Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[C:24]2[C:33]3[C:28](=[CH:29]C=CC=3)[CH:27]=[CH:26][C:25]=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C1[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]1=[O:66])CCCC.BrC1C=CC=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:28]1([CH3:29])[CH:27]=[CH:26][CH:25]=[C:24]([C:15]2([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]2=[O:66])[CH:33]=1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: CCCCCC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Brc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC1(c2cccc(C)c2)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 468.4 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (11.2 mg, 0.05 mmol, 10 mol % Pd), (S)-BINAP (46 mg, 0.075 mmol, 15 mol %) and 2-pentyl-5-(N-methyl-anilinomethylene)-cyclopentanone (136 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. Bromobenzene (157 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 127 mg (70%) of the title compound. The ee was determined to be 99% by chiral HPLC analysis.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[S:25].NCCC(O)=O.O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:23]2[N:19]([CH3:18])[C:20](=[S:25])[NH:21][C:22]2=[O:24])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CN1CC(=O)NC1=S
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (19.0 g, 81 mmols), 1-methyl-2-thioxo-4-imidazolidinone (10.6 g, 81 mmols) and beta-alanine (4.7 g, 53 mmols) in acetic acid (150 ml) is stirred under an inert atmosphere and heated to reflux. After 5 hours the mixture is allowed to cool, and is stirred into water (1.5 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (17.5 g), mp 242°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[H][H]>CN(C)C=O.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1
Reactant: [H][H]
Reactant: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1

Procedure:
A solution of 50 g (0.115 mol) 3-(2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one in dimethylformamide and tetrahydrofuran was reduced with 35 psi hydrogen and Raney nickel catalyst. Removal of the catalyst by filtration and concentration of the filtrate gave 21 g (0.052 mol) light yellow solid 3-(2-chloro-5-aminoanilino-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one. To an acetic acid solution containing 6.9 g (0.017 mol) of this amine and 9.5 g potassium acetate was added, in small portions, 9.5 g (0.019 mol) of the acid chloride B2Cl prepared in Example 2. After stirring overnight, the mixture was concentrated to a third of its volume, poured into a large volume of water and extracted with diethyl ether. The organic layers were washed, dried, concentrated, and crystallized from methanol to give 14 g (0.016 mol) buff-colored solid acetate ester of the desired coupler, mp 115°-116° C. To a solution of this product in dimethylformamide stirred under nitrogen was added an aqueous solution containing 2 g potassium hydroxide. After 15 minutes the mixture was acidified with hydrochloric acid, poured into dilute hydrochloric acid, extracted with diethyl ether, washed, dried, concentrated, and crystallized from methanol to give 9.2 g white crystalline coupler M-28, mp 127°-130° C.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]([CH:15]=1)[C:13]#[N:14])(=[O:7])C.Cl>O.O1CCOCC1>[C:13]([C:12]1[CH:15]=[C:8]([CH:9]=[CH:10][C:11]=1[O:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:7])=[O:1])#[N:14]
Reactant: [OH-]
Reactant: CCCOc1ccc(C(C)=O)cc1C#N
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1C#N
Reaction time: 2 h
Yield: 93.2 %

Procedure:
NaOH (5.52 g, 0.138 mol) was dissolved in water (35 ml) under ice-bath, followed by slow addition of liquid bromine (3.5 ml, 0.068 mol) under cooling. After a solution of 5-acetyl-2-n-propoxybenzonitrile (7 g, 0.034 mol) in dioxane (35 ml) was slowly added dropwise thereto, the reaction continued for 2 h. The reaction mixture was adjusted slowly to a pH of about 2 with a diluted hydrochloric acid to generate a large amount of light yellow solid. After filtered, the resultant solid was washed with ethyl acetate, and filtered to obtain the title compound (6.5 g, yield: 92%). 1H NMR (CDCl3) δ: 13.21 (1H, br), 8.18 (1H, d), 8.15 (1H, dd), 7.34 (1H, d), 4.18 (2H, t), 1.79 (2H, m), 1.00 (3H, t).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1)=O.[F:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[F:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(F)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-fluoro-phenyl)-1H-pyridazin-4-one (A-13) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=351.3 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[N:13][CH:14]=1
Reactant: CC(C)CO
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Br)cn1
Yield: 86.3 %

Procedure:
To 2-methyl-propan-1-ol (10 g, 0.41 mol) was added NaH (60%, 8.2 g, 0.204 mol) portionwise under a nitrogen atmosphere at room temperature over 10 minutes. The mixture was refluxed for 30 minutes. A solution of 5-bromo-2-fluoro-pyridine (24 g, 0.136 mol) in DMF (400 mL) was added dropwise and the mixture refluxed for 18 hours. The reaction mixture was then diluted with water (1 L) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine (3×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was purified by flash column chromatography eluting with petroleum ether to yield the title compound as a colourless oil (27 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[O:25]=[C:26]1[C:30]2([CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]2)[CH2:29][CH2:28][NH:27]1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Cu]I>[O:25]=[C:26]1[C:30]2([CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:32][CH2:31]2)[CH2:29][CH2:28][N:27]1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccnc3)ncc21
Reactant: O=C(OCc1ccccc1)N1CCC2(CCNC2=O)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(N2CCC3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c2cc(-c3cccnc3)ncc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A solution containing 3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (0.196 g, 0.434 mmol), benzyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.250 g, 0.867 mmol), N,N′-Dimethylethylenediamine (0.103 mL, 0.954 mmol), Copper(I) iodide (0.0908 g, 0.477 mmol) and Cesium Carbonate (0.311 g, 0.954 mmol) in 1,4-Dioxane (7.08 mL, 90.7 mmol) was stirred at 75° C. for 2 h. The reaction was filtered thru celite and concentrated. The crude product purified by Isco column (EtOAc/Hep eluted at 50% EtOAc) to give benzyl 1-oxo-2-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (140 mg, 52.7% yield). ESI MS m/z=613.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4][C@H:3]1[CH2:22][NH:23]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:23][CH2:22][C@H:3]1[C@@H:2]([OH:1])[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4]1
Reactant: COc1cnc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3C[C@@H](CN)[C@@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
To a solution of phenylmethyl [((3R,4R)-4-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.76 g, 1.68 mmol) in MeOH (10 mL) was added 10% Palladium on carbon (0.20 g) and the resulting solution subjected to H2 at 20 PSI on a Parr shaker for 1 hour. No reaction was observed. The solution was then subjected to H2 at 50 PSI on a Parr shaker. The solution was filtered through a pad of Celite® and concentrated under reduced pressure (0.408 g, 76%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:26])(=[O:25])[NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:26])=[O:25]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCN(C)C)sc2Br)s1
Agent: [Li]CCCC
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCCCN(C)C)c2)s1
Temperature: -70 °C
Yield: 68 %

Procedure:
N-{5-[2-Bromo-5-(3-dimethylamino-propylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (200 mg; 0.42 mmol; 1 eq), is dissolved in anhydrous TBF (50 ml). The reaction mixture is cooled to down to −70° C. and put under nitrogen. n-Butyllithium (2.1 ml; 1.6 M; 3.32 mmol; 8 eq) is added dropwise. After 2 h30, the reaction is complete and is quenched with water. Solvents are evaporated and the resulting mixture is purified by preparative HPLC affording Compound (27) as a brown oil (120 mg; 68%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])=[N:7]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>CCOC(C)=O>[NH2:18][C:15]1[CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][N:25]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:17][CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: Nc1cnc(-c2ccc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(5-chloro-1,8-naphthyridin-2-yl)-5-(trifluoromethyl)pyridin-3-amine (64.8 mg, 0.2 mmol) and 2-amino-5-trifluoromethylpyridine (64 mg, 0.4 mmol) at 180° C. for 2.0 hours. Cool the mixture, dilute with EtOAc/1.0 N aq. NaOH (5.0 mL each), and separate the organic layer. Extract the aqueous layer with EtOAc (3×5 mL) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify the crude product by HPLC to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.15 (s, 1H), 8.96 (d, 1H, J=2.2 Hz), 8.89 (m, 1H), 8.67 (s, 1H), 8.41 (m, 1H), 8.29(s, 1H), 8.25 (d, 1H, J=0.7 Hz), 8.07 (dd, 1H), 7.94 (d, 1H, J=2.2 Hz), 7.41 (d, 1H, J=0.6 Hz), 6.17 (s, 2H). MS=451.36 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]CCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28]CC(Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)CSc1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Yield: 64 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-(phenylthio)acetyl chloride (0.222 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.102 g, 1.19 mmol) and triethylamine (0.240 g, 2.37 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-(phenylthio)acetamide (0.179 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 4H), δ 7.18 (m, 2H), δ 3.60 (s, 2H), 3.34 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 134.8, 129.5, 128.6, 127.1, 50.8, 39.3, 37.7 ppm; HRMS (ESI) calcd for C10H12N4OS (M+) 236.0732, found 236.0729.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29](OCC)=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)CN
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCC(C)(C)C)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 2,2-dimethylpropan-1-amine.
Reaction SMILES: [OH:1][CH:2]1[CH:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](Cl)=[O:22])=[CH:13]1>>[CH:2]1([O:1][C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][CH:13]=2)=[O:22])[CH:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1
Reactant: OC1CCCN2CCCCC12
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(OC1CCCN2CCCCC12)c1c[nH]c2ccccc12

Procedure:
eq-1-Hydroxyquinolizidine (H. S. Aaron et al, J. Org. Chem. 1964, 29, 2248) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether to afford the title compound (E11a) as a white solid, mp 230°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)/[CH:28]=[CH:29]/[CH2:30][OH:31])CCC.[Cl-].[Li+]>CN(C)C=O>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:28]=[CH:29][CH2:30][OH:31])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Reactant: COc1cc2c(SC)ncnc2cc1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc2c(SC)ncnc2cc1C=CCO
Temperature: 65 °C
Yield: 43.7 %

Procedure:
A suspension of 4-(methylthio)-6-methoxy-7-(trifluoromethanesulphonyloxy)quinazoline (1.1 g, 3.1 mmol), E-3-(tributylstannyl)-2-propen-1-ol (1.12 g, 3.23 mmol), bisdichloro(triphenylphosphine)palladium (44 mg, 0.06 mmol) and lithium chloride (395 mg, 9.32 mmol) in dimethylformamide (14 ml) was heated at 65° C. for 3 hours. The mixture was cooled to ambient temperature, the solid was recovered by suction filtration and washed with ether. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-(3-hydroxyprop-1-enyl)quinazoline (355 mg, 44% yield):
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][C:9]=1[OH:10].[Br:15]Br>O>[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[C:8]([Br:15])[C:9]=1[OH:10]
Reactant: CCC(=O)c1ccc(O)c(CN)c1
Reactant: BrBr
Agent: Cl
Solvent: O
Product: CCC(=O)c1cc(Br)c(O)c(CN)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 22 g of 3'-aminomethyl-4'-hydroxypropiophenone hydrochloride in 300 ml of ice-cold water is added dropwise 17 g of bromine with stirring under ice cooling for about 10 minutes. After addition, the reaction mixture is stirred under ice cooling for 3 minutes and then at room temperature for 5 minutes. To the resulting mixture is added 200 ml of water and insoluble substances are filtered off. The filtrate is neutralized with powdery sodium hydrogencarbonate and the liquid layer is adjusted pH to about 7 to precipitate fine powder. The powder is collected by filtration and dried to give 25 g of 3'-aminomethyl-5'-bromo -4'-hydroxypropiophenone, melting at 186°-187° C. with decomposition.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C:10]=1[CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O.O1CCCC1>C(OCC)(=O)C>[C:14]1([C:8]2[O:9][C:10]([CH2:11][CH2:12][CH3:13])=[C:6]([CH2:5][OH:4])[N:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COCOC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1oc(-c2ccccc2)nc1CO
Yield: 95.7 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-5-propyloxazole (2.64 g), 10% sulfuric acid (10 mL) and tetrahydrofuran (100 mL) was heated under reflux for 24 hrs. To the reaction mixture was added ethyl acetate, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2-phenyl-5-propyl-4-oxazolyl)methanol as a colorless oil (2.10 g, 96%).
Reaction SMILES: [C:1](#[N:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19].C([O-])(O)=[O:22].[Na+].OOS([O-])=O.[K+].C(Cl)Cl>CC(C)=O.O>[O:22]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[N:20])[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19]
Reactant: O=C([O-])O
Reactant: N#CCCCCCCC/C=C/CCCCCCCC#N
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N#CCCCCCCCC1OC1CCCCCCCC#N
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A mixture of 0.1000 g (E)-octadec-9-enedinitrile and 0.2334 g NaHCO3 in 4.0 mL acetone was cooled in an ice water bath. While stirring, a solution of 0.5365 g Oxone® in 4.0 mL water was added in portions during 30 min. The mixture was allowed to warm to room temperature over 18 h, then 200 mL CH2Cl2 and 10 mL water were added to the reaction mixture to afford a clear 2-phase system. The organic phase was dried over Na2SO4 and evaporated to afford 0.10 g of product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:29][CH2:28][CH2:27][N:9]2[C:10](=[O:26])[C:11]2[N:12]([CH:14]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>O1CCOCC1.O.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:29][CH2:28][CH2:27][N:9]2[C:10](=[O:26])[C:11]2[N:12]([CH:14]=[C:15]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH:16]=2)[CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C23Cn4cc(B5OC(C)(C)C(C)(C)O5)cc4C(=O)N2CCN3)cc1
Reactant: Brc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C23Cn4cc(-c5ccccn5)cc4C(=O)N2CCN3)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
A suspension 10a-(4-methylphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (100 mg, 0.25 mmol) in 1,4-dioxane (3 mL) was degassed by flushing the reaction vessel with argon for 20 minutes. Cesium carbonate (165 mg, 0.51 mmol) in water (100 μL) was added followed by 2-bromopyridine (29 μL, 0.30 mmol). The mixture was flashed with argon prior adding bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18 mg, 0.025 mmol). The mixture was heated at 100° C. for 2 hours. Water was added (5 mL) and the mixture extracted with CH2Cl2 (5 mL). The organic layer was dried (MgSO4), filtrated and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4 gradient 0-5% MeOH in CH2Cl2) to give 10a-(4-methylphenyl)-7-(pyridin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one (50 mg). The crude was used in the next step without purification. ESI-MI m/z [M+H]+ 345.1.