Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl>[OH-].[Na+]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc3[nH]ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cccc3[nH]ccc23)cc1
Yield: 65.7 %

Procedure:
0.15 g (0.00045 mol) of N-[4-(1H-indol-4-ylsulfamoyl)-phenyl]-acetamide was dissolved in 4 ml of 1N NaOH and boiled at reflux for 1 hour. After cooling the mixture was adjusted to pH 6 with 0.1N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed with copious water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.085 g (66%) of 4-amino-N-(1H-indol-4-yl)-benzenesulfonamide as a white amorphous solid; m.p.: 215° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.I(O)(=O)(=O)=O.OS(O)(=O)=O.II.[CH3:45][C:46]([OH:48])=O>>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]3[C:46](=[O:48])[C:45]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:26]3=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: CC(=O)O
Agent: II
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc21
Reaction time: 3 h

Procedure:
(S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (300 mg, 0.683 mmol) was taken up in AcOH (15 mL) and treated with periodic acid (156 mg, 0.683 mmol) and H2SO4 (0.018 mL, 0.341 mmol). The reaction mixture was heated to 80° C. for 20 min after which time iodine (104 mg, 0.410 mmol) was added and heating was continued for an additional 3 h. After cooling, the volatiles were evaporated. The residue was taken up in ethyl acetate (25 mL) and organic layer was washed with saturated aqueous NaHCO3 (10 mL), then brine (10 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-(1-(4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (300 mg, 0.61 mmol, 90% crude yield) as a brown solid. This was taken to the next step without further purification. LC/MS (ESI) m/e 466.1 [(M+H)+, calcd for C20H25IN3O2 466.1]; LC/MS retention time (method F): tR=0.58 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:29](Cl)(OC1C=CC=CC=1)([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([PH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@H](C(=O)OCCOC(=O)C(C)C)[PH](=O)Oc1ccccc1
Yield: 91 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (2-methylpropanoyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (29) (1.0 g, 2.4 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.46 mL (1.9 g, 7.0 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.17 g, 1.4 mmol) and triethylamine (TEA) (0.97 mL, 0.71 g, 7.0 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 1.2 g (80% yield) of the title compound (49a) as a colorless oil. Rf=0.55 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.15 (m, 12H), 1.40-1.46 (2d, J=5.6, 5.6 Hz, 3H), 1.85 (s, 3H), 2.01-2.08 (m, 2H), 2.45-2.55 (m, 1H), 3.13-3.17 (m, 2H), 3.28-3.33 (m, 2H), 3.97-4.04 (m, 2H), 4.84-4.88 (2d, J=7.2, 7.6 Hz, 1H), 6.32-6.36 (br. m, 1H), 6.88-6.93 (m, 1H), 7.18-7.26 (m, 6H), 7.31-7.38 (m, 4H) ppm. MS (ESI) m/z 658.25 (M+H)+. The analytical data was consistent with proposed structure.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C>[CH3:4][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][CH2:22][N:23]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:28]([F:30])([F:31])[F:29])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
7-{5-[4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 19) (160 mg, 0.353 mmol), DIPEA (0.234 ml, 1.342 mmol) and ethyl 4-bromobutanoate (0.110 ml, 0.767 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 h, and allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.055 ml, 0.383 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (183 mg, 0.310 mmol) as an orange solid. MS (ES): C28H32F3N3O4 requires 531; found 532 [M+H]+.
Reaction SMILES: C(O[CH:5]1[O:28][CH2:27][C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:15]([O:16][CH3:17])[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Si]([C:33]#[N:34])(C)(C)C.B(F)(F)F.CCOCC>[N+](C)([O-])=O>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH3:17])[C@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][O:28][CH:5]1[C:33]#[N:34])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO[C@H]1[C@H](OCc2ccccc2)COC(OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CO[C@H]1[C@H](OCc2ccccc2)COC(C#N)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2,4-di-O-benzyl-3-O-methyl-a,b-D-xylopyranosyl acetate (20 g, 0.052 mole) and Me3SiCN (20 ml, 0.16 mole) in anhydrous nitromethane (300 ml) was added boron trifluoride etherate (1.0 g, 0.007 mole) at room temperature. After the mixture was stirred at room temperature for 30 min, the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using CH2C12 /AcOEt (99:1) as an eluent to give 2,4-di-O-benzyl-3-O-methyl-a,b-D-xylopyranosyl cyanide as colorless oil (13.0 g, 71% yield); EI-MS: m/z 353 (M+), 262 (M+ -Bn); 1 H-NMR of b-cyano-isomer (CDCl3)d; 3.15 (1H,dd,J=10, 11 Hz), 3.23 (1H,t,J=10 Hz), 3.49 (1H,m), 3.59 (1H,t,J=10 Hz), 3.66 (3H,s), 3.96 (1H,dd,J=5 & 11 Hz), 3.97 (1H,d,J=10 Hz), 4.61 (1H,d,J=12 Hz), 4.73 (1H,d,J=12 Hz), 4.84 (1H,d,J=11 Hz), 4.88 (1H,d,J=11 Hz), 7.29-7.42 (10H,m).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:49]([N:48]([CH3:47])[C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N(C)Cc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH:1](=[C:8]([CH2:13][O:14]C(=O)C)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1](=[C:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1ccccc1)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
A crude product (5.99 g, 25.57 mmols) of methyl 2-benzylidene-3-acetoxypropionate was dissolved in 26 ml of methanol, and 3.53 g (25.5 mmols) of potassium carbonate were added thereto. The mixture was stirred at room temperature for 1 hour. Insoluble matters were separated by filtration, and the resulting solution was concentrated under reduced pressure. To the resulting residue were added 30 ml of water and 40 ml of toluene to extract an organic layer. The thus-obtained organic layer was washed with 30 ml of water and with 30 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (silica gel 100 g, mixture of hexane and ethyl acetate at a ratio of from 3:1 to 2:1) to obtain 3.02 g (15.71 mmols) of the above title compound (yield: 61.4%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O:7][N+:8]12[CH2:15][CH2:14][N:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2.B(F)(F)[F:17].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[F:17][N+:11]12[CH2:14][CH2:15][N+:8]([O:7][CH3:6])([CH2:13][CH2:12]1)[CH2:9][CH2:10]2
Reactant: CO[N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CO[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-methoxy-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (23 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10 % V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with DME and dried to afford 1 -fluoro-4-methoxy- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Reaction time: 2 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.163 mmol), Ethanol (6 mL), THF (1 mL), and added sodium hydroxide (1.939 mL, 5.82 mmol) wherein the reaction time was 2 h. The final product was collected as 330 mg (90%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6 H), 5.26-5.47 (m, 1 H), 7.62 (d, J=8.6 Hz, 2 H), 8.20 (s, 1 H), 8.28 (d, J=8.6 Hz, 2 H), 8.38 (s, 1 H), 14.03 (s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2c[nH]nn2)cc1
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
5 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -60° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 2.4 g of cyclopentanone, and heated to 25°. Then the mixture is combined with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Reaction time: 2 h

Procedure:
At room temperature, 0.12 ml (0.76 mmol) of diethyl azodicarboxylate (DEAD) is added dropwise to a suspension of 150 mg (0.49 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 148 mg (0.73 mmol) of tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate and 199 mg (0.76 mmol) of triphenylphosphine in 1.95 ml of absolute THF. After 2 h at room temperature, the mixture is concentrated and the residue is separated by chromatography on silica gel (dichloromethane/methanol mixture) and the product is isolated. Yield: 184 mg (76.8% of theory); MS (LC-MS): m/z (%)=279 (M+H, 100); LC-MS (Method 4): rt (%)=3.88 (98.9).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:18][C:14]1[C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][CH:30]([C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:31][CH2:32]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cccc(Cl)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cccc(Cl)c32)CC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 18 %

Procedure:
A mixture of 4.4 parts of 3-(7-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, 3.4 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 5 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 6 hours at 50-60° C. The reaction mixture is cooled and poured onto water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1 part (18%) of 4-chloro-3-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]-propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 138° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:26][CH2:25][CH2:24][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH:17]4[C:21]([OH:23])=O)[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:26][CH2:25][CH2:24][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH:17]4[C:21]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:23])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a solution of 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (200 mg, 0.566 mmol) in DMF (2 mL) was added 3-amino pyridine (265 mg, 2.824 mmol), HATU (257 mg, 0.672 mmol) and DIPEA (0.166 mL, 0.902 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide (25 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide (10 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.56-0.70 (m, 2H), 0.78-0.87 (m, 2H), 1.69-1.81 (m, 1H), 2.00-2.19 (m, 4H), 2.21-2.39 (m, 2H), 2.68-2.81 (m, 4H), 3.58-3.72 (m, 1H), 3.78-3.89 (m, 1H), 4.65-4.78 (m, 1H), 6.25 (s, 1H), 7.33 (dd, 1H), 7.94 (s, 1H), 8.22 (d, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][N:11]2[C:18]([NH2:19])=[C:17]([NH2:20])[C:15](=[O:16])[NH:14][C:12]2=[S:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26](O)=O>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][N:11]2[C:18]3[N:19]=[CH:26][NH:20][C:17]=3[C:15](=[O:16])[NH:14][C:12]2=[S:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CO
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OC1CCCC1
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)cc1OC1CCCC1

Procedure:
14.62 g (40 mmoles) of 1-(3-cyclopentyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil were dissolved in 200 ml of formic acid. The solution was concentrated in vacuo at room temperature to remove the water. 50 ml of formic acid were added and the procedure repeated. After a total of 1 hour the formic acid solution was concentrated to 30 ml at 25° and diluted with 300 ml of water. The crystals were collected, washed, and dried: 13.48 g (86.3%) of crude 5-formamide (mp 210-30° C.), which was refluxed in 86 ml of 1N NaOH for 15 min. The turbid solution was treated twice with 0.6 g of charcoal, filtered, acidified with 5N HCl to pH 2, and neutralized to pH 6.5. The amorphous solid was collected, washed, and dried at 60° C.: 11.93 g (80.1%) of crude 2-thioxanthine, which was dissolved in 150 ml of THF, treated with charcoal (5%), filtered, concentrated to 40 ml, and diluted with 250 ml of ethanol. After concentration to 120 ml the formed solid is collected, washed, and dried: 9.21 g (61.9%) of 2-thioxanthine with mp 254-65° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Br[CH2:31][C@H:32]([CH3:52])[CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[Si:35]([O:34][CH2:33][C@@H:32]([CH3:52])[CH2:31][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:7]([F:6])[CH:8]=1)([C:48]([CH3:49])([CH3:50])[CH3:51])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To an N,N-dimethylformamide solution (30 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (Example 1-3) (1.0 g) and {[(2R)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane (1.5 g) was added at room temperature cesium carbonate (2.4 g), followed by stirring at 60° C. for 1 hour. Ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford benzyl 2′-{[(2S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylate (1.5 g).