Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.CI>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
5-(2-Methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester (13.14 g, 46.3 mmol) was dissolved in tetrahydrofuran (250 mL), 1.09 M lithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (65 mL, 70.9 mmol) was added dropwise at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added methyl iodide (11.7 g, 82.4 mmol) at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate and 0.5N-hydrochloric acid solution, the organic layer was extracted, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were collected, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate. The solvent of the filtrate after filtration was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12.36 g, 41.4 mmol, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:18])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:26])C(=O)C1>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([Cl:26])=[C:12]([C:14](=[O:18])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)c(Cl)s1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 86.4 %

Procedure:
To a suspention of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (23.5 g, 86 mmol) in 1,4-Dioxane (200 mL) was added NCS (12.22 g, 91 mmol) portionwise. The mixture was stirred at 40° C. for 2.5 h. The mixture was cooled to r.t. and filtered to remove the insoluable material. The filtrate was concentrated under vacuum. The residue was taken with Et2O and filtered. The filtrate was diluted with EtOAc and washed with water and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. To the oily residue was added n-hexane and Et2O, and the mixture was concentrated in vacuo. After trituration, 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid (22.8 g, 74.3 mmol, 86% yield) was obtained as a light yellow solid. LCMS: (M+Na)+: 329.0.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Yield: 83.1 %

Procedure:
A solution of 2-O-Octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 ml water-free pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 ml water-free pyridine under stirring. After 2 days at room temperature 162 ml diethyl ether are added and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 ml), 0.5N HCl (2×29 ml), 0.5N sodium carbonate (2×29 ml), and water (4×50 ml). Evaporation of the solvent under vacuum gives an oily product which becomes solid after drying in vacuo. The product, 1-p-toluenesulfonyl-2-O-Octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[NH:14][N:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([C:42](=O)[CH2:43][CH2:44][CH3:45])[C:37](OCC)=[O:38])=[CH:31][CH:30]=1)#[N:22].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:37](=[O:38])[C:36]([CH2:35][C:32]4[CH:33]=[CH:34][C:29]([C:24]5[C:23]([C:21]#[N:22])=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:30][CH:31]=4)=[C:42]([CH2:43][CH2:44][CH3:45])[N:13]4[N:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:16]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: FC(F)(F)c1nc(NC2CCC3(CC2)OCCO3)n[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C(F)(F)F)nn12
Yield: 40.6 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (9.87 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (23.59 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.05 mL) in N,N-diethylaniline (50 mL) was stirred at 180° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)], and crystallized from diisopropyl ether to give the title compound as a colorless solid (7.91 g, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:28])[C:20]1[C:25](Br)=[CH:24][N:23]=[C:22]([Cl:27])[CH:21]=1)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:25]2=[CH:24][N:23]=[C:22]([Cl:27])[CH:21]=[C:20]2[C:19]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)ncc1Br
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2cnc(Cl)cc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 5-bromo-2-chloroisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (9/1) gives the desired product as brown solid;
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Ca+2].[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24]([CH2:27][N+:28]([O-:30])=[O:29])(=[O:26])=[O:25])=[C:19]([CH3:31])[CH:18]=1.C(=O)=O>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH3:23][C:21]1[CH:22]=[C:17]([NH:16][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[C:19]([CH3:31])[C:20]=1[S:24]([CH2:27][N+:28]([O-:30])=[O:29])(=[O:26])=[O:25]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(NC(=O)Cc2ccccc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 54 %

Procedure:
Phenylacetyl chloride (1.16 g, 7.5 mM) was added to a stirred suspension of calcium carbonate (1.0 g, 10.0 mM) and (4-amino-2,6-dimethylphenylsulfonyl)nitromethane (1.22g, 5.0 mM) in dry tetrahydrofuran (THF; 20 mL). The mixture was stirred for 16 hours during which time carbon dioxide was slowly released. Ethanol (1.0 mL) was then added and the mixture stirred for a further hour in order to decompose excess phenylacetyl chloride. Ethyl acetate (100 mL) was then added and the insoluble material removed by filtration. The filtrate was washed first with water (50 mL) containing 2M hydrochloric acid (2.0 mL) and then with saturated sodium chloride solution (2×40 mL) and then dried (MgSO4). The solvent was evaporated and the residue recrystallised from ethyl acetate. The solid obtained was washed with ether and air dried to give (2,6-dimethyl-4-[phenylacetamido]phenylsulfonyl)nitromethane as white crystals, having m.p. 158°-159° C. and in 54 % yield after recrystallisation from ethanol; microanalysis, found: C, 56.7; H, 5.0; N, 8.0%; C17H18N2O5S requires: C, 56.4: H, 5.0; N, 7.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][CH2:15][CH2:16][CH2:17][CH3:18])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCCCN
Solvent: O
Product: CCCCNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (10.8 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 25 ml of butylamine, the reaction medium being cooled as necessary so as not to exceed 50° C. When the addition has ended, stirring is maintained for 5 minutes and the reaction medium is then poured into 100 ml of iced water. The expected product precipitates and is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 52° C.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[O:3]1.C([Mg]Cl)(C)C.[F:18][C:19]([F:38])([F:37])[C:20]1[O:24][C:23]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:12][C:2]1([F:1])[O:3][C:4]2[CH:10]=[C:9]([OH:11])[C:8]([C:28]3([OH:35])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]([CH2:25][C:23]4[O:24][C:20]([C:19]([F:38])([F:37])[F:18])=[CH:21][CH:22]=4)[C:27]3=[O:36])=[CH:7][C:5]=2[O:6]1
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Reactant: Oc1ccc2c(c1)OC(F)(F)O2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2,2-difluoro-1,3-benzodioxol-5-ol (Jacobus et al., WO 2004/4048320) (1.15 g, 6.60 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 3.3 mL, 6.6 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (1.95 g, 6.60 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 96 h. A saturated aqueous solution of ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 35% gradient of ethyl acetate in hexanes afforded 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (2.54 g, 73%) as a pale orange solid: MS (ES+) 451.3 (M−17).
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:3][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1
Reactant: Cc1cc(O)cc(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(=O)[nH]1
Temperature: 110 °C

Procedure:
16 mmol of phosphorus oxybromide are added under an argon atmosphere to a solution of 21 mmol of 4-hydroxy-6-methyl-1H-pyridin-2-one [3749-51-7] in 9 ml of N,N-dimethyl-formamide. The reaction mixture is heated to 110° C. for 30 minutes—subsequently, the mixture is cooled to room temperature and 10 ml of water are added. The solution is brought to pH 7 by adding sodium carbonate and cooled to 0° C. The precipitate is filtered off and washed with water and diethyl ether. The title compound is identified on the basis of the Rf value.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]2[N:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH3:17][S:18]SC>O1CCCC1>[CH3:6][O:7][C:8]1[C:13]2[N:14]=[C:15]([S:18][CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2ocnc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2oc(SC)nc12
Reaction time: 18 h

Procedure:
n-Butyllithium (20.13 ml of a 1.6N solution in hexanes) was added gradually to a solution of 4-methoxybenzoxazole (4.0 g) in tetrahydrofuran (150 ml) cooled in a cardice-acetone bath under an atmosphere of nitrogen. After stirring for 20 minutes dimethyl disulfide (2.9 ml) was added. The mixture was warmed to room temperaturee and stirred for 18 hours. The tetrahydrofuran was removed by evaporation in vacuo and the residue partitioned between ethyl acetate (150 ml) and water (150 ml). The organics were washed with water (150 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 10% ethyl acetate in heptane afforded the title compound as a white solid (2.63 g).
Reaction SMILES: [C:1]([C@@:11]([C:28](O)=[O:29])([CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH2:17])[NH2:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:46]([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:46]([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH:56][C:28](=[O:29])[C@:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[NH2:17])[NH2:12])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: NC(CCC[C@](N)(C(=O)O)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: NC(CCC[C@](N)(C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of α,ε-dicarbobenzoxy-L-lysine (4) (96 mmol, 39.69 g), toluene (310 ml) and triethylamine (96 mmol, 9.70 g) at 0° C., was added, over a period of 15 minutes, iso-butyl chloroformate (109 mmol, 14.88 g), maintaining the temperature between -5° and 0° C. The resulting jelly-like reaction mixture was stirred for 30 minutes at 0° C. and then a slurry of L-phenylalanine benzyl ester, p-toluene sulphonate (1) (96 mmol, 40.99 g) in chloroform (470 ml) and triethylamine (96 mmol, 9.70 g) was added quickly in one portion and the clear solution was allowed to stir at ambient temperature overnight.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:18][CH:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[N:1]1([CH:6]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(Cl)c1ccccc1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccccc1)C(C(=O)c1ccc(Cl)cc1)n1cncn1

Procedure:
2-(1,2,4-Triazol-1-yl)-4'-chloroacetophenone (0.01 mol) was dissolved in dimethylformamide (5.0 ml) at room temperature and treated with sodium hydride (0.01 mol). When the reaction was complete (3 hours), the mixture was cooled to 0° and α-methylbenzyl chloride (0.01 mol) was added dropwise with stirring. After stirring at room temperature for 20 hours, the mixture was poured into water and the product filtered off. Recrystallisation from chloroform/petroleum ether (60°-80°) gave the title compound as a colourless crystalline solid, m.p. 163°-5°.
Reaction SMILES: CS(O[C@H:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][C@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[O:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>CN1C(=O)CCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[N:43]2[C:42]2[CH:41]=[CH:40][C:39]([N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:45][CH:44]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)O[C@@H](CC[C@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(N3CCOCC3)cc2)cc1

Procedure:
The product from Example 38A and 4-morpholinoaniline were processed using the method described in Example 1D using NMP for the solvent to afford the title compound. MS (ESI) m/z 475 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]3[CH2:14][CH:13]3[C:15]3[CH:16]=[C:17]([CH:21]4OCC[O:22]4)[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.CCOC(C)=O>C1COCC1.CC(O)=O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]3[CH2:14][CH:13]3[C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH:21]=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccc(C3CC3c3cccc(C4OCCO4)c3)nc2c1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1

Procedure:
The dioxolane (step 3) (500 mg, 1.42 mmoles) was heated at reflux in 9 mL of THF:AcOH:H2O 6:2:1 for 2 hours. Addition of 25% NH4OAc, extraction with EtOAc, drying, evaporation, and flash chromatography on silica with EtOAc:toluene 2.5:97.5 afforded the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4].O[Li].O.Cl>CO.O>[F:38][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:21])[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (580 mg, 1.13 mmol) and LiOH.H2O (94 mg, 2.25 mmol) in MeOH (20 mL) and water (2 mL) was heated at 45° C. for 3 h. Additional LiOH.H2O (94 mg) was added and the mixture heated at 80° C. for 16 h. After further addition of LiOH.H2O (94 mg), stirring at 75° C. was continued for 18 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1N HCl. The organic solvent was removed under reduced pressure and EtOAc was added to the crude mixture. After sonication of the suspension, the organic solvent was removed in vacuo. The solid was collected by filtration and dried in vacuo to afford the title compound (412 mg, 73%). LCMS (Method C): RT 2.40 min [M+H]+ 502.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:17])[C:15]#[CH:16]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[C:16]#[C:15][CH2:14][OH:17]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc2nccc(C#CCO)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 8-bromo-2-methoxy-[1,5]naphthyridine (4.0 g, 16.7 mmol, prepared as in WO 2006/032466) and propargylalcohol (1.9 g, 33.5 mmol) in DMF (50 mL) and TEA (10.16 g, 100 mmol) was degassed by bubbling N2 through for 10 min. CuI (0.318 g, 1.6 mmol) and Pd(PPh3)2Cl2 (0.588 g, 0.84 mmol) were added and the brown solution was stirred at rt overnight. The mixture was partitioned between water and EtOAc and the org. layer was washed several times with water and a sat. NH4Cl solution, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1, EA) followed by crystallization from ether gave the coupling product as a beige solid (1.95 g, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]=[C:20]1[NH:19][C:16]2=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=[C:15]2[C:21]1=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3)cc(OC)c1OC
Reactant: N#Cc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3c(c2)C(=Cc2ccc(C#N)cc2)C(=O)N3)cc(OC)c1OC
Yield: 53.6 %

Procedure:
A mixture of 5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Intermediate BY, 42 mg, 0.14 mmol), 4-cyanobenzaldehyde (22 mg, 0.168 mmol), triethylamine (22 μl, 0.168 mmol) and molecular sieves 4 Å (100 mg) in toluene (2 ml) was reacted at 80° C. for Id. The mixture was partitioned between DCM and water, the aqueous phase extracted with DCM, combined organic phases dried, evaporated and purified by silica gel chromatography (0-5% MeOH:DCM) to obtain 31 mg (54%) of the title compound as a mixture of (E)- and (Z)-isomers.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.Br[CH2:18][CH2:19]Br>>[N:16]1[CH:15]=[CH:14][N:13]2[C:12]=1[C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[O:1][CH2:19][CH2:18]2
Reactant: COC(=O)c1ccc(O)c(-c2ncc[nH]2)c1
Reactant: BrCCBr
Product: COC(=O)c1ccc2c(c1)-c1nccn1CCO2
Yield: 76 %

Procedure:
Following the procedure in Example 17, methyl 4-hydroxy-3-(1H-imidazol-2-yl)benzoate reacted with 1,2-dibromoethane to give methyl 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 76%. MS(ESI+): 245.0. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.2, 1H), 7.91 (dd, J=8.6, 2.2, 1H), 7.20 (t, J=4.8, 1H), 7.05 (d, J=8.6, 1H), 7.00 (d, J=0.8, 1H), 4.53-4.48 (m, 2H), 4.43-4.39 (m, 2H), 3.91 (d, J=5.9, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[N:4][C:5]2[C:10]([C:11]=1C(OCC)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2>ClC1C=CC=CC=1Cl>[OH:1][C:2]1[C:3]([CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1c(O)c(C)nc2ccccc12
Solvent: Clc1ccccc1Cl
Product: Cc1nc2ccccc2cc1O
Temperature: 150 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Ethyl 3-hydroxy-2-methyl-quinoline-4-carboxylate (2.10 g) was suspended in o-dichlorobenzene (50 ml), and the mixture was stirred at 150° C. overnight and was further stirred at 160° C. for one day. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give 3-hydroxy-2-methyl-quinoline (976 mg, yield 60%).