Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.N>ClCCl>[O:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]3\[C:5](=[O:25])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: N
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(N2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-morpholinoaniline in dichloromethane and subsequent treatment with methanolic ammonia.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]([NH:17][C:18]([C:20]2[NH:29][C:23]3=[CH:24][N:25]=[C:26]([Cl:28])[CH:27]=[C:22]3[CH:21]=2)=[O:19])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[H-].[Na+]>CN(C=O)C>[CH2:32]([O:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C@@H:7]([NH:17][C:18]([C:20]2[NH:29][C:23]3=[CH:24][N:25]=[C:26]([Cl:28])[CH:27]=[C:22]3[CH:21]=2)=[O:19])[CH2:6][C:5]2[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(OCc2ccccc2)CC1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 16 h

Procedure:
To 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide (EXAMPLE 5, 50 mg, 0.11 mmol) in anhydrous DMF (3 mL) under argon was added benzylbromide (16 μl, 0.13 mmol) followed by sodium hydride (6.3 mg, 0.16 mmol) and the reaction stirred for 16 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate (2×20 mL) and water (20 mL). The organic fractions were washed with 1M HCl (20 mL), NaHCO3 (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Crude material was purified by chromatography on silica gel with dichloromethane/methanol (9:1) as the eluent to give the title compound as an off-white powder. m/z (ES+)=535.33 [M+H]+; RT=3.44 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:22])=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[CH:14][C:4]=2[O:3]1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:23][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:22][C:31](=[O:32])[CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: O=C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)c1cc(OC(=O)CN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-7-(2-heptyl)-9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran with methyl magnesium bromide in a procedure similar to that described hereinabove in Example 8, there is obtained 1,2-dihydro-4,4-dimethyl-7-(2-heptyl)-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide to yield the desired ester.
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:13][C:12](=[O:26])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(O)C>[CH2:3]([N:10]1[CH2:11][CH:12]([OH:26])[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)[CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=C(c2ccc(C(F)(F)F)cc2)CN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: OC1C=C(c2ccc(C(F)(F)F)cc2)CN(Cc2ccccc2)C1
Yield: 72.8 %

Procedure:
A solution of 1-benzyl-1,6-dihydro-5-(p-trifluoromethylphenyl)-3-(2H)pyridone hydrochloride hydrate (11.6 g) in ethanol (250 ml) was treated with sodium bicarbonate (2 g) followed by sodium borohydride (1.5 g). After 2 hours the solvents were removed under reduced pressure and the residue partitioned between water (100 ml) and ether (400 ml). The organic phase was dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (7.3 g), m.p. 88°-90°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1I)#[N:2].[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1[C:38]1[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:2]
Reactant: OB(O)c1cccnc1F
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccccc2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccccc2)cc1-c1cccnc1F
Reaction time: 0.08 h
Yield: 28.3 %

Procedure:
10 mg (0.02 mmol) of 3-cyano-4-((4-iodo-6-phenylpyridin-3-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (2-fluoropyridin-3-yl)boronic acid was added thereto, and then 2.0 mg (10 mol %) of Pd(PPh3)4, 5.6 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 3 mg (30% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([CH:10]2[OH:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOCC.O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([C:10]2=[O:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dichloro-9-hydroxy-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (3.03 g, 0.089 mol) in a mixture of acetone (75 ml), ether (75 ml) and water (7 ml) cooled to 5° C. was added Jones reagent (3.4 ml, 2.67N). The reaction mixture was stirred for 1/2 hour at 5° C. then for 11/2 hours at 25° C. The reaction mixture was diluted with ether and H2O, the ether layer washed with NaHCO3, dried over MgSO4, evaporated and chromatographed on silica gel eluting with ethyl acetate-hexane (1:1.5) to give 5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3,9-dione which melts at 167°-9° C.
Reaction SMILES: C(Cl)(Cl)Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].COC1C=C([C@H:23]2[C@H:32]3[C:33]([O:35][CH2:36][C@@H:31]3[C@@H:30]([OH:37])[C:29]3[CH:28]=C4OCOC4=CC2=3)=O)C=C(OC)C=1OC>O1CCCC1.Cl>[CH:31]12[CH:32]3[CH:33]([CH2:28][CH2:29][CH:30]1[O:37][CH2:23]3)[O:35][CH2:36]2
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C1CC2OCC3C1OCC23
Yield: 220.6 %

Procedure:
187 mg of podophyllol ([α]D25=−180° (CHCl3, c 0.7)) incorporating two methyleneoxy bridges was prepared by the lithium aluminum hydride reduction of 205 mg of podophyllotoxin in dry tetrahydrofuran. Five drops of 1N aqueous hydrogen chloride was added to a solution of 185 mg of the podophyllol. The resulting mixture was stirred and heated to reflux under an atmosphere of nitrogen for 1 h. Thin layer chromatography on silica gel eluted with ethyl acetate indicated no podophyllol (Rf 0.35) remained. After cooling the mixture, it was washed three times with 15 mL portions of water. The combined aqueous wash was extracted three times with 10 mL portions of ethyl acetate. The combined ethyl acetate extract was added to the chloroform solution and the resulting mixture was washed once with 10 mL of water and then 10 mL of brine, and thereafter dried over anhydrous magnesium sulfate. Removal of the magnesium sulfate by filtration and evaporation of the solvent from the filtrate at reduced atmospheric pressure gave 153 mg of the 6-oxabicyclo[3.2.1]octane ([α]D=+183° (CHCl3, c 2.9); Rf 0.60, ethyl acetate) wherein the oxygen of the methyleneoxy bridge had bonded to the benzylic carbon. This intermediate was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][O:32][C:33](=[O:35])[N:34]=3)=[CH:20][CH:19]=2)[C:6]2=[N:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][O:32][C:33](=[O:35])[N:34]=3)=[CH:22][CH:23]=2)[C:6]2=[N:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C(=O)OC)nc2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C(=O)O)nc2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a suspension of the compound (0.9 g) obtained in Example (56g) in methanol (20 ml) was added 1N aqueous solution of sodium hydroxide (4.5 ml), and the mixture was stirred for 3 hours at 60° C. To the reaction mixture was added 1N HCl to adjust the pH to 3-4. Resulting crystalline precipitates were collected by filtration and dried. Crude crystals thus obtained were recrystallized from ethyl acetate--methanol afforded the title compound as colorless crystals (0.61 g, 69%), m.p.261°-164° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH:19][CH2:20][CH:21]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>C1C=CC=CC=1.[Ag]=O>[F:18][C:14]1[CH:13]=[C:12]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:19][CH2:20][CH:21]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:36]=4)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]=3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1cccc(-c2nc3c(CBr)cccc3s2)c1
Reactant: COC(=O)CCCCC(CO)Cc1ccc(C(=O)OC)cc1
Agent: O=[Ag]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCCCC(COCc1cccc2sc(-c3cccc(F)c3)nc12)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under argon, 102.8 mg (0.32 mmol) of 4-bromomethyl-2-(3-fluorophenyl)-benzothiazole and 300 mg of MS3A are dissolved in 5 ml of benzene. At room temperature, 82 mg (0.27 mmol) of methyl 6-hydroxymethyl-7-(4-methoxycarbonyl-phenyl)heptanoate (synthesis cf. EP-A-0 341 551, p. 31, Ex. 42) and 92 mg (0.40 mmol) of silver oxide are added. The mixture is stirred at room temperature for 6 days. About 0.2 ml of water is added, the mixture is filtered through Extrelut, which is washed with toluene, and the filtrate is concentrated under reduced pressure and chromatographed.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cn1
Yield: 93.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylate (0.35 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylic acid as crystals (0.31 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 151-152° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29][CH2:28]CC[C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.[Cl:31]C1C=C(C2N3C(=CC=N3)N=C3C=2CCC3)C=CC=1OCCCCl.C[C@@H]1CCCN1>>[Cl:31][C:12]1[CH:13]=[C:14]([C:17]2[N:18]3[C:22](=[CH:21][CH:20]=[N:19]3)[N:23]=[C:24]3[C:25]=2[CH2:28][CH2:29][CH2:30]3)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1Cl
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1Cl

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[(3-chloro)-4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 2-(R)-methyl-pyrrolidine provided the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:31]1[CH:35]=[CH:34][CH:33]=[CH:32]1.[Na+].[I-].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][CH2:25][N:31]1[CH:35]=[CH:34][CH:33]=[CH:32]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1cc[nH]c1
Reactant: CCCCOC(=O)N1C[C@H](SCc2ccc(OC)cc2)C[C@H]1CCCOS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1C[C@H](SCc2ccc(OC)cc2)C[C@H]1CCCn1cccc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 130 mg (0.257 mmol) (2R,4R)-2-(3-methane-sulfonyloxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester, 0.037 ml (0.514 mmol) pyrrole and 38.6 mg (0.257 mmol) NaI in 0.4 ml DMF was treated at 0° C. with 22.4 mg (0.514 mmol) 55% NaH and warmed up over night to room temperature. The reaction was neutralized with cooled aqueous saturated NH4Cl and extracted (EtOAc 3×). The organic phase was washed with aqueous 10% NaCl, dried (Na2SO4) evaporated and purified by flash silica gel column (Hexane/EtOAc 9:1) to give 75 mg (68%) of (2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(3-pyrrol-1-yl-propyl)-pyrrolidine-1-carboxylic acid butyl ester, MS: 431 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([Br:27])[CH:33]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(O)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(Br)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 65B and 3-bromophenylboronic acid were processed as described in Example 48A to provide the title compound. MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:12])[CH:6]([OH:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2ccccc2C1O

Procedure:
To a solution of 2,2-dimethyl-benzofuran-3-one (1.58 g, 9.7 mmol) in methanol (30 mL) at 0° C. is added NaBH4 (0.36 g, 9.7 mmol). The reaction is placed at room temperature and another equivalent of NaBH4 (0.36 g, 9.7 mmol) is added. After three hours the reaction is quenched with saturated aqueous NH4Cl. The reaction is concentrated to approximately ¾ of its original volume, diluted with ethyl acetate, and washed with 2N aqueous HCl, followed by brine. The organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:8) to provide 2,2-dimethyl-2,3-dihydro-benzofuran-3-ol; 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 3 H), 1.49 (s, 3 H), 1.96 (d, J=8.6 Hz, 1 H), 4.71 (d, J=8.6 Hz, 1 H), 6.79 (d, J=8.1 Hz, 1 H), 6.87-6.95 (m, 1 H), 7.21-7.26 (m, 1 H), 7.39 (d, J=7.3 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.I[CH3:14].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][O:12][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of (3-bromo-5-nitrophenyl)methanol (500 mg, 2.155 mmol) in DMF (7.2 mL) was added iodomethane (0.40 mL, 6.46 mmol. The solution was cooled to 0° C. before NaH (60% dispersion in mineral oil, 172 mg, 4.31 mmol) was added. The reaction was stirred at 0° C. and allowed to come to room temperature. After 2 hours the reaction was quenched with water and ethyl acetate was then added. Extraction was done with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate and then filtered. Ethyl acetate was then removed in vacuo to afford 1-bromo-3-(methoxymethyl)-5-nitrobenzene (470 mg, 1.910 mmol, 89% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 4.53 (s, 2H), 3.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][C:10]3(OCC[O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Temperature: 70 °C
Reaction time: 64 h

Procedure:
To a mixture of Compound [XXXVI] (3.25 g, 7.85 mmol, 1.0 eg.) in acetone (300 mL), was added p-toluenesulfonic acid (1.49 g, 7.85 mmol, 1.0 eq.) with stirring and heated to 70° C. After 64 hours at 70° C., the reaction was cooled and poured into saturated aqueous NaHCO3 and extracted with ethyl acetate (×3). The combined organic phases were concentrated and the resulting residue purified by silica gel chromatography eluting with heptane and ethyl acetate (gradient of 0% to 40% ethyl acetate) to give Compound [XXXVII]: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.92-4.01 (m, 2H) 4.20-4.33 (m, 2H) 7.44-7.52 (m, 4H) 7.74 (dd, J=5.37, 3.12 Hz, 2H) 7.84 (dd, J=5.54, 3.00 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH3:21].C(O)C.C(=O)=O.[Li]CCCC.[I:35]I>CCCCCC.C1COCC1>[I:35][C:6]1[N:7]([CH3:21])[C:8]2[C:4]([N:5]=1)=[C:3]([C:2]([F:1])([F:22])[F:23])[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:9]=2
Reactant: Cn1cnc2c(C(F)(F)F)nc(NCCc3ccccc3)nc21
Reactant: II
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(I)nc2c(C(F)(F)F)nc(NCCc3ccccc3)nc21
Yield: 91.3 %

Procedure:
6-Trifluoromethyl-9-methyl-2-phenethylaminopurine (compound 10) (0.500 g, 1.56 mmol) was dried in vacuo at 100° C. for 2.5 h. After cooling, dry THF (18 ml) was added at room temperature and the solution was cooled to −72° C. (ethanol/dry ice). After addition of n-BuLi (2.4 ml of a 1.6 M solution in hexane, 3.9 mmol) the colourless solution turned yellow. After 15 minutes I2 (0.633 g, 2.49 mmol) was added and after 5 minutes the reaction was complete (HPLC: Rt,product=4.7). To the red solution silica gel (˜4 g) was added and the suspension was evaporated to dryness. Flash chromatography (1% MeOH in MTBE) and freezedrying afforded the product (0.637 g, 91%) as fluffy white crystals, mp 139-142° C. 1H-NMR (400 MHz, CDCl3), δ [ppm]: 7.33-7.21 (m, 5H, Har), 5.96 (br s, 1H, NH), 3.93 (br m, 2H, NHCH2), 3.77 (s, 3H, CH3), 2.98 (t, J=7.1 Hz, 2H, CH2). 19F-NMR (500 MHz, CDCl3), δ [ppm]: −70.12 (6-CF3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (1.22 g, 3.05 mmol) and lithium hydroxide monohydrate (641 mg, 15.3 mmol) in methanol (30 ml) and water (5 ml) is stirred for 6 hours at 50° C. The solvent is evaporated, the residue diluted with water, acidified to pH=0 with 2N aqueous hydrochloric acid. The precipitated solid is collected by filtration, washed with ethyl acetate and dried affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (851 mg, 75%) as a light yellow solid. MS: m/z=369.9 (M−H+).