Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:48])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[O:38][N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cc(CO)no3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-morpholin-4-yl-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M23) (57 mg, 0.08 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (11 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:14]1[N:19]=[C:18](Cl)[C:17]2[N:21]=[CH:22][N:23]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[C:16]=2[N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][NH:13][C:18]3[C:17]4[N:21]=[CH:22][N:23]([C:16]=4[N:15]=[CH:14][N:19]=3)[C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2cccc(Cl)c2)CCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5cccc(Cl)c5)CCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 82.1 %

Procedure:
The above amine (1.96 g, 10 mmol) is reacted with 6-chloropurine riboside (2.87 g, 10 mmol) and purified as described in Examples 1 and 7 above. N6-((1-(3-chlorophenyl)cyclobutyl)methyl)adenosine (3.66 g, 82%) as a pale yellow solid foam is obtained m.p. 92°-8° C. Found: C, 56.11; H, 5.33; N, 15.44; Cl, 8.99%. C21H24ClN5O4 calculated requires: C, 56.57; H, 5.39; N, 15.71; Cl, 7.97%.
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CO.[Pd]>[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:21]34[CH2:28][CH:24]([CH2:23][CH2:22]3)[CH:25]3[CH:20]4[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:18](=[O:37])[CH:17]=[C:26]3[OH:27])=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1.[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Product: O=C1C=C(O)C2C3CCC(C4=NS(=O)(=O)c5cc(C6CCCS6(=O)=O)ccc5N4)(C3)C2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 176 %

Procedure:
(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 20, 30 mg, 0.05 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, rinsed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (26 mg, 0.044 mmol, 86%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.40-1.60 (4H, m), 2.12 (1H, m), 2.67 (1H, m), 2.36 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 3.03 (1H, m), 3.23 (1H, m), 3.32 (1H, m), 3.53 (1H, d, J=10.0 Hz), 4.42 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=11.6, 6.8 Hz), 4.97 (1H, d, J=15.6 Hz), 7.14 (2H, m), 7.33 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz); LC-MS (ESI) calcd for C28H28FN3O6S2 585.14, found 586.3 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 78.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (55 mg, 0.053 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (63 mg, 0.106 mmol) and cesium carbonate (1.3 g, 3.99 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-quinoline (compound of example 2) (1 g, 2.66 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.28 g, 3.19 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 80:20 to give a yellow solid (800 mg, 78%). MS: m/z=383 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[Si:14]([O:21][CH2:22]/[CH:23]=[N:24]/[S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1(C)C=CC=CC=1>[Si:14]([O:21][CH2:22][C@@H:23]([NH:24][S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of toluene (500 mL) at −78° C. was added butyl lithium (1.6 M in hexanes, 75.6 ml, 121 mmol) at a rate such that the internal temperature did not exceed −50° C. To this solution was added 2-bromo-5-fluoropyridine (23.2 g, 132 mmol) in toluene (200 mL) at a rate such that the internal temperature did not exceed −68° C. The reaction was stirred at −78° C. for 1 hour. To the reaction was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (30.5 g, 110 mmol) in toluene (200 mL) at a rate such that the internal temperature did exceed −68° C. The reaction was again stirred at −78° C. for 1 hour. To the reaction was added 200 mL of water and the layers separated. The toluene solution was washed with water (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 4:1 hexanes/ethyl acetate as eluent to yield (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (20 g, 48%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])=[CH:6][CH:5]=1)[CH3:3])(=[O:30])=[O:29]
Reactant: CC(O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reaction time: 4 h

Procedure:
tert-Butyl [2-[4-(1-hydroxyethyl)phenyl]ethyl]carbamate (606 mg) was dissolved in dichloromethane (20 ml), triethylamine (0.38 ml) and then methanesulfonyl chloride (0.195 ml) were added at 0° C., and the mixture was stirred for 4 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-[4-[2-[(tert-butoxycarbonyl)amino]ethyl]phenyl]ethyl methanesulfonate. The obtained compound, (3S)-3-fluoropyrrolidine hydrochloride (287 mg) and N,N-diisopropylethylamine (1.18 g) were mixed with DMF (10 ml), and the mixture was stirred at 50° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 (volume ratio)→ethyl acetate→ethyl acetate:methanol=9:1 (volume ratio)) to give tert-butyl [2-[4-[1-[(3S)-3-fluoropyrrolidin-1-yl]ethyl]phenyl]ethyl]carbamate (133 mg) as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].O=[C:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]([CH3:13])[CH3:12])[N:1]=[C:15]([CH3:22])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile (Tachdjian, C. et al. PCT Int. App. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q, J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH+).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][O:9]C(=O)C)(=[O:6])[O:4][CH3:5].C(OC)(=O)C.CO>CO.S(=O)(=O)(O)O>[CH3:1][O:2][P:3]([CH2:7][CH2:8][OH:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CCOC(C)=O)OC
Agent: O=S(=O)(O)O
Solvent: COC(C)=O
Solvent: CO
Product: COP(=O)(CCO)OC
Yield: 85 %

Procedure:
A solution of 50 g of 2-acetoxyethane phosphonic acid dimethyl ester in 100 ml of anhydrous methanol is heated to 65°-70°C for 5 hours, while adding one drop of concentrated sulfuric acid. A mixture of methyl acetate/methanol is removed continuously by distillation in the course of the reaction. After a distillation under reduced pressure 33.5 g of 2-hydroxyethane-phosphonic acid dimethyl ester are obtained, corresponding to a yield of 85% of the theoretical.
Reaction SMILES: [O-]P(OP([O-])[O-])[O-].CC(C1C=[C:16]([O:18]C)[CH:15]=[C:14]([C:20]2[C:25]([O:26]P3OC4C(=CC=CC=4)C4C(=CC=CC=4)O3)=[C:24](C(C)(C)C)[CH:23]=[C:22](OC)[CH:21]=2)C=1OP1OC2C(=CC=CC=2)C2C(=CC=CC=2)O1)(C)C.C=CCC([OH:71])CC=C.C(=O)=O>>[CH:21]([CH2:22][CH2:23][CH2:24][CH:25]1[O:26][CH:16]([OH:18])[CH2:15][CH2:14][CH2:20]1)=[O:71]
Reactant: C=CCC(O)CC=C
Reactant: COc1cc(-c2cc(OC)cc(C(C)(C)C)c2Op2oc3ccccc3c3ccccc3o2)c(Op2oc3ccccc3c3ccccc3o2)c(C(C)(C)C)c1
Agent: O=C=O
Agent: [O-]P([O-])OP([O-])[O-]
Product: O=CCCCC1CCCC(O)O1
Temperature: -60 °C

Procedure:
To a 300 mL stainless steel autoclave with two sapphire windows containing Rh(acac)(CO)2 (1.5 mg, 6×10-3 mmol) and a diphosphite ligand, BIPHEPHOS or MCP-1, (1.2×10-2 mmol) was added 1,6-heptadien-4-ol (112 mg, 1.0 mmol). The air was replaced by CO and CO (7 atm) was introduced followed by H2 (7 atm). The reaction vessel was cooled to -60° C. and CO2 (85 atm) was introduced. The mixture was allowed to stir at 65° C. and 100 atm overnight. The autoclave was cooled to 0° C. and all the gasses were carefully released. The reaction mixture was then concentrated under vacuum and the residue was chromatographed on silica gel using hexane/AcOEt as the eluant to give 6-(3-formylpropyl)-2-hydroxytetrahydropyran in nearly quantitative yield: 1H NMR (CDCl3) (two diastereomers) δ 1.14-2.02 (m, 10 H), 2.43 (t, J=6.8 Hz, 2 H), 3.16 (br s, 1 H), [3.36-3.44 (m), 3.88-3.96 (m)] (1 H), [4.66 (d, J=9.1 Hz), 5.26 (br s)] (1 H), 9.74 (s, 1 H); 13C NMR (CDCl3) δ [17.50, 18.04], 21.95, [30.26, 30.99], [32.55, 32.03], [35.01, 35.18], [43.13, 43.52], [72.96, 75.64], [91.36, 96.21], [201.90, 202.74]; IR (neat, cm-1) 3420, 2942, 2867, 2723, 1724, 1458, 1440, 1412, 1390, 1352, 1184, 1116, 1066, 1035, 977.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][N:15]=1.CN(C=O)C>C(OCC)(=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>[CH3:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)Cc1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccnc(-c2ccnc(C)c2)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing methyl 2-(2-chloropyridin-4-yl)acetate 238-1 (1.00 g, 5.38 mmol), 2-methyl-4-(tributylstannyl)pyridine (2.06 g, 5.38 mmol), Pd(PPh3)4 (594 mg, 0.54 mmoL) under argon was added DMF (15 mL). The reaction mixture was stirred at 120° C. for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 5% methano in dichloromethane to give methyl 2-(2′-methyl-2,4′-bipyridin-4-yl)acetate 238-2 as dark orange oil. MS m/z 243.1 (M+1).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28]
Reactant: COC(=O)CCCCC(=O)O
Reactant: COc1ccccc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z=308.1 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:25][CH2:24]3)=[O:22])[C:12](=[O:19])[N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:40][CH:41]([CH2:44][CH3:45])[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:27][CH2:28]3)=[O:22])[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:40][CH:41]([CH3:42])[CH2:44][CH3:45])[CH2:15][CH2:14]3)=[O:19])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCC(C)C=O
Reactant: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCNCC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(C)CN1CCN(C(=O)C(Cc2ccc3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)CC1
Reaction time: 1 h
Yield: 50 %

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[1-(1H-indazol-5-ylmethyl)-2-oxo-2-piperazin-1-yl-ethyl]-amide (100 mg, 0.188 mmol) in methanol (25 mL) was treated with 2-methyl-butyraldehyde (0.03 ml, 0.376 mmol). After 1 h at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was allowed to stir overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with methanol and then with a 1M solution of ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LC/MS: tR=1.31 min, 601(MH)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[O:21][CH:20]1[OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)[O:21][C:20]1=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(COCC2(COCc3ccc(OC)cc3)OC(O)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(COCC2(COCc3ccc(OC)cc3)OC(=O)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of oxalyl dichloride (1.9 mL, 23 mmol) in dichloromethane (65 mL) at −78° C. was added a solution of dimethyl sulfoxide (3.3 mL, 47 mmol) in dichloromethane (5 mL) and the resulting solution was stirred at this temperature for 30 minutes. A solution of starting material ((3R,4S,5S)-3,4,5-tris-benzyloxy-6,6-bis-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-2-ol, (I-1d, 5.6 g, 7.7 mmol) in dichloromethane (15.0 mL) was then added dropwise and the resulting mixture was stirred for 30 minutes allowing the temperature to rise to −60° C. Triethylamine (9.7 mL, 69.5 mmol) was added dropwise and the mixture allowed to warm up to 0° C. over 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel eluting with a gradient of 0 to 60% ethyl acetate in heptane to produce the product (I-1e) (4 g, 72% yield).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.ClC1C=CC(C2C(C=O)=CC=CC=2)=CC=1>>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:3][CH2:2][C@@H:6]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:5]2)[CH2:15]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=Cc1ccccc1-c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2COC2)C1

Procedure:
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and 3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[NH:18][C:19](=[O:26])[C:20]3[S:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:8]=1.CO.O1CCOC[CH2:30]1>>[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([O:13][CH3:30])=[O:12])=[C:9]([C:17]2[NH:18][C:19](=[O:26])[C:20]3[S:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:8]=1
Reactant: C1COCCO1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[C:15]([F:29])[C:16]([CH3:28])=[C:17]([C:19]3[N:20]=[CH:21][C:22]([C:23]([NH:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])=[O:25])=[CH:26][CH:27]=3)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: CCC(N)CC
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
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: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminopentane (147 μl) in DMF (8 ml) was added to a mixture of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid (Intermediate 8, 200 mg), HATU (228 mg) and DIPEA (348 μl) in DMF (8 ml) and the reaction stirred for 18 hours at room temperature. The DMF was evaporated under vacuum and the residue dissolved in ethyl acetate and applied to an SCX SPE (10 g). The SPE was washed with ethyl acetate then methanol/ethylacetate (1:9) and the product elutes with 0.880 ammonia/methanol/ethyl acetate (1:1:8). The product fraction was reduced to dryness under vacuum and purified on a silica SPE (500 mg) eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvents 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide.