Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20].CN1CCOCC1.[Br-].[Mg+2].[Br-].[Mg].BrCCBr.[CH:36]([C@@H:39]1[CH2:43][C@@H:42]([C@@H:44]([N:52]=[N+:53]=[N-:54])[CH2:45][C@@H:46]([CH:49]([CH3:51])[CH3:50])[CH:47]=[O:48])[O:41][C:40]1=[O:55])([CH3:38])[CH3:37].[Cl-].[NH4+].[Cl-].[Na+]>O1CCCC1>[CH:36]([C@@H:39]1[CH2:43][C@@H:42]([C@@H:44]([N:52]=[N+:53]=[N-:54])[CH2:45][C@@H:46]([CH:49]([CH3:50])[CH3:51])[CH:47]([OH:48])[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[C:9]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:10]=2)[O:41][C:40]1=[O:55])([CH3:37])[CH3:38]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C=O)C(C)C)N=[N+]=[N-])OC1=O
Reactant: COCCCOc1cc(Br)ccc1OC
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCCOc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OC
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwise at -75° C. to a mixture of 12.1 g of 4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of 4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture is stirred for a further 20 minutes at -75° C. and then, at from -75° C. to -60° C., a suspension of magnesium bromide in tetrahydrofuran (freshly prepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethane in 150 ml of tetrahydrofuran) is added. The reaction mixture is stirred for a further 30 minutes and then, at -75° C. (2, a solution of 8.84 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 75 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 15 minutes at -75° C. and subsequently 70 ml of saturated ammonium chloride solution are added. The reaction mixture is then poured into 180 ml of saturated sodium chloride solution:water (1:1) and extracted with ethyl acetate (2×360 ml). The organic phases are dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained by purifying the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2)=Rf (ethyl acetate/hexane=1:2)=0.16; HPLC Rt =18.53 and 19.49 minutes (diastereoisomeric mixture).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[F:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16]>ClCCl>[CH3:9][C:5]1[C:4]([Cl:10])=[C:3]([OH:11])[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][C:18]([NH:17][C:15](=[O:16])[C:14]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:13]=1[F:12])=[O:19]
Reactant: Cc1cc(N)c(C)c(Cl)c1O
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Into a reaction flask containing 1.9 grams (11.0 mmol) of 2,5-dimethyl-6-chloro-4-aminophenol in 100 milliliters of dichloromethane was added 2.23 grams (12.2 mmol) of 2,6-difluorobenzoyl isocyanate. After stirring at ambient temperature for one hour, the resulting precipitate was filtered to afford 3.44 grams of 1-(2,5-dimethyl-3-chloro-4-hydroxyphenyl)-3-(2,6-difluorobenzoyl)urea having a melting point of 218° C.-219° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Na].C1(S([NH2:11])(=O)=O)C=CC=CC=1.[C:12]1([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:20])[NH2:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: NC(=O)N(c1ccccc1)c1ccccc1

Procedure:
6.5 g of sodium salt of 4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonamide were refluxed for 3 hours with 3.9 g of diphenylcarbamic acid chloride in 60 ml of toluene. The crude N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N',N'-diphenyl-urea obtained was suction-filtered, suspended in dioxane and, after addition of 1 g of acetic acid and 1.6 g of cyclopentyl-amine, the substance was refluxed for 11/2 hours. After acidification with dilute hydrochloric acid the precipitate was separated by suction-filtration and treated with 0.5 %-ammonia. The aqueous alkaline solution was acidified and the crystals were re-crystallized from methanol. N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea was obtained having a melting point of 182° - 184°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Methyl 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylate (5.0 g, 14.03 mmol), ammonium formate (4.42 g, 70.14 mmol) and palladium (5% on activated carbon, 200 mg) in ethanol (80 mL) were stirred and refluxed for 1 hour. The resulting mixture was cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was concentrated by evaporation then treated with dilute aqueous ammonium chloride (100 mL) and extracted with ethyl acetate. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and evaporated to a colourless solid. The solid was triturated with ether, then collected by filtration and air dried to give methyl 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-indole-5-carboxylate (4.59 g, 91%) as a colourless solid.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1(C)[O:12]C(=O)C[C:9](=O)[O:8]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][CH2:2][C:3](=[O:4])[CH2:6][C:7]([O:8][CH3:9])=[O:12]
Reactant: O=C(Cl)CF
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
Fluoroacetyl chloride (7.1 g, 73 mmoles) was added dropwise to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.65 g, 74 mmoles) and pyridine (16.85 ml, 210 mmoles) in methylene chloride (75 ml) keeping the temperature below 10°. After stirring for 16 hours at room temperature the solution was diluted with methylene chloride (100 ml and then washed with 1N hydrochloric acid (200 ml) and water (100 ml). The organic extract was dried (Na2SO4) and the solvent removed in vacuo. The residue was dissolved in methanol (150 ml) and the solution heated at reflux for 2.5 hours. Removal of the solvent followed by distillation at 60°-80° (bath temp)/14 mm Hg gave methyl 4-fluoro-3-oxobutanoate (6.4 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:12]1=[O:29].[OH-].[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:12]2=[O:29])=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(OC)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cn2c(=O)n(CCCCCCCC(=O)O)c3ccccc32)cc1

Procedure:
The product is produced as described in example 22 from 7 g. of 8-[3-(4-methoxybenzyl)-2-oxo-benzimidazolin-1-yl]-caprylic acid methyl ester and 1.4 g. of NaOH. Recrystallization from ether.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[CH2:40][CH:41]([C:47]([O:49][CH3:50])=[O:48])[CH2:42]2.O>ClCCl>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:37][C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH2:40][CH:41]([C:47]([O:49][CH3:50])=[O:48])[CH2:42]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1Cc2cccc(N)c2C1
Reactant: O=C(Cl)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
337 mg (0.821 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl chloride (enantiomer 1; Example 81A) were dissolved in 8 ml of dichloromethane, and 83 mg (0.821 mmol) of triethylamine were added. 157 mg (0.821 mmol) of methyl 4-amino-2,3-dihydro-1H-indene-2-carboxylate (enantiomer 1; Example 89A), dissolved in 2 ml of dichloromethane, were added to the mixture. The mixture was stirred at room temperature overnight. Water was then added, and the reaction solution was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 3:1→1:1). This gave 182 mg (0.32 mmol, 39% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)/[C:9]/2=[CH:12]\[C:13]#[N:14])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[CH:12][CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)/C(=C/C#N)C(c1ccccc1)C2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)C(=CCN)C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of (E)-(6-methoxy-2-phenylindan-1-ylidene)acetonitrile (0.45 g, 1.72 mmol.) in ethanol (30 ml) were added a saturated ammonia/ethanol solution (10 ml) and Raney cobalt (0.3 g). The mixture was stirred for 10 hours at 10 hours at room temperature under hydrogen atmosphere (5 kgf/cm2). The Raney cobalt was filtered off, then the solvent was filtered off under reduced pressure to leave 2-(6-methoxy-2-phenylindan-1-ylidene)ethylamine., which was dissolved in a hydrogen chloride/ethanol solution. The solvent was then distilled off under reduced pressure to afford the titled compound (0.3 g, yield 58%). This compound was used for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI>>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:24])[C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(NC(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Reactant: CN(C)C=O
Solvent: CI
Product: Cc1ncc(N(C)C(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 1.83g (5.80 mmol) (2-methyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 25 ml N,N-dimethylformamide 0.35 g (68.7 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 h. After the addition of 0.65 ml (10.4 mmol) methyl iodide at 0°, the reaction mixture was stirred for 2 hrs. The reaction mixture was poured into 100 ml ice-water and three times extracted with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) to give 1.90 g (99%) methyl-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester as a colorless oil, MS (ISP): 330.4 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([C:28]#[N:29])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][NH:30][C:23]2[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]3[C:28]#[N:29])[CH:26]=[CH:25][N:24]=2)=[CH:34][CH:35]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C#N)C1
Product: N#CC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 139 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+—CN of 388. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (d, 1H) 8.27 (s, 1H) 8.23 (d, 1H) 7.75 (d, 1H) 7.62 (t, 1H) 7.55 (d, 1H) 7.14 (d, 2H) 6.71 (d, 2H) 4.38 (s, 2H) 3.92 (dd, 1H) 3.80 (d, 2H) 3.40 (t, 2H) 3.24 (t, 2H) 2.95 (t, 2H) 2.84 (t, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[N:24]=[C:23]([C:25](=O)[CH3:26])[CH:22]=[N:21][C:20]=2[NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>O1CCCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(Cl)Cl>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([NH:28][C:20]2[C:19]([C:14]3[N:15]=[C:16]([CH3:18])[N:17]=[C:12]([NH2:11])[CH:13]=3)=[N:24][C:23]([CH:25]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH3:26])=[CH:22][N:21]=2)=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(N)nc(C)n2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)nc2-c2cc(N)nc(C)n2)cn1
Temperature: 75 °C
Reaction time: 48 h
Yield: 61.2 %

Procedure:
A mixture of 1-(methylsulfonyl)piperazine (5.61 mg, 0.034 mmol, Apollo), 1-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(6-methoxypyridin-3-ylamino)pyrazin-2-yl)ethanone (6 mg, 0.017 mmol) and tetraisopropoxytitanium (19.41 mg, 0.068 mmol, Aldrich) in tetrahydrofuran (0.5 mL) was stirred at 75° C. for 48 h. The mixture was cooled down to 20° C. and CH2Cl2 (1 mL) was added followed by sodium triacetoxyborohydride (14.48 mg, 0.068 mmol). The reaction mixture was stirred at room temperature for 5 h. Ammonia (1 mL, 30% in water) was added and the mixture was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give 6-(3-(6-methoxypyridin-3-ylamino)-6-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyrazin-2-yl)-2-methylpyrimidin-4-amine (5.2 mg, 10.41 μmol, 61.0% yield). 1H NMR (300 MHz, CDCl3) δ 1.48 (d, J=6.87 Hz, 3H) 2.64 (s, 3H) 2.78 (s, 4H) 3.14-3.40 (m, 4H) 3.81 (q, J=6.72 Hz, 1H) 5.10 (s, 2H) 6.78 (d, J=8.77 Hz, 1H) 7.46 (s, 1H) 8.08 (dd, J=8.84, 2.70 Hz, 1H) 8.20 (s, 1H) 8.43 (d, J=2.63 Hz, 1H). m/z (ESI, +ve ion) 500.1 (M+H)+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[NH:59][C:60](=[O:63])[O:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[NH:59][C:60](=[O:63])[O:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:47][CH:48]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)oc54)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)oc54)c3=O)cc2)CCC1
Yield: 58 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(2,6-dioxo-8-phenyl-3,6-dihydro-2H-chromeno[7,8-d]oxazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (31 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 7.64 (d, J=8.2 Hz, 1H), 7.43-7.38 (m, 5H), 7.37-7.31 (m, 2H), 7.26-7.22 (m, 2H), 7.02 (d, J=8.2 Hz, 1H), 2.58-2.49 (m, 2H), 2.42-2.32 (m, 2H), 2.16-2.05 (m, 1H), 1.82-1.71 (m, 1H). LCMS (Method E): RT=3.08 min, [M+H]+=425.
Reaction SMILES: I[C:2]1[N:3]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4](I)=[C:5]([I:7])[N:6]=1.[Li]C(C)(C)C.O>C1COCC1>[I:7][C:5]1[N:6]=[CH:2][N:3]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: Ic1nc(I)n(CCN2CCCC2)c1I
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Ic1cn(CCN2CCCC2)cn1
Yield: 96 %

Procedure:
To a solution of 2,4,5-triiodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazole (166) (1.75 g, 3.22 mmol) in THF (32 mL) at −78° C. was added tBuLi (7.57 mL, 12.88 mmol) dropwise over a period of an hour. The reaction mixture was poured into water, extracted with EtOAc, and the organic extract was separated, dried over Na2SO4, and concentrated in vacuo to give the title compound 167 (0.9 g, 96% yield) as a dark yellow syrup. 1H NMR (DMSO-d6) δ (ppm): 7.59 (s, 1H), 7.36 (s, 1H), 4.02 (m, 2H), 2.78 (m, 2H), 2.42 (m, 4H), 1.63 (m, 4H). MS (m/z): 292.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:38]([C:35]2[CH:36]=[C:37]3[C:32]([CH:31]=[CH:30][NH:29]3)=[CH:33][CH:34]=2)=[O:39])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3cc[nH]c3c2)cc1
Yield: 49.6 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (1.15 g, 2.9 mmol) and indole-6-carboxylic acid (0.46 g, 2.9 mmol) yielded 780 mg (50%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>CCO>[CH3:15][CH:16]1[CH2:21][N:20]([C:2]2[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Yield: 47.7 %

Procedure:
A solution of Intermediate 39, 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (550 mg, 2.01 mmol), (±) tert-butyl 2-methylpiperazine-1-carboxylate (403 mg, 2.01 mmol), DIPEA (2 mL) in EtOH (6 mL) was stirred at 130° C. for 2 hours in a microwave oven. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE:EtOAc (1:1) as eluting solvents to afford tert-butyl (±)-2-methyl-4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)piperazine-1-carboxylate as yellow solid (377 mg, 48%). MS (ESI) m/z: 394 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:26][CH2:25][C:15]3([S:20][C:19]4[S:21][CH:22]=[CH:23][C:18]=4[C:17](=[O:24])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=[O:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].[ClH:34]>C(O)(=O)C.O>[OH2:2].[ClH:34].[ClH:34].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([S:20][C:19]4[S:21][CH:22]=[CH:23][C:18]=4[C:17](=[O:24])[CH2:16]3)[CH2:25][CH2:26]2)=[CH:6][CH:5]=1.[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([S:20][C:19]4[S:21][CH:22]=[CH:23][C:18]=4[C:17](=[O:24])[CH2:16]3)[CH2:25][CH2:26]2)=[CH:6][CH:5]=1.[ClH:34].[ClH:34]
Reactant: O=C1CC2(CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)Sc2sccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CCN2CCC3(CC2)CC(=O)c2ccsc2S3)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution Of 1.1 g (2.8 mmoles) of 1-(2-(p-nitrophenyl)ethyl)spiro(piperidine-4,6'-(6H)-thieno-[2,3-b]thiopyran)-4'(5'H)-one in 15 mL acetic acid and 20 mL H2O was treated with 15 mL of a solution of 15% TiCl3 in 20% HCl. The dark purple reaction mixture was stirred at room temperature for 45 minutes and poured into 200 mL water. The pH was adjusted to 9 with 2 N NaOH and saturated sodium bicarbonate. The aqueous mixture was extracted several times with ethyl acetate. The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 955 mg. A small amount was treated with excess ethanolic HCl and the hydrochloride was crystallized from ethanol to give 55 mg of product, m.p. 240° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH2:36][C:35](=[CH:38][Sn](C)(C)C)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([N:32]1[CH2:37][CH2:36][C:35](=[CH:38][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N1CCC(=C[Sn](C)(C)C)CC1
Product: CC(C)(C)N1CCC(=Cc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 1-tert-butyl-4-[(trimethylstannyl)methylene]piperidine (INTERMEDIATE ABA3)by a procedure analogous to that described in EXAMPLE HHH1, Step A. Mass spectrum (ESI) 554 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([OH:31])[CH:23]=[N:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29]>CC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([O:31][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:23]=[N:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cnc(OCC(C)C)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of methyl 4-(bromomethyl)benzoate (250 mg, 1.09 mmol) in acetone (20 mL) were added potassium carbonate (302 mg, 2.18 mmol) and 5-chloro-6-isobutoxypyridin-3-ol (Preparation 1, 220 mg, 1.09 mmol) and the reaction heated at reflux overnight. The reaction was allowed to cool to room temperature, the solvent removed under reduced pressure and the resulting yellow solid dissolved in ethyl acetate (30 mL). The solution was transferred to a separating funnel containing water (50 mL), the organic layer separated and the aqueous extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with sodium hydroxide (1.0 M aqueous solution, 30 mL), then brine (50 mL), dried over sodium sulphate and filtered to give the title compound as pale yellow solid (369 mg, 97%).