Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:18]/[C:17](=[N:19]\[O:20][C:36](=[O:37])[CH2:35][CH2:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH2:29][CH2:30]1)/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCN(CCC(=O)O/N=C(\N)[C@@H]2CCCCN2S(=O)(=O)CC2CCCCC2)CC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28] and 3-[4-(tert-butoxycarbonyl)piperazino]propanoic acid [see Preparation 90] to afford tert-butyl 4-(3-[((Z)-amino(2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidylmethylidene)amino]oxy-3-oxopropyl)-1-piperazinecarboxylate as a brown oil.
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12]Br)=[CH:7][CH:6]=2)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[C:29]3[CH:36]=[C:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[F:40][C:38]([F:39])([F:41])[CH2:37][C:35]1[S:34][C:30]2[N:31]=[CH:32][N:33]=[C:28]([NH:27][CH:24]3[CH2:23][CH2:22][N:21]([CH2:12][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3]([C:1]#[N:2])=[CH:11]5)[CH2:26][CH2:25]3)[C:29]=2[CH:36]=1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(C)(C)OC(=O)n1c(C#N)cc2cc(CBr)ccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 68 %

Procedure:
16.7 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate (0.05 mmol) and 15.8 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.05 mmol) were dissolved in 0.6 mL of DCM. 12.9 mg of DIPEA (0.1 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent boc-protected intermediate was dissolved in 0.5 mL of ACN and 0.06 mL of SnCl4 (0.5 mmol) was added. The homogenous reaction mixture was stirred for 1 h and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate-MeOH 1:1:0.1 to produce 16 mg of 5((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 175). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. The hydrochloride salt was recrystallized from methanol. 1H NMR (600 MHz, DMSO-d6): δ 12.62 (s, 1H), 10.74 (br, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J=7 Hz), 7.93, s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=12 Hz), 7.56 (d, 1H, J=12 Hz), 7.45 (s, 1H), 4.36 (s, 1H), 4.30 (m, 1H), 4.03 (q, 2H, J=11 Hz), 3.41 (m, 2H), 3.11 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:24](=[O:25])[CH:23]2[CH:11]([CH2:12][CH2:13][C:14]3[NH:15][C:16]4[C:21]([C:22]=32)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[C:24](=[O:25])[C:23]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[CH:13]=[CH:12][C:11]=2[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CCc3[nH]c4ccccc4c3C2C(=O)N1Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1c2ccc3[nH]c4ccccc4c3c2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
150 mg of N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide was dissolved in 5 ml of methylene chloride. To this solution was added 220 mg of 2,3-dichloro-5,6-dicyano-p-benzoquinone (abbreviated to hereinafter as DDQ). The mixture was stirred at room temperature for 10 minutes. Then, thereto were added 20 ml of methylene chloride and 10 ml of an aqueous 10% potassium carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 120 mg (yield: 81%) of N-benzylcarbazole-3,4-dicarboximide as orange needles.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:9]([NH2:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]>C(O)(=O)C.CCOCC>[NH2:1][C@@H:2]([C:9]([NH2:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]
Reactant: NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)[C@H](N)c1ccccc1
Yield: 87.5 %

Procedure:
20.0 g (70 mmoles) of Z-D-Phg-NH2, prepared as described in Step 1, are dissolved in 40 ml of acetic acid, and 70 ml of a 8 n HBr solution in acetic acid are poured to the solution. After 1 hour the reaction mixture is diluted with ether and the hydrobromide is filtered off. The salt, containing a great excess of HBr, is recrystallized from a tenfold amount of ethanol. 14.15 g (87.5%) of H-D-Phg-NH2.HBr are obtained; m.p.: 263.0°-263.5° C. (determined on a Koffler apparatus). Rf8 (HBr): 0.25; Rf8 base: 0.40. [α]D =-75.6° (c=1.0, in dimethyl formamide).
Reaction SMILES: [Br:1]Br.C(P(CCCC)CCCC)CCC.[PH:16](=[O:19])([OH:18])[OH:17].[CH2:20]([C:22]([CH2:50][CH3:51])([CH:24](O)[C:25]1[N:29]=[CH:28][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)[CH3:23])[CH3:21].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[PH:16](=[O:17])([OH:19])[OH:18].[CH2:20]([C:22]([CH2:50][CH3:51])([CH:24]([Br:1])[C:25]1[N:29]=[CH:28][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)[CH3:23])[CH3:21]
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrBr
Agent: CCCCP(CCCC)CCCC
Agent: O=[PH](O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A solution of bromine (0.53 g) in dichloromethane (1 ml) was added dropwise to a solution of tri-n-butylphosphine (0.68 g) in dichloromethane (12 ml), whilst maintaining the temperature below 0° C. The mixture was stirred for ten minutes at this temperature then treated, dropwise with stirring, with a solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.5 g, prepared as described in Example 24) and triethylamine (0.30 g) in dichloromethane (20 ml), maintaining the temperature below 0° C. It was allowed to warm slowly to room temperature, to stand for two days, then diluted with ethyl acetate, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.27 g, m.p. 108-110° C.). NMR (CDCl3): δ 1.13(6H,dt), 1.6-2.1(2H,m), 2.5-2.6(2H,m), 4.1(4H,m), 5.15(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 567,569.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]3[N:30]=[CH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[C:29]([O:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:39])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[N:30]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (480 mg, 0.88 mmol) was dissolved in 15 mL of dichloromethane. The solution was cool to 0° C. followed by the addition of 5 mL of TFA. The resulting mixture was stirred at room temperature for 4 hrs. Solvent was removed by rotavap and the residue was washed with MeOH. Solid thus obtained was dried overnight under vacuum to afford 60 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 14% yield.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=[O:44])=[N:8]1.[OH-].[Na+]>CO>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([OH:45])=[O:44])=[N:17]1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 60 °C
Yield: 30 %

Procedure:
The title compound was prepared using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.125 g, 0.19 mmol), 6 N sodium hydroxide (aqueous) (3 mL), and methanol (3 mL) heated at 60° C. for 6 hours. The reaction was allowed to cool to room temperature, and extracted with diethyl ether (2×). The aqueous fraction was dropwise added to a 6 N hydrochloride solution (aqueous) to form a white precipitate, which is filtered and dried in a vacuum oven (0.018 g, 30% yield): 1H NMR (DMSO-d6) δ 8.91 (m, 2H), 8.60 (s, 1H), 8.36 (d, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.75 (m, 2H); ES-MS (m/z) 306 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.Cl[C:15]1[N:23]2[CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][O:26][C:21]3=[C:22]2[C:17](=[C:18]([F:40])[CH:19]=[C:20]3[C:33]2[C:34]([CH3:39])=[N:35][O:36][C:37]=2[CH3:38])[N:16]=1>CN1CCCC1=O.CO>[CH3:39][C:34]1[C:33]([C:20]2[C:21]3[O:26][CH2:25][CH:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:23]4[C:15]([N:8]5[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]5)=[N:16][C:17]([C:22]=34)=[C:18]([F:40])[CH:19]=2)=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: OC1CCNC1
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1-c1cc(F)c2nc(N3CCC(O)C3)n3c2c1OCC3c1cccnc1
Temperature: 150 °C
Yield: 13.8 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and 3-pyrrolidinol (0.2 mL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (2.4 mg, 14%). LCMS calc. for C23H23FN5O3 (M+H)+: m/z=436.2. found: 436.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4cnc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of [3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D111) (2 g, 2.488 mmol) in Dichloromethane (DCM) (10 mL) was added ethyl 4-piperidinecarboxylate (0.430 g, 2.74 mmol). The reaction solution was stirred for 5 min before sodium triacetoxyborohydride (0.791 g, 3.73 mmol) was added. The reaction solution was stirred overnight. The reaction solution was washed with water, dried, concentrated and purified by ISCO column chromatography to afford the crude product ethyl 1-{2-[3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D112) (450 mg). MS (ES): C28H35ClN4O3S requires 542.2. found 543.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11](Cl)[C:12](Cl)=[C:13](Cl)[C:14]=1Cl)[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:14]=1[S:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2c(Sc3ccc(C)cc3)c(Sc3ccc(C)cc3)c(C(O)=NCCO)c(C(=O)O)c2Sc2ccc(C)cc2)cc1

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 3.1 g (24.93 millimols) of p-thiocresol, 5.08 g (36.78 millimols) of potassium carbonate and 20 ml of N,N-dimethylformamide are stirred at 25° C. for 1 hour. After evaporation, the residue is acidified with dilute HCl solution and extracted with methylene chloride. After recrystallisation from toluene/cyclohexane, 3.21 g (78% of theory) of the title compound are obtained; melting point 161°-2° C.
Reaction SMILES: [C:1](CC(O)=O)#[N:2].[CH:7]1([NH:12][C:13]([NH:15][CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O[C:21](=[O:23])[CH3:22])(=O)C>>[NH2:2][C:1]1[N:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:13](=[O:14])[N:15]([CH3:16])[C:21](=[O:23])[CH:22]=1
Reactant: CNC(=O)NC1CCCC1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)O
Product: Cn1c(=O)cc(N)n(C2CCCC2)c1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 47 g (0.55 mol) of cyanoacetic acid and 150 ml of acetic anhydride was added 73.1 g (0.51 mol) of 1-cyclopentyl-3-methylurea (XX). The solution was stirred at 70° C. for two hours. It was then evaporated and the residual oil (XXI) was dissolved in 400 ml of ethanol and 400 ml of water and 110 ml of 5 N NaOH was added in portions until the pH was over 7, under which the solution was boiled. It was then partly evaporated and crystals were filtered off. These crystals were a mixture of XX (~30%) and XXII (~70%) which was used for synthetizing XXII. Yield 30.8 g. NMR.
Reaction SMILES: [P:1]([O-:6])([O-:5])[O:2]CC.[Na].S(C1C=CC(C)=CC=1)(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O>O1CCCC1>[CH2:27]([P:1](=[O:2])([OH:5])[OH:6])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOP([O-])[O-]
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCP(=O)(O)O
Yield: 60.4 %

Procedure:
To ethyl phosphite (1.6 g) dissolved in 5 ml of tetrahydrofuran was added sodium (180 mg), and the mixture was dissolved. To this solution was added cetyl tosylate (514 mg), and the mixture was refluxed for ten hours. The reaction solution was concentrated to dryness under reduced pressure. To the residue was added water, which was acidified with concentrated hydrochloric acid, followed by extraction with ether and dried on Na2SO4. From the extract was removed the solvent by evaporation, and the residue was subjected to a silica-gel (7 g) chromatography. Fractions eluted with chloroform were collected and concentrated to dryness. To the residue was added concentrated hydrochloric acid (3 ml), which was refluxed for 18 hours. The resulting precipitates were collected by filtration, followed by recrystallization from n-hexane to give 240 mg (60%) of colorless needles.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: COC(=O)CC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CC1CC(NC[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.88 mmol) and methyl 2-(3-oxocyclobutyl)acetate (100 mg, 0.70 mmol) [prepared using the procedure found in US Patent Application Publication 2009/0118287] in 1,2-dichloroethane (12 mL) was treated dropwise with acetic acid (50 uL, 0.88 mmol). The solution was treated with sodium triacetoxyborohydride (260 mg, 1.2 mmol) in one portion and allowed to stir at room temperature until complete by HPLC. After 4 h, HPLC indicated the reaction was about 80% complete. An additional 20 mg of ketone was added and stirring was continued for 2.5 h. The reaction mixture was diluted with 30 mL CH2Cl2 and washed with 15 mL sat NaHCO3. The aqueous phase was washed with 15 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The organic phase was filtered and concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (270 mg, 66%) as a colorless glass: MS (ESI+) for C30H39N5O7 m/z 582.2 (M+H)+; HPLC purity >95% (ret. time, 2.88 min).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=12)=[O:9])[C:4](O)=[O:5].[CH:29]([NH2:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:29]([NH:32][C:4](=[O:5])[C@@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=12)=[O:9])[C:2]([CH3:27])([CH3:28])[CH3:1])([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: CN1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of Compound 471 (30 mg, 0.078 mmol) and isopropylamine (33 μL, 0.39 mmol) in DMF was added TBTU (38 mg, 0.15 mmol). After stirring at room temperature overnight, the crude reaction mixture was purified by a prep LC-MS with 5% to 95% MeCN/water in 15 min to give pure Compound 472 at 66% yield. 1H-NMR (400 MHz, CDCl3) δ: 1.04 (s, 9H), 1.11-1.28 (m, 6H), 1.95 9(br, 2H) 2.59 (s, 3H), 3.25 (br, 2H), 4.01-4.16 (m, 1H), 4.23 (d, J=9.3 Hz, 1H), 5.80 (br, 1H), 7.47-7.55 (m, 5H), 7.95 (d, J=9.3 Hz, 1H). LCMS (+ESI) m/z 426.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C(=O)Cl)c1ccccc1

Procedure:
(±)-2-Phenylpropionic acid in the amount of 7.50 g (50 mmol) and 7.14 g (60 mmol) of thionyl chloride were heated for 1 hour under reflux in carbon tetrachloride. The solvent and unaltered thionyl chloride were evaporated under reduced pressure to give (±)-2-phenylpropionic acid chloride as a pale yellow oil. To the oil were added 30 ml of benzene, 7.30 g (52.5 mmol) of p-nitrophenol and 4.75 g (60.0 mmol) of pyridine were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 10 ml of aqueous 10% hydrochloric acid, extracted with ethyl acetate, followed by solvent evaporation from the organic layer, to obtain 13.9 g of a pale yellow solid. Recrystallization of the solid from ethanol gave 10.4 g (38.4 mmol, yield 77%) of (±)-p-nitrophenyl 2-phenylpropionate as colorless crystals.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[C:17]([C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:34][C:32]1[CH:33]=[C:25]2[C:26](=[CH:30][CH:31]=1)[C:27](=[O:28])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)[C:4]([C:3](=[O:2])[CH2:15][CH3:16])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(O)CNCc1ccc(C#N)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C#N)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxybutylamino)methyl]benzonitrile hydrochloride and 2-benzoyl-4-chlorobenzoic acid.