Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Br:12][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:11])=[CH:6][C:7]=1[OH:10]
Reactant: [Br-]
Reactant: CC(C)c1ccc(O)cc1O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1cc(Br)c(O)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
4-isopropyl-benzene-1,3-diol (IMO-a: 9.13 g, 60 mmol) and benzyltrimethyl ammoniumtribromide (24.6 g, 63 mmol) and methylene chloride 250 mL were placed in a 500 mL three-neck flask and were stirred at room temperature for 4 hours. After the reaction was finished, the reaction mixture was washed twice with saturated ammonium chloride and once with saturated sodium chloride, and then dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM1-a: 10.5 g, 76%).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[CH2:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]>CCOCC>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[C:5]([N:11]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:9][CH3:10])=[O:6]
Reactant: O=C(Cl)/C=C/CCl
Reactant: CCCNCCC
Solvent: CCOCC
Product: CCCN(CCC)C(=O)/C=C/CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chlorocrotonyl chloride (1.02 g, 7.35 mmol) in ether (10 ml) is combined with dipropylamine (1.64 g, 16.17 mmol) in ether (5 ml) at -15° C. in a flame dried flask. The reaction is warmed to ambient temperature, stirred for 1 to 2 hours, quenched with water (30 ml), extracted with ethyl acetate (2×30 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.53, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give 4-chloro-N,N-dipropylcrotonamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (5 ml) and sodium hydride (0.06 g, 2.55 mmol) at ambient temperature followed by the addition of 4-chloro-N,N-dipropylcrotonamide (0.23 g, 1.13 mmol). The reaction is stirred for 2 to 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.40, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 139-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Cl.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccn3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 75.4 mg (0.46 mmol) of 2-picolyl chloride hydrochloride are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 104 mg (81% of theory) of product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=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>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1cn(N)c2cnccc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2ccncc21
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A mixture of 3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (224 mg, 1.53 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (354 mg, 1.53 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol) in DMF (8 mL) is stirred at 1500 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (55 mg). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 8.24 (s, 1H), 8.20 (d, 1H), 7.68 (d, 1H), 7.55 (q, 1H), 7.47 (s, 1H), 7.29 (t, 1H), 2.84(s, 3H), 2.39 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH:19]=[CH:20]N(C)C)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc(Cl)c3)ccnc12
Yield: 43.7 %

Procedure:
A mixture of 13.9 g of 4-amino-5-imidazolecarboxamide hydrochloride, 24.0 g of 3'-chloro-3-dimethylaminoacrylophenone (U.S. Pat. No. 4,209,621, Ex. 50) and 200 ml glacial acetic acid was heated at reflux for 5 hours. The liquid was evaporated in vacuo to give a yellow solid. The excess acid was neutralized with saturated sodium bicarbonate solution and this mixture was filtered and the solid was washed with water and then was dried. Recrystallization from ethanol-methanol gave 10.2 g of the desired product as yellow crystals, mp 252°-254° C.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1>CN(C=O)C>[C@H:2]([O:5][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@@H](C)O
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C)Oc1nn2c(N)nnc2c(C)c1C

Procedure:
(R)-Butan-2-ol (0.5 ml) was deprotonated analogously to W1.056 with sodium hydride (85 mg) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 100 mg), suspended in DMF (2 ml), and worked up. 75 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[C@@H:29]([NH2:32])[CH2:30][CH3:31])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20](=[O:22])[NH:32][C@H:29]([C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:33])[CH2:30][CH3:31])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccc(O)cc1)OCc1ccccc1
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine (Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester (1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30 ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel DCM:Acetone—60:40). The product was crystallized from toluene (20 ml) giving 1.85 g of the desired product as a white solid. NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m).
Reaction SMILES: C(O[C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=1)CCC.[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>CCOCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]3[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=[C:6]([OH:10])[C:24]=3[C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: CCCCOc1cnc(C(=O)OCC)o1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
In a heavy walled round bottom flask with screw top were combined ethyl 5-butoxy-1,3-oxazole-2-carboxylate (2.53 g, 11.88 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (1.22 g, 5.94 mmol; see Example 1, Step 3) and trifluoroacetic acid (0.46 mL, 5.94 mmol). The vessel was sealed and placed in an oil bath heated to 130° C. The reaction mixture was stirred for 3 days. The dark brown reaction mixture was cooled and a crystalline precipitate formed. The mixture was diluted with ether and the solids collected by filtration and washed with ether to give the product as tan shiny plates. Further product can be obtained by evaporating the mother liquor, adding more trifluoroacetic acid and re-heating the mixture.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[NH2:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[N+:1]([CH:4]=[C:5]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Reactant: NCCSCc1ncccc1Br
Product: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCSCc1ncccc1Br

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with 2-[(2-aminoethyl)thiomethyl]-3-bromopyridine according to the process of Example 1(a)(ii) yields the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)C(OC(C)(C)C)=O)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Br)cc(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Yield: 194.7 %

Procedure:
2-(3-Benzyloxy-5-bromophenyl)malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) was dissolved in glacial AcOH (50 mL) and heated to reflux for 12 h. The AcOH was removed under reduced pressure. The residue was poured into Na2CO3 solution (sat aq) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester as a yellow liquid yield 6.8 g (97%). 1H NMR (CDCl3) δ 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[K].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>CS(C)=O>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:2]2[C:7]([O:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:3]=2)(=[O:37])=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 93 %

Procedure:
10.7 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidin-2-yl]-morpholine and 21.6g of p-t-butyl-benzene sulphonamide potassium in 150 ml of dry dimethyl sulphoxide were heated to 120° C. under argon for 16 hours. Thereafter, the dimethylsulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1N hydrochloric acid and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from dichloromethane-ethanol. There were obtained 14.7 g 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p 154° C., MS: M=546.
Reaction SMILES: N[C:2]1[CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=2[S:7][C:8]=1[C:9]#[N:10].Cl.[Cl-].[NH4+].C([OH:22])C>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:5]2[O:4][CH2:3][C:2](=[O:22])[CH:8]([C:9]#[N:10])[S:7][C:6]=2[CH:11]=1
Reactant: CCO
Reactant: COc1ccc2c(c1)SC(C#N)=C(N)CO2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2c(c1)SC(C#N)C(=O)CO2
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In 60 ml of ethanol is suspended 6.0 g of 3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile, and 18 ml of concentrated hydrochloric acid is added to the suspension, followed by stirring at 80 to 90° C. for 30 minutes. After the reaction mixture is cooled, ammonium chloride, which separates out, is filtered off, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give colorless prisms of 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 5.1 g, m.p. of 132°-133° C.
Reaction SMILES: C([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11](O[C:14](=[O:15])[CH:5]21)=[O:12])C=C.[C:16]1([CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[CH:17]=1>C1(C)C(C)=CC=CC=1>[C:16]1([CH2:24][N:25]2[C:11](=[O:12])[CH:6]3[CH:5]([C:4]4([CH2:11][CH:6]=[CH2:7])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:11](=[O:12])[CH:6]3[CH:5]([C:4]4([CH2:9][CH:4]=[CH2:5])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])[CH:17]=1
Reactant: NCc1cccc(CN)c1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Solvent: Cc1ccccc1C
Product: C=CCC12C=CC(C1)C1C(=O)N(Cc3cccc(CN4C(=O)C5C6C=CC(CC=C)(C6)C5C4=O)c3)C(=O)C12
Temperature: 200 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a 1000 ml flask replaced with nitrogen 257.4 g (1.26 mol) of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 300 ml of xylene were charged. To the mixture was added 81.4 g (0.60 mol) of m-xylylenediamine over 1.5 hours with heating and stirring while refluxing xylene. The reaction was continued for 3 hours while separating and removing water produced by the reaction by a water separator, and then the solvent, xylene, was removed by distillation. Thereafter, the content of the flask was treated with heat at 200° C. under reduced pressure of 1 Torr for 1 hour while stirring, thus obtaining 301.8 g (yield:99%) of the target N,N'-m-xylylene-bis(allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboximide), of which the chemical structure is shown by the following formula [6]. This compound is hereinafter abbreviated to BANI-mX. ##STR10##
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:54]6[CH2:55][CH2:56][CH2:57][N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:52][CH2:53]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
236(a) To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-5-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (130 mg, 0.19 mmol) in DCM (2 mL) was added tert-butyl 1-homopiperazine carboxylate (0.04 mL, 0.21 mmol), AcOH (0.01 mL, 0.23 mmol) followed by NaBH(OAc)3 (57.2 mg, 0.27 mmol). The reaction mixture was stirred at RT overnight. LC-MS showed minor amount of starting material remaining so 0.5 equiv. of tert-butyl 1-homopiperazine carboxylate and 1 equiv of NaBH(OAc)3 were added to the mixture. It was stirred for an additional 4 h. LC-MS showed no more starting material. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 0 to 10% MeOH (2M NH3 in MeOH) in DCM. The product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl 4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}hexahydro-1H-1,4-diazepine-1-carboxylate (131 mg, 79%). LC-MS m/z 859 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(O)C.O>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(OCCCCl)ccc2N1
Solvent: CC(C)O
Solvent: O
Product: O=C1CCc2cc(OCCCN3CCCC3)ccc2N1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 6-(3-chloropropoxy)-3,4-dihydroquinolin-2(1H)-one prepared in Example 10-(1) (10 g) and pyrrolidine (15 g) in 2-propanol (15 mL) was stirred at 90° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1), and the resulting solid was subjected to recrystallization from ethyl acetate to give the titled compound (7.5 g, 65%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24]([C:26]3[S:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)=[O:25])[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@H:15]([NH:23][C:24]([C:26]3[S:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][CH:30]=3)=[O:25])[C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a stirring solution of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate INT-17 (15.7 g, 28.8 mmol) in DCM (30 mL) was treated with TFA (30.0 g, 263.1 mmol). The reaction mixture was stirred at room temperature for 18 hours to complete. The solvent was evaporated and then co-evaporated with toluene (3×20 mL) to remove trace TFA. The compound was dried under vacuum overnight to afford 13.7 g (97%) of (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid as powder. LCMS-ESI (m/z) calculated for C22H22BrN3O3S: 487.1. found 488.1 [M+H]+, tR=2.55 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.05 (d, J=5.0 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.1 Hz, 2H), 7.62 (d, J=3.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.92 (d, J=3.8 Hz, 2H), 4.64 (td, J=10.5, 4.5 Hz, 1H), 3.26 (dd, J=13.8, 4.4 Hz, 1H), 3.11 (dd, J=13.7, 10.7 Hz, 1H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][CH2:25][CH2:26]Cl)=[O:23])=[CH:18][CH:17]=1)[CH3:15]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:26][CH2:25][CH2:24][C:22](=[O:23])[C:19]2[CH:18]=[CH:17][C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=2)=[N:5][N:4]=[N:3]1
Reactant: CCc1ccc(C(=O)CCCCl)cc1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(C(=O)CCCSc2nnnn2C)cc1
Reaction time: 2 h
Yield: 49 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 4-ethylphenyl ketone (3.2 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by cilica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole (yield 49%) as colorless needles, m.p. 68°-69° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]3[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:32])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1)[CH3:34]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C25H27ClN6O2, 479.0