Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58]([NH:60][C@H:61]([C:71](=[O:77])[NH:72][CH2:73][CH2:74][CH:75]=O)[CH2:62][CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:75][CH2:74][CH2:73][NH:72][C:71](=[O:77])[C@H:61]([CH2:62][CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:60][C:58](=[O:59])[O:57][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 82.5 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-oxo-5-[(3-oxopropyl)amino]pentanoate (60 mg, 0.152 mmol, obtained from Reference Example 26), acetic acid (2 drops), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred under nitrogen at room temperature for 3.5 hours. The product was purified by chromatography (flash column, silica gel, 4% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[3-(tert-butoxy)-3-oxopropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (126 mg, 83%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Br:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1>>[Br:7][C:8]1[C:9]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: Clc1cccs1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ncc(Br)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 2-chlorothiophene and 5-bromo-2-chloropyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 311.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[NH2:29][CH2:30][C@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[OH:36]>C(Cl)Cl.CCCCCC>[NH2:29][CH2:30][C@H:31]1[C@@H:32]([OH:36])[CH2:33][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: NC[C@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: NC[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 48 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and cis-4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 80.1). The crude product was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was suspended in DCM/n-hexane, filtered and dried to afford the title product as a beige solid. HPLC (Condition 7) tR=5.38 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=479 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.05 (m, 1H) 2.38-2.86 (m, 2H) 2.88-3.06 (m, 1H) 3.08-3.23 (m, 1H) 3.24-3.37 (m, 2H) 3.91-4.18 (m, 1H) 6.33-6.42 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.68-7.91 (m, J=9.00 Hz, 3H) 7.97-8.06 (m, 1H) 8.68-8.78 (m, 1H) 10.20 (s, 1H) 12.94 (br. s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10]>O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:2]([CH3:3])[CH3:1])=[O:10]
Reactant: CNC
Reactant: O=C(Cl)CCCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCCl
Yield: 84.6 %

Procedure:
A solution of 20.0 g (0.44 mole) of dimethylamine in 100 ml of cold tetrahydrofuran (THF) was added dropwise to a solution of 20.0 g (0.13 mole) of 5-chlorovaleryl chloride in 100 ml of THF. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure to yield 18.0 g (85%) of yellow oil. An analytical sample was prepared by filtering this oil through a small bed of silica gel and eluting with ethyl acetate-hexane (1:1). The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]2[N:6]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:7](=[O:37])[CH:8]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[N:19](C(OC(C)(C)C)=O)[C:18](=[O:27])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:48]=[CH:47][C:5]2[N:6]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[C:7](=[O:37])[CH:8]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[NH:19][C:18](=[O:27])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)n(C(=O)OC(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)[nH]c4c3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
tert-Butyl 6-(7-chloro-3-(2-chlorophenethyl)-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxylate (90 mg) was dissolved in 4 N HCl in dioxane (10 mL), and stirred at room temperature for 2 h, then concentrated delivering pure product (50 mg, 75% yield). MS (ES+) m/z 607.9 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:31]3[CH2:32][CH2:33][C:28]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:29][CH2:30]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC2CO2)C1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC3(CC2)OCCO3)C1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a stirred solution of 3.20 g (9.64 mmol) of 1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 2.07 g (14.5 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane in CH2Cl2 (65 mL) was added 1.79 g (2.89 mmol) of Yb(OTf)3.H2O. The reaction was stirred overnight and was then directly purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 3.70 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.35. MS (electrospray), m/z calculated for C24H31ClN4O4 [M++H], 475.20, observed 475.1.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[N:7]=[C:6]3[C:2]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:29])[F:30])[CH:21]=4)=[CH:3][O:4][C:5]3=[CH:10][CH:9]=2)=[N:15][N:14]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3n2)o1
Yield: 57 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 57%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:31]2[CH2:32][CH2:33][C:34]([CH3:37])([CH3:38])[CH2:35][CH2:36]2)=[CH:8][C:9]=1[N:10]([C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[CH:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.472 g, 0.88 mmol) in acetic acid (4.4 ml) was added 20% wet palladium hydroxide on charcoal (0.141 g). The resulting reaction mixture was placed under H2 atmosphere, stirred at room temperature for 16 h, and then filtered through celite and evaporated to dryness to obtain 5-(4,4-dimethyl-cyclohexyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.470 g, 95%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([CH3:23])[C:17]2=[CH:16][C:15]=1[C:24]1[CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=1)[CH3:13])=O)C1C=CC=CC=1>CCO.[Pd]>[NH2:11][C@H:12]([C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([CH3:23])[C:17]2=[CH:16][C:15]=1[CH:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25]1)[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1C1=CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)c1nc2ccn(C)c2cc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 27 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
A mixture of tert-butyl (S)-3-(5-(1-(((benzyloxy)carbonyl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (900 mg, 1.89 mmol) and Pd/C (100 mg) in EtOH (50 mL) was stirred at 27° C. for 3 hours under H2 (50 psi). The reaction mixture was subsequently filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to afford a mixture of the diastereomers of the title compound as a yellow oil (350 mg, 54%). 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (d, J=6.4 Hz, 1H), 7.22 (d, J=3.2 Hz, 1H), 6.61 (d, J=3.2 Hz, 1H), 4.51 (q, J=6.4 Hz, 1H), 3.86-3.37 (m, 1H), 3.76 (s, 3H), 2.31-2.30 (m, 1H), 1.50 (s, 9H), 1.44 (d, J=6.4 Hz, 3H); ESI-MS m/z [M+H]+ calc'd for C19H28N4O2, 345. found 345.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)OCCC[O:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH3:4].Cl>C(O)C.O>[C:14]([C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([CH:3]([CH3:4])[CH2:2][OH:1])[CH:6]=1)(=[O:15])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(CO)c1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(CO)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a solution of 2-(3-(2-hydroxy-1-methylethyl)-4-nitrophenyl)-2-phenyl-1,3-dioxane (18) (23.6 g; approx. 69 mmol) in ethanol (350 mL) was added water (70 mL) under vigorous stirring. Concentrated hydrochloric acid (about 12 N aqueous solution, 35 mL) was then added drop wise. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with water and extracted with ethyl acetate. The organic phase was successively washed with an aqueous, saturated solution of NaHCO3 and with water. The organic phase was then concentrated in vacuo and seeded with crystals of the product 4f to provide a yellow solid. Finally, the powdered solid was washed with hexane and air dried to yield 17.83 g (62.5 mmol, 91%) of a yellow powder. 1H NMR (250 MHz, DMSO-d6) δ 7.91-7.52 (m, 8H, arom.), 4.75 (br. s., 1H, OH), 3.53 (d, 2H, α-CH2), 3.23 (sextet, 1H, β-CH), 1.24 (d, 3H, γ-CH3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+]>O1CCOCC1>[CH3:12][O:13][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(OCCO)cn1
Temperature: 130 °C

Procedure:
A mixture of the product of Example 203, Step 1(513 mg, 2.96 mmol) and freshly prepared NaOMe (3.06 g, 56.6 mmol) in dry dioxane (25 mL) was heated in a sealed Pyrex tube at 130° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The organic phase was washed with brine, dried (MgSO4), and concentrated to give the crude product as an oil (430 mg). Purification by column chromatography, using isohexane/EtOAc (1:1) as an eluent, gave the title product as a white solid. Yield 258 mg (51%); MS m/z 169 (M)+. Anal. (C8H11NO3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
Reacting the 2-(2,4,6-trichlorophenoxy)-ethanol with thionyl chloride in the presence of a catalytic amount of a tetra-alkyl ammonium halide at a temp. of from 30° C. to 100° C., optionally in the presence of a solvent to form 2-(2,4,6-trichlorophenoxy)-ethyl chloride;
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Yield: 80 %

Procedure:
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 5-amino-2-methylindole (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 80%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C

Procedure:
4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (1.08 g) was heated at reflux in 10 ml of acetic anhydride for 2 h, cooled to RT, diluted with water (100 ml), neutralized to pH7 with NaHCO3 (solid) and extracted with EtOAc. The organic portion was washed with brine, removal of the solvents afforded 1-(4,4-dimethyl-7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone as a solid.
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 62 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (3 mL) provided 41 mg (62%) of product 11 as a white solid, mp 186-188° C. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7 Hz, 3H), 2.59 (s, 3H), 4.31 (q, J=7 Hz, 2H), 6.88 (d, J=7 Hz, 1H), 6.94-6.98 (m, 2H), 7.23 (t, J=8 Hz, 1H), 7.25-7.30 (m, 2H), 7.42 (d, J=8 Hz, 1H), 12.48 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.53; H, 4.59; N, 4.08; S, 9.27; Cl, 10.35.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[C:20](Cl)(Cl)=[S:21]>O1CCOCC1>[F:11][C:10]([F:12])([F:13])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:3]=[C:2]([N:1]=[C:20]=[S:21])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: C1COCCO1
Product: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
2-Amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (20.0 g, 68.7 mmol) was added to a solution of thiophosgene (15.7 mL, 206 mmol) in anhydrous dioxane (100 mL) under an N2 atmosphere. The resulting solution was heated to reflux. After 18 h the heat was removed and the reaction cooled to room temperature. The dioxane was evaporated to give a dark oil. The dark oil was distilled to afford the product as a light yellow oil (13.7 g, 60% yield); bp 83-86° C., (ca 0.2 mmHg): 1H NMR (CDCl3) δ 6.24 (s 1H), 4.78 (q, 4H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 333 (M+).
Reaction SMILES: [C:1](=[O:43])([O:33][C:34]1C=CC([N+]([O-])=O)=C[CH:35]=1)[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2.OCC[N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:1](=[O:43])([O:33][CH2:34][CH2:35][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52])[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)Oc4ccc([N+](=O)[O-])cc4)c3C(=O)N12
Reactant: O=C1CCCN1CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCN4CCCC4=O)c3C(=O)N12

Procedure:
The title compound was prepared from {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 4-nitrophenyl carbonate (50 mg, 0.83 mmol), 1-(2-hydroxyethyl)-2-pyrrolidinone (9 μL, 0.083 mmol), triethylamine (35 μL, 0.250 mmol), and DMAP (10 mg, 0.083 mmol), in a process similar to that described in example 10. Purification by silica-gel chromatography and reverse-phase hplc afforded the title compound as a white solid. 1H NMR (CDCl3) δ 10.28 (m, 1H), 8.45 (s, 1 H), 7.32 (m, 1H), 6.80 (m, 2H), 5.93 (d, J=6.8 Hz, 1H), 5.80 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.6 Hz, 1H), 4.64-4.23 (m, 8H), 3.94 (m, 1H), 3.68-3.50 (m, 4H), 2.42 (t, J=8 Hz, 2H), 2.02 (m, 2H), 1.37 (d, J=6 Hz, 3H). ES+ MS: 591 (M+1).
Reaction SMILES: C(OC([C:6]1[C:7](=[O:26])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C@@H:9]2[C@H:14]([C:15]=1[OH:16])[C@@H:13]1[CH2:17][C@H:10]2[CH2:11][CH2:12]1)=O)C.S(=O)(=O)(O)O>O1CCOCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]2[C:7](=[O:26])[CH:6]=[C:15]([OH:16])[C@H:14]3[C@@H:9]2[C@H:10]2[CH2:17][C@@H:13]3[CH2:12][CH2:11]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N(Cc2ccc(F)cc2)C1=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1C=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 110 °C
Yield: 54 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-ene-5-carboxylic acid ethyl ester was suspended in a 1/1 mixture of 1,4-dioxane and 1.0 M aqueous sulfuric acid solution (200 mL). The mixture was heated to 110° C. for 40 min, and then was allowed to cool to 25° C. The cooled mixture was poured into a separatory funnel and was extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford a white solid. This material was triturated with hexanes and was collected by filtration, washed with hexanes (2×15 mL) and air-dried to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (2.24 g, 7.80 mmol, 54% over three steps), as a white solid. 1H NMR (major tautomer, 400 MHz, CDCl3) δ: 1.11-1.16 (1H, m), 1.20-1.39 (3H, m), 1.57-1.69 (2H, m), 2.53 (1H, d, J=8.4 Hz), 2.63 (1H, bs), 2.73 (1H, bs), 3.39 (1H, d, J=4.1 Hz), 3.51 (1H, d, J=9.5 Hz), 4.29 (1H, d, J=14.9 Hz), 5.20 (1H, d, J=14.9 Hz), 6.98-7.04 (2H, m), 7.19-7.24 (2H, m).