Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 mg of 3-(S)-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 1.5 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature under nitrogen overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford 51 mg of the title compound as free base. Yield 84%, Treatment with 1 equiv. of 1M HCl in dioxane gave the HCl salt. ES MS(+) m/z 453
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:13]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[S:24][CH:25]=[C:26]([C:28]#[C:29][Si](C)(C)C)[N:27]=3)[CH2:19][CH2:18]2)=[O:16])[N:12]=[C:11]([C:34]([F:37])([F:36])[F:35])[CH:10]=1.Br[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C:29]#[C:28][C:26]2[N:27]=[C:23]([CH:20]3[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:13]4[C:9]([CH3:8])=[CH:10][C:11]([C:34]([F:36])([F:35])[F:37])=[N:12]4)[CH2:18][CH2:19]3)[S:24][CH:25]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C#C[Si](C)(C)C)cs2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C#Cc2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)cc1
Temperature: 85 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (25 mg), copper(I) iodide (8 mg) and triethylamine (53 mg) are added to a solution of 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(trimethylsilyl)ethynyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (I-98, 200 mg) and 1-bromo-4-methoxybenzene (91 mg) in degassed N,N-dimethylformamide (2 ml). After warming to 85° C., tetra-n-butylammonium fluoride (1M in THF, 0.48 ml) is added dropwise. The reaction mixture is then diluted with water and extracted with ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives 1-(4-{4-[(4-methoxyphenyl)ethynyl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (84 mg).
Reaction SMILES: [CH2:1]([Si:3]([CH2:9]C)([CH2:7]C)[C:4]#[C:5][CH3:6])C.[Li]CCCC.CCCCCC.Br[CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>C1COCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]#[C:24][CH2:23][CH2:6][C:5]#[C:4][Si:3]([CH3:1])([CH3:7])[CH3:9])=[CH:27][CH:28]=1
Reactant: CC#C[Si](CC)(CC)CC
Reactant: Fc1ccc(C#CCBr)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of triethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stirring 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1 h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])O[C:8](=[O:9])[C:7]=12.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=1>CN1CCCC1=O>[C:18]1([N:23]2[C:8](=[O:9])[C:7]3=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]3[C:11]2=[O:12])[CH:19]=[CH:20][C:21]([N:22]2[C:11](=[O:12])[C:6]3=[C:5]([Cl:13])[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]3[C:8]2=[O:9])=[CH:16][CH:17]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CN1CCCC1=O
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccc(N2C(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C2=O)cc1
Temperature: 200 °C
Yield: 52.9 %

Procedure:
In a 5 liter round-bottom flask equipped with a heating mantle, a stirrer, a thermometer, a condenser and a nitrogen purge, there were reacted 457.5 grams (1.6 mole) of tetrachlorophthalic anhydride and 86.5 gms (0.8 mole) of p-phenylenediamine in 2000 ml. of N-methyl-2-pyrrolidone (NMP), the reactants going into solution as the mixture was heated with stirring. At 170° C., precipitation began and continued as the temperature was raised to 200° C. where it was maintained for 90 minutes. The reaction mixture was then allowed to cool overnight. The cooled mixture was filtered and the yellow precipitate was recovered. The precipitate was washed with NMP, thoroughly stirred in acetone, filtered and washed with more acetone. The product was dried under vacuum at 150° C. for 16 hours. 272.7 gms (yield=53%) of an ivory-yellow material was obtained, having a melting point in excess of 500° C., with some sublimation at about 425° C. The IR spectrum had the characteristics of an imide with the absorption bands at 1710s and 1770w cm-1. The product was insoluble in water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](I)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: ICc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1

Procedure:
5-fluoro-2-nitrophenol (300 mg), benzyl iodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL) and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Reactant: Clc1ccccc1CBr
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1ccccc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH2:16]=[C:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:18](=[O:19])[C:17](=[CH2:16])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.10 mL, 0.022 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (2.84 g, 0.020 mol, 1.1 eq) in anhydrous dichloromethane (100 mL) (see FIG. 6). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 17 (3 g, 0.018 mol, 1 eq) and dicyclohexylcarbodiimide (4.19 g, 0.020 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate (100 mL), 1N aqueous solution of HCl (100 mL), brine (100 mL) and was then dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent:hexane/EtOAc=8:2). The desired product 18 was obtained as a solid (3.79 g, 83%). Rf=0.14 (hexane/EtOAc=7:3). m.p. 51° C. 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.65 (s, 2H), 4.05 (d, 2H), 4.20 (q, 2H), 5.30 (s, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.15–7.35 (m, 5H). [M+H]+ 248.0, tR=3.03 min; purity: 99.5%.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[O:23][CH3:24].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CN)ccc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)c2ccc(S(=O)(=O)Cl)cc2)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF (25 mL) and cool to −78° C. Slowly add a pre-mixed solution of 4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooled solution over 1 h. Stir the resulting mixture at −78° C. for 1 h, then warm to RT and stir for 4 h. Remove all solids by filtration and wash with THF (5 mL). Concentrate the filtrate and re-dissolve the crude material in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate the organic and aqueous layers and extract the aqueous phase with additional EtOAc (30 mL). Combine the organic solutions dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the title compound as a white solid (1.36 g, 28%). MS (ES−) 356.1 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd, 1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+]>O1CCOCC1.CO>[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][CH:13]5[CH2:17][CH2:16][O:15][CH2:14]5)[C:7](=[O:18])[C:6]5([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]5[C:4]=4[N:3]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC12COCCN1c1nc(Cl)ncc1N(CC1CCOC1)C2=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC12COCCN1c1nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc1N(CC1CCOC1)C2=O
Temperature: 100 °C
Yield: 15.4 %

Procedure:
2-Chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (390 mg, 1.151 mmol) PdCl2(dppf)-CH2Cl2 (188 mg, 0.230 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (417 mg, 1.381 mmol) and sodium 2-methylpropan-2-olate (1.5 ml, 1.151 mmol) were combined in 1,4-dioxane (3 ml). The suspension was heated by microwave irradiation at 100° C. for 30 minutes, the reaction was filtered, cooled, and purified by mass-triggered preparative HPLC using 22-25% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column). Product containing fractions were evaporated in vacuo to give a residue. The residue was dissolved in methanol for transfer. The solvent was removed under a stream of nitrogen gas to give 85 mg of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 0.48-0.57 (m, 2 H) 0.71-0.79 (m, 2 H) 1.73 (s, 3 H) 1.73 (m, 1 H) 2.02-2.14 (m, 1 H) 2.61 (m, 1 H) 2.68-2.80 (m, 1 H) 3.55-3.65 (m, 2 H) 3.68 (dd, J=12, 4 Hz, 1 H) 3.71-3.81 (m, 3 H) 3.84 (d, J=12 Hz, 2 H) 3.91-4.05 (m, 2 H) 4.08-4.21 (m, 2 H) 4.75 (d, J=16 Hz, 1 H) 7.67 (d, J=8 Hz, 2 H) 8.03 (s, 1 H) 8.11 (dd, J=8, 4 Hz, 2H) [M+H] found 479.
Reaction SMILES: O1CCOCC1.O.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:36]([F:39])([F:38])[F:37])[O:21][N:20]=[C:19]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([O:34]C)=[O:33])=[CH:24][CH:23]=3)[CH2:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15].[Li]>CCCCCCC.CCOC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:36]([F:37])([F:39])[F:38])[O:21][N:20]=[C:19]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([OH:34])=[O:33])=[CH:24][CH:23]=3)[CH2:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a 7:1 dioxane:water mixture (80 mL) containing methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoate (Preparation 6, 2.9 g, 5.9 mmol) was added lithium hydroixide (430 mg, 18.0 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours. Thin layer chromatography (TLC) 25:75 EtOAc:heptane showed consumption of starting material. 1N HCl (25 mL) was added. The reaction was partitioned between water (25 mL) and ethyl acetate (150 mL). The organic phase was collected, dried over Na2SO4, and concentrated under vacuum to give a solid (2.77 g, 98%). 1H NMR (CDCl3) δ ppm: 9.10 (1H), 8.82 (1H), 8.34 (1H), 7.76-7.66 (4H), 7.60 (1H), 4.32 (1H), 3.93 (1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)=O.[Cl:18][C:19]1[C:27]([CH3:28])=[N:26][C:25]2[N:21]([N:22]=[C:23]3[CH2:31][N:30]([C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH:42]4[CH2:46][CH2:45][NH:44][CH2:43]4)=[O:33])[CH2:29][C:24]3=2)[C:20]=1[CH3:47].[CH3:48][C:49]([CH3:51])=O.CC(O)=O>C(Cl)Cl>[Cl:18][C:19]1[C:27]([CH3:28])=[N:26][C:25]2[N:21]([N:22]=[C:23]3[CH2:31][N:30]([C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH:42]4[CH2:46][CH2:45][N:44]([CH:49]([CH3:51])[CH3:48])[CH2:43]4)=[O:33])[CH2:29][C:24]3=2)[C:20]=1[CH3:47]
Reactant: CC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CCNC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CCN(C(C)C)C1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Sodium triacetoxyborohydride (90 mg; 0.42 mmol; 4 eq.) was added to a solution of (6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]inden-2-yl)-[2-(pyrrolidin-3-ylmethoxy)-phenyl]-methanone formic acid salt (50 mg; 0.11 mmol; 1 eq.), acetone (47 μL; 0.64 mmol; 6 eq.) and AcOH (7 μL; 0.13 mmol; 1.2 eq.) in DCM (3 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with sat. aq. NaHCO3, dried over sodium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (47 mg, 76%) as a white solid. 1H NMR (CDCl3) δ 7.44-7.30 (m, 2H), 7.12-6.98 (m, 1H), 6.98-6.87 (m, 1H), 5.07-4.92 (m, 2H), 4.63 (br s, 2H), 4.09-3.86 (m, 2H), 2.88 (d, J=18.2 Hz, 4H), 2.65 (d, J=23.0 Hz, 5H), 2.50-2.05 (m, 3H), 2.04-1.84 (m, 1H), 1.58 (dt, J=13.2, 5.8 Hz, 1H), 1.02-0.81 (m, 6H). HPLC (max plot) 94.3%, Rt 2.92 min. UPLC/MS: (MS+) 468.5 ([M+H]+).
Reaction SMILES: Cl[C:2]([F:25])([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16]C)=[O:14])=[C:5]([O:18]CC)[C:4]=1[C:21]([OH:23])=[O:22].[CH2:26](N(CC)CC)C.[OH-].[K+].S(Cl)(Cl)=O>CCO.CCOCC.[Pd].CO.O>[F:24][CH:2]([F:25])[C:3]1[C:4]([C:21]([O:23][CH3:26])=[O:22])=[C:5]([OH:18])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([F:10])([F:12])[F:11])[N:8]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)O)c1OCC
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1O
Yield: 13 %

Procedure:
Product of Example 18 (23.34 g, 0.032 mol), 9.0 ml (0.064 mol) of triethylamine and 0.62 g of Pd/C (10% ) in 100 ml of EtOH were reacted as described by the preparation of product of Example 22 affording 9.99 g of dark orange oil. A portion of this oil (5.0 g, 0.014 mol), 4.51 g (0.070 mol) of 87% KOH, 1 ml of H2O in 30 ml of EtOH was stirred at reflux for 5 days. Reaction mixture was concentrated and the residue was poured into water and washed with ether. The aqueous layer was acidified with conc HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 4.26 g of foamy oil. This oil was treated as described in Example 19: 4.26 g (0.013 mol) of this foamy oil, 25 ml of thionyl chloride and 25 ml of MeOH were reacted affording a dark solid residue which was taken up in ether and extracted with 15% K2CO3 and water, acidified with concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 2.7 g of solid. Recrystallization from hexane-ether afforded 1.37 g (32.0%) of product as a tan solid: mp 83°-84.5° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C@@H:16]([C@H:19]1[CH2:21][O:20]1)[CH2:17][CH3:18]>CO>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:21][C@@H:19]([OH:20])[C@@H:16]2[CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](Br)[C@H]1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: CC[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Yield: 48.6 %

Procedure:
Benzhydrylamine (1.04 mL, 6.06 mmol) was added to a solution of (2R*)-2-[(1R*)-1-bromopropyl]oxirane obtained in Example (234a) (1.00 g, 6.06 mmol) in methanol (6 mL), and the mixture was heated under reflux for 17 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium carbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 787 mg of the title compound as a colorless oily substance (49%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][C:7]([OH:25])=[C:6]1[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=21.[C:30](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][C:7]([O:25][CH3:30])=[C:6]1[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2cc(O)c2ccccc32)cc(Br)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: COc1cc(C2C(C#N)=C(N)Oc3c2cc(OC)c2ccccc32)cc(Br)c1OC
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-Amino-6-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (9) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (40 mg, 85.6%).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][CH:35]=1)([CH3:41])[CH3:40]
Reactant: CC(C)c1ccc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(C)C)cc1

Procedure:
Compound 39 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. The title compound was isolated as the major product (white solid). LC/MS [365 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.47 (d, J=8.6 Hz, 1H), 9.03 (d, J=4.3 Hz, 1H), 8.63 (s, 1H), 8.41 (d, J=4.3 Hz, 1H), 8.22 (s, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 5.92-5.76 (m, 1H), 3.89-3.65 (m, 1H), 3.39 (d, J=12.6 Hz, 1H), 2.94-2.81 (m, 1H), 2.61 (s, 3H), 1.16 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1B1OBOBO1.N1C=CC=CC=1.Cl>[Cu].C(OCC)(=O)C.CN(C)C=O>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1ccc(B2OBOBO2)c(C)c1
Reactant: FC(F)(F)c1nc[nH]n1
Agent: [Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer were placed 1.37 g (10 mmol) of 3-trifluoromethyl-1H-1,2,4-triazole, 1.32 g (3.33 mmol) of 2,4-dimethylphenylboroxine, 64 mg (1 mmol) of a copper powder, 0.8 g (10 mmol) of pyridine and then 5 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 4 hours. Thereto were added 30 ml of ethyl acetate and 3% hydrochloric acid to give rise to phase separation. The aqueous phase was extracted with 30 mol of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to distill off ethyl acetate to obtain a title compound as 2.3 g of a crystal. Yield: 95%