Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:17]S(C2C=CC(C)=CC=2)(=O)=O)=[C:9]([CH:16]=1)/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:10]1[C:9]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:16]=2)[NH:17][C:34]=1[C:33](=[O:36])[C:32]1[CH:37]=[CH:38][C:29]([Cl:28])=[CH:30][CH:31]=1
Reactant: COC(=O)/C=C/c1cc(C(C)(C)C)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(C(C)(C)C)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (Example 143, step 2) and 4-chlorophenacyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][NH:6]1)=[O:4].[CH:22]1([O:27][C:28]([NH:30][C@@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:32](O)=[O:33])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][N:6]1[C:32](=[O:33])[C@@H:31]([NH:30][C:28]([O:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:4]
Reactant: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Product: COC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C
Yield: 42.3 %

Procedure:
Following the same procedure as Example 1 step G using (5S,8S)-methyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (30 mg, 97 μmol) and (S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoic acid (28 mg, 116 μmol, 1.2 eq.) gave 22 mg (41 μmol) of (5S,8S)-methyl-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C3). 1H NMR (300 MHz, CDCl3) 7.35-6.8 (m, 4H), 5.21-5.06 (m, 1H), 4.86 (m, 1H), 4.55-3.56 (m, 8H), 2.65-2.48 (m, 1H), 2.0 (m, 1H), 1.7-1.1 (m, 9H), 0.9-0.7 (m, 9H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)C=C.Cl[C:17]1[CH:22]=CC=C[C:18]=1Cl>>[CH2:22]([C:10]1[CH:9]=[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:17]=[CH2:18]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(CC(=O)OC)cc1
Product: C=CCc1cc(CC(=O)OC)ccc1O

Procedure:
A solution of methyl 4-alloxyphenylacetate (3.1 grams) in dry ortho-dichlorobenzene (50 mL) was refluxed for 25 hours. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, 50% methylene chloride in hexane) to afford the tittle compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[C:24]=3[F:27])[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (17 mg, 19%), MS (ISP) m/z=356.5 [(M+H)+], mp 238° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: CN(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 166.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium hydride (1.94 g, 45 mmol) under an atmosphere of nitrogen. To the suspension was added a tetrahydrofuran solution of 1-(3-hydroxyphenyl) ethanone (5.05 g, 37 mmol) in an ice bath. After stirring the mixture for 15 minutes dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise into the mixture and the resulting mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium chloride solution was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford the desired compound (6.54 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH:14]C(OCC2C=CC=CC=2)=O)[C:8]2[C:25]([CH3:29])=[N:26][N:27]([CH3:28])[C:7]1=2)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH2:14])[C:8]2[C:25]([CH3:29])=[N:26][N:27]([CH3:28])[C:7]1=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(c(C)nn2C)C(NC(=O)OCc2ccccc2)CC1CC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)N1c2c(c(C)nn2C)C(N)CC1CC
Temperature: 40 °C
Yield: 75.5 %

Procedure:
4-Benzyloxycarbonylamino-6-ethyl-1,3-dimethyl-1,4,5,6,-tetrahydro-pyrazolo[3,4-b]pyridine-7-carboxylic acid ethyl ester (0.34 g, 0.85 mmol) obtained in step (iii), methanol (5 mL), and ammonium formate were charged to a flask under a nitrogen atomsphere. To this mixture was added 10% Pd/C (50% wet) (0.1 g), and the resulting slurry was heated at about 40° C. for around 1 hour. The reaction mixture was then cooled to room temperature and filtered through Celite™, and the filtrate was concentrated under vacuum to afford the title compound (0.171 g, 76%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:41])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N1CCOCC1

Procedure:
The method described in Part F of Example 37 was used to treat 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.42 g, 3.70 mmol) with mCPBA (0.958 g, 5.55 mmol), ammonium hydroxide (4 mL), and p-toluenesulfonyl chloride (0.776 g, 4.07 mmol). Following the chromatographic purification, the resulting solid was dried for 48 hours under high vacuum at 120° C. to provide 0.614 g of 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a tan powder, mp 156-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2(O)[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)=[C:4]([F:16])[CH:3]=1.Cl.O.N>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
4-(4-Amino-2,6-difluoro-phenyl)-tetrahydro-thiopyran-4-o1 (16.7 g, 68 mM) was suspended in a mixture of concentrated hydrochloric acid (200 ml), water (50 ml) and acetic acid (200 ml), BHT (50 mg) added, and the whole stirred under nitrogen at 800 for 18 hours. After cooling, the mixture was made basic by cautious addition of concentrated ammonia, and ice-water. The mixture was then extracted with diethyl ether (2×300 ml), the extracts washed with water (100 ml), brine (200 ml) and dried (magnesium sulfate). Evaporation gave the desired product as a cream solid (15.2 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.Cl[C:23]([O:25][CH3:26])=[O:24]>C(N(CC)CC)C>[CH3:26][O:25][C:23]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([F:2])[CH:4]=3)[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)=[O:24]
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 95 %

Procedure:
The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and methyl chloroformate with triethylamine as the base. Yield: 95% of theory as a colourless oil; MS: m/e=330 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[CH3:17].[CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([C:21]1[N:22]([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:23]=[CH:24][N:25]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ncc[nH]1
Reactant: Cc1cc([N+](=O)[O-])ccc1OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1OCCCn1ccnc1C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a stirred solution of 50% sodium hydride (200 mg, 4 mmol) in DMF (5 mL) at 0° C. was added a solution of 1-(3-chloro-propoxy)-2-methyl-4-nitro-benzene (700 mg, 3 mmol) in dry DMF (3 mL). To this was added a solution of 2-isopropyl imidazole (300 mg, 3 mmol) in DMF (4 mL). The mixture was allowed to warm to r.t. and stirred for 5 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate. Concentration in vacuo gave a residue which was purified by column chromatography on silica gel, eluting with 20% methanol in chloroform to afford 2-isopropyl-1-[3-(2-methyl-4-nitro-phenoxy)-propyl]-1H imidazole (380 mg, 41%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:12])[CH:9]([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[C:8]#[N:12]
Reactant: CC(C)C#N
Reactant: Fc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C#N)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of fluorobenzene (5.85 mL, 62.4 mmol) in 100 mL of anhydrous toluene is added isobutyronitrile (22.5 mL, 250 mmol) followed by 200 mL (100 mmol) of a 0.5 M solution of KHMDS in toluene. The reaction is then stirred at 80° C. for 24 hours. The reaction is then allowed to cool to room temperature, diluted with diethyl ether, and washed with water and brine. The organic fraction is then dried over sodium sulfate and concentrated under reduced pressure. The product is purified by flash chromatography using an ethyl acetate/hexanes gradient to yield 4.57 g (50% yield) of the objective compound as a brown oil. MS: (ESI, Pos) m/z 168.0 (M+23); 1H NMR (500 MHz, CDCl3): δ (ppm) 7.48 (d, 2H), 7.39 (t, 2H), 7.31 (t, 1H), 1.73 (s, 6H).
Reaction SMILES: C(ON=O)(C)(C)C.[CH2:8]([O:10][C:11]([C:13]1[C:24]2[CH:23]3[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[CH2:18][CH2:17][C:16]=2[S:15][C:14]=1N)=[O:12])[CH3:9]>C(O)C.O.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH2:8]([O:10][C:11]([C:13]1[C:24]2[CH:23]3[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:22]3)[CH2:18][CH2:17][C:16]=2[S:15][CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(N)sc2c1C1CN(C(=O)OC(C)(C)C)CC1CC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc2c1C1CN(C(=O)OC(C)(C)C)CC1CC2
Temperature: 60 °C
Yield: 36 %

Procedure:
Tert-butylnitrite (7.09 g, 0.069 mol) was added to the product of step d) (16.8 g, 0.046 mol) dissolved in 200 mL of ethanol followed by the addition of copper diacetate (12.5 g, 0.069 mol). The reaction mixture was heated for one hour at 60° C., cooled to room temperature, diluted with 200 mL of water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 5-50% ethylacetate-hexane gradient to afford the subtitle compound (5.8 g, yield: 36%). MS calculated for C18H25NO4S +H: 352, observed: 352.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:9][C:10]=1[C:11](O)=[O:12].C(OCC)(=O)C>O1CCCC1>[F:25][C:2]([F:1])([F:24])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[O:9][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
1.0 g 4-(2,2,2-Trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid were dissolved in 30 ml tetrahydrofuran. At 0-5° C. 6.6 ml of a one molar solution of borane tetrahydrofuran complex were added. The reaction mixture was stirred at room temperature for three hours and at 60° C. for one hour. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate and washed with 50 ml water. The organic phase was dried over MgSO4 then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 422 mg [4-(2,2,2-trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Sn](Cl)Cl.Cl>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
To a solution of {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-nitro-biphenyl-3-yl}-acetic acid ethyl ester (0.70 g, 1.75 mmol) in EtOH (70 mL) was added tin (II) chloride (1.97 g, 8.75 mmol). The reaction was heated to reflux for 5 h, and then the mixture was acidified to pH 1 with concentrated HCl and diluted with EtOAc. The resulting biphasic mixture was filtered through Celite, and the organic layer was separated. The aqueous layer was neutralized to pH 7 with solid NaOH and extracted with EtOAc. The combined organic extracts were dried and filtered, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[N:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[CH2:20]2>O1CCCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21]1([OH:26])[CH:22]2[CH2:25][N:19]([CH2:24][CH2:23]2)[CH2:20]1)[CH3:18]
Reactant: O=C1CN2CCC1C2
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CN2CCC1C2
Temperature: 25 °C

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.65 ml. 0.0203 moles) in tetrahydrofuran (150 ml) was added 2.5M n-BuLi in hexanes (8.1 ml. 0.0203 moles) dropwise over one minute. After ten minutes, ethyl acetate (1.97 ml. 0.0203 moles) was added dropwise over one minute. After a further ten minutes, 1-azabicyclo[2.2.1]heptan-3-one (1.5 g, 0.0135 moles, prepared by the method of J Chem Soc, Chem Commun, 1618, 1988) in tetrahydrofuran (25 ml) was added dropwise over five minutes. After twenty five minutes, the cold bath was removed and the mixture was allowed to warm to ambient temperature. To this mixture was added water (100 ml) followed by chloroform (250 ml). The organic layer was separated and the aqueous layer was extracted with chloroform (100 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the subtitle compound (1.12 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[S:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:16]1[N:15]=[N:14][S:13][CH:17]=1
Reactant: O=Cc1csnn1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=Cc1csnn1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (35 mg, 0.21 mmol) and 1,2,3-thiadiazole-4-carboxaldehyde (33mg, 0.287 mmol) similar to Example 3 and isolated as a white solid (47 mg, 80%). 1H NMR (CDCl3): 9.95 (s, 1H), 8.85 (s, 1H), 7.70 (brs, 1H), 6.16 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.27 (t, J=8.7 Hz, 1H), 3.06 (s, 1H), 2.96 (s, 1H), 1.92 (ddd, J=7.6, 7.0, 2.4 Hz, 1H), 1.67 (m, 1H), 1.51-1.40 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: Clc1ccc2sc(CBr)nc2c1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Yield: 96.1 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (297 mg, 1 mmol) was dissolved in N,N-dimethylformamide (8 ml). 2-bromomethyl-5-chloro-1,3-benzothiazole (263 mg, 1 mmol) and potassium carbonate (213 mg, 1.5 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 3b (460 mg, light yellow solid), yield: 96%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]=[O:59])=[CH:54][CH:53]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].CC(=CC)C.Cl([O-])=[O:79].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([C:58]([OH:79])=[O:59])=[CH:56][CH:57]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C=O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C(=O)O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg) in tert-butanol (1.0 mL) was added 2-methyl-2-butene (250 mL) followed by 0.5 mL of an aqueous solution of sodium chlorite (41 mg) and sodium dihydrogen phosphate (48 mg), and the mixture stirred at room temperature. After 1.5 hours, the mixture was concentrated and redissolved in ethyl acetate:hexane (1:1) and washed with water. The organic portion was dried over sodium sulfate, and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (4:1) +1% methanol +0.5% acetic acid) to give the title compound (43 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([OH:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O[C@H]1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 3.72 g (13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholinone, prepared from (R)-phenyl-glycine as described in Example 14, in 28 mL of CH2Cl2 was cooled in a −78° C. bath under a N2 atmosphere and 14 mL of a 1.5 M solution of DIBAL-H (21 mmol) in toluene were added. After stirring the resulting solution for 0.5 h, it was allowed to warm to −50° C. and mantained at this temperature for 0.5 h. The reaction mixture was quenched by adding 10 mL of aqueous potassium sodium tartarate. The mixture was diluted with CH2Cl2 and the layers were separated. The aqueous layer was extracted 3 times with CH2Cl2. The CH2Cl2 layers were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate furnished 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:11]4[C:2]([Cl:1])=[CH:3][C:4]5[S:9][CH2:8][CH2:7][NH:6][C:5]=5[CH:10]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C(O)c1cc2c(cc1Cl)SCCN2
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCCN5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (37 mg, 51% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (29 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine as starting materials.