Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].CC(C)([O-])C.[Na+].[Na+].[Cl-]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reactant: CN(C)CCN
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(NCCN(C)C)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (713 mg, 2.02 mmol, Eq: 1.00), N,N-dimethylethylenediamine (1.07 g, 1.32 ml, 12.1 mmol, Eq: 6) and bis(tri-tert-butylphosphine)palladium(0) (206 mg, 404 μmol, Eq: 0.2) were combined with toluene (2 ml) to give a yellow solution. Sodium tert-butoxide (582 mg, 6.05 mmol, Eq: 3) was added. The reaction mixture was heated to 80° C. and stirred for 1 h, then poured into 20 mL sat NaCl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 2% to 5% MeOH in DCM) to give N1,N1-dimethyl-N2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)ethane-1,2-diamine (405 mg, 56%) as yellow oil that solidified upon standing.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.ClC1C=CC(C([NH:56][C@@H:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[CH3:58])=O)=C(NS(C2C3N=CC=NC=3C=CC=2)(=O)=O)C=1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:56][C@@H:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride (EXAMPLE 7, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18BrFN4O3S, 528.0; m/z found, 527/529 [M−H]−. HPLC (reverse phase): RT=10.03 min. 1H NMR (500 MHz, CDCl3): 11.34 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=7.4, 1.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.13 (br d, J=6.5 Hz, 1H), 5.25-5.15 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([CH:14]=[C:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Li+]>C1COCC1.O>[CH2:19]([O:18][C:16](=[O:17])/[C:15](=[CH:14]\[C:12]1[O:13][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1)/[C:21]([OH:23])=[O:22])[CH3:20]
Reactant: CCCCCCC#Cc1ccc(C=C(C(=O)OCC)C(=O)OCC)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC#Cc1ccc(/C=C(/C(=O)O)C(=O)OCC)o1
Temperature: 70 °C

Procedure:
Diethyl 2-[5-(1-octynyl)-2-furanylmethylene]propan-1,3-dioate (1.04 g, 3 mmole from Example 10) was added to a solution of lithium hydroxide monohydrate (0.13 g, 1 eq) in THF/water (1:1, 15 ml) and the mixture was heated to 70° C. for 3 hr. The resulting clear solution was acidified and then extracted into diethyl ether (2×50 ml). The etheral solution was dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a yellow solid which was recrystallised from hexane 0.65 g (68%), mp 89°-90° C., νmax (mull), 2600(broad), 2220, 1740, 1695, 1615, 1555, 1270, 1235, 1215 cm-1 ; δ(CDCl3), 0.89(3H, distorted t), 1.43(3H, t, J=7.5 Hz), 1.45(8H, m), 2.42 (2H, t, J=6.5 Hz), 4.40(2H, q, J=7.5 Hz), 6.54(1H, d, J=3.0 Hz), 6.86(1H, d, J=3.0 Hz), 7.57(1H, s), 11.5(1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(SCCO)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.3 mmol) and Intermediate 35c (140 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 90° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (115 mg, 56%). LCMS (Method 5): Rt 3.47 min, m/z 681 [MH+]. 1H NMR (400 MHz, do-DMSO): 1.28 (9H, s), 1.83-2.26 (11H, m), 2.31-2.39 (1H, m), 3.04 (2H, t, J 6.8), 3.09 (1H, m), 3.59 (2H, q, J 6.0), 3.99 (1H, t, J 8.2), 4.78-4.86 (1H, m), 4.95 (1H, t, J 5.6), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.08 (1H, d, J 8.4), 7.24-7.46 (9H, m), 7.75 (1H, d, J 9.6), 8.12 (1H, s), 8.25 (1H, br d).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([O-])=[O:27])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:16]=[CH:17][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:11])=[CH:13][CH:14]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:27])[CH2:35][CH2:33]1
Reactant: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.9 %

Procedure:
Sodium 1-(4-{[(2-morpholin-4-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylate (642 mg, 1.34 mmol) obtained in Example 61b), HOBt (91.6 mg, 0.671 mmol, 0.5 eq.) and cyclopropylamine (0.125 ml, 1.74 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (315 mg, 1.61 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (397 mg, 0.932 mmol, 69.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)[CH:15]=2)[CH2:10][C@H:9]1[C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:67][C@@H:68]([CH2:77][CH2:78][CH3:79])[C@H:69]([OH:76])[C:70]([NH:72][CH:73]1[CH2:75][CH2:74]1)=[O:71]>C(Cl)Cl.CN(C)C=O>[CH:73]1([NH:72][C:70](=[O:71])[C@@H:69]([OH:76])[C@@H:68]([NH:67][C:31]([C@@H:9]2[CH2:10][C@@H:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:15]=3)[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])[CH2:77][CH2:78][CH3:79])[CH2:74][CH2:75]1
Reactant: COc1ccc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3cccn3)nc2c1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxylic acid (5.0 g, 11.0 mmol) dissolved in a mixture of methylene chloride (135 mL) and N,N-dimethylformamide (45 mL) was added 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, (4.97 g, 42.6 mmol) and diisopropylethylamine (7.2 mL, 41.11 mmol), followed by the hydrochloride salt of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (2.45 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Completion of reaction was monitored by TLC. The reaction mixture was diluted with methylene chloride (200 mL) and washed with 10% hydrochloric acid (100 mL), followed by with 10% sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide 5.4 g (67.6%) of (2S,4R)-tert-butyl 2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-1-carboxylate as an off-white solid (HPLC purity: 98.59% by area, HPLC retention time: 14.74 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:13].[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].CCCCCC>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[NH:31][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:30]=2)=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:13]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(C=O)ccc(Cl)c2C1O
Reactant: Nc1ccccc1N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2c(-c3nc4ccccc4[nH]3)ccc(Cl)c2C1O
Temperature: 130 °C
Reaction time: 5.2 h
Yield: 33.8 %

Procedure:
4-Chloro-3-hydroxy-7-formyl-2-(1-methyl-1-phenylethyl)isoindolinone (100 mg, 0.303 mmol) was dissolved in nitrobenzene (2 mL), and the solution was added with o-phenylenediamine (49 mg, 0.45 mmol), followed by stirring at 130° C. for 5.2 hours. The reaction mixture was added with hexane and the obtained solid was collected by filtration and purified by preparative thin-layer chromatography (hexane/ethyl acetate=2/1, 1/1) to obtain 4-chloro-3-hydroxy-7-(1H-benzoimidazol-2-yl)-2-(1-methyl-1-phenylethyl)isoindolinone (42.8 mg, yield 34%).
Reaction SMILES: OC1CCNCC1.[NH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C([O:30][C@@H:31]1[C@H:35]([O:36]C(=O)C2C=CC=CC=2)[C@@H:34]([CH2:45][O:46]C(=O)C2C=CC=CC=2)[O:33][C@H:32]1[N:55]1[CH:63]=[N:62][C:61]2[C:56]1=[N:57][C:58]([Cl:65])=[N:59][C:60]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:65][C:58]1[N:59]=[C:60]([NH:8][N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[C:61]2[N:62]=[CH:63][N:55]([C:56]=2[N:57]=1)[C@@H:32]1[O:33][C@H:34]([CH2:45][OH:46])[C@@H:35]([OH:36])[C@H:31]1[OH:30]
Reactant: NN1CCC(Oc2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Agent: OC1CCNCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Oc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 56.1 %

Procedure:
This compound was prepared from 4-hydroxypiperidine using the methodology described in Example 16. 1-Amino-4-phenoxypiperidine (0.96 g, 5.0 mmol) was reacted with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenoxy-1-piperidinyl)adenosine (1.07 g, 57%) as a foam, 1H NMR (DMSO-d6) δ 3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.43-4.54 (2H, m, H-2' and --C--H), 5.07 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 6.90-7.33 (5H, 2m, Ar--H), 8.42 (1H, s, H-8), 9.49 (1H, s, N--H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][NH:39][CH3:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CN1CCCC1=O>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[CH:8]=[C:7]([OH:27])[CH:6]=[CH:5][C:4]=2[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C@@H:16]([OH:20])[CH2:15][CH2:14]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCCCOCc1ccccc1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCOCc1ccccc1
Yield: 44.1 %

Procedure:
A solution of 486 mg of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 540 mg of (3-benzyloxy-propyl)-methyl-amine for 3 hours at a bath temperature of 80° C. Then, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with methylene chloride/methanol/ammonia. 237 mg of 7α-{5-[(3-benzyloxy-propyl)-methyl-amino]-pentyl}-11β-fluor-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam [α]D=+48° (c=0.5 in CHCl3).
Reaction SMILES: C(C1C=C2C(C3C(=O)C4C=CC([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24])=CC=4C(C)(C)C=3N2)=CC=1)#N.[CH2:31]([C:33]1[C:54]([OH:55])=[CH:53][C:36]2[C:37]([CH3:52])([CH3:51])[C:38]3[NH:39][C:40]4[N:41]=[C:42]([C:49]#[N:50])[CH:43]=[CH:44][C:45]=4[C:46]=3[C:47](=[O:48])[C:35]=2[CH:34]=1)[CH3:32]>>[C:49]([C:42]1[CH:43]=[CH:44][C:45]2[C:46]3[C:47](=[O:48])[C:35]4[CH:34]=[C:33]([CH2:31][CH3:32])[C:54]([O:55][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])=[CH:53][C:36]=4[C:37]([CH3:52])([CH3:51])[C:38]=3[NH:39][C:40]=2[N:41]=1)#[N:50]
Reactant: CCc1cc2c(cc1O)C(C)(C)c1[nH]c3nc(C#N)ccc3c1C2=O
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CCc1cc2c(cc1OS(=O)(=O)C(F)(F)F)C(C)(C)c1[nH]c3nc(C#N)ccc3c1C2=O

Procedure:
According to the method used for synthesizing Compound B1, 7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile was subjected to trifluoromethanesulfone esterification to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13. found, m/z 356.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H), 6.98-6.94 (m, 2H), 5.26 (s, 2H), 2.89-2.86 (m, 4H), 2.80-2.78 (m, 2H), 2.73-2.70 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([C:26]5[N:27]([C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=6[F:38])[N:28]=[CH:29][N:30]=5)[S:19][C:18]=4[C:17]=3[N:39]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([C:26]5[N:27]([C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=6[F:38])[N:28]=[CH:29][N:30]=5)[S:19][C:18]=4[C:17]=3[N:39]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4CNC4)ccc2OCC3)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylic acid tert-butyl ester (558 mg, 1.0 mmol) was dissolved in EtOAc (10 mL). Hydrogen chloride dissolved in Ethyl acetate (EtOAc—HCl, 10 mL) was added by drop to the solution and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered to gather the solid which was washed with DCM (10 mL) to give 435 (0.43 g, yield: 87%). 1HNMR (DMSO-d6, 400 MHz): δ7.99 (s, 1H), 7.74-7.72 (m, 1H), 7.36-7.27 (m, 2H), 7.14 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.38-6.26 (m, 2H), 4.11-4.09 (m, 6H), 3.56 (s, 1H), 3.02 (t, J=4.8 Hz, 2H). ESI-MS: m/z=453 [M+H+]
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][C:18]([CH2:21][OH:22])=[N:19][N:20]=1.Cl>N1C=CC=CC=1>[OH:22][CH2:21][C:18]1[S:17][C:16]([NH:15][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:20][N:19]=1
Reactant: Nc1nnc(CO)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (510 mg, 2.18 mmol) in pyridine (6 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (260 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (4×50 mL). The organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 82% yield (533 mg, 1.62 mmol); 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 4.56 (d, 2H, J=5.1 Hz), 6.09 (t, 1H, J=4.8 Hz), 7.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 59.1, 119.3, 127.7, 136.2, 143.5, 161.7, 168.1, 169.6; MS (LCQ, ESI+) Calcd for C11H13N4O4S2 329.0. found 329.1 (M+H)+. HRMS (ESI+, m/z) Calcd for C11H13N4O4S2 329.0378. found 329.0376 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:9][C:8](=[O:10])[O:7][C:5](=[O:6])[CH2:4]1.[Cl:13][C:14]1[C:20]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][C:17]([NH2:18])=[C:16]([F:25])[CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:20]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][C:17]([NH:18][C:8](=[O:10])[CH2:9][CH:3]([C:2]([F:1])([F:12])[F:11])[CH2:4][C:5]([OH:7])=[O:6])=[C:16]([F:25])[CH:15]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Solvent: ClCCl
Product: C#CCOc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl

Procedure:
Into a 1 liter three-necked round-bottomed flask equipped with overhead stirrer, dropping funnel, thermometer and nitrogen (N2) inlet were placed 3-(trifluoromethyl)glutaric anhydride (18.2 g, 0.100 mol) and methylene chloride (CH2Cl2) (250 ml). The mixture was stirred to homogeneity and a solution of 4-chloro-2-fluoro-5-propargyloxyaniline (19.9 g, 0.100 mol) in CH2Cl2 (50 ml) was added dropwise over 10 minutes to give a clear solution. The mixture was stirred overnight at ambient temperature, during which time a thick white precipitate was formed.
Reaction SMILES: [CH2:1]([C:3]1[C:13]2[NH:12][C:11](=[O:14])[CH2:10][N+:9]([O-])=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([O:26][CH:10]1[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:13]=2[NH:12][C:11]1=[O:14])(=[O:25])[CH3:24]
Reactant: CCc1cccc2c1NC(=O)C[N+]([O-])=C2c1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cccc2c1NC(=O)C(OC(C)=O)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of 9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (9.0 g) and acetic anhydride (32 ml) in chloroform (32 ml) was stirred at room temperature overnight. The reaction mixture was evaporated to remove chloroform. Diisopropyl ether was added to the residue to afford powder, which was collected by filtration and washed with diisopropyl ether to give (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.30 g, 61.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:11][C:12]1[CH:13]=[C:14]([C:22]2[S:26][C:25]([NH2:27])=[N:24][C:23]=2[CH3:28])[CH:15]=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[NH:27][C:25]1[S:26][C:22]([C:14]2[CH:15]=[CH:16][C:17]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:12]([F:11])[CH:13]=2)=[C:23]([CH3:28])[N:24]=1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 60 °C

Procedure:
Methyl-4-(chloroformyl)butyrate (4.0 mmol) is added to a stirred solution of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (0.77 g, 2.69 mmol) and heated to 60° C. for 1.5 hours. The reaction mixture is allowed to cool to room temperature and the solvent removed in vacuo. The residue is washed with saturated sodium bicarbonate solution (2×50 ml) and water (1×50 ml). The product is extracted with ethyl acetate (2×50 ml) and the combined organic extracts dried (MgSO4). Removal of the solvent followed by recrystallisation from ethyl acetate affords the titled compound.