Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30]3([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]3)[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(N)=O)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (1.68 g, 6.81 mmol) was added to a suspension of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarboxamide (1.70 g, 5.24 mmol) in chloroform (25 mL); the reaction was stirred for two hours at ambient temperature and then cooled to 0° C. Ammonium hydroxide (5 mL) and p-toluenesulfonyl chloride (1.10 g, 5.76 mmol) were added. The reaction was stirred for one hour at 5° C. and then filtered to isolate a precipitate. The precipitate was triturated with 2 M aqueous sodium hydroxide, isolated by filtration, triturated with hot acetonitrile, isolated by filtration, and recrystallized from ethanol. The crystals were dried overnight at 85° C. in a vacuum oven to provide 0.78 g of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanecarboxamide as tan needles, mp 230.5-232.5° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]1=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of ethyl 3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (4.4 g) under ice-cooling. The reaction mixture was stirred for 10 minutes, to which was added benzyl bromide (2.4 g). The reaction mixture was stirred at room temperature for 3 hours, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (3.6 g).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl.N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:20])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C2(N)CC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)NC1(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 0 °C

Procedure:
3 g of tert-butyl 4-(1-aminocyclopropyl)benzoate was placed in 30 mL of dichloromethane and 1.8 mL of pyridine. The solution was cooled to 0° C. and 1.2 mL of allyl chloroformate (dissolved in 5 mL of dichloromethane) was added dropwise at 0° C.-5° C. The mixture was left to react for 30 minutes at 0° C. and 2 hours at RT. The solution was combined with silica gel and evaporated down to the residue. This was chromatographed with dichloromethane on silica gel 70. Yield: 1.46 g of oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].O.[C:14](OCC)(=O)[CH3:15]>C1COCC1>[OH:2][CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:14][CH3:15]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
5-Formyl-2,2'-bithiophene (3 g) was dissolved in THF (50 ml) and ethyl-magnesium bromide Grignard reagent (9.3 ml) was added dropwisely under nitrogen gas atmosphere in ice bath and stirred for 1 hour. The mixture was stirred for 1 hr. and then continuously stirred at room temperature. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (30 ml) and ethyl acetate (200 ml) were added to the mixture and extracted and purified by column chromatography, eluted with ethyl acetate/n-hexane (1/9). Light yellowish product was thus obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0 mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and add propionyl chloride dropwise at RT. After stirrng overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the organic solvent down to a residue, treat with ether, collect the solid: mass spectrum (APCI) (m/e): 248.1 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23-7.15 (m, 4H), 4.73 (d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[BH3-]C#[N:14].[Na+]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:14]
Reactant: Cc1cccc2c1CCC2=O
Reactant: [BH3-]C#N
Agent: [Na+]
Product: Cc1cccc2c1CCC2N

Procedure:
The title amine was generated from 4-methyl-indan-1-one (5.00 g, 34.20 mmol), NaBH3CN (15.00 g, 0.24 mol) and NH4OAc (79.00 g, 1.02 mol) according to the protocols as outlined in general procedure B described above.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-1H-indole (2.5 g, 12.8 mmol) in DMF (10 ml) was slowly added NaH (354 mg, 14.0 mmol) at room temperature. The resulting mixture was stirred for 20 min at RT after which MeI (956 μl, 15.4 mmol) was added. The mixture was stirred for 1 hour at room temperature and then partitioned between DCM and brine. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 6-Bromo-1-methyl-1H-indole CXLII in quantitative yield (2.7 g).
Reaction SMILES: ClC[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]1([S:18]([O-:21])(=O)=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].O.[CH3:24]N(C=O)C>>[C:12]1([S:18]([C:3]2[O:4][C:5]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:24])[C:6]=3[N:7]=2)(=[O:21])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: ClCc1nc2ccccc2o1
Reactant: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Product: Cc1cccc2oc(S(=O)(=O)c3ccccc3)nc12
Temperature: 70 °C

Procedure:
33 g (0.2 mole) of 2-chloromethylbenzoxazole and 32.8 g of sodium benzene sulfonate were dissolved in 200 ml of DMF, heated within one-half hour to 70° C., for 1 hour at 70° C., for 1 hour to 80° C. and for 1 hour to 90° C., and after cooling, allowed to flow into 300 ml of H2O, while stirring well. The reaction mixture was filtered with suction, washed well with H2O and dried. 48.8 g (98.4 % of the theory) were obtained. After recrystallization from ethanol, 41 g of colorless cristals melting at 108° to 109° C. were obtained. ##STR28##
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[CH:16][CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:16][CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27]
Reactant: CC(C)N
Reactant: COc1ccc2cc(CCc3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1
Product: COc1ccc2cc(CCc3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1
Yield: 77 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)=[C:9]([CH:21]2[O:25]CCO2)[CH:8]=1.CON(C)[C:29](=[O:31])[CH3:30]>C1COCC1>[C:29]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18]2)=[C:9]([CH:8]=1)[CH:21]=[O:25])(=[O:31])[CH3:30]
Reactant: CON(C)C(C)=O
Reactant: CC1CN(c2ccc(Br)cc2C2OCCO2)CC(C)O1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CC(C)OC(C)C2)c(C=O)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
t-Butyl lithium in hexanes (3.8 ml of a 1.7 M solution, 14.5 mmol) is added to THF at −78° C. in a flame dried round-bottomed flask. 4-[4-Bromo-2-(1,3-dioxolan-2-yl)phenyl]-2,6-dimethylmorpholine (from Step 2) (1.0 g, 2.9 mmol) is dissolved in THF (5 mL) and is slowly added to the t-BuLi solution over 7 minutes keeping the temperature below −70° C. The mixture is stirred for 30 minutes and N-methoxy-N-methyl-acetamide (0.34 mL, 3.2 mmol) is slowly added dropwise. The reaction is stirred at −78° C. for 30 minutes and then stored at 0° C. overnight. The reaction is quenched with 1 M HCl (22.5 mL) and then heated at 65° C. for 1 hour. The mixture is basified with 1 M aqueous Na2CO3 and extracted with EtOAc (2×). The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. The resulting residue is adsorbed onto silica gel and purified by silica gel chromatography using 15-20% EtOAc in heptane as the eluent to afford 0.35 g (45%) a clear oil. 1H NMR (400 MHz, CDCl3) δ 10.1, 8.35, 8.12, 7.08, 3.93, 3.25, 2.76, 2.60, 1.25.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5](CN(CC)CC)C=[CH:7][C:8]=1[Cl:9].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1.[CH2:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:26]>C(O)C>[Cl:9][C:8]1[CH:7]=[C:26]([CH2:25][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:5]=[CH:4][C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN(CC)CC
Reactant: CCN(CC)Cc1ccc(Cl)c(CBr)c1
Solvent: CCO
Product: CCN(CC)Cc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of {[3-(bromomethyl)-4-chlorophenyl]methyl}diethylamine (13.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.07 g, 7.5 mmol), and triethylamine (8 mL, 57.4 mmol) in absolute ethanol (50 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solution was extracted with dichloromethane (5×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-15% MeOH/CH2Cl2), affording the title compound (932 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.11 (t, 6H, J=6.8 Hz), 2.21 (s, 3H), 2.86 (m, 4H), 4.09 (s (br), 2H), 4.45 (s, 2H), 6.01 (s (br), 1H), 7.45 (m, 1H), 7.52 (m, 1H), 7.72 (s, 1H); M+ 352.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:38])(=[O:37])[N:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:23]([N:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Reactant: BrCc1ccccc1
Product: O=S(=O)(c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using general procedure H with the above aniline (970 mg, 1.81 mmol) and benzyl bromide (0.66 mL, 5.52 mmol) followed by general procedure C afforded N,N-dibenzyl-4-(benzyl-piperidin-4-yl-amino)-benzenesulfonamide as a white solid (679 mg, 72% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:8][CH2:7]1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=2)[CH:36]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:40]([C:38]3[N:39]=[C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]4[CH:37]=3)=[O:41])[CH2:14]2)[CH2:8][CH2:7]1
Reactant: O=C(Cl)c1cn2cc(F)ccc2n1
Reactant: Clc1ccc(OC2CCN(CC3CNCCO3)CC2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cn2cc(F)ccc2n1)N1CCOC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 2 h
Yield: 8.2 %

Procedure:
The product of Example 2, Step (c) (0.2 g) was dissolved in dichloromethane (4 ml) and triethylamine (0.16 ml) added. The product of Step (c) (0.12 g) was then added and the reaction stirred for 2 hrs. Saturated aqueous NaHCO3 solution was added and the product was extracted with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH3(aq) (0.1%) to 95% MeCN/NH3(aq) (0.1%)) gave the title compound (0.024 g).
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:14])=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2].[Br:31]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[C:1]([N:3]=[S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:20](=[O:21])[C:19]([Br:31])=[C:18]([CH3:22])[N:17]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:14])=[CH:29][CH:30]=1)([CH3:6])=[O:5])#[N:2]
Reactant: Cc1cc(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-methyl-1-(2-methyl-2H-pyrazol-3-yl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-(N-cyano-S-methylsulfonimidoyl)-benzylamide (preparation 4b, 150 mg, 0.118 mmol) in dichloromethane (2 mL) is added N-bromosuccinimide (21 mg, 0.35 mmol) and five drops of glacial acetic acid. After stirring for 18 h at room temperature the reaction mixture is concentrated under reduced pressure and purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 40 mg (23% of theory); ESI mass spectrum: [M+H]+=503 (bromine isotope pattern); r.t. HPLC: 0.82 min (Z012_S04).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21]O)[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:65]=[N+:66]=[N-:67])=O)=CC=1>C1COCC1>[N:65]([CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[CH:10]=[CH:9]2)[CH2:12]1)=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (2.68 g, 8.28 mmol) was dissolved in THF (32 mL), treated with PPh3 (3.05 g, 11.6 mmol), and the reaction vessel was cooled in an ice-brine bath. Diisopropyl azodicarboxylate [DIAD] (2.3 mL, 12 mmol) was added dropwise via syringe and the mixture was stirred for 10 min. A solution of diphenylphosphonic azide [DPPA] (2.50 mL, 11.6 mmol) in THF (7.8 mL) was added dropwise via syringe to afford a off-white mixture, which was stirred for 21 h, allowing the ice bath to warm to RT; HPLC/LC MS indicated complete consumption of starting material and formation of product. At 22.5 h the reaction mixture was concentrated in vacuo and purified by column chromatography (4×22 cm silica; 0-25% EtOAc/Hex) to afford the title compound (2.27 g, 78%) as a clear, colorless oil: MS (ESI+) for C15H17ClN6O2 m/z 349.2 (M+H)+; MS (ESI−) for C15H17ClN6O2 m/z 393.2 (M+HCO2)−; HPLC purity >95% (ret. time, 4.169 min).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:51])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(O)C>[Pd].C(Cl)Cl.CO>[C:47]([O:46][C:44]([CH:24]1[CH2:25][CH:26]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:37])=[O:36])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:51])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 59.4 %

Procedure:
A The process is performed as described in Example 2A, but starting with 2.5 g of (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-morpholinosulphonylpyrrolidine, 0.25 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 1.3 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-morpholinosulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.43; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:18]=[CH:19][CH2:20]O)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH:19]=[CH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC=Cc1nc(-c2ccc(F)cc2)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
258 μl (3.3 mmol) of methanesulfonyl chloride were slowly added to 265 mg (1.12 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)prop-2-en-1-ol and 456 mg (4.5 mmol) of triethylamine in 10 ml of dichloromethane at room temperature and the mixture was stirred for 3 h. After standing at room temperature over the weekend, the mixture was extracted with a sodium hydrogencarbonate solution. Evaporation of the organic phase yielded 280 mg of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][CH3:29])=[C:11]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=3[N:18]=2)[CH:12]=1>N1C=CC=CC=1>[CH2:28]([O:27][C:10]1[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(C)(=O)=O)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
Methanesulphonyl chloride (0.157 g, 0.00137 mol) was added to a stirred solution of 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.45 g, 0.00137 mol) in dry pyridine (30 ml) at 0° C. The mixture was stirred for 18 hours at room temperature and then evaporated under vacuum. The residue was suspended in saturated aqueous sodium bicarbonate solution (50 ml) and the mixture extracted with dichloromethane (2×30 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) an evaporated under vacuum. The residue was triturated with ether, chromatographed on silica gel (12 g), eluting with a 98.5:1.5 mixture of dichloromethane and methanol, and the required product crystallised form ethyl acetate-hexane to give the title compound as a white powder (0.32 g, 58%), m.p. 205°-206° C. Found: C,53.63; H,5.66; N,17.24. C18H23N5O4S requires C,53.32; H,5.72; N,17.27%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:12])[C:8]([F:11])([F:10])[F:9].[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18](Cl)[CH:17]=[CH:16][N+:15]=1[O-:23]>O>[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:12][CH2:7][C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][N+:15]=1[O-:23]
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Temperature: 0 °C

Procedure:
6.7 g of potassium tert-butoxide were added in portions, at -20° C., while stirring and under a nitrogen atmosphere, 5 to 20 ml of trifluoroethanol. After the mixture had been warmed to 0° C., 5.2 g (30 mmol) of 2-methyl-3-methoxy-4-chloropyridine N-oxide were added in portions. The mixture was heated under reflux for 3 hours, and then left to cool down to room temperature; a further 3.45 g of potassium tert-butoxide were then added and the mixture was heated under reflux for 2 hours. After it had cooled down, 40 ml of water were added to the reaction mixture, which was then extracted with dichloromethane; the extract was then dried over MgSO4 and freed from the solvent in vacuo. The resulting oily product was subjected to further reaction.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:17](=[O:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC#CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27 (4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride (3.0 mL, 31.8 mmol). After 18 h, the solvent was evaporated and the residue co-evaporated with toluene. The residue was used directly in the next step.