Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CCOC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=4[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=3)=[O:9])[CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26, 50 mg, 0.159 mmol) and 4-chlorophenylacetic acid (27.2 mg, 0.159 mmol) in pyridine (1 mL) was added HATU (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% MeOH in DCM to afford the title compound (28 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N=CC=CN=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:27][CH3:26])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: Clc1ncccn1
Agent: [Na+]
Solvent: CO
Product: COc1ncnc2c1CN(Cc1ccccc1)CC2
Yield: 100 %

Procedure:
A 1 L flask was charged with 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (39.6 g, 0.152 mol) and methanol (300 mL), and the mixture was heated to dissolve the chloropyrimidine. 4.37 M of sodium methoxide in methanol (105 mL) was added slowly to the warm mixture and the stirred mixture rapidly turned cloudy. The resultant suspension was heated under reflux for 2 h. After cooling, the mixture was concentrated in vacuo to ca 100 mL. The residue was poured into water (600 mL), and extracted with CH2Cl2 (200 mL×2). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield a light brown oil (38.9 g, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 4-fluorobenzonitrile (1 g, 8.26 mmol), piperidine (0.90 mL, 9.08 mmol) and potassium carbonate (2.28 g, 16.51 mmol) in dry 1-methyl-2-pyrrolidinone (10 mL) was stirred at 120° C. under nitrogen for 20 hours. The cooled reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford an orange oil. Purification by flash chromatography using a solvent gradient of 1 to 7% ethyl acetate in hexane gave an orange oil that was crystallized from hexane to afford the title compound (1.41 g, 92%) as an orange crystalline solid, m.p. 54° C.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C@@:11]1([CH2:25][CH3:26])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[O:23][CH3:24])[CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=1>CS(C)=O>[CH2:25]([C@:11]1([C:9]([N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)=[O:10])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:18]([O:23][CH3:24])[CH2:19][O:20][CH2:21][CH2:22]2)[CH2:12]1)[CH3:26]
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3)CC[C@@H](N[C@@H]2CCOC[C@H]2OC)C1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3c2cc(C(F)(F)F)ccn2)CC[C@@H](N[C@H]2CCOC[C@H]2OC)C1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a solution of HCl salt of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl((1S,3R)-1-ethyl-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)methanone (118 mg, 0.33 mmol) in DMSO (2 ml) was added triethylamine (0.15 ml, 1.08 mmol) and the 2-chloro-4-(trifluoromethyl)pyridine (183 mg, 1.01 mmol). The reaction was heated to 120° C. for 15 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40 mg 26%). LC/MS (M+H)=497.2739 exp, 497.2884 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.25-8.24 (1H), 6.75-6.74 (1H), 6.51-6.45 (1H), 5.13-4.76 (2H), 4.10-4.03 (1H), 3.95-3.90 (1H), 3.72-3.16 (11H), 2.82-2.67 (1H), 2.58-2.36 (1H), 2.06-1.36 (12H), 0.86-0.67 (3H)
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:16][C:10]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2cc(F)ccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Reaction time: 4 h

Procedure:
A solution of 6.44 g. of titanium (IV) chloride in 25 ml. of benzene is added dropwise over a period of 15 minutes with cooling to a solution of 9.12 g. of 2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 18 g. of 1-methyl-piperazine in 100 ml. of benzene in such a manner that the temperature does not exceed 25° C. The mixture is subsequently stirred for 4 hours at reflux. The resulting mixture is cooled and poured into a solution of 10 g. of sodium bicarbonate in 100 ml. of water. The precipitated titanium dioxide is removed by filtration and washed carefully with benzene and chloroform. The benzene solution and the chloroform solution are washed four times with water, combined, dried over sodium sulfate, evaporated in vacuo, and there is obtained crude, crystalline 1-[2-fluoro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[N:21]1([CH:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CCN(CC)CC>CC#N>[N:21]1([CH:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:2]3[C:3]4[C:10]5[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:31][CH2:32]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc2sc3ncnc(Cl)c3c2c1
Reactant: NC1CCC(N2CCOCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Yield: 66.8 %

Procedure:
A solution of ethyl 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (500 mg, 1.7 mmol, 1.00 equiv), 4-(morpholin-4-yl)cyclohexan-1-amine chloride (1.1 g, 4.25 mmol, 2.5 equiv) and potassium carbonate (2.3 g, 17 mmol, 10.17 equiv) in CH3CN (100 mL) was Et3N (2 mL) at room temperature under nitrogen. The resulting solution was heated to reflux overnight. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give the desired ethyl 3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate (500 mg, 66%) as a yellow solid. LCMS: (ES, m/z) 441 [M+H]+. 1H-NMR (300 MHz, CD3OD): δ 1.44-1.53 (4H, m), 1.57-1.65 (3H, m), 2.24-2.29 (2H, m), 2.25-2.33 (3H, m), 2.56-2.67 (4H, m), 3.45-3.75 (4H, m), 4.31-4.43 (1H, m), 4.45-4.50 (2H, m), 8.07-8.16 (2H, m), 8.49 (1H, s), 8.78 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[C:27]([CH3:40])[NH:26][C:25]=1[CH:41]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:41]\[C:25]1[NH:26][C:27]([CH3:40])=[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[O:32])[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark orange brown solid. 1HNMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H, NH), 11.25 (s, 1H, NH), 8.18 (d, 1H), 7.75 (s, 11H), 7.48 (s, 1H), 7.46 (s, 1H), 7.38 (m, 2H), 6.99 (d, J=8 Hz, 1H), 4.85 (s, 2H), 3.3-3.42 (m, 2H), 2.62 (m, 2H), 2.44 (m, 2H), 2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.1-2.2 (m, 4H), 2.11 (s, 3H, CH3). MS m/z 613 [M−1].
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.7 %

Procedure:
tert-butyl(3R)-6-cyclohexyl-3-{3-[(ethylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 74) (288 mg, 0.76 mmol) was treated with TFA (5 ml) and stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and the solvents removed under reduced pressure. The residue was azeotroped from toluene (×3) and DCM (×3) to afford the title compound (373 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[CH3:8].C1COCC1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(NS(=O)(=O)c4ccccc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (101.9 mg, 0.342 mmol) and 4-dimethylaminopyridine (4.2 mg, 0.034 mmol) were suspended in pyridine (2.0 ml) and THF (2.0 ml) and benzenesulfonyl chloride (0.21 ml, 1.637 mmol) was added. The reaction was stirred under nitrogen at room temperature. After 1 day, more DMAP (21.3 mg) was added and stirring was continued. After about 2 hours, more benzenesulfonyl chloride (0.18 ml) was added, and stirring was continued. After 3.5 hours, flask put in preheated oil bath (65° C.) and stirring continued. After 45 minutes, LCMS shows mostly product, so reaction cooled to room temperature, concentrated and purified on a silica gel column (20:1 to 10:1 DCM/MeOH to 10:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, treated with DCM, and filtered. Solid washed with DCM and Et2O, collected, and dried under high vacuum to afford N-(6-(6-methyl-5-(phenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (38.0 mg, 25% yield). MS (ESI pos. ion) m/z: 439. Calculated exact mass for C21H18N4O3S2: 438.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:15][CH:12]2[CH2:13][CH2:14][N:9]([C:4]3[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: NC1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: O=S(=O)(NC1CCN(c2ncccc2C(F)(F)F)CC1)c1cccc(Cl)c1
Yield: 40.3 %

Procedure:
Using the procedure from Example 17A, Step 17C, 1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42 mmol) was reacted with 3-chlorobenzenesulfonyl chloride (106 mg, 0.50 mmol) to afford the title compound (71 mg), a white solid, in 40% yield.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:16](I)[CH2:17][CH3:18].C([O-])(=O)C([O-])=O>CCOC(C)=O>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: CC(=O)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])C(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2cccc(C(C)=O)c2)CC1

Procedure:
Beginning with 1-(3-Piperazin-1-yl-phenyl)-ethanone and n-Pr-I: m.p. 119° C. (oxalate), MS m/z (rel. intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).
Reaction SMILES: [CH2:1]([N:5]([C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH3:17])[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3].[OH2:20].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CO>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[OH:20][NH:6][C:7]([C@H:8]([C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([NH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:14](=[O:19])[CH2:15][N:16]([CH3:17])[CH3:18])=[O:13])[CH2:9]/[CH:10]=[CH:31]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13]
Reactant: O
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)CN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CN(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.590 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(dimethylamino)acetyl]valerohydrazide in 10 ml of methanol was treated with 0.210 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.478 g of (E)-2(R)-[1(S)-(hydroxy-carbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(dimethylamino)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].Cl.[Cl:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C=O)C>[ClH:37].[ClH:1].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)[C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(Cc6cccnc6)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and 3-chloromethylpyridine hydrochloride (20 mg). Yield, 20 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=4[Cl:36])[CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cccc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 94 mg (0.20 mmol) of the compound from Example 102A were reacted with 56 mg (0.23 mmol) of 2,3-dichlorophenylboronic acid. This gave 48 mg (45% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13][C:14](C)([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+].C1(=O)CCC1>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[C:14]4([CH2:16][CH2:24][CH2:15]4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C1CCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2(CCC2)C2c3ccccc3Oc3ccc(Cl)cc3N12
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of 1.0 g (3.0 mmol) of 1 in 20 mL of anhydrous THF was added 1.2 equivalent of lithium diisopropylamide at -78°. After 30 minutes, approximately 2 equivalent of cyclobutanone was added as the electrophile. The stirring was continued for 3 hours at -78°, followed by room temperature overnight, and was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with brine and dried with magnesium sulfate or sodium sulfate. Purification by HPLC on silica gel with 7% ethyl acetate/hexane as the eluent followed by lyophilization from acetonitrile/water gave 355 mg (36%) of Compound 21. 1H NMR (CDCl3): δ 7.62 (s, 1H, ArH), 7.16-7.40 (m, 6H, ArH), 5.19 (s, 1H, ArCH), 2.75-2.84 (m, 1H, c-butyl), 2.45-2.60 (m, 1H, c-butyl), 2.28-2.42 (m, 1H, c-butyl), 2.12-2.26 (m, 1H, c-butyl), 1.82-2.00 (m, 1H, c-butyl), 1.30-1.45 (m, 1H, c-butyl). FABMS: m/z 334 (M+Li). HRMS calculated for C18H14 NO3LiCl (M+Li) 334.0822, found 334.0867. Analysis Calculated for C18H14NO3Cl: C, 65.96; H, 4.31; N, 4.27; Cl, 10.82. Found: C, 65.86; H, 4.31; N, 4.31; Cl, 10.46.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:36]1([O:41][C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH:45]=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([O:41][C:42]2[CH:43]=[C:44](/[CH:45]=[CH:5]/[C:4]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:3]=3[Cl:2])[CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A stirred suspension of 2,6-dichlorobenzyltriphenylphosphonium bromide (2.5 g) in dry tetrahydrofuran (30 mL) is treated dropwise with a solution of potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL) at 0° C. After stirring at this temperature for 1 hour, it is treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g) in dry tetrahydrofuran (15 mL). The reaction mixture is stirred from 0° C. to 5° C. for 1 hour and 30 minutes, and then allowed to warm to room temperature. After stirring overnight, the mixture is concentrated and the resulting residue is treated with ethyl acetate (200 mL). The resulting organic solution is filtered. The filtrate is concentrated and the resulting residue is subjected to flash chromatography, eluting with dichloromethane, to give trans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene (1.16 g), m.p. 47°-49° C. [Elemental analysis: C,66.4; H,5.6; Cl,19.4%, calculated: C,66.1; H,5.55; Cl19.5%].
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl([O-])=[O:14].[Na+].O1CCOCC1.S(=O)(=O)(O)N>O>[F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
In a round bottom flask, 2-fluoro-3-nitro-benzaldehyde (15, 1.02 g, 6.03 mmol) is combined with sodium chlorite (1.26 g, 11.15 mmol), 60 mL of 1,4-dioxane, 20 mL of water, and sulfamic acid (4.47 g, 46.0 mmol) and the reaction is stirred at room temperature for 30 minutes. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified on column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum, then suspended in dichloromethane. The resulting solid is collected by filtration to provide the desired compound (16, 151 mg). MS (ESI)[M−H+]−=184.4.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C:20]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[C:36]=4[CH2:41][NH:42][CH2:43][CH:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH3:45])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].C=O>>[CH2:15]([O:17][C:18]([C:20]1([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[C:36]=4[CH2:41][N:42]([CH3:1])[CH2:43][CH:44]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH3:45])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:19])[CH3:16]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Agent: C=O
Agent: [Na+]
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(C)CC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using sodium triacetoxyborohydride instead of sodium borohydride and the following starting materials: 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and formaldehyde.