Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22](Cl)[CH:21]=1)[CH3:19]>CN(C)C=O>[CH2:18]([C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH:21]=1)[CH3:19]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCc1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Yield: 65.9 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(3.5 ml, 28 mmol), triethylamine(3.9 ml, 28 mmol),N,N-dimethylformamide (20 ml) and 6-ethyl-2,4-dichloropyrimidine(4.9 g, 27.7 mmol) prepared in Preparation 2 were used as starting materials, 5.0 g of the titled compound was prepared. (Yield: 66%)
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12](O)=[O:13])=[C:4]([F:31])[CH:3]=1.S(Cl)([Cl:34])=O.Cl>C1CCCCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([Cl:34])=[O:13])=[C:4]([F:31])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)O)c1Cc1ccc(Br)cc1F
Agent: Cl
Solvent: C1CCCCC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)Cl)c1Cc1ccc(Br)cc1F

Procedure:
A mixture of 672 mg (1.32 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxylic acid (from Step C), 2.3 mL of thionyl chloride, and 6 mL of cyclohexane was stirred at reflux under N2 for 4 hours, during which time HCl gas was evolved. The cooled solution was concentrated in vacuo to yield an orange oil, which was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[C:13]3[CH:21]=[C:22]([CH3:24])[CH2:23][C:12]=23)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([Cu])#N.Cl[Si:34]([CH:37]1[C:45]2[C:40](=[C:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=3)[CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH:56]([CH3:58])[CH3:57])([CH3:36])[CH3:35]>CCOCC.CCCCCC.O>[C:52]([C:49]1[CH:50]=[CH:51][C:46]([C:41]2[CH:42]=[CH:43][CH:44]=[C:45]3[C:40]=2[CH:39]=[C:38]([CH:56]([CH3:58])[CH3:57])[CH:37]3[Si:34]([CH:21]2[C:13]3=[CH:14][C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=4)=[C:12]3[CH:23]=[C:22]2[CH3:24])([CH3:36])[CH3:35])=[CH:47][CH:48]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)C1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)Cl
Reactant: CC1=Cc2cc3c(c(-c4ccc(C(C)(C)C)cc4)c2C1)CCCC3
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2c(cc3c(c2-c2ccc(C(C)(C)C)cc2)CCCC3)C1[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solution of 9-(4-tert-butylphenyl)-2-methyl-5,6,7,8-tetrahydro-1H-cyclopenta[b]naphthalene (4d, 2.97 g, 9.38 mmol) in Et2O (50 ml) was cooled to −60° C., and n-BuLi (1.6 M in hexane, 6.04 ml, 9.67 mmol) was added. The resulting mixture was allowed to warm to room temperature, stirred for 3 h, cooled to −60° C., and CuCN (50 mg, 0.55 mmol) was added. After 15 min, solution of chloro-(4-(4-tert-butylphenyl)-2-isopropyl-1H-inden-1-yl)-dimethylsilane (9.67 mmol) in Et2O (24 ml) was added, and resulting mixture was allowed to warm to room temperature and stirred for 16 h. Water (5 ml) and hexane (200 ml) were added, organic phase was separated, dried over MgSO4, passed through silica gel and evaporated. The product was dried in vacuo and used without purification.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([Si:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])([CH3:9])[CH3:8])=[C:5](C)[C:4]([CH3:20])=[C:3]1[CH3:21].[CH2:22]([Li:26])CCC.[CH3:27]CCCC>C(OCC)C.CCCCCC>[CH3:20][C:4]1[C:3]([CH3:21])=[C:2]([CH3:1])[C:6]([Si:7]([N-:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])([CH3:8])[CH3:9])([CH3:22])[CH:5]=1.[Li+:26].[Li+:26].[CH3:20][C:4]1[C:3]([CH3:21])=[C:2]([CH3:1])[C:6]([Si:7]([N-:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])([CH3:8])[CH3:9])([CH3:27])[CH:5]=1
Reactant: COc1ccccc1N[Si](C)(C)C1=C(C)C(C)=C(C)C1C
Reactant: CCCCC
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccccc1[N-][Si](C)(C)C1(C)C=C(C)C(C)=C1C
Product: [Li+]

Procedure:
To 1.4 g (4.6 mmol) ((tetramethylcyclopenta-dienyl)dimethylsilyl)(2-methoxyphenyl)amine in diethyl ether was added dropwise 3.9 mL of 2.5 M butyl lithium (9.8 mmol) in hexane solvent. A white precipitate formed. Pentane was added to the mixture. The slurry was filtered and the solids washed with pentane.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].Br[CH2:21][CH:22]1[CH2:24][N:23]1[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26].[CH3:37][OH:38]>O1CCOCC1>[CH3:37][O:38][C:10](=[O:19])[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]([N:9]1[CH2:24][CH:22]([NH:23][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])[CH2:21][O:8]1)=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1CBr
Reactant: CO
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1C(=O)N1CC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CO1
Temperature: 50 °C
Yield: 74 %

Procedure:
Triethylamine (0.11 ml, 0.1 equiv) was added to a mixture of N-hydroxyphthalimide (1.13 g, 6.9 mmol) and 2-Bromomethyl-1-(2-nitro-benzenesulfonyl)-aziridine (7.6 mmol, 1.1 equiv) (prepared according to Org. Biomol. Chem. 2008, 6, 1902-1904) in anhydrous dioxane (4.5 ml). The reaction mixture was then heated to 50° C. over the weekend. Then methanol (2.5 ml) and triethylamine (1.1 ml, 1 equiv) were added and the reaction mixture was heated at 50° C. for another 4 hours. Volatiles were then removed in vacuo. Flash chromatography eluting with cyclohexane/ethyl actetate (1/1 then 3/7) afforded 2.46 g of the title compound (5.67 mmol, 74%). LCMS (Method E) 1.55 min, M+H 435. 1H-NMR (CDCl3, 400 MHz): 8.21-8.11 (m, 1H), 8.00 (d, 1H), 7.90-7.67 (m, 3H), 7.63-7.56 (m, 1H), 7.55-7.46 (m, 1H), 7.41 (d, 1H), 6.87-6.73 (m, 1H), 4.77-4.67 (m, 1H), 4.22-3.95 (m, 5H), 3.93-3.75 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:14][C:11]1([F:13])[CH2:12][NH:8][CH:9]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2)cc1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (830 mg, 2.23 mmol) and TFA (5 ml) in CH2Cl2 (5 ml) was stirred for 3 h and concntrated in vacuo. The residue was made basic with sat. NaHCO3 and extracted with CHCl3 (2×200 ml). The combined extracts were dried over K2CO3 and concntrated in vacuo to give methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (550 mg, 91%) as a pale yellow solid. 1H-NMR (CDCl3) δ2.19 (m, 1 H), 2.43 (m, 1 H), 3.19-3.41 (m, 2 H), 3.77 (m, 1 H), 3.89 (s, 3 H), 4.00-4.09 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.99 (d, J=9.0 Hz, 2 H); MS (FAB) m/z 272 (M++1); Anal. Calcd. for C13H15F2NO3: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.65; H, 5.67; N, 5.16.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][CH3:10])[CH2:4][C:5]([O:7]C)=O)=O.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH2:9]([C:3]1[CH2:1][N:19]([CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:7])[CH:4]=1)[CH3:10]
Reactant: CCC(C=O)CC(=O)OC
Reactant: NCCc1ccccc1
Solvent: CC(=O)O
Product: CCC1=CC(=O)N(CCc2ccccc2)C1

Procedure:
4-Ethyl-1-phenethyl-1H-pyrrol-2(5H)-one is synthesized by a cyclocondensation between methyl 3-formylpentanoate and 2-phenylethylamine in glacial acetic acid at 70° C. according to a procedure of R. Fisher (DE 4127111, 1992)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]>CN(C)C=O.C(OCC)C>[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
313 mg of sodium azide was added to 1.63 g of (1R, 2R, 3S, 5R, 6R)-2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 16.3 mL of N,N-dimethylformamide, and the mixture was stirred for 1 hour at room temperature, and then for 20 hours at 35° C. 104 mg of sodium azide was further added thereto, and the mixture was stirred for 18 hours at 35° C. After being diluted with 50 mL of diethyl ether, the mixture was washed twice with water and then with a saturated aqueous solution of sodium chloride. The organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 775 mg of (1R, 2R, 3R, 5R, 6R)-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[O:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+].O>C(Cl)(Cl)(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:39][N:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1ccc(CNC(=O)C(F)(F)F)cc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Cn2nnnc2C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-bromo-4-(trifluoroacetamido)methylanisole (5 g, 16 mmol) was suspended in carbon tetrachloride (125 ml). Triphenylphosphine (8 g, 30.5 mmol) was added and the mixture stirred at 80° C. for 16 hours. Solvent was removed in vacuo and the residue poured into hexane (100 ml) and stirred at reflux for 30 minutes. The suspension was filtered through Hyflo™ and the filtrate concentrated to an oil. The oil in N,N-dimethylformamide (15 ml) was added to a stirred solution of sodium azide (1 g, 15 mmol) in N,N-dimethylformamide at 0° C. The mixture was stirred at ambient temperature for 2 hours then poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (3×200 ml), dried over sodium sulfate and the solvent was removed in vacuo leaving a yellow oil. Chromatography on silica gel, eluting with 10-50% ethyl acetate in hexane, gave the title compound as a yellow oil (230 mg, 5%, δH (360MHz, CDCl3) 4.90 (1H, d, J 7.6Hz, NCHAHBAr), 4.95 (1H, d, J 7.6 Hz, NCHAHBAr), 7.00 (1H, d, J 8.6Hz, 6-H), 7.52 (1H, dd, J 2.2, 8.5Hz, 5-H), 7.80 (1H, d, 2.2Hz, 3-H); m/z (ES+) 337, 339 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OC)=O.[OH-].[Li+]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Yield: 66.2 %

Procedure:
Methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (9.2 g, 33.54 mmol) [prepared as in Example 21, Step (a)], was dissolved in methanol (100 ml) and an aqueous solution of lithium hydroxide (3.52 g in 50 ml of water) was added. After 1.5 h the reaction mixture was concentrated to dryness in vacuo and the resulting residue was dissolved in water (100 ml). The solution was acidified to pH 1 with 6 M HCl and then extracted with ethyl acetate. The organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane-ethyl acetate, 9:1) to give 4-(1-methylpyrrol-2-ylmethyl)nitrobenzene (4.8 g, 66%) as a yellow oil. ##STR62##
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)C>[CH3:16][O:15][C:10]1[N:9]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:14][C:13]2=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2nc(OC)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(C(=O)O)cc2n1
Temperature: 70 °C

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (Preparation 35, 128 mg, 0.58 mmol) in ethanol (10 mL, absolute) was added aqueous sodium hydroxide (0.35 mL, 2M) and the mixture heated to 70° C. for 3 h then cooled to rt. The solution was adjusted to pH 4 by addition of glacial acetic acid and the solvents removed under reduced pressure. Ethyl acetate (20 mL) was added to the resulting oil and the mixture sonicated until a fine suspension formed. The mother liquor was decanted and the remaining solid was washed with ethyl acetate and dried in vacuo to give the title compound as a pale orange powder. δH (CD3OD): 3.92 (3H, s), 6.63 (1H, d), 6.94 (1H, s), 7.72 (1H, d).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](OS(C(F)(F)F)(=O)=O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([CH:10]=[CH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: PCCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition was complete the reaction flask was purged with argon. The mixture was stirred at 80–85° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/ether (95/5). After removal of the solvent under vacuum, the solid was triturated with pentane/ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (63 mg, 49%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(Cl)nc2)cc1F
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(N3CCCC3)nc2)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
3-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (15 mg, 0.413 mmol) was added to pyrrolidine (0.5 ml) and the mixture was stirred for 12 hrs at 90° C. The resulting residue was dissolved in EtOAc, then washed three times with H2O, and neutralized with 1N HCl to pH 5˜7. The resulting solution was washed with brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2) to yield the title compound (4 mg, 24%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1.[I:19]I.O>C1COCC1>[Cl:9][C:10]1[C:11]2[S:18][C:17]([I:19])=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Clc1ncnc2ccsc12
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ncnc2cc(I)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of LDA (1.8M, 20.6 mL, 37.1 mmol) in THF (65 mL) at −78° C. was added 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) in THF (50 mL) dropwise over 1 hour. After stirring for 20 minutes, I2 (12.7 g, 50 mmol) in THF (40 mL) was added to the mixture at −78° C. dropwise. The mixture was stirred at the same temperature for 20 minutes and then warmed up to room temperature for 2 hours. The mixture was poured into water (100 mL) and stirred for 30 minutes. The solid was filtered and washed with water and Hexane-Hexanes/DCM (50:1) to afford the product 4-Chloro-6-iodothieno[3,2-d]pyrimidine (6.86 g, 75%). 1H NMR (DMSO, 400 Hz) δ 8.97 (s, 1H), 8.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)[C:9]2[C:10]3[N:17]=[N:16][N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[C:5](=[O:34])[N:4]2[C:35]3([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[NH:36][C:37](=[O:38])[C:3]=12.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]3[N:17]=[N:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C:5](=[O:34])[N:4]2[C:35]3([NH:36][C:37](=[O:38])[C:3]=12)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)c2n(c1=O)C1(CCCCC1)NC2=O)c1ncnc2c1nnn2COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ncnc3[nH]nnc13)c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-chloro-6-[2-trimethylsilylethoxymethyl-[3-(2-trimethylsilylethoxymethyl)triazolo[4,5-d]pyrimidin-7-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (7, 0.3 g, 0.46 mmol) in dichloromethane (15 mL), trifluoroacetic acid (5 mL, 4.63 mmol) was added drop wise at 0° C. The reaction mass was stirred for overnight at room temperature. After completion, reaction mass was concentrated and co-evaporated with diethyl ether. The crude was then dissolved in tetrahydrofuran/ethanol solution and potassium hydroxide (5 mL, 0.46 mmol) solution (3 M in water) was added and stirred the mixture for 16 h. After completion of the reaction the aqueous layer was separated and organic layer was dried over sodium sulfate, filtered and concentrated to get crude. The crude was washed with methanol and n-pentane and dried to afford 8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (Cpd. No. 146) as brown solid. Yield: 70 mg, 39%; MS (ESI) m/z 387.39 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.45 (brs, 1H), 9.29 (s, 1H), 8.88 (s, 1H), 7.77 (s, 1H), 2.94 (t, J=2.32, 2H), 1.79-1.76 (m, 2H), 1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O.C[O-].[Na+].Cl>CO.O>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27](/[CH:25]=[CH:16]/[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:17])=[CH:28][CH:29]=1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccn1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
A mixture of the trifluoroacetic acid salt of 1-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-ethanone (273 mg, 757 μmol) in methanol (3.78 mL) at 25° C. was treated with methyl 4-formylbenzoate (124 mg, 757 μmol) and sodium methoxide in methanol (4.37M, 520 μL, 2.27 mmol). The reaction was stirred at 25° C. for 3 d. At this time, the reaction was diluted with water (50 mL), neutralized with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-{(E)-3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propenyl}-benzoic acid methyl ester (287.3 mg, 96.6%) as an orange solid. The material was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CC(O)=O.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C@@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-amino-2-phenylacetate (1.0 g, 6.06 mmol) in anhydrous MeOH (20 mL) was added 4-methoxy benzaldehyde (0.82 g, 6.06 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., NaBH4 (0.69 g, 12.12 mmol) was added and the contents were stirred at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), MeOH was removed under reduced pressure and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and (S)-methyl 2-((4-methoxybenzyl)amino)-2-phenylacetate thus obtained was taken directly for step 2. MS: [M+H]+ m/z 286.