Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(CCc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 34.8 %

Procedure:
To a solution (10 ml) of 3,4-bis(benzyloxy)-6-[(E)-2-(4-chlorophenyl)vinyl]pyridazine (200 mg) in dichloromethane were added triethylamine (200 μL) and 2,4,6-triisopropylbenzenesulfonylhydrazide (700 mg), and the mixture was stirred at room temperature for 40 hr. Triethylamine (200 μL) and 2,4,6-triisopropylbenzenesulfonylhydrazide (700 mg) were added, and the mixture was further stirred at room temperature for 24 hr. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3,4-bis(benzyloxy)-6-[2-(4-chlorophenyl)ethyl]pyridazine (70 mg).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[N:10]=1>CN(C=O)C.CCOC(C)=O>[CH:2]([O:5][C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:20]([F:21])([F:23])[F:22])[N:10]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)Oc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
2-Butanol (70.1 mg, 0.945 mmol) and sodium hydride (70 mg, 1.8 mmol) were added in DMF. The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0.266 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=1/1) to give the title product (52 mg).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([Br:60])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([Br:60])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Yield: 78 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (20 mg, 0.035 mmol) was reacted to give the title compound (13 mg, 78%). LCMS (Method E): RT=3.93 min, [M+H]+=476/478. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=8.7 Hz, 1H), 7.42-7.26 (m, 8H), 7.09 (d, J=7.8 Hz, 2H), 3.99 (s, 3H), 2.56 (bs, 2H), 2.37-2.25 (m, 2H), 2.10-1.87 (m, 3H), 1.66-1.53 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23]([OH:25])=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.O[NH:51][C:52](=[NH:54])[CH3:53]>CN(C=O)C.ClCCl>[Br:1][C:2]1[C:3]([CH2:22][C:23]2[O:25][N:54]=[C:52]([CH3:53])[N:51]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: CC(=N)NO
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(Cc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A vial was charged with 2-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)acetic acid (0.0863 g, 0.2063 mmol) in 5 ml of DMF and DIEA (0.03953 ml, 0.2269 mmol), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.060 g, 0.227 mmol) were added consecutively. The mixture was stirred for 30 minutes and N-hydroxyacetamidine (0.0168 g, 0.227 mmol) was added. The mixture was heated at 100° C. overnight. The mixture was then cooled, diluted with dichloromethane, and washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate/hexane to provide N-(5-bromo-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)pyridin-2-yl)-4-phenethylthiazol-2-amine (11 mg, 11.58% yield) as a yellow solid. 1H NMR (CDCl3) δ 2.37 (s, 3H), 2.94-2.98 (m, 4H), 4.25 (s, 2H), 6.39 (s, 1H), 6.89 (s, 1H), 7.14-7.26 (m, 5H), 8.45 (s, 1H).
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].Cl>O>[CH2:21]([NH:25][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCNC1=CCC(C)n2c1ncc(C(=O)O)c2=O
Reaction time: 72 h
Yield: 31 %

Procedure:
14.35 g. (0.05 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 100 ml. of anhydrous chloroform. To the solution 15.0 ml. (0.15 mole) of n-butyl amine are added. The reaction mixture is allowed to stand for 3 days at room temperature, whereafter 70 ml. of water are added. The pH-value of the aqueous layer is adjusted under vigorous stirring to 2 by adding 10% by W/V hydrochloric acid solution. The organic layer is separated and the aqueous layer is shaken out with 2×50 ml. of chloroform. The combined organic layers are dried above calcinated sodium sulfate, finally the solvent is distilled off at reduced pressure. The residue is crystallized from methanol. 4.3 g. (31%) of 9-(n-butyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 13.5°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([N:1]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:11])=[N:7][C:6]=1[CH3:8]
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1nc(N)nc(C)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.00 g (9.89 mmol) of 2-amino-5-bromo-4,6-dimethylpyrimidine in 16 mL of anhydrous toluene was added 1.36 mL (11.5 mmol) of 2,5-hexanedione followed by 96 mg (0.50 mmol) of p-toluenesulfonic acid. The reaction mixture was heated and stirred at reflux for 12 h. The reaction mixture was poured into 150 mL of water and then extracted with 200 mL of ethyl acetate. The organic solution was washed with 150 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as light yellow crystals: yield 2.23 g (81%); mp 64-65° C.; silica gel TLC Rf 0.65 (6:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.67 (s, 6H) and 5.89 (s, 2H); 13C NMR (CDCl3) δ 14.5, 14.5, 24.9, 24.9, 108.7, 108.7, 118.6, 129.5, 129.5, 155.3, 155.3 and 166.9; mass spectrum (APCI), m/z 280.0458 (M+H)+ (C12H15N3Br requires 280.0449).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:11][CH:10]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Cc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Oc2ccc(OCCCCCCCCCCCO)cc2)cc1
Temperature: 80 °C

Procedure:
9.3 g (0.042 mol) of 4-hydroxyphenyl 4-methylbenzoate are dissolved in 80 ml of absolute dimethylformamide (DMF), and 6.8 g (0.05 mol) of potassium carbonate are added. 11.3 g (0.045 mol) of 11-bromo-1-undecanol are then added, and the mixture is heated at 80° C. for 24 hours. During this time, a further 0.6 g of potassium carbonate is added. For work-up, the reaction mixture is poured into ice water and acidified by means of dilute hydrochloric acid, and the precipitate is filtered off with suction. The residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate and freed from solvent under reduced pressure. The product is purified by column chromatography (silica gel, eluent toluene/ethyl acetate 5:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[C:5]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=3)=[N:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 85.6 %

Procedure:
10.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine was dissolved in 50 ml 1-methyl-2-pyrrolidone, then 43.32 g of 4-hydroxypiperidine and 10 ml diisopropylethylamine were added thereto, and the mixture was heated at 170° C. for 8 hr. After cooling, ethyl acetate was added thereto, and the mixture was washed 3 times with water and once with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to give 10.1 g of 1-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine as yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:42].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)C>[ClH:42].[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:17][CH2:16][CH2:15][NH:14][C:13](=[O:33])[C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:24][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.42 h

Procedure:
To a solution of (S)-{1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester (1.4 g, 3.8 mmol, Example 6) in CH2Cl2 (15 mL) was added trifluoroacetic acid (5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 60 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was then dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 1.2 g (99.6%) of crude product. A portion of the crude product, a HCl salt, was converted back to the free amine by treatment with saturated aqueous NaHCO3 solution; the crude free amine was further purified by flash chromatography (straight EtOAc, then 10% MeOH in HCCl3) and converted into HCl salt as described above. Pure titled compound was obtained as a white foam (0.3 g); mp 65-80° C. APCI-MS m/z 375.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:25])[N:9]=[C:10]([C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([O:21][CH3:22])=[C:15]([S:17](O)(=[O:19])=[O:18])[CH:16]=3)[C:5]2=[CH:4][N:3]=1.S(Cl)([Cl:28])=O>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:25])[N:9]=[C:10]([C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([O:21][CH3:22])=[C:15]([S:17]([Cl:28])(=[O:19])=[O:18])[CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: COc1cc(OC)c(S(=O)(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Reactant: O=S(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-benzenesulfonic acid (Example 113) (629 mg, 1.72 mmol) is suspended in thionyl chloride (25 ml), the reaction mixture is heated to 120° C. for 5 hours then stood overnight at room temperature. The resulting precipitate is removed by filtration, the filtrate is concentrated in vacuo and the resulting residue is azeotroped with toluene to afford the title compound as a solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(O)=[O:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:14][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:1][OH:2])=[CH:13][C:9]=1[CH:10]=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)c(C(=O)O)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(CCO)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese (IV) dioxide (1.00 g) was added to a solution of 2-(4-chloro-3-(hydroxymethyl)phenyl)ethanol [Aromatic Intermediate 7, step c] (0.200 g) in DCM (5 mL), and the resulting suspension was stirred at room temperature overnight. The mixture was then filtered through Celite, washing the residue well with DCM. The filtrate and washings were concentrated in vacuo to afford the subtitled compound as a colourless oil. Yield 0.197 g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19]Br)(=[O:3])[CH3:2].[C:21](=[S:24])([O-:23])[CH3:22].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19][S:24][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(CSC(C)=O)n(C(C)=O)c2ccccc12
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (I-4A, 640 mg, 1.9 mmol) in acetone (10 ml) was added potassium ethanethioate (1.3 g, 11.2 mmol). The solution was heated at reflux for 1 hour. The solution was cooled and then diluted with EtOAc (50 ml) and washed with NaHCO3 (aq) (2×25 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (10-30 EtOAc/hexanes) to get 533 mg (1.6 mmol, 84%) product. MS (m/z) 334 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[NH2:13][C:12]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: CCOC(=O)c1cnc(N)c(N)c1
Yield: 89.7 %

Procedure:
To a solution (150 ml) of ethyl 6-amino-5-nitronicotinate (5.0 g) and 6N aqueous calcium chloride solution (50 ml) in ethanol was added zinc powder (77 g) with heating under reflux. The reaction mixture was heated under reflux for 2 hr, and the zinc powder was removed by filtration. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give the title compound (3.85 g, yield 89%) as pale-brown crystals. 1H NMR (DMSO-d6) δ: 1.37 (3H, t, J=7.0 Hz), 4.38 (2H, q, J=7.1 Hz), 4.95 (2H, s), 6.28 (2H, s), 7.15 (1H, d, J=2.1 Hz), 7.94 (1H, d, J=2.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (29.5 g, 0.1 mol) and triethylamine (20.2 g, 0.2 mol) were dissolved in toluene (147.7 g) and then cooled to 0° C. To the mixture was added dropwise methanesulfonyl chloride (13.8 g, 0.12 mol) at 0° C. over 40 min. The mixture was further kept at 0° C. for 25 min. The reaction mass was washed with 5% hydrochloric acid (72.9 g) and 5% aqueous sodium bicarbonate (84.0 g), dried over magnesium sulfate, and then concentrated under reduced pressure with a rotary evaporator. After crystallization from the concentrate mass with n-hexane, precipitated crystals were collected by filtration and dried to give N-Boc-O-methanesulfonyl-L-tyrosine methyl ester 6 (36.0 g, yield 96%) as white crystals.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:9][C:10]([C:12]1[N:16]2[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=3)([CH3:29])[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C@@:17]2([CH3:29])[N:16]3[C:12]([C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:38])=[O:5])=[O:11])=[CH:13][N:14]=[C:15]3[N:19]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)[C:18]2=[O:28])=[CH:36][CH:35]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester (3.0 g, 4.8 mmol) in CH2Cl2 (20 mL) was added TFA (1 mL). The reaction was allowed to stir for 30 minutes and then the solvent removed in vacuo to afford 2.2 g of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid as a white solid, m/z 442.2 [M+]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[O:47][C:48]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:49]=2[CH:50]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]1[C:48]2[O:47][C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([CH2:13][O:12][C:11]5[CH:14]=[C:15]6[C:19](=[CH:20][C:10]4=5)[CH2:18][CH2:17][O:16]6)[C:2]3=[O:21])=[CH:50][C:49]=2[CH:51]=[CH:52][CH:53]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: Fc1cccc2cc(CBr)oc12
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cc3cccc(F)c3o2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-7-fluorobenzofuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ7.31-7.24 (m, 2H), 7.22-6.96 (m, 5H), 6.77-6.74 (m, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 5.31-5.23 (m, 1H), 5.03-4.95 (m, 2H), 4.75-4.68 (m, 1H), 4.59-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 161.8, 161.2, 152.8, 147.8 (d, JC-F=249.7 Hz), 141.9 (d, JC-F=11.3 Hz), 141.4, 132.7, 131.6 (d, JC-F=3.2 Hz), 128.8, 123.9, 123.7, 123.6, 120.1 (d, JC-F=5.2 Hz), 119.0, 116.6 (d, JC-F=3.9 Hz), 110.8 (d, JC-F=16.1 Hz), 109.0, 105.6 (d, JC-F=2.1 Hz), 93.2, 80.4, 72.4, 57.7, 37.5, 29.0; MS (ES+) m/z 428.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:34])=[CH:17][N:16]=1>>[Cl:34][C:18]1[C:19]([NH:21][C:22]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)CCNC(=O)C2
Reactant: CNC(=O)c1cc(C)cc(C)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(C)cc(C)c1Nc1nc(Nc2ccc3c(c2)CCNC(=O)C3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 7-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,5,N-trimethyl-benzamide were converted to 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-3,5,N-trimethyl-benzamide. TFA salt: 1H NMR (300 MHz, 5% CD3OD in CDCl3) δ 8.00 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 6.94 (s, 2H), 3.58 (bs, 2H), 3.12 (s, 2H), 3.06 (t, 2H), 2.90 (s, 3H), 2.44 (s, 3H), 2.21 (s, 3H); MS (m/e) 465 (M+1).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[NH:13][C:12]4=[N:31][NH:32][CH:33]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12>FC(F)(F)C(O)=O>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)[NH:13][C:12]4=[N:31][NH:32][CH:33]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(C2=C(C#N)C(c3cccc4nonc34)c3c[nH]nc3N2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Yield: 62.9 %

Procedure:
4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.7 g) was added to trifluoroacetic acid (20 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.83 g) as yellow crystals.