Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)nc(Cl)c1
Reactant: N#Cc1cnc(Cl)s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Cl)nc(Nc2ncc(C#N)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven dried flask under N2 was charged with 4-(tert-butyl-dimethyl-silanyloxymethyl)-6-chloro-pyridin-2-ylamine (11-5, 0.488 g, 1.79 mmol), 2-chloro-5-cyanothiazole (1-2, 0.310 g, 2.15 mmol), cesium carbonate (0.816 g, 2.50 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.033 g, 0.040 mmol) and Xantphos (0.062 g, 0.060 mmol). Anhydrous dioxane, 6 mL, was added and the reaction was heated to reflux. After 3 hours the reaction was cooled to room temperature and stirred overnight. The reaction was diluted with water and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with ether, and filtered to afford the product as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[O:24][CH3:25])[OH:4].C(N(C(C)C)CC)(C)C.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:21]([C:19]1[CH:18]=[CH:17][C:16]([O:24][CH3:25])=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:5]=2[CH:3]2[O:4][C:36](=[O:38])[NH:1][CH2:2]2)[CH:20]=1)([CH3:23])[CH3:22]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(O)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 0.44 g of 2-amino-1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanol in 15 mL of CH2Cl2 was added 0.241 g of diisopropylethylamine, then 0.185 g of triphosgene. The mixture was stirred at 0° C. for 30 min, and then diluted with 30 mL of EtOAc and 20 mL of saturated NaHCO3. The phases were separated and the organic phase was washed with 20 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 5 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 380.2 (M+1). 1H NMR signals are doubled because of atropoisomerism 1H NMR (500 MHz, CDCl3): δ 7.90, 7.86 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.27 (dd, J=2.5 Hz, 8.5 Hz 1H), 7.03 (d, J=2.5 Hz, 0.5H), 6.87-6.93 (m, 1.5H), 5.65, 5.50 (t, J=8 Hz, 1H), 5.23, 5.09 (s, 1H), 3.75 (s, 1.5H), 3.69 (s, 1.5H), 3.68, 3.51 (t, J=9 Hz, 1H), 3.31, 3.19 (t, J=8.5 Hz, 0.5H), 2.90 (septet, J=7 Hz, 1H), 1.25, 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(Br)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(-c2ccccn2)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A solution containing the product from Example 23K (11.0 g, 20.5 mmol) in DMF (90 mL) was treated with LiCl (8 g, 188.7 mmol), tetrakis(triphenylphosphine)palladium(0) (5 g, 4.3 mmol), and 2-tri-n-butylstannylpyridine (22 g, 59.8 mmol), heated at 80° C. for 16 hours, cooled, filtered and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient 0-25% ethyl acetate/hexanes to give the title compound (7.6 g, 72% yield).
Reaction SMILES: [C:1](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](OC)(C)(C)C>O1CCCC1>[C:1](=[N:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH3:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)C
Reactant: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Solvent: CI
Solvent: C1CCOC1
Product: CN(N=C(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
N-Benzhydrylidene-N′-(4-chlorophenyl)hydrazine (0.2 g, 0.65 mmol, 1 eq.) and 3.2 mL of tetrahydrofuran are placed in a predried 20 mL round-bottomed flask under argon. The solution is cooled to a temperature in the region of −10° C. and 0.5 M potassium hexamethylbis-silylamide solution (1.43 mL, 1.1 eq.) is then added. The solution darkens, and is left to react at this temperature for 30 minutes, followed by addition of a solution of methyl iodide in methyl tert-butyl ether (0.49 mL, 1.5 eq.). The mixture is then allowed to return to a temperature in the region of 25° C. and is left stirring for 4 hours. After treatment with sodium hydrogen carbonate, the mixture is extracted with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. The residual oil is purified by chromatography on silica gel, eluting with an ethyl acetate/heptane mixture (10/90 by volume). N′-Benzhydrylidene-N-(4-chlorophenyl)-N-methylhydrazine is obtained in a yield of 96% in the form of a yellow solid, which product is used directly in the following step.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a mixture of 4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (85.0 mg, 0.14 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (83.0 mg, 100%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1474.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1(C)C=CC=CC=1>[F:19][C:3]1[C:2]([B:25]([OH:30])[OH:26])=[CH:7][C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COCc2cnc(F)c(Br)c2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COCc2cnc(F)c(B(O)O)c2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine (1.615 g, 4.952 mmol) was dissolved in PhMe (25.0 mL) and the reaction flask was cooled under nitrogen in a dry ice/acetone bath. Then, n-butyllithium solution (Fluka, Buchs, Switzerland, 1.6 M in hexane, 3.7 mL, 5.9 mmol) was added via syringe, turning the solution yellow. The reaction was stirred at −78° C. for 45 minutes and then triisopropyl borate (Alfa Aesar, Ward Hill, Mass. 98+%, 1.7 mL, 7.2 mmol) was added via syringe. The reaction was allowed to slowly warm up to room temperature, and after 90 minutes, the dry ice/acetone bath was removed. After another 25 minutes, the reaction was quenched with water and diluted with 10:1 DCM/MeOH. The biphasic solution was treated with 5N HCl to lower the pH of the aqueous phase from 9 to about 4, and the aqueous phase extracted with 10:1 DCM/MeOH. The organic extracts were concentrated and dried under high vacuum in water bath (about 45° C.-60° C.), and then the solid was washed with Et2O and dried again under high vacuum at room temperature over the weekend to afford 2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-ylboronic acid (1.389 g, 68% purity, 66% yield). MS (ESI pos. ion) m/z 292 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[CH:14]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(-c2ccncn2)c[nH]c1=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccncn2)c[nH]c1=O

Procedure:
2.5 ml of acetic anhydride are added to a suspension of 4.0 g of 3-amino-5-(4-pyrimidinyl)-2-(1H)-pyridone in 60 ml of pyridine. The mixture is heated on a steam bath for 2 hours and then cooled in an ice bath. The solid is filtered, washed with ethanol and dried. Recrystallization from dimethyl formamide yields the desired product, M.P.>250° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39](O)=[O:40])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:40])=[CH:31][CH:32]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: C[C@@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (37 mg, 162 μmol) from the previous step in DMF was added DIPEA (85 μl, 486 μmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (57 mg, 243 μmol) and HATU (123 mg, 324 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give rac-trans-tert-butyl ((1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in DCM was added TFA (1:1 v/v). The reaction was aged at rt. When analytical reverse-phase HPLC indicated disappearance of starting material, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil (34 mg, 60%). MS (ESI) 348.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:35]2[CH2:44][CH2:43][C:38]3([O:42][CH2:41][CH2:40][O:39]3)[CH2:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:39]1[C:38]2([CH2:43][CH2:44][CH:35]([N:11]3[C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]([C:12]4[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=4)=[N:10]3)[CH2:36][CH2:37]2)[O:42][CH2:41][CH2:40]1
Reactant: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (500 mg) obtained in Step A of Example 100 in DMF (8 mL) was added sodium hydride (60% dispersion in mineral oil, 131 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (1.03 g), and the mixture was stirred overnight at 60° C. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (283 mg).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.Cl.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>C(O)C>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:5]1[N:6]=[CH:1][N:2]=[C:3]2[C:4]=1[N:8]=[CH:9][N:10]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: NCc1cccc(I)c1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 85 °C
Yield: 87.5 %

Procedure:
A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and 3-iodobenzylamine hydrochloride (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85° C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172° C.; 1H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2O, N6H,).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH2:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of benzyloxycarbonyl-L-valyl-L-proline t-butyl ester (51.8 g) dissolved in absolute ethanol (1 liter) was placed in a 2 liter hydrogenation bottle. The reaction mixture was purged with nitrogen, and 10% (w/w) palladium on carbon catalyst (10 g, 50% (w/w) water wet) was added. The reaction was placed on a large shaker apparatus and shaken at room temperature under a hydrogen atmosphere (3.4 bar). After 1 h, hydrogen uptake ceased. The reaction mixture was checked by TLC [chloroform:ethyl acetate (85:15)] and shown to contain considerable starting material (Rf =0.55). Fresh catalyst (10 g) was added, and the reaction was placed back on the apparatus for another 4 h, at which point hydrogen uptake ceased. TLC of the reaction mixture showed complete absence of starting material. The reaction mixture was filtered through a pad of diatomaceous earth, and the filter cake was washed with ethanol. Evaporation of the ethanol from the condensed solution left a cloudy yellow oil. This oil was dissolved in ether (1 liter), filtered to remove a small amount of precipitate (dicyclohexylurea) and evaporated to give crude L-valyl-L-proline t-butyl ester as a yellow oil (32.1 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cnn(C)c3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3cnn(C)c3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 223, Step A using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 2-fluorobenzenesulfonyl chloride (0.124 mg, 0.639 mmol), the title compound was obtained as an off white solid (60 mg, 57% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19].[OH-].[K+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH:17]([OH:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(O)C(Sc1cc(Oc2ccccc2)ccc1N)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(Oc2ccccc2)cc1SC(c1ccc2c(c1)OCO2)C(O)C(=O)O
Yield: 55 %

Procedure:
Following a procedure similar to that described in Example 1(b), 15.2 g of ethyl 3-(2-amino-5-phenoxy- phenyl)thio-2-hydroxy-3-(3,4-methylenedioxyphenyl)propionate [prepared as described in step (a) above] were hydrolyzed with caustic potash to give 7.84 g of the title compound as a powder, melting at 158-159° C. This product was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH2:25]Cl)=[N:23][N:24]=[C:20]3[CH2:19][N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:16]=2[CH:34]=1)([O-:11])=[O:10].[I-].[K+]>O1CCCC1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH2:25][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:23][N:24]=[C:20]3[CH2:19][N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:16]=2[CH:34]=1)([O-:11])=[O:10]
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine and potassium iodide in tetrahydrofuran to give 8-nitro-1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15])=O)(C)(C)C.C(OCC)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 6.0 g of N-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide, and left at a temperature of 20° C.~25° C. for 30 minutes. The mixrure was condensed under reduced pressure. To the reaction solution was added ethyl ether, and the crystals precipitated were separated by filtration. The crystals thus obtained were washed with ethylether to give 4.54 g of N-(4-amino-3-phenylbutyl)-5-isoquinolinesulfonamide in a yield of 97%.