Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>ClCCl>[N:23]1([CH2:22][CH2:21][O:18][C:14]2[CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[N:11]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCCC1
Reactant: Nc1ncnc2ccc(-c3cccc(O)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cccc(OCCN4CCCC4)c3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a 4 mL screw-cap vial was added 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)phenol (100 mg; 0.32 mmol) followed by 1-(2-chloroethyl)pyrrolidine hydrochloride (CAS 7050-67-1) (1.1 equiv., 0.35 mmol, 59 mg) cesium carbonate (5 equiv., 1.57 mmol, 513 mg) and dimethylformamide (0.6 mL). The reaction was capped at shaken at 80° C. overnight. The reaction was cooled to room temperature, diluted with dichloromethane, and washed with water. Organic phase was concentrated, then purified by reverse phase HPLC yielding 16 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.48-8.39 (m, 2H), 8.15-8.08 (m, 2H), 8.00-7.89 (m, 3H), 7.47-7.40 (t, J=7.9 Hz, 1H), 7.12-7.03 (dd, J=8.1, 2.3 Hz, 1H), 4.27-4.18 (t, J=5.9 Hz, 2H), 2.90-2.81 (t, J=5.9 Hz, 2H), 2.59-2.53 (m, 4H), 1.76-1.66 (m, 4H). LCMS M/Z (M+H)=336.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=4)[N:15]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:32][O:33][C:34]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=4)[N:15]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccc(Cl)nn3)c2)c2ccc(F)cc21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(-n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5cc(F)ccc45)cn3)nn2)c(OC)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A mixture of 3-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 44; 136 mg; 0.30 mmol) and 2,4-dimethoxybenzylamine (100 mg; 0.60 mmol) in NMP (2 mL) was stirred at 200° C. for 2 hours under a microwave reactor. The reaction mixture was diluted with EtOAc (30 mL), washed water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel column chromatography (petroleum ether/EtOAc=4/1 to 2/1) to afford 120 mg (68%) of the title compound as a white solid.
Reaction SMILES: N1(S(C2C=CC([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=CC=2)(=O)=O)CCC1.Br[C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:43]([CH3:50])[CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1>>[CH3:50][N:43]([CH2:44][CH:45]1[CH2:49][CH2:48][CH2:47][O:46]1)[S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:14]2[CH:15]=[C:16]3[N:22]=[C:21]([CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:31]4)[NH:20][C:17]3=[N:18][CH:19]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(Br)cc1
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) from 458 mg of 4-bromo-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound C7) and 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-20 vol. % ethanol) yields 174 mg of the title compound as a waxy solid. ESI-MS: 512.4 (MH+). TLC: Rf=0.30 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6 g, 21.65 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (7.25 g, 21.65 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (5.67 ml, 32.5 mmol) and Pybrop (15.08 g, 32.5 mmol) in Dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [9.0 g, 74%] as a white solid: LCMS (ES) m/z 558 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH:11](=[N:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccc(F)cc1F
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(CN=Cc2ccccc2)c(F)c1

Procedure:
50.2 g (0.35 mol) of 2,4-difluorobenzylamine and 37.1 g (0.35 mol) of benzaldehyde are dissolved in 140 ml of toluene and heated to reflux. The water produced is separated off using a water separator. The reaction is complete (GC check) after two hours. The solution is evaporated on a vacuum rotary evaporator. 78.9 g (97% of theory) of a slightly yellow liquid are obtained.
Reaction SMILES: [C:1]([O:8]C)(=O)[CH2:2][C:3]([O:5]C)=O.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.[NH4+].[Cl-]>CN(C=O)C.O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)([CH2:1][OH:8])[CH2:3][OH:5])=[CH:15][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC(CO)(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To dimethyl malonate (6.60 g, 50 mmol) in DMF (100 mL) was added NaH (2.00 g, 50 mmol) and 4-bromomethyl bromobenzene (25 g, 100 mmol). After a period of 6 h at room temperature, 200 mL of saturated NH4Cl and 200 mL of H2O were added. The crude product was extracted with a mixture of toluene and ether, dried over Na2SO4, filtered and evaporated. To the oil dissolved in THF (300 mL) at 0° C. LAH (4.5 g) was added. After a period of 2 h at room temperature, the reaction was quenched with 20 mL of acetone and 300 mL of 20% potassium, sodium tartrate. The compound was extracted with EtOAc, dried over Na2SO4, evaporated and purified by flash chromatography to provide 19 g of material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:12]O)[CH2:6][CH2:5]2.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: ON=C1CCc2cc(Br)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1CCc2cc(Br)ccc2C1
Temperature: 25 °C

Procedure:
A solution of BH3-THF complex (1 M) (35.9 mL, 35.9 mmol) was added drop-wise to a stirred solution of 6-bromo-3,4-dihydro-1H-naphthalen-2-one oxime (3.450 g, 14.37 mmol) in THF (125 mL) at 0° C. The mixture was warmed to RT and to reflux for 24 h. The reaction was cooled to RT and 1 N aqueous HCl was added carefully until the mixture was acidic and the system was stirred until no further gas was evolved. The solution was made basic by the addition of NaOH and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated in vacuo to afford the crude title compound, which was purified by flash column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]O[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[CH3:35])[CH2:16]C=O)[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.[N:37]1[NH:38]C=C2C=1CCC(N)C2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)C(C)C)(C)C>ClC(Cl)C.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([CH3:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:8]3[CH2:12][CH2:6][C:7]4[C:2](=[CH:3][NH:37][N:38]=4)[CH2:1]3)[C:14]2=[O:36])=[C:25]([CH3:26])[CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC1CCc2n[nH]cc2C1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C[C@H](CC=O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)cc(C)c1C[C@@H]1CCN(C2CCc3n[nH]cc3C2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Combine a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dimethyl-benzyl)-4-oxo-butyraldehyde (3.0 g, 6.2 mmol) and racemic 4,5,6,7-Tetrahydro-2H-indazol-5-ylamine (0.85 g, 6.2 mmol) in Dichloroethane (50 mL) and Acetonitrile (50 mL). Treat the solution with sodium triacetoxyborohydride (6.6 g, 31 mmol) and stir 1 hr at room temperature. Treat the reaction with N,N-Diisopropylethylamine (5.6 mL, 31 mmol) and stir overnight at room temperature. Concentrate the reaction to a residue. Quench the residue with saturated sodium carbonate and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using CH2Cl2 and 2M Ammonia in MeOH to elute the pure product. Remove the solvent to afford 1.66 g (62%) of desired product. MS (m/e): 430 (M+1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[NH:3]1.B.O1CCCC1>O1CCCC1>[C:4]12([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]13)[C:5]1[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)[CH2:2][NH:3]2
Reactant: N#Cc1ccc2c(c1)C(=O)NC21CCCn2cncc21
Agent: B
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CNC21CCCn2cncc21
Temperature: 50 °C

Procedure:
To a solution of 1.0 mmol of 3′-oxo-2′,3′,6,7-tetrahydro-5H-spiro[imidazo[1,5-a]pyridine-8,1′-isoindole]-5′-carbonitrile (Example 13) in 10 ml of tetrahydrofuran are added 3.0 mmol of a solution of borane-tetrahydrofuran complex (1M in tetrahydrofuran). The reaction mixture is stirred over night at 50° C., then cooled to room temperature and quenched carefully with 10 ml of methanol. After the gas evolution ceases, the reaction mixture is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (500 mg, 1.80 mmol) in ethyl acetate (15 mL) and methanol (15 mL) was treated with 10% palladium on activated carbon (wet, 50 mg) The flask was charged with hydrogen gas via balloon. The reaction stirred at 25° C. for 16 h. The reaction was then filtered through a plug of silica gel (Merck, 60, 40-63 μm) layered with diatomaceous earth and concentrated in vacuo to afford 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (391 mg, 90%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.83 (9H, s), 3.78 (2H, t, J=4.8 Hz), 3.87 (2H, t, J=6.0 Hz), 4.48 (2H, s), 5.33 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=2.0 Hz).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C(CN)c2cccc(Br)c2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
3-Bromophenylethylamine hydrochloride (9.44 g) was added to THF (60 ml) containing triethylamine (12.24 ml) and stirred-under argon at 5° C. during the portionwise addition over 15 minutes of 4-methylphenylsulphonyl chloride (11.44 g). The slurry was diluted with THF (50 ml) and stirred for 16 h. The solid was filtered off, washed with THF and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, brine and dried (MgSO4). Chromatography on flash silica, eluting with 0 to 25% ethyl acetate in isohexane gave the product (9.67 g).
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[CH:1]12[C:9](=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:20][CH:19]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Oc1ccc(C(=C2C3CCCC2CCC3)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
Compound 43 (0.32 g, 0.834 mmol), t-butyl acrylate (0.734 mL, 5.01 mmol), P(o-tolyl)3 (0.11 g, 0.359 mmol), Pd(OAc)2 (0.0394 g, 0.175 mmol) and Et3N (0.7 mL, 5.01 mmol) were added to a flask containing CH3CN (13 mL) and the stirred reaction mixture was heated at 85° C. for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at RT and then partitioned between water and EtOAc. The layers were separated, and the organic phase was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oily residue. The crude oil was adsorbed onto silica and purified by flash column chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 44 as a yellow foam (0.33 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.53 (m, 10H), 1.72-1.73(m, 7H), 1.96-2.01(m, 2H), 2.53-2.64 (m, 4H), 6.42 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:31][C@H:30]([CH2:32][O:33]CC3C=CC=CC=3)[C@@H:21]([O:22]CC3C=CC=CC=3)[C@@H:12]2[O:13]CC2C=CC=CC=2)=[C:4]([NH2:41])[N:3]=1.N.[Na].[Cl-].[NH4+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:21]([OH:22])[C@@H:12]2[OH:13])=[C:4]([NH2:41])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1

Procedure:
To 1 g. of the product of example II was added 200 ml. of liquid ammonia. Small pieces of sodium were added until the blue color persisted for several minutes. A total of 350 mg. of sodium was used. The blue color was discharged with a few crystals of ammonium chloride. The ammonia was evaporated under a stream of nitrogen and the residue was triturated with 50 ml. of benzene. The insoluble residue was taken up in a few ml. of water and neutralized with acetic acid. The product (500 mg.), after recrystallization from water, melted at 257°-259° with decomposition. The 2,6-diamino-9-(β-D-arabinofuranosyl)purine showed a λ max = 253,290 mμ at pH 1, and λ max = 257,279 mμ at pH 11.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>C(OCC)(=O)C>[CH3:26][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:11]=1)([CH3:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(C)(C)OCCCCCCC(=O)CCl
Reactant: NC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)OCCCCCCc1coc(-c2ccccc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A mixture of 956 mg of benzamide and 1.1 g of methyl 2-(8-chloro-7-oxooctyloxy)-2-methylpropionate was stirred for 2 hours at 120° C. The reaction solution was cooled, dissolved in ethyl acetate, washed by adding sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 658 mg of the objective compound as colorless oil.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].O.[CH3:12]I>C(O)C>[CH3:12][S:3][C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: CI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nccc(=O)[nH]1
Temperature: 30 °C
Yield: 42.2 %

Procedure:
A mixture of 12.8 g (99.9 mmol) of 2-thiouracil and 4.3 g (108 mmol) of sodium hydroxide was placed in 500 ml Erlenmeyer flask, and dissolved on the oil bath with a minimum amount of water. Twice the volume of 99% ethanol was then added, the solution cooled to 30° C., and 6.3 ml (99.9 mmol) of methyl iodide added. The solution was heated to 60° C. for 20 min, then cooled to room temp. The precipitate was filtered off, and, after acidifying the filtrate with acetic acid, the excess solvent was removed in vacuo. The combined precipitates were thoroughly washed with water and recrystallized from ethanol to give 6.0 g (47%) of product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][CH2:27][CH:28]1[CH2:31][CH2:30][NH:29]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][N:29]1[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC3CN)nc21
Yield: 51.5 %

Procedure:
A suspension of 1.08 g (4.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.93 g (5.0 mmol) of 2-[(t-butoxycarbonylamino)methyl]azetidine, 1.01 g (10 mmol) of triethylamine and 50 ml of acetonitrile was stirred at reflux for two hours. The solvent was removed in vacuo and the residue was dissolved in 25 ml of trifluoroacetic acid. After stirring at room temperature for two hours, the solvent was removed in vacuo. The residue was suspended in water and the pH adjusted to 11 with 10% sodium hydroxide. The resulting solution was filtered through a fiber glass pad to clarify and the filtrate acidified to pH 7.2 with 1M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, ethanol, ether and dried in vacuo to give 0.66 g (52%) of the title compound, mp 198°-200° C.
Reaction SMILES: Cl.Cl.N[C:4]1[CH:10]=[C:9]([NH2:11])[C:7]([OH:8])=[CH:6][C:5]=1O.[CH3:13]S(O)(=O)=O.O(C1C=CC(OC2C=CC=CC=2)=CC=1)C1C=CC=CC=1>>[O:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:10][C:9]=2[N:11]=[CH:13]1
Reactant: CS(=O)(=O)O
Reactant: Nc1cc(N)c(O)cc1O
Agent: Cl
Agent: c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Product: c1ccc2ocnc2c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
Under nitrogen atmosphere, 1.00 g (4.69 mmoles) of 4,6-diaminoresorcinol dihydrochloride and 1.62 g (6.26 mmoles) of oxy-bis(4-benzoic acid) are mixed and 29.1 ml of 10-1 methanesulfonic acid solution is added. The mixture is stirred and heated to 95° C. for 24 hours and then cooled to 50° C. A 0.41-g (1.56-mmole) quantity of p-diphenoxybenzene is added and stirring is continued at 50° C. for 48 hours. The resulting copolymer is precipitated in aqueous potassium hydroxide in a blender, washed with water until neutral and dried to constant weight in a vacuum oven at about 50° C. Its inherent viscosity in concentrated sulfuric acid at 25° C. and about 0.2028 g/dL concentration is measured to be about 0.99 dL/g. Its inherent viscosity in methanesulfonic acid at about 0.05 g/dL concentration and about 25° C. is measured to be 4.42 dL/g.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[K].[CH3:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH:23]1([N:22]([CH3:21])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNC1CCCCC1
Reactant: O=C(O)c1ccc(Cn2cnc3cnccc32)cc1
Agent: [K]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cn2cnc3cnccc32)cc1)C1CCCCC1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A stirred suspension of 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)benzoic acid, potassium salt (0.78 g, 0.0027 mol) in dry dimethylformamide (5 ml) was treated with N-methylcyclohexylamine (0.36 g, 0.0032 mol) and triethylamine (0.54 g, 0.0054 mol). The reaction mixture was cooled to -5° C. and then treated with diphenylphosphoryl azide (0.81 g, 0.0030 mol). The resulting mixture was allowed to warm up to room temperature and stirred for an additional 15 hours. The solvent was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) and recrystallized from ethyl acetate to yield N-cyclohexyl-N-methyl-4-(1H-imidazo[4,5-c]pyridin-1-yl-methyl)benzamide as a colorless crystalline solid, having a melting point of 132°-134° C. and the following physical characteristics: