Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CCO.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][N:15]([CH2:18][CH2:19][NH2:20])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2ccn[nH]2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 14.6 %

Procedure:
5-(3-methoxy-4-nitrophenyl)-1H-pyrazole (0.555 g, 2.53 mmol), tert-butyl 2-hydroxyethylcarbamate (0.449 g, 2.79 mmol) and triphenylphosphine (0.863 g, 3.29 mmol) and THF (20 ml) were mixed. DIAD (0.997 ml, 5.06 mmol) was added. The mixture was stirred for 3 h. 10% EtOH/HCl (50 ml) was added. The mixture was stirred overnight. The solvent was removed by evaporation. Water (20 ml) was added to the residue. This mixture was washed with DCM (2×20 ml). 1 M NaOH was added until pH 14 was reached followed by extraction with DCM (3×20 ml). The organic layers were pooled and evaporated to dryness. Flash chromatography (gradient of DCM:MeOH) gave 97 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 3.19-3.26 (m, 2H), 4.04 (s, 3H), 4.20-4.28 (m, 2H), 6.63 (m, 1H), 7.38-7.43 (m, 1H), 7.52 (m. 1H), 7.59 (m, 1H), 7.91-7.97 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([F:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[F:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)C(F)Cl
Reactant: COC(=O)c1cscc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)C(F)Cl
Temperature: -15 °C

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2 g) in dichloromethane (25 mL) was added chlorofluoroacetyl chloride (1.16 mL) and the reaction mixture was stirred to −15° C. Then a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was added slowly to the cold reaction mixture which was then allowed to warm up and stirred at room temperature for one hour. The reaction mixture was then diluted with further methylene chloride and washed several times with water, dried with sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid. MS (EI): 251.1; mp=51-54° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:52])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[C:31]([O:32][C@H:33]([CH2:35][CH:36]=C)[CH3:34])=[CH:30][CH:29]=[C:28]([F:38])[C:27]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:40])=[C:13]([CH3:41])[C:12]=2[C@H:42]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:43]([O:45][CH3:46])=[O:44])[CH2:7][CH2:6]1)[CH:2]=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:48]([O:47][C@@H:42]([C:12]1[C:13]([CH3:41])=[C:14]([CH3:40])[C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:52])([O:4][CH2:1][CH:2]=[CH:36][CH2:35][C@H:33]([CH3:34])[O:32][C:31]2[CH:30]=[CH:29][C:28]([F:38])=[C:27]([F:39])[C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:43]([O:45][CH3:46])=[O:44])([CH3:51])([CH3:50])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5F)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1

Procedure:
Prepared in 41.6% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′,3′-difluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 688.3.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][C:36]1([CH2:42][OH:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:39]3[CH2:40][CH2:41][C:36]([CH2:42][OH:43])([CH3:35])[CH2:37][CH2:38]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: CC1(CO)CCNCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(C)(CO)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with (4-methyl-piperidin-4-yl)-methanol trifluoroacetate and N,N-diisopropylethylamine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH:30]2[CH2:35][CH2:34][N:33]([C:11]([CH:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:10][CH2:9]3)=[O:13])[CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)CCN1CCC(C(=O)O)CC1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)C2CCN(CCC(C)C)CC2)CC1
Reaction time: 4 h
Yield: 17.7 %

Procedure:
The preparation of Example 13: 1-(3-Methyl-butyl)-piperidine-4-carboxylic acid (0.1 g, 0.50 mmol) was dissolved in DMF (5 mL) and treated with (4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (0.175 g, 0.50 mmol), diisopropylethylamine (0.26 mL, 1.5 mmol), and HBTU (0.19 g, 0.50 mmol). The reaction was stirred for 4 hours, then diluted with EtOAc (125 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 47 mg (18%) of {4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl }-[1-(3-methyl-butyl)-piperidin-4-yl]-methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CO)cn2)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)C=O)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.6 %

Procedure:
To a suspension of 6-chloro-4-(5-(1-hydroxy-2-methylpropan-2-yloxy)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (750 mg, 2.31 mmol, Eq: 1.00) in DCM (100 ml) was added Dess-Martin periodinane (1.27 g, 3.00 mmol, Eq: 1.30). The reaction mixture was stirred at room temperature for about 40 minutes. Ether was added (100 mL) followed by 50 ml NaOH solution (1 M). The mixture was stirred for additional 15 minutes and transferred to separatory funnel. The organic layer was washed with equal volume of NaOH (1M) water (50 mL), dried (Na2SO4) and evaporated under vacuum to afford the desired product (668 mg) as a light brown powder. (M+H)=323 m/e. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.36 (s, 6 H) 3.68 (s, 3 H) 7.43-7.47 (m, 1 H) 7.51-7.55 (m, 1 H) 8.10 (dd, J=3.03, 0.51 Hz, 1 H) 8.27 (s, 1 H) 9.69 (s, 1 H) 9.82 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:23]3[CH:24]=[CH:25][C:26]4[C:30]([CH:31]=3)=[N:29][N:28]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:27]=4)[CH:9]=[C:10]([CH:11]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([N:28]1[CH:27]=[C:26]2[C:30]([CH:31]=[C:23]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:24]=[CH:25]2)=[N:29]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a dry flask was added tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]pyrrolidine-1-carboxylate (420 mg, 0.824 mmol) followed by a solution of 1:1 trifluoroacetic acid in dichloromethane (3 mL). The mixture was stirred under N2 atmosphere for 1.5 h. The reaction was then partitioned between dichloromethane (150 mL) and 10% aqueous potassium carbonate. The aqueous layer was back extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) then dried with sodium sulfate. The solvent was evaporated under reduced pressure to yield 320 mg (95%) of the desired product as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.89 (s, 1 H), 7.78 (d, 1 H), 7.58 (s, 1 H), 7.50-7.30 (m, 4H), 7.14 (d, 1 H), 6.58 (s, 1 H), 5.64 (s, 2 H), 3.98 (m, 1 H), 3.35-3.25 (m, 3 H), 2.10 (m, 1 H), 1.92 (m, 1 H); ES-MS m/z 410.4 [M+H]+, HPLC RT (min) 2.00.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[NH2:60][C@@H:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN1C(=O)CCC1.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:60][C@@H:61]([C:67]2[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COC(=O)C[C@@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 104.1 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.579 g, 1.52 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.5 g, 1.38 mmol) and DIPEA (0.503 mL, 3.04 mmol) in NMP (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 5 minutes. (R)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (Intermediate 40) (0.346 g, 1.38 mmol) was then added to the solution and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (50 mL), water (50 mL), and water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (R)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (0.800 g, 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:34]([CH2:36]C=C)[CH3:35])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:50])([O:4][CH2:1][CH:2]=[CH:3][CH2:35][C@H:34]([CH3:36])[O:33][C:27]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:47])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Yield: 83 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-7-methyl-2-(5′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 83% yield following the same procedure as (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (400 MHz, CDCl3) δ 8.23-8.16 (m, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.57-7.50 (m, 1H), 7.43-7.38 (m, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H), 7.11 (dd, J=8.3, 2.0 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.24-6.12 (m, 1H), 6.04 (br. s., 1H), 5.86-5.73 (m, 1H), 4.57-4.46 (m, 1H), 4.10-3.93 (m, 3H), 3.82-3.74 (m, 1H), 3.69 (s, 3H), 3.08 (d, J=8.0 Hz, 1H), 2.68 (d, J=7.5 Hz, 1H), 2.47 (s, 3H), 2.42-2.35 (m, 2H), 2.34 (s, 3H), 2.01-1.93 (m, 2H), 1.81-1.73 (m, 2H), 1.32 (s, 3H), 1.25 (s, 9H), 1.09 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 652.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([NH2:21])=[C:7]([C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=O)[CH3:2]>C(O)(=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:5]2[N:4]=[C:1]([CH3:2])[NH:21][C:6]=2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCc1ccc(NC(C)=O)c(N)c1C(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc2nc(C)[nH]c2c1C(=O)OC
Temperature: 80 °C
Yield: 94.6 %

Procedure:
A solution of methyl 3-(acetylamino)-2-amino-6-(3-methoxy-3-oxopropyl)benzoate (490 mg, 1.66 mmol) in acetic acid (15 mL) was stirred with heating at 80° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→15/85) to give the title compound (434 mg, yield 95%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C1C=CC2N(O)N=NC=2C=1.[C:16]([N:23]1[CH2:31][CH2:30][CH:26]([C:27]([OH:29])=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:24][CH2:25][CH:26]([C:27]([N:3]([CH3:2])[O:4][CH3:5])=[O:29])[CH2:30][CH2:31]1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 18 °C
Reaction time: 12 h

Procedure:
A 100 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was charged with DMF (51 L), N,O-dimethylhydroxyamine hydrochloride (2.62 Kg, 26.55 mol), HOBT (1.2 Kg, 8.85 mol), and N-Boc isonipecotic acid (4.10 Kg, 17.70 mol). The mixture warmed to 18° C. as the diisopropylethylamine (4.60 Kg, 6.2 L, 35.41 mol) was added over 15 min. The EDC.HCl (5.09 Kg, 26.55 mol) was added in three portions over 3 h maintaining an internal temperature of 18° C. with gentle cooling. The reaction mixture was held at 18° C. for 12 h. HPLC analysis shows no remaining 1. The reaction mixture was pumped into an extractor containing 74 L of water at 5° C. The resulting solution (39.3 g/L of 2) was extracted with ethyl acetate (4×37 L).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH:3]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19].[NH:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O.CN(C=O)C>[CH3:1][CH:2]([CH3:30])[CH:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:31]2[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32]2)=[O:26])=[CH:28][CH:29]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19]
Reactant: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(Nc1ccc(C(=O)O)cc1)C(C)C
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(c3ccc(-n4cc5c(n4)CCCC5)cc3C)C(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-((2-methyl-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)propyl)amino)benzoic acid obtained in step C, ethyl (3R)-piperidine-3-carboxylate (0.106 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (132 mg), 1-hydroxybenzotriazole (93 mg), N,N-diisopropylethylamine (0.180 mL), 4-dimethylaminopyridine (4.2 mg) and DMF (0.860 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (152.3 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][OH:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][C@H:38]([CH2:46][OH:47])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:9]1)(C)(C)C>Cl.CO>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][OH:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][C@H:38]([CH2:46][OH:47])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CC#Cc2nc(N[C@H](CO)Cc3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: CO
Product: N[C@@H]1CCN(CC#Cc2nc(N[C@H](CO)Cc3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
((R)-1-{3-[9-[(1R,2S,3R,4S)-2,3-Dihydroxy-4-(2-hydroxy-acetylamino)-cyclopentyl}-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purin-2-yl]-prop-2-ynyl]-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Intermediate XC) is dissolved in 1.25 M HCl in MeOH. After stirring at RT for 3 days, the solvent is removed in vacuo to yield the title compound. This is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2.3 g (6.95 mmol) of 8-(t-butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one in 40 ml of dry dimethylformamide at 0° C. was added 0.4 g (13 mmol) of sodium hydride (80% in mineral oil). The mixture was stirred at 0° C. under argon for 30 minutes and then ethyl 5-bromopentanoate (2.09 g, 10 mmol) was added dropwise. After being allowed to come to ambient temperature, the mixture was stirred for an additional 20 hours. The mixture was quenched with aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium surf ate and concentrated. The residue was purified by column chromatography (silica gel, 0-25% gradient of ethyl acetate in hexane) to provide 2.4 g (75.2%) of the indicated ester as a colorless liquid.
Reaction SMILES: OC1C(OC)=C(OC)C(OC)=CC=1C(O)=O.COC1C=CC(OC)=C(OC)C=1OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O[C:46]1[C:67]([O:68][CH3:69])=[C:66]([O:70][CH3:71])[C:65]([O:72][CH3:73])=[CH:64][C:47]=1[C:48]([C:50]1[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[C:51]=1[O:62]C)=[O:49]>CS(O)(=O)=O>[CH3:57][O:56][C:54]1[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[C:51]2[O:62][C:64]3[C:47](=[CH:46][C:67]([O:68][CH3:69])=[C:66]([O:70][CH3:71])[C:65]=3[O:72][CH3:73])[C:48](=[O:49])[C:50]=2[CH:55]=1
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2OC)c(O)c(OC)c1OC
Agent: COc1cc(C(=O)O)c(O)c(OC)c1OC
Agent: COc1ccc(OC)c(OC)c1OC
Agent: CS(=O)(=O)O
Product: COc1cc2c(=O)c3cc(OC)c(OC)c(OC)c3oc2c(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
2-hydroxy-3,4,5-trimethoxybenzoic acid (1.14 g, 0.005 mol) and 1,2,3,4-tetramethoxybenzene (0.99 g, 0.005 mol) and 25 ml of a 9% solution of P2O5 in methanesulfonic acid were shaken in a 50 ml cylindrical glass tube with a Teflon-lined screw-cap at room temperature for 54 hours. The dark orange mixture was then poured onto crushed ice (150 ml). After melting, the product was extracted with methylene chloride (3×40 ml). After removal of the solvent, the residue was chromatographed on silica gel (30 g) with CH2Cl2. Of the three fractions obtained (the eluent was monitored by thin-layer chromatography), the middle one was uniform and left pure 2-hydroxy-3,4,5,2',3',4',5'-heptamethoxybenzophenone (0.51 g, 25%) as a yellow oil upon evaporation of the solvent. This was dissolved in 100 ml 75% alcohol whereafter 5 ml of 10N NaOH were added and the mixture was heated to boiling in a beaker for three hours; the volume was kept at 100 ml by occasional addition of water. The mixture was then transferred to a 250 ml round bottom flask and refluxed for another 17 hours. After cooling, suction filtration yielded 0.36 g of 2,3,4,5,6,7-hexamethoxyxanthone as a white product (small needles, matted, 77%). In a deprotection procedure, similar to the one described above for pentamethoxyxanthone, 0.42 g of the hexamethoxyxanthone produced 0.296 g of hexahydroxyxanthone (91%) as a pale yellow powder. It was found advantageous to circumvent the need for centrifugation by stirring the methylene chloride-water mixture (from the quenching of the BBr3 -solution) in a wide-mouthed container for several hours, leading to the evaporation of the methylene chloride; the mixture is then easily filterable.