Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:7]1=2.O.NN>CO.[Ni]>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:7]1=2
Reactant: CN(C)CCCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)CCCN1CCSc2cc(N)ccc21
Yield: 99.4 %

Procedure:
A solution of N,N-dimethyl-3-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)propan-1-amine (0.27 g, 0.960 mmol) in dry methanol (10 mL) was treated with hydrazine hydrate (0.349 mL, 9.60 mmol), followed by Raney-Nickel (0.1 g, 0.096 mmol) at room temperature. The resulting mixture was refluxed for 5 minutes in a pre-heated oil bath. The reaction was then brought to room temperature, filtered through a pad of Celite, and washed with methanol (3×10 mL). The combined methanol layers were evaporated, and the crude material was purified by flash column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.24 g, 99%) as a syrup. 1H NMR (DMSO-d6) δ 6.50 (dd, 1H, J=2.4, 7.0 Hz), 6.26-6.23 (m, 2H), 4.41 (s, 2H), 3.32-3.30 (m, 2H), 3.09 (t, 2H, J=7.2 Hz), 2.98-2.95 (m, 2H), 2.21 (t, 2H, J=6.9 Hz), 2.11 (s, 6H), 1.63-1.54 (m, 2H); ESI-MS (m/z, %): 252 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Li][Li].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(O)=O>>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[O:5]
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: [Li][Li]
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1C

Procedure:
2-Methyl-4-bromobenzoyl chloride (29.1 g, 0.13 mol) was treated with the dilithium salt of ethyl hydrogen malonate (28.0 g, 0.21 mol) and the product was isolated by the procedure described in Example 1 (ii). The crude product was purified on flash silica, eluting with dichloromethane-hexane (1:1 then 3:2) to give ethyl 2-methyl-4-bromobenzoylacetate as an oil.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:22]=[CH:23][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)=[N:3][C:4]=2[CH3:24])=[O:7])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 209 mg of 1-Boc-piperizine in 1 mL of BuOH. The reaction mixture was evaporated to afford tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate. 150 mg of tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate was treated with TFA (1 mL) containing trace amounts of H2O for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 0.1N sodium hydroxide and brine, dried (MgSO4) and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide. MS (Q1) 408.3 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]2[C:14](=O)[O:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].O.[NH3:31].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11][C:10]([C:14]([NH2:31])=[O:13])=[N:9]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCOCc1cc(NN=C2N=C(c3ccccc3F)OC2=O)ccc1Cl
Reactant: N
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2F)ccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
In 10 ml of acetone, 1.294 g (3 mmol) of 4-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl hydrazono]-2-(2-fluorophenyl)-2-oxazolin-5-one synthesized in the similar way to Synthesis Examples 1-3 was suspended, followed by the addition of 0.6 ml of concentrated ammonia water and 30-minute stirring at room temperature. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product, and this crude product was purified by subjecting it to silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and recrystallized from ethyl acetate-hexane to obtain 1.062 g (82.3% yield) of 1-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl]-5-(2-flurophenyl)-1H-1,2,4-triazole-3-carboxamide (m.p. 113°-115° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH2:15][CH3:16])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)C>Cl.O>[CH:17]1([N:7]2[CH2:8][CH:9]([CH2:14][CH2:15][CH3:16])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCCC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Yield: 69.5 %

Procedure:
step d A mixture of 0.208 g (0.00065 mole) of (rac)-2-chloro-9-cyclopentyl-5-methyl-7-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-16), 0.13 g (0.00078 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.205 g of (rac)-4-(9-cyclopentyl-5-methyl-7-propyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-16) as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].CC([O-])(C)C.[K+].Br[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:23][C:22]=2[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31])[CH:18]=[CH:19][CH:20]=1>CS(C)=O.C(Cl)Cl>[N:1]1([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:23][C:22]=3[S:30]([NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])(=[O:31])=[O:32])[CH:18]=[CH:19][CH:20]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(CN3CCCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-pyrrolidinone (26.5 mg, 0.312 mmol) in DMSO (1 mL) and t-BuOK (48.9 mg, 0.436 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (92.3 mg, 0.208 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (2:98) as eluent to give the sub-title compound in 77% yield as a colourless syrup (72.3 mg, 0.161 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[Cl:5][C:6]1[CH:7]=[C:8]([C:12](=O)/[CH:13]=[C:14](\O)/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:11]=1.C(O)(=O)C>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[NH:4][N:3]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(/C=C(O)/C=C/c1ccc(O)cc1)c1cccc(Cl)c1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(/C=C/c2cc(-c3cccc(Cl)c3)n[nH]2)cc1
Temperature: 80 °C
Yield: 41 %

Procedure:
Hydrazine dihydro-chloride (0.263 g, 2.50 mmol) was added to a sealed tube charged with (2Z,4E)-1-(3-chlorophenyl)-3-hydroxy-5-(4-hydroxyphenyl)penta-2,4-dien-1-one (0.717 g, 2.39 mmol) in absolute ethanol (8 mL) and a catalytic amount of acetic acid. The reaction tube was sealed and heated to 80° C. After 12 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol and precipitated with water, and the solid was collected by vacuum filtration to provide the title compound in (288 mg, 41% yield) as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 7.79 (bs, 1H), 7.68 (bd, J=7.6 Hz, 1H), 7.37 (m, 3H), 7.29 (bd, J=7.6 Hz, 1H), 7.12 (d, J=16.4 Hz, 1H), 6.86 (d, J=16.4 Hz, 1H), 6.81 (bs, 1H), 6.77 (m, 2H); MS (EI) for C17H13 ClN2O: 297.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][CH:7]=1)[CH3:2].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:10][C:11]=1[N+:24]([O-:26])=[O:25])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
(4-Phtalimido-phenyl)-carbamic acid ethyl ester (99.0 g, 0.32 mol) is suspended in glacial acetic acid (1.5 L) and heated to 90° C. Fuming nitric acid (17.2 mL, 0.41 mol) is added dropwise over 30 minutes at 90-95° C. The reaction mixture is then stirred at 100° C. for 1 hour and cooled to ambient temperature. Crystallised solids are filtered off and washed with glacial acetic acid (500 mL), water (1 L) and diethylether (1 L) on the filter, then dried in vacuo to furnish 101 g (90%) of the title compound as a yellow solid. LC/MS (m/z) 355.0 (MH+); tR=3.34 min. 1H NMR (DMSO-d6): 1.25 (t, 3H); 4.16 (q, 2H); 7.81 (m, 2H); 7.93 (ddd, 2H); 7.99 (ddd, 2H); 6.15 (dd, 1H); 9.99 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A 100 mL 3-neck round bottom flask was charged with 4-bromo-2-fluoro-1-iodobenzene (1000 mg, 3.32 mmol) and diethyl ether (30 mL). The solution was cooled to −78 °C., and n-butyllithium (1.329 mL, 3.32 mmol) was added dropwise, keeping the temperature below −68° C. After stirring for 15 min, cyclobutanone (0.249 mL, 3.32 mmol) was added dropwise, keeping temperature; below −68° C. The solution was stirred at −78° C. for 15 min. The reaction was then quenched by the addition of saturated ammonium chloride (25 mL). The layers were separated, and the organic was washed with water (1×10 mL) and brine (1×10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue Was purified by flash chromatography (SiO2 gel), eluting with 3% ethylacetate/hexanes to give the desired product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.69 (m, 1 H), 1.91-2.05 (m, 1 H), 2.19-2.28 (m, 2 H), 2.46-2.55 (m, 2 H), 5.59 (s, 1 H), 7.33-7.40 (m, 2 H), 7.44-7.48 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].ClC1C=C(C=CC=1)C(OO)=[O:42]>C(Cl)Cl.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophene-carboxamide (0.052 g, 0.1 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DMF (0.5 mL). Then 3-chloroperoxybenzoic acid (50-60%) (0.03 g, ˜0.1 mmol) was added and the mixture stirred for 45 min at room temperature. Solvent was pumped off in vacuo to give the title compound plus a small amount of the corresponding sulfone. The mixture was used without further purification. LC-MS m/z 540 (M+H)+, 1.76 min (ret. time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(F)cc1OC
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1OC
Yield: 66.3 %

Procedure:
Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K2CO3 (1.3 gr, 9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at 100° C. in DMSO (5 mL) for 20 hours. Reaction mixture was diluted with DCM and washed with water. Organic phase was dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g (yield 66%) of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S(=O)(=O)(O)O.[CH:15](O)(C)C>>[C:1]([O:7][CH:8]([CH3:15])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(=O)CC(=O)OC(C)C

Procedure:
A solution of ethyl acetoacetate (250 g.) and concentrated sulphuric acid (10 ml.) in isopropanol (1500 ml.) was heated at reflux for 3 hours. The solvent was removed by distillation, the residue was neutralised by treatment with barium carbonate, filtered and distilled under reduced pressure to give isopropyl acetoacetate (139 g.), b.p. 79°-82° C./20 mm Hg, in the form of a colourless liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:28]=[CH:29][C:4]([CH2:3][CH2:2][NH:1][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]4[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:22][CH:23]=1
Reactant: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(4-methylphenyl)propyl]-1-piperidine-carboxamide foramte (0.44 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.40 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.185 g, 0.23 mmol).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:13][C@H:10]2[CH2:9][CH2:8][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:20])=[CH:17][CH:16]=1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(N[C@H]1CC[C@H](c2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
from trans-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 232°-234° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][OH:52])[C:47]([F:50])([F:49])[F:48])[CH:41]=3)[N:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][O:52][S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:47]([F:50])([F:48])[F:49])[CH:41]=3)[N:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reaction time: 1 h
Yield: 113.6 %

Procedure:
Tosyl chloride (0.048 g, 0.251 mmol) was added portionwise to a cold mixture of methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.130 g, 0.229 mmol), 4-dimethylaminopyridine (2.79 mg, 0.023 mmol) and triethylamine (0.038 mL, 0.274 mmol) in DCM (10.00 mL) to give a white suspension. After one hour at room temperature, the amber solution was diluted with DCM (10 mL) and washed with water (3×10 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (188 mg, 99% yield) as a tan foam: MS m/z 723.2 (M+H)+; HPLC >89%, RT=2.09 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=1)[C:44](Cl)=[O:45]>O1CCCC1>[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([C:44]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:45])[CH:47]=[CH:48][N:49]=1
Reactant: O=C(Cl)c1ccnc(CCl)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(CCl)c3)CC4)nc12
Yield: 91.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.09 ml N-ethyldiisopropylamine and 0.017 g 2-chloromethyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.037 g (68%) (2-chloromethyl-pyridin-4-yl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=540 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]>>[C:1]1([CH:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2cccnc2)cc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2cccnc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-(phenyl-3-pyridylmethoxy)piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-(phenyl-3-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:18][NH:19][CH:20]1[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:20]1([N:19]([CH3:18])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:22][CH2:21]1
Reactant: CNC1CC1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL), was added N-methylcyclopropanamine hydrochloride (175 mg, 1.63 mmol) and DIEA (325 mg, 2.52 mmol) with stirring for 2 h at 75° C. in an oil bath. Then the reaction was quenched by the addition of water (10 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as an off-white solid (297 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](O)(=[O:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), terephthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid (21.5 mg, 37.6%). HRMS (ES+) m/z Calcd for C30H26Cl2F2N2O3+H [(M+H): 571.1362; Found: 571.1363.