)C)=O>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])=[CH:31][CH:30]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.8 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.30 mmol) and 4-fluoroaniline (0.113 mL, 1.19 mmol) in DMA (1 mL) were stirred at RT for 4 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. A further purification was done by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford a oil which was triturated with pentane to give 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (80 mg, 59%) as a white solid.