Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-(4-Bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2—H2O (Aldrich, 55%, 9.1 mL, 156 mmol) in EtOH (Aldrich, 100 mL) at refluxing for 2 h. It was cooled down to ambient temperature and the white solid was filtered off to give the title compound (24.2 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 2.50-2.76 (m, 2H), 2.85-3.09 (m, 2H), 7.43-7.71 (m, 4H), 8.55 (s, 1H) ppm. MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+, 270 (M+NH4)+, 272 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([OH:17])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]2[O:22][C:23]([CH3:27])([CH3:26])[CH:24]=[CH:25][C:3]=12.N1C=CC=CC=1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:38]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]2[O:22][C:23]([CH3:26])([CH3:27])[CH:24]=[CH:25][C:3]=12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](C)[C@@H](O)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a solution of 9 (1.44 g, 3.89 mmol) in dry CH2Cl2 (50 mL) at -20° C. was added pyridine (6 mL), DMAP (1.10 g, 9.00 mmol) and tert-butylchlorodimethylsilane (1.40 g, 9.28 mmol). The reaction mixture was stirred under nitrogen at room temperature for 1.5 h until disappearance of the starting material was observed. Water (15 mL) was then added, and the mixture was stirred for an additional 15 min. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were evaporated under reduced pressure at room temperature. The oil obtained was submitted to silica gel chromatography (solvent B) to obtain 10 (1.80 g, 95%) as a syrup: [α]D20 +26° (c 3.8, acetone); 1H NMR (CDCl3): δ -0.11, 0.08 (2s, 6H, --SiCH3), 0.80 [s, 9H, --C(CH3)3 ], 0.90 (d, 3H, J=6.90 Hz, --CHCH3), 0.96 (t, 3H, J=7.30 Hz, --CH2CH3), 1.39, 1.43 (2s, 6H, --C(CH3)2), 1.60 (m, 2H, --CH2CH3), 2.54 (m, 1H, --CHCH3), 2.80 (m, 2H, --CH2CH2CH3), 4.86-5.00 (m, 2H, --CH=CH2), 5.22 [d, 1H, J=6.85 Hz, --CHOSi(CH3)2 --], 5.46 (d, 1H, J=10.0 Hz, H-3), 5.68-5.87 (m, 1H, --CH=CH2), 5.83 (s, 1H, H-9), 6.59 (d, 1H, J=10.0 Hz, H-4), 9.20 (s, 1H, Ar--OH); 13C NMR (CDCl3): δ -0.42, -0.22, 13.90, 16.14, 17.95, 23.02, 25.58, 27.47, 27.90, 38.49, 44.45, 74.08, 77.49, 102.63, 106.65, 106.72, 110.00, 115.60, 116.51, 126.61, 139.63, 150.99, 151.69, 155.33, 158.33, 160.90; Anal. Calcd for C28H40O5Si: C, 69.38; H, 8.32. Found C, 68.55; H, 8.42. MS (negative-ion FAB): m/z 483 (M-1)-, 351, 297.
Reaction SMILES: [NH2:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]12.CN(C)C(=O)C.[N:29]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1.C(=O)([O-])O.[Na+:42]>ClCCl>[Na+:42].[Na+:42].[N:29]1([CH2:34][C:35]([NH:1][C@@H:2]2[C:21](=[O:22])[N:4]3[C:5]([C:18]([O-:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]23)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1.[N:29]1([CH2:34][C:35]([NH:1][C@@H:2]2[C:21](=[O:22])[N:4]3[C:5]([C:18]([O-:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]23)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CCC(=O)O)CS[C@H]12
Reactant: O=C(Cl)Cn1cnnn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(O)CCC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1

Procedure:
In dichloromethane (7 ml) was suspended 7β-amino-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (660 mg), followed by the addition of N,N-dimethylacetamide (0.7 ml). Then, under ice-cooling and stirring, a solution of (1H-tetrazol-1-yl)acetyl chloride (294 mg) in dichloromethane (2 ml) was added. The mixture was stirred at room temperature for 1 hour, after which time it was poured in an aqueous solution of sodium hydrogen carbonate and separated. The water layer was taken, washed with dichloromethane, made acidic with phosphoric acid and extracted with ethyl acetate. The extract was re-extracted with aqueous sodium hydrogen carbonate solution to bring the desired compound into the aqueous phase. This aqueous solution was purified by column-chromatography on Sephadex LH-20. The fractions containing the dominant product were pooled and lyophilized. The procedure provided 7β-[2-(1H-tetrazol-1-yl)acetamido]-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid disodium salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>C1COCC1>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137-139° C.; 1H-NMR (CDCl3) δ1.25-1.29 (m, 3 H), 3.59 (s, 2 H), 4.15-4.20 (m, 2 H), 7.05 (br s, 1 H), 7.13-7.23 (m, 6 H), 7.47-7.51 (m, 1 H), 7.54-7.56 (m, 1 H), 8.01-8.03 (m, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:26]=[C:27]=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:18]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(NCCc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with phenethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (22.0 mg, 38%) having the following characteristics.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2cc(-c3ccc4cc[nH]c4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 22 %

Procedure:
6-bromo-1H-indole (28.8 mg, 0.147 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (109.2 mg, 0.288 mmol), Fibercat palladium catalyst (Johnson-Matthey, 55.5 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml; 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via HPLC (10%->95% MeCN/water with 0.1% TFA), silica gel (4:1->3:1->2:1->1:1 hexanes/EtOAc) to afford crude product. This crude material was then purified again via HPLC (same conditions as above) to afford title compound (11.9 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:29][C:30]([C@H:32]1[CH2:34][C@H:33]1[C:35](O)=[O:36])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>O1CCCC1.O>[CH2:1]([CH:8]1[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:21])=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:29]1[C:35](=[O:36])[CH:33]2[CH:32]([CH2:34]2)[C:30]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)[C@H]2C[C@H]2C(=O)O)CC3)c1
Solvent: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2C(=O)C4CC4C2=O)CC3)c1

Procedure:
cis-2-{[1-Benzyl-7-({[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamoyl}cyclopropanecarboxylic acid (382 mg, 0.731 mmol) was dissolved in tetrahydrofuran (10 mL) and acetyl chloride (5 mL, 88 mmol) was added. The reaction mixture was heated under reflux for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated in vacuo. The crude product was used for the next step without further purificiation. Yield: 377 mg (light orange oil).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4].Br[CH:28]([SiH](C1C=CC=CC=1)C1C=CC=CC=1)[CH:29]([O:31]C(C)(C)C)[CH3:30].O>CCCCCC.CN(C=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:21]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1
Reactant: CC(OC(C)(C)C)C(Br)[SiH](c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3sccc23)CC1
Reaction time: 0.75 h
Yield: 90 %

Procedure:
66% sodium hydride (0.26 g, 1.2 equivalents) was washed with n-hexane and was then suspended in DMF of 1 ml, and the mixture was stirred under ice-cooling. To the resulting mixture was added 4-(4-ethylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine of 2.00 g (5.88 mmol) dissolved in DMF of 20 ml, followed by the agitation at room temperature for 45 min. To the resulting product was added 1-bromo-O-(t-butyl)diphenylsilyl-2-propanol of 4.44 g (2.0 equivalents) dissolved in DMF of 15 ml, which was stirred in nitrogen atmosphere at 50° C. for 18 hr. Water was added to the resulting mixture, and then extracted with ethyl acetate. The organic layer was washed sequentially with water (three times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (eluent solvent/ethyl acetate system), to give the title compound as a pale yellow oil (3.38 mg, yield; 90%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][N:8]1[N:12]=[C:11]([CH2:13][N:14]([C:22]([N:31]2[CH2:34][CH:33]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[N:9]1.[CH:44]([O:57][C:58]([C:60]1([O:63]/[N:64]=[C:65](/[C:69]2[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=2)\[C:66](O)=[O:67])[CH2:62][CH2:61]1)=[O:59])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=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>C(Cl)Cl.CN(C=O)C>[C:17]([O:16][C:15]([N:14]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C@@H:3]2[C@H:2]([NH:1][C:66](=[O:67])/[C:65](=[N:64]\[O:63][C:60]3([C:58]([O:57][CH:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:59])[CH2:62][CH2:61]3)/[C:69]3[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=3)[C:5](=[O:6])[NH:4]2)[N:12]=1)[C:22]([N:31]1[CH2:34][CH:33]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[N:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@H]2NC(=O)[C@H]2N)n1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1)C(=O)OC(C)(C)C
Yield: 75.9 %

Procedure:
Prepared in analogous manner to example 126 step 3, using tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)((3-(((tert-butoxycarbonyl)amino)methyl)azetidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate (460 mg, 0.76 mmol), (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (407 mg, 0.76 mmol), DMF (8 mL), DCM (8 mL), HATU (345 mg, 0.91 mmol) and DIPEA (0.33 μL, 1.89 mmol). The crude residue was purified via silica gel chromatography (EtOAc-heptane, 0-100%) to afford the title compound (0.65 g, 76%). LCMS: Rt=1.15 min, m/z=1127.9 (M+1) Method 2m_acidic.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:34]=[CH:33][C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=1.C([Li])CCC.Cl[Si:41]([CH3:44])([CH3:43])[CH3:42].C1(C)C=CC=CC=1>C1COCC1>[CH3:42][Si:41]([CH3:44])([CH3:43])[N:25]1[C:24]2[CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:12]([Si:41]([CH3:44])([CH3:43])[CH3:42])[C:13]=4[CH:1]=3)[CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: c1ccc2c(c1)[nH]c1cc(OCCCCCCOc3ccc4c(c3)[nH]c3ccccc34)ccc12
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)n1c2ccccc2c2ccc(OCCCCCCOc3ccc4c5ccccc5n([Si](C)(C)C)c4c3)cc21
Yield: 84 %

Procedure:
To a solution of 1,6-bis(carbazol-2-yloxy)hexane (30 g) in dry THF (200 ml) was added butyllithium (56 ml; 1.6M in hexane). Once the butyllithium addition was completed, the solution was heated to reflux for 1.5 hours and then allowed to cool. Chlorotrimethylsilane (12 ml) was added dropwise to the cooled mixture and then heated to reflux for 4 hours. Toluene (150 ml) was added to the cool mixture which was then filtered to remove LiC1. The filtrate was collected and the solvent removed under vacuum leaving a crude gray compound. The crude product was further purified by vacuum distillation to give a white compound (E.1) in an 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:9]2=[O:10])=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][C:5]([N:8]2[C:9](=[O:10])[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: -3 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(4-chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide (24.4 g, 86.7 mmol) in sulfuric acid (150 mL) is cooled to -3° C., treated dropwise with nitric acid (70% real, 6.70 mL, 104 retool) while maintaining the temperature at 0°-2° C., stirred at room temperature for 90 minutes, and poured onto ice. The aqueous mixture is stirred for several minutes, and filtered to obtain a solid which is washed with water and dried to give the title product as a white powder (28.6 g, mp 152°-155° C.).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[N:34][N:35]=2)[N:32]=1>CN(C)C=O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[N:34][N:35]=4)[N:32]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2nncn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCOc3ccc4nncn4n3)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
0.311 g of 4-(diphenylmethyl)-1-piperazinepropanol was dissolved in 5 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added; the reaction mixture was stirred in an oil bath (60° C.) for 30 minutes. After cooling, 0.232 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added; the reaction mixture was stirred in an oil bath. (bath temperature 60° C.) for 40 minutes. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with ethyl ether, and dried, to yield 0.339 g of the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@H:38]([OH:42])[C@H:37]([NH:43]C(=O)OC(C)(C)C)[CH2:36]2)=[C:27]2[CH2:33][CH2:32][CH:31]([OH:34])[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@H:38]([OH:42])[C@H:37]([NH2:43])[CH2:36]2)=[C:27]2[CH2:33][CH2:32][CH:31]([OH:34])[C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCC3O)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (7.0 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had the following properties:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44](O)[CH:45]([CH3:47])[CH3:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:44]([O:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)CO
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OC(C)C)c2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 6-[(3-hydroxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (0.300 g, 0.91 mM), triphenylphosphine (0.238 g, 0.91 mM), iso-butanol (0.084 ml, 0.91 mM) and THF (8 ml) were combined and diisopropylazodicarboxylate (0.18 ml, 0.91 mM) was added dropwise. The mixture was stirred for 15 mins at ambient temperature. The reaction was concentrated under reduced pressure and the resulting brown oil was purified by column chromatography on Kieselgel 60, eluting with a gradient of 50–100% methylene chloride in iso-hexane and then 20% ethyl acetate in methylene chloride to give methyl 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless solid (0.232 g); [M+H]+ 387; [M−H]− 385.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)[C@@H:11]([NH:13][C:35](=[O:34])[CH2:36][OH:37])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: Cl
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)c1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (22a) (50 mg, 0.12 mmol), and Acetoxyacetyl chloride (14 μL, 0.13 mmol).