Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 54.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 169 mg of 3,4-difluoroaniline, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 180 mg of N-(3,4-difluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][CH2:3]1.CN1CCOCC1.[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26](Cl)=[O:27]>CCOCC>[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:27]
Reactant: CC1(C)CCc2c(N)cccc21
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2cccc3c2CCC3(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 15 ml of an ether solution of 1.5 g (8.57 mmols) of 1,1-dimethylindane-4-amine,2 ml of N-methyl morpholine and 1.4 g (8.83 mmols) of 2,5-dimethyl-3-furan carboxylic acid chloride were added under cooling. The mixture was stirred at room temperature for 1 hour and then washed sequentially with water and brine. The solution was dried with magnesium sulfate. The resultant concentrate was purified with silica gel column chromatography (solvent for elution; ethyl acetate/ n-hexane =1/4), thereby obtaining 2.1 g of light yellow crystals (Compound No. 20 shown in Table 6). The yield was 85.8%.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCc1cccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The suspension of 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (example 1a, 3.0 g, 10.5 mmol), thiophene methyl amine (2.4 g, 21.0 mmol) and diisopropylethylamine (DIEA) (3.66 mL, 21.0 mmol) in acetonitrile (30 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-[(thiophen-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (2.5 g, 67%) as a light yellow solid: LC-MS m/e 352 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:32][CH:33]1[N:38]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:42][CH2:41][CH2:40][CH2:39][N:38]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[CH3:32])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CC1CCCCN1CCCN
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCN2CCCC[C@H]2C)c(C(=O)O)c1OC

Procedure:
A mixture of Example 318E (50 mg, 0.14 mmol), triethylamine (0.1 mL, 0.71 mmol), acetonitrile (1 mL) and 1-(3-aminopropyl)-2-pipecoline (177 mg, 1.1 mmol) was purged with argon, sealed in a vial and microwaved at 150° C. for 55 minutes. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired product. MS (ESI(+)) m/e 490 (M+H)+; (ESI(−)) m/e 488 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.24 (br s, 1H), 9.71 (br s, 1H), 7.58 (dd, 1H), 7.42 (t, 1H), 7.13 (d, 1H), 6.87 (dd, 1H), 6.67 (m, 2H), 6.05 (m, 1H), 3.69 (s, 3H), 3.36 (m, 2H), 3.12 (m, 2H), 3.05 (m, 2H), 2.88 (m, 1H), 2.54 (q, 2H), 1.86 (m, 4H), 1.64 (m, 2H), 1.43 (m, 2H), 1.20 (d, 3H), 1.10 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.C(Cl)CCl.[CH3:58][C:59]1[O:60][C:61]([CH3:67])=[C:62]([C:64](O)=[O:65])[N:63]=1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:7]=[CH:8][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:10][CH:11]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:64]([C:62]5[N:63]=[C:59]([CH3:58])[O:60][C:61]=5[CH3:67])=[O:65])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM. In a separate vial EDC (5 equiv) and 2,5-dimethyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. This solution was added to the above mixture stirred 4 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (10 mg). LCMS (m/z): 862.
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([N:9]1[C:13]([CH3:14])=[N:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]1)[C:6](=O)[CH3:7])C.[NH2:20][NH2:21]>CCO>[CH3:7][C:6]1[C:5]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([F:16])([F:17])[F:18])=[N:10]2)=[C:4]([OH:19])[NH:20][N:21]=1
Reactant: CCOC(=O)C(C(C)=O)n1nc(C(F)(F)F)nc1C
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c(O)c1-n1nc(C(F)(F)F)nc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-methyl-3-trifluoromethyl-[1,2,4]triazol-1-yl)-3-oxo-butyric acid ethyl ester (890 mg, 3.19 mmol) in EtOH (15 ml) is added hydrazine (0.500 ml, 15.94 mmol) and the mixture left to stir at 50° C. overnight. The solvent is removed in vacuo and trituration of the resulting pale yellow oil with ether and EtOAc affords the title compound as a fine white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccc(C#N)cn1
Yield: 52.3 %

Procedure:
The title compound (1.54 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g) and 2-chloro-5-cyanopyridine (1.29 g) in the presence of diisopropylethylamine (1.21 g) according to the method of D28.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: ClC(c1ccccc1)c1ccc2cccnc2c1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccc3cccnc3c2)n2ccnc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 33.2 %

Procedure:
A mixture of 3.4 parts of 7-[chlorophenylmethyl]quinoline, 4.5 parts of 1H-imidazole and 72 parts of N,N-dimethylformamide was stirred for 6 hours at 80° C. The reaction mixture was evaporated to dry and the residue was taken up in water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 1.27 parts (33.2%) of 7-[(1H-imidazol-1yl)phenylmethyl]quinoline; mp. 110.7° C.(compound 26).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6](C(O)=O)[C:5]=1[OH:16])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:6][C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)O)c(O)c(C(C)C)c1
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
A mixture of 3,5-diisopropylsalicylic acid (Intermediate 9, 25 g, 0.11 mol, available from Aldrich) and quinoline (50 mL) was refluxed for 4 h. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1M HCl (2×200 mL) until acidic, then with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% then 10% EtOAc-hexanes) to yield the title compound as a yellow oil (20 g, ˜100%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:37]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C=O)cc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccc(C=O)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(4-{2-[2-(4′-formylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf 0.14 in 6:4 ethyl acetate:hexanes; MS (EI) 486.1 (M+H)+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([CH2:18]OC)[O:16]C>>[CH2:7]([O:16][CH2:15][C:18]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
S-α,β-Isopropylidene glycerol (2.53 g, 0.0191M) was added dropwise to a stirred slurry of sodium hydride (1.08 g of a 50% dispersion in oil, 0.021M) in dry dimethoxyethane (15 ml) containing dry dimethylsulphoxide (3 ml). The reaction mixture was stirred at room temperature for 0.25 hours and then treated with benzyl chloride (2.66 g, 0.021M). The reaction mixture was heated at 80° C. for 3 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with ether. The combined extracts were dried (MgSO4) and the solvent was evaporated off under reduced pressure to give the crude S-α,β-isopropylidene glycerol, benzyl ether. The crude product was dissolved in acetone (4 ml) and treated with hydrochloric acid (2 ml of 1 Ml-1) and heated at 70° C. for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (120 ml), washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, 10% ethanol in chloroform) to give R-1-benzyloxy-2,3-dihydroxypropane (3.2 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[NH:18][C:17]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[N:45]([C:46]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:44]=[N:43][N:42]=2)=[CH:31][CH:30]=1)=[N+]=[N-]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[N:18]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[N:45]([C:46]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[N:44]=[N:43][N:42]=4)=[CH:33][CH:34]=3)[C:17]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)[nH]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 81 %

Procedure:
The alkylation of 2-[4-(benzyloxy)phenyl]-5-n-butyl-2.4-dihydro-3H-1,2,4-triazol-3-one with 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D. After work-up, flash chromatography over silica gel using 0.4-0.5% MeOH/CH2Cl2 gave an 81% yield of the product, homogeneous by TLC in 1% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 800 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:11]1([Si:17]2(CCCCC)[CH2:22][CH2:21][CH:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)C=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:11]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)=[O:28])=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3cc(F)c(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4,5-trifluorophenol and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a stirred solution of piperazine-2-one (353.3 mg, 3.5 mmol) and naphthalene-2-sulfonyl chloride (800 mg, 3.5 mmol) in anhydrous dichloromethane (15 mL) was added diisopropylethylamine (1.54 mL, 8.8 mmol). The mixture was stirred for 30 min. Reaction was complete as determined by TLC. The reaction mixture was filtered, washed with hexane to give a first batch. The mother liquor washed with saturated ammonium chloride, then washed with saturated brine, separated, dried over sodium sulphate. Then hexane was added, lots of precipitate formed. The was filtered, washed with hexane to give a second batch. The two batches were combined to yield 4-(naphthalene-2-sulfonyl)-piperazin-2-one in 92.5% yield (947 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.35-3.40 (m, 2H) 3.42-3.48 (m, 2H) 3.79 (s, 2H) 6.11 (s, 1H) 7.63-7.73 (m, 2H) 7.77 (dd, J=8.72, 1.89 Hz, 1 H) 7.94 (d, J=7.83 Hz, 1H) 7.98-8.05 (m, 2H) 8.38 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH2:11][CH2:10]2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=4)[CH:17]=3)[O:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)COC1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@@]2(CCOc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)COC1
Yield: 54 %

Procedure:
The condensation of (R)-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.2) and 5-chloropicolinic acid yielded the title compound (54% yield) as a pale yellow solid. MS (ISP): m/z=423.2 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:26][C:18]1[C:17]2[N:27]=[C:14]3[CH2:13][O:12][CH2:11][C@H:10]([CH2:9][OH:8])[N:15]3[C:16]=2[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Reaction time: 18 h
Yield: 38.1 %

Procedure:
(11S)-11-[(Benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (297 mg, 0.825 mmol) was dissolved in 20 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 230 mg) and 0.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 18 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CH2Cl2 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-75% CMA/CHCl3) gave a white powder. Crystallization from ethyl acetate gave 85 mg of the title compound as white, fluffy crystals, mp 238.6-239.8° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: OCc1ccc(F)cc1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 4-fluorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1cccnc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccnc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-picolylamine (35 mg, 0.32 mmol). The title compound was obtained as a yellow solid (21 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.42 (1H, m), 8.99 (2H, s), 8.51 (1H, s), 8.47 (1H, s), 7.69 (1H, m), 7.36 (1H, m), 4.43 (2H, m). MS m/z: 441.17, 443.16 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](N3CCN(CCS(C)(=O)=O)CC3)=[O:21])[C:10]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:49])([CH3:48])[C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=3[O:50][CH2:51][CH3:52])=[N:9]2)=[CH:4][CH:3]=1.[N:53]1([C:59](=[O:67])[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:64]3[CH2:63][CH2:62][N:61]([CH2:60][C:59]([N:53]4[CH2:54][CH2:55][O:56][CH2:57][CH2:58]4)=[O:67])[CH2:66][CH2:65]3)=[O:21])[C:10]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:49])([CH3:48])[C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=3[O:50][CH2:51][CH3:52])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Product: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Yield: 84.6 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-[4-(1-diethylcarbamoyl-1-methyl-ethyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (27 mg, 0.0439 mmol, example 157) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (14 mg, 0.0659 mmol, Oakwood Products) using the procedure described in example 25 to give cis-2-(4-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide (29.4 mg, 85% yield) as white solids. HR-MS (ES, m/z): observed 791.3445, calculated for C42H52Cl2N6O5 [(M+H)+] 791.3449.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:12]=[CH:11]1>>[NH:10]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:7](=[O:9])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:12]=[CH:11]1
Reactant: NCCCCc1c[nH]cn1
Reactant: O=C(O)CC1CCCC1
Product: O=C(CC1CCCC1)NCCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 1 with 2-cyclopentylacetic acid and 4-(1H-imidazol-4-yl)butanamine. The title compound is extracted from water with diethyl ether and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.