Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][N:12]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:25][C:26]([OH:28])=[O:27])[CH2:8][CH2:7][N:6]([CH2:29][C:30]([OH:32])=[O:31])[CH2:5][CH2:4][NH:3]1>C(O)(=O)C>[CH3:1][CH:2]1[CH2:16][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][N:12]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:25][C:26]([OH:28])=[O:27])[CH2:8][CH2:7][N:6]([CH2:29][C:30]([OH:32])=[O:31])[CH2:5][CH2:4][N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC1CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN1
Solvent: CC(=O)O
Product: CC1CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN1CC(=O)O
Yield: 49.3 %

Procedure:
9 g of crude product 12a are obtained on evaporation of the 0.1M acetic acid. 2.5 g of crude product 12b are obtained on evaporation of the 0.8M acetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:33])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(CCC(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of methyl 3-[4-({[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}amino)phenyl]propanoate (Example 196, 0.52 g, 1.15 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 3 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.54 g, quant.) as a yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]([OH:26])[C:23]([OH:25])=[O:24])[CH:5]=[C:6]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>ClCCl.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:22]([OH:26])[C:23]([O:25][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:24])[CH:5]=[C:6]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOCOc1cc(C(O)C(=O)O)cc(F)c1OCOCCOC
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COCCOCOc1cc(C(O)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.3 g of the acid of Step A were dissolved in 66 ml of dichloromethane and then 46 ml of a solution of diphenyl diazomethane at 6.5 g in ether were added at 15° C. The mixture was stirred for 16 hours at ambient temperature and then water was added, followed by decanting and acidifying with acetic acid. Washing with a saturated solution of sodium bicarbonate, drying and evaporating the solvents yielded after chromatography on silica and eluting with an ethyl acetate-hexane mixture (50-50) 4.0 g of the desired product with a Rf=0.17.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)N=C=O
Reactant: CC1=NC(=NO)SC1(C)C
Product: CC1=NC(=NOC(=O)NC(C)C)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with isopropyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(isopropylcarbamoyl)-oxime, m.p. 114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:31]3[CH:32]=[CH:33][C:28]([CH2:27][NH2:26])=[CH:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4ccc(CN)cc4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.6 g, 4.06 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (0.913 g, 4.87 mmol), potassium carbonate (2.5 g, 18 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.028 g, 0.041 mmol), DME (15 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at 110° C. for 18 hours and allowed to cool to room temperature. An analysis by LC/MS indicated the reaction was incomplete, and additional dichlorobis(triphenylphosphine)palladium(II)(0.050 g) was added. Heating was continued for another six hours, but the reaction did not progress. Additional (4-aminomethylphenyl)boronic acid hydrochloride (0.400 g), potassium carbonate (0.500 g) and dichlorobis(triphenylphosphine)palladium(II)(0.050 g) were added. The reaction was heated at 110° C. for six hours, allowed to cool to room temperature, and concentrated under reduced pressure. Chromatographic purification was carried out as described in Examples 351-365 to provide 1.13 g of 1-[4-amino-7-[4-(aminomethyl)phenyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([CH2:15][CH3:16])[CH:13]=[O:14]>Cl.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:13]([OH:14])[C:12]([Cl:17])([Cl:11])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: CCC(Cl)(Cl)C=O
Agent: Cl
Solvent: C1COCCO1
Product: CCC(Cl)(Cl)C(O)NC(=O)c1ccc(Br)cc1
Yield: 51 %

Procedure:
4-Bromobenzamide 118 (1.0 g, 4.85 mmol), 2,2-dichlorobutanal (2 mL) and HCl (3 drops) in dioxane (4 mL) were heated to 120° C. (bath temperature) for 18 hours. The mixture was concentrated, and absorbed onto silica gel. Chromatography (CH2Cl2) produced an off-white solid as 4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g, 51%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:5][CH:4]=1.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH:37][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([S:15](=[O:16])(=[O:17])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:27]=[CH:28][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Phosphorus oxychloride (500 μL, 1.3 mmol) and N,N-dimethylformamide (704 μL, 9 mmol) were dissolved in 15 mL of anhydrous dichloromethane under stirring at room temperature, and the reaction solution was stirring for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5e (586 mg, 2 mmol) was dissolved in 8 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed. The reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution. The mixture was extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×5). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, yield 78.8%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](OC)=[O:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a solution of methyl 1-(tert-butoxycarbonyl)-1H-indole-3-carboxylate (2.5 g, 9.08 mmol) in anhydrous tetrahydrofuran (40 ml) was added 1.5 M diisobutylaluminum hydride-toluene solution (14 ml, 21 mmol) under ice-cooling, and the mixture was stirred for 2 hrs. An aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.3 g, 100%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38]([NH:40][CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][N:43]2C(OC(C)(C)C)=O)=[O:39])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]1[CH2:41][NH:40][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:56])([F:1])[F:55])=[CH:4][CH:5]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)n(COCC[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCCCN1)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A solution of tert-butyl 2-((5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamido)methyl)piperidine-1-carboxylate from step (a) above (200. mg, 0.247 mmol) in TFA:DCM (4:1) was stirred at RT for 7 min. The solvent was removed and the residue was added H2O (0.5 mL). Then, saturated NaHCO3 was added at 0° C. until pH ˜7 and the solvents were removed. The residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 582 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:3]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([N:16]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[S:17]([CH3:20])(=[O:19])=[O:18])[C:3]=1[CH3:21]
Reactant: COc1nc2cc(Cl)c(C)c(NS(C)(=O)=O)c2nc1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN(c1c(C)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of N-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide (694 mg, 2.09 mmol), potassium carbonate (347 mg, 2.51 mmol) and acetone (21 ml) was heated at reflux for 10 minutes and was then allowed to cool to room temperature. Methyl bromoacetate (396 μl, 640 mg, 4.19 mmol) was added and the mixture was heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with water and then brine and then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane to give N-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide as a white solid (407 mg, 48%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:32][C:26]1[CH:25]=[C:24]([C:18]2([C:20]([F:21])([F:23])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[CH:10][CH:11]=3)[CH2:19]2)[CH:29]=[C:28]([Cl:30])[C:27]=1[Cl:31]
Reactant: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.4 %

Procedure:
To a stirred suspension of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methyl ester (Preparation 11, 1.91 g, 3.77 mmol) in THF:MeOH:H2O (1:1:1, 60 mL) was added lithium hydroxide (0.791 g, 18.87 mmol) at room temperature and stirred at room temperature for 24 hours. After consumption of starting material, reaction mixture was concentrated in vacuo; suspension was diluted with water (20 mL) and acidified with 1N HCl up to pH ˜4. Acidified aqueous layer was extracted with ethyl acetate (5×50 mL). Combined organic layer washed with brine (150 mL), dried over sodium sulphate and evaporated under reduced pressure to afford yellow semi solid, which was triturated with chloroform:n-pentane (1:9) to afford yellow solid (1.57 g, 85%). 1H NMR (400 MHz, DMSO) δ: 3.49-3.52 (m, 1H), 3.90 (t, 2H, J=6.7 Hz), 4.04 (t, 2H, J=8.12 Hz), 4.13-4.25 (m, 2H), 6.46 (d, 2H, J=8.64 Hz), 7.48 (d, 2H, J=8.6 Hz), 7.79 (s, 2H); LC-MS (M+H): =492.60.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([OH:17])[C:6]=2[CH:7]=1)[CH3:2].I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1.[Cu]I>[CH3:26][N:25]([CH3:27])[C:23]([C:22]1[CH:28]=[CH:29][C:19]([O:17][C:8]2[C:6]3[CH:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=3[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2cc(CC)oc2c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.8 g, 3.4 mmol), 4-iodo-N,N-dimethylbenzamide (0.9 g, 3.3 mmol), Cs2CO3 (1.12 g, 3.4 mmol) and CuI (400 mg, 2.1 mmol) in pyridine (30 mL) was heated to 100° C. for 24 hours. TLC (petroleum ether/EtOAc 4:1) indicated the complete consumption of the phenol. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via silica gel column chromatography using petroleum ether/EtOAc (20:1 to 1:1) to afford the desired compound (400 mg, 30%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.56 (s, 1H), 7.43 (d, 2H), 7.00 (d, 2H), 6.27 (s, 1H), 4.44-4.35 (q, 2H), 3.15-3.04 (d, 6H), 2.83-2.78 (q, 2H), 1.45-1.37 (t, 3H), 1.37-1.26 (t, 3H).
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[S:35]([O-:39])([O-:38])(=[O:37])=[O:36]
Reactant: O=S(=O)(O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
A suitable reactor is charged with acetone (38 mL). The acetone solution is sequentially charged with carvedilol (10.25 grams) and water (6 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution, 1N aqueous sulfuric acid (1 equiv., 25.2 mL) is added. The reaction mixture is stirred at between 17° C. and 35° C. and the solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water at 2 volumes or 20.5 mL. The cake is then added a mixture of acetone and water (10 to 1) for ripening between 20° C.-35° C. over 24 hours to 48 hours. The slurry is filtered and the cake is dried under vacuum to a constant weight. The final weight is 5.48 grams.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[O:13]3)[C:6]=2[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C:16](=[O:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 74.6 %

Procedure:
To a solution of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38d, 3.3 g, 7.8 mmol) in THF (100 mL) was added Dess-Martine periodinane (3.68 g, 8.76 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 methanol in DCM) to afford 2.4 g crude product of 5-amino-3-[(2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxo-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38e). MS obsd. (ESI+) [(M+H)+]: 413.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].CO.O1CCCC1>O1CCOCC1.C(O)(=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:9](=[O:10])[NH:8][C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=3)=[CH:20][CH:21]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2cccnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1

Procedure:
16.7 g (0.0453 mol) of the product obtained in step b) were dissolved in 150 ml of absolute dioxane, and the resulting solution was admixed with 6.7 g (0.14 mol) of a 50% dispersion of sodium hydride in mineral oil. Thereafter, the mixture--while protected against the external atmosphere by a low flow of nitrogen--was refluxed until no starting material could be detected by TLC. The surplus of sodium hydride was decomposed by cautious addition of 10 ml of a mixture of methanol and tetrahydrofuran (50/50 v/v). The reaction mixture was neutralized by addition of acetic acid and then was evaporated in vacuo. The residue was purified by column chromatography on silica gel (0.2-0.5 mm) using successively dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/ethyl acetate 1/1 (v/v) as eluents. The crystalline product obtained by evaporation of suitable fractions was recrystallized from acetonitrile and 2-propanol. The product had a m.p. of 213°-215° C. and was identified as 5,11-dihydro- 11-[(4-methoxyphenyl)-methyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one. The yield was 10.3 g (68% of theory).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([C:19]2[NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:27]=2)=[O:18])[CH:11]=1)(=O)C1C=CC=CC=1>[OH-].[NH4+]>[NH:20]1[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:27]=[C:19]1[S:17]([CH2:16][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: O=C(Oc1cccc(CS(=O)c2nc3cnccc3[nH]2)c1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: O=S(Cc1cccc(O)c1)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[(1H-Imidazo[4,5-c]pyridin-2-ylsulfinyl)methyl]phenol benzoate (ester) (2.65 g, 0.007 mol) was dissolved in 260 mL of ammonium hydroxide. The reaction mixture was stirred for 1 1/2 hours at room temperature. The ammonia was removed in a rotary evaporator and the reaction mixture was chilled in ice. The precipitate that formed was collected on a filter and rinsed with water giving 1.70 g of product. (m.p. 224°-227° C.) (dec.).