Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:42])([F:41])[C:31]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][NH:33][N:32]=1>C(Cl)Cl.CN(C)C=O>[CH2:39]([O:38][C:36]([C:35]1[C:31]([C:30]([F:41])([F:42])[F:29])=[N:32][N:33]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 55 %

Procedure:
(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.57 mmol, 692 mg) was dissolved in DCM (10 mL), thionyl chloride (5.14 mmol, 0.373 mL, 611 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with dichloromethane (4×10 mL) to give a yellow oil. To this oil was added dimethylformamide (10 mL) and potassium carbonate (7.71 mmol, 1.07 g) followed by ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.57 mmol, 0.54 g). The mixture was heated to 70° C. with stirring for 1 h. The reaction was concentrated to remove DMF before partitioning between EtOAc/water. The phases were mixed and separated and the aqueous phase further washed with EtOAc (×2). Combined organics were dried and concentrated to give a light yellow oil which was purified on silica eluting with 30% EtOAc/heptane. Desired fractions were collected and concentrated to give (S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a colourless solid (0.65 g, 55.1%). 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H) 1.39 (d, 6H) 2.9 (m, 2H) 3.17 (sept, 1H) 3.30 (m, 2H) 4.30 (m, 4H) 5.29 (s, 2H) 7.12 (m, 2H) 7.24 (d, 1H) 7.89 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccc(Cl)cc5)c[nH]4)C3)nc(N)n2)cc1F
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 125.7 %

Procedure:
A mixture of 4-(2-amino-6-{2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-4-pyrimidinyl)-2-fluorobenzonitrile (155 mg, 0.326 mmol) and hydrazine (1.033 mL, 32.6 mmol) in ethanol (4 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The solvent was evaporated to get 200 mg of residue, which was purified by preparative HPLC to afford the title compound (19 mg) as a yellow powder. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.32-3.08 (m, 2H), 3.72 (t, J=11.2 Hz, 1H), 4.06-4.01 (m, 1H), 4.31-4.34 (m, 1H), 4.61 (d, J=14.0 Hz, 1H), 4.72 (bs, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.75 (s, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.76-7.46 (m, 3H), 7.81 (d, J=8.4 Hz 2H), 7.99 (s, 1H), 11.53 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:29][C@H:28]4[CH2:30][C@@H:25]3[CH2:26][O:27]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.O>[C@@H:28]12[CH2:30][C@@H:25]([N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]=34)[CH2:29]1)[CH2:26][O:27]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A suspension of (1R,4R)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (0.50 g, 1.2 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (50 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a gray foam (0.44 g, 93%). MS (ES+): 391.2 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[F:8][C:9]([F:29])([C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][OH:12].[H-].[Na+]>CN(C)C=O>[F:8][C:9]([F:29])([C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][O:12][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1
Reactant: CC1(CBr)COC1
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 66 %

Procedure:
In a manner similar to that described above, 12.0 grams of 3-bromomethyl-3-methyloxetane (73 mmol) was reacted with 26.5 grams of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol (72.7 mmol) in 300 milliliters of dimethylformamide in the presence of 3.9 grams of a 50 weight percent dispersion of sodium hydride (81 mmol) in mineral oil at 85° C. for 24 hours to give 21.5 grams (70% yield) of 3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxymethyl)-3-methyloxetane, a colorless oil with a boiling point of 66-68° C./2-2.5 mm-Hg; 1H NMR (CDCl3) δ4.50 and 4.36 (AB, J=5.5 Hz, 4 H), 3.78 (t, J=6.6 Hz, 2 H), 3.53 (s, 2 H), 2.42 (triplet of triplets, J=6.6 and 18 Hz, 2 H), and 1.31 (s, 3 H); 13C NMR (CDCl3) δ79.89, 78.30, 63.31, 39.9, 31.64 (t), and 21.1 (signals due to carbons bearing fluorines are not included due to the complex splitting patterns and low peak intensities); 19F NMR δ−81.4 (3 F), −113.8 (2 F), −118.2 (2 F), −112.3 (2 F), −124.1 (2 F) and −126.7 (2 F). The elemental analysis was: Calculated for C13H13F13O2: C, 34.8; H, 2.9; F, 55.1. Found: C, 35.1; H, 3.0; F, 54.7.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[N:27]1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:31]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)(=[O:33])=[O:32])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Add triethylamine (0.852 mL, 6.116 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.500 g, 1.529 mmol) in dichloromethane (10 mL). Add 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.331 g, 1.834 mmol) at room temperature. Stir at room temperature for 18 hr. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous layer with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 6:4 to 4:6 to afford the title preparation (0.514 g, 84% yield). MS ES: m/z=400 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([C:18]([N:20]2[CH2:25][C:22]3([O:24][CH2:23]3)[CH2:21]2)=[O:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[F:12].[N+:26]([NH:29][C:30]([NH2:32])=[NH:31])([O-:28])=[O:27].[OH-].[Na+].[ClH:35].O1CCOCC1>O1CCCC1.CO>[ClH:35].[F:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=2[F:12])=[C:13]([C:18]([N:20]2[CH2:21][C:22]([CH2:23][NH:32][C:30]([NH:29][N+:26]([O-:28])=[O:27])=[NH:31])([OH:24])[CH2:25]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(CO2)C1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N=C(NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)N[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a mixture of 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-(1-oxa-5-azaspiro[2,3]hex-5-ylcarbonyl)aniline (0.15 g, 0.33 mmol), prepared using procedures similar to those described in Example 21, and nitroguanidine (0.1 g, 1.00 mmol) in tetrahydrofuran (3.00 mL) an aqueous solution of sodium hydroxide (1.0 mL, 2.0 mmol) was added and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (80 μL, 0.33 mmol) was added to the solution. A white precipitate formed and was collected by filtration. The solid was washed with hexane, and dried to afford 76 mg (38%) 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidine hydrochloride. 1H NMR (400 MHz, d4-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H), 7.29 (m, 1H), 7.02 (m, 1H), 6.63 (m, 1H), 4.22 (m, 1H), 4.01 (m, 2H), 3.86 (m, 1H), 3.51 (d, 2H); MS (EI) for C18H16F3IN6O4: 565 (MH+).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1ccccc1F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3ccccc3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=230.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:19])[CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]>[Pt].C(OCC)(=O)C.CO>[N+:1]([C:4]1[C:5]([NH:14][CH2:15][C:16]2([OH:19])[CH2:18][CH2:17]2)=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:19])[CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1NCC1(O)CC1
Product: O=[N+]([O-])c1cc2ccccc2nc1NCC1(O)CC1
Reaction time: 3 h

Procedure:
A mixture of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol (3.50 g, 13.5 mmol) and 5% platinum on carbon (350 mg) in ethyl acetate (70 mL) and methanol (7 mL) was hydrogenated under 35 psi (2.4×105 Pa) on a Parr apparatus for 3 hours. The mixture was filtered through CELITE filter agent, which was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to yield 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopropanol 1-{[(3-nitroquinolin-yl)amino]methyl}cyclopropanol an orange oil that was used immediately in the next step.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[CH:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH3:20])[CH2:10][C:9]=12)[CH2:3][CH3:4]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:20][N:11]1[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]2[CH:7]=[N:6][C:5]([C:2](=[O:1])[CH2:3][CH3:4])=[C:9]2[CH2:10]1
Reactant: CCC(O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.84 g (6.8 mmol) of 4,5-dihydro-3-(1-hydroxypropyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 16 g of manganese dioxide and 150 ml of methylene chloride is stirred at room temperature under an argon atmosphere for 2 hours. The manganese dioxide is filtered off under suction over a glass filter and the filtrate is evaporated in vacuo. After recrystallisation of the residue from 100 ml of ethyl acetate, there is obtained 4,5-dihydro-5-methyl-3-propionyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 215°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42](O)=[O:43])=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:42]([C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=[CH:33][CH:34]=3)=[O:43])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: NC1CCC(CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1)c1ccnc2ccccc12

Procedure:
According to the procedure described in Example 22.5, the title compound was synthesized from Trans(4-{2-[4-(2,4-Difluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexylamine; trifluoro-acetic acid salt and quinoline-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:16][CH2:15][CH2:14][CH2:13][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClCCCBr
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCCCCl)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
With stirring at room temperature, 5.6 g (39.9 mmols) of 4-methoxythiophenol was added by small portions to 20 ml of a solution of 0.98 g (40.8 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 40 ml of a solution of 6.3 g (40.0 mmols) of 1-bromo-3-chloropropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further an hour. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate 3 times. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to afford 7.8 g (yield: 90%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:24][C:23]=4[CH3:37])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:28][C:27]1[CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:24]=[C:23]([CH3:37])[C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH:17]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of methyl[(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.438 g, 0.813 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.377 g, yield 88%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([S:34][CH2:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:26]([S:34][CH2:35][C@@H:36]([CH3:40])[C:37]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
4-Nitrophenol (10.2 g) and dicyclohexylcarbodiimide (15.2 g) are added successively to a solution of (2S)-3-(benzoylthio)-2-methylpropionic acid (15 g) in methylene chloride (100 ml) under ice-cooling. The mixture is stirred under ice-cooling for 30 minutes and at room temperature for 4.5 hours. The resulting precipitate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained oily residue is purified by silica gel column chromatography to give 26.01 g (quantitatively) of the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[C:8]12([CH2:21][CH2:20][CH2:19][CH2:18]1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10](=[O:17])[CH2:9]2.C1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1([OH:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:9]1
Reactant: COCCCBr
Reactant: O=C1CC2(CCCC2)c2ccccc21
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COCCCC1(O)CC2(CCCC2)c2ccccc21

Procedure:
The Grignard reagent is prepared from γ-methoxypropyl bromide (30.6 g; 0.2 moles) and magnesium flakes (4.8 g; 0.2 gram-atoms) in tetrahydrofuran and reacted with spiro(cyclopentane-1,1'-indane)-3'-one (18.6 g, 0.1 moles) in a manner analogous to example 1. The reaction product is shaken out with benzene, the combined benzene solutions are dried with anhydrous magnesium sulphate and the solvent is distilled off in vacuum. 3'-γ-methoxypropyl-spiro(cyclopentane-1,1'-indan)-3'-ol is obtained as a yellowish oil (yield 27.1 g). The crude methoxy compound is refluxed for 62 hours with 48% hydrobromic acid (50 ml) and acetic acid (100 ml). The solution is concentrated in vacuum, ether is added to the oil obtained, and then the solution is washed with water and 2 N sodium hydroxide solution. After drying with magnesium sulphate the solvent is distilled off and a brown oil is obtained, which essentially consists of 3'-γ-bromopropyl-spiro(cyclopentane-1,1'-indene). The compound can be purified by distillation in vacuum and is then obtained as a colourless oil of mp, 148° C./1 mm Hg. nD25 =1.5769.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1N
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 103.3 %

Procedure:
Dibenzylamine (1.95 mL, 10 mmol), triethylamine (1.37 mL, 10 mmol), 4-amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethyl ester (2.45 g, 10 mmol) and toluene (73 mL) were combined and heated at reflux over night. The reaction mixture was cooled to room temperature and filtered through a short column of silica gel (eluting first with dichloromethane then ethyl acetate). The organics were concentrated to provide 10 as a yellow oil (4.2 g). 1H NMR (400 MHz, d6-DMSO) δ: 1.28 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 4H), 7.14–7.31 (m, 10H), 8.35 (s, br, 2H), 8.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21][C@H:12]1OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[FH:52].F.F.C(N(CC)CC)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:21][C@@H:12]1[F:52]
Reactant: O=S(=O)(O[C@@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21)C(F)(F)F
Reactant: F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: F[C@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.8 %

Procedure:
22.9 mg (0.0356 mmols) of 6-chloro-9-[2-O-(trifluoromethanesulfonyl)-3-deoxy-5-O-(triphenylmethyl)-β-D-erythro-pentofuranosyl]-9H-purine was dissolved in 2.0 ml of toluene, to which were added 10.8 mg (0.107 mmols) of triethylamine and 34.5 mg (0.214 mmols) of triethylamine trihydrofluoride, and stirred at room temperature for about 5 days. After having been cooled, all the mixture was dissolved in methanol, and analyzed through liquid chromatography. The intended product was obtained at an yield of 57.8%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[N:34]2[N:35]=[C:36]([C:38]([OH:40])=O)[CH:37]=[C:33]2[N:32]=[C:31]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH:30]=1.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:49]([NH:56][C:38]([C:36]1[CH:37]=[C:33]2[N:32]=[C:31]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[CH:30]=[C:29]([NH2:28])[N:34]2[N:35]=1)=[O:40])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCc1ccccc1
Reactant: Nc1cc(-c2ccc(Cl)c(Cl)c2)nc2cc(C(=O)O)nn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)nc2cc(C(=O)NCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.081 g, 0.184 mmol) was added to a suspension of 7-amino-5-(3,4-dichloro-phenyl)-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.050 g, 0.154 mmol) and benzylamine (0.034 mL, 0.308 mmol) in tetrahydrofuran (5 ml) containing triethylamine (0.064 mL, 0.462 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (5 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography to give 7-amino-5-(3,4-dichloro-phenyl)-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.026 g, 55%).