Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][CH2:34][C:35]([NH2:37])=[O:36])(OC(C)(C)C)=O.Cl.O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:33][CH2:34][C:35]([NH2:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC(N)=O

Procedure:
Eight-hundred milligrams of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-glycineamide were dissolved in 3 ml of dichloromethane, and 3 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 2 hours. Thirty milliliters of diethyl ether were added thereto, and the resulting mixture was filtered. The thus-obtained powder was hot-washed with a mixture of chloroform, isopropanol and toluene at a ratio by of 6:8:20 to produce 483 mg (1.11 mmols) of the final compound in a yield of 65%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[C:24]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:35]2[CH2:36][CH2:37][N:32]([C:24]3[C:25]([CH3:31])=[C:26]([CH3:30])[CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:33][CH2:34]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(C)c(C)cc(C)c3C)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]=2[NH2:25])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[C:10]=2[NH:25][C:28](=[O:32])[C:29]([NH:25][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:30])=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1)C(=O)Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4,4″-Bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-ylamine (700 mg, 1.84 mmol) in pyridine (5 mL) was treated with oxalyl chloride (73 μL, 0.837 mmol). The resulting suspension was stirred at rt overnight under Ar, then poured into H2O. The precipitate was filtered, washed with H2O and dried in vacuo. The resulting solid was crystallized from toluene/heptane, then recrystallized from toluene to afford N,N′-Bis-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yl)-oxalamide (430 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1CC[N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30]OCC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:15]=2)[CH2:10]1.Cl[C:58]1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][CH3:58])[C@@H:25]([OH:40])[C@H:24]2[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:15]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (Example 1 step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with ethylene diamine. (MH+ 545.4)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=1)[O:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][O:55][C:54]2[CH:59]=[CH:60][CH:61]=[C:52]([F:51])[CH:53]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCOc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCOc4cccc(F)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 61.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (56 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (78 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(3-fluorophenoxy)-1-ethanol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 57%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:36][CH3:37])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:36][CH3:37])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:22]1)=[O:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-tert-butoxycarbonylaminobutyrylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.732 g, 1.4 mmol) in DCM (25 mL) was added TFA (6 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and volatiles removed in vacuo, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a brown gum (0.59 g, 100%). LCMS (Method B): RT 1.76 min [M+H]+ 423.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[N:11]=1)=[O:13]
Reactant: c1c[nH]cn1
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Cl)c2cccnc2c1O
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(-n2ccnc2)c2cccnc2c1O

Procedure:
The chloride from Example 44 Step 5 (8.0 mg, 0.021 mmol) and imidazole (80 mg) were fused at 160 C for 1 hr under argon. The residue was dissolved in DMF (0.5 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C(OCC)(=O)C>CCCCCC>[CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
By the method of Example 1, N-methyl-N-(2-phenylethyl)-4-(bromomethyl)benzenesulfonamide (10.6 mmol, 3.9 g) and thiazolidine-2,4-dione (11.7 mmol 1.4 g,), using 1:2 ethyl acetate:hexane as eluant, were converted to 3.3 g purified title product as a gum.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[F:9][C:10]([F:40])([F:39])[C:11]1[CH:12]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=C)[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=[O:5])[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:12]=[C:11]([C:10]([F:39])([F:40])[F:9])[CH:16]=1
Reactant: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
N-Methylmorpholine N-oxide (1 g, 8.6 mmol) and osmium tetroxide (2 ml, 2.5% solution in tert-butanol) were added to a solution of (2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727; 2 g, 4.3 mmol) in tetrahydrofuran (25 ml) and water (10 ml). The mixture was stirred at room temperature for one hour before sodium periodate (9 g, 43 mmol) was added. This mixture was stirred for 45 minutes and then filtered through Celite™. The filtrate was diluted with ethyl acetate (50 ml) and washed with brine. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/iso-hexanes to give the title compound (1.6 g, 80%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][CH:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[NH:16][C:15]1=[O:26].[F:27][C:28]([F:33])([F:32])[C:29](O)=[O:30]>CN(C)C1C=CN=CC=1.CN(C)C=O.C(O)(C)C.C(Cl)(Cl)Cl>[O:21]=[C:20]1[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[NH:16][C:15](=[O:26])[CH:14]1[NH:13][C:29](=[O:30])[C:28]([F:33])([F:32])[F:27]
Reactant: O=C(O)C(F)(F)F
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C1Nc2ccccc2NC(=O)C1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g, 40.0 mmol), and 4-(dimethylamino)pyridine (0.244 g, 2.00 mmol) to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (7.65 g, 40.0 mmol) in anhydrous N,N-dimethylformamide (50 mL). Rinse solids into reaction with anhydrous N,N-dimethylformamide (50 mL), and cool reaction to 0° C. in an ice/water bath. Add via syringe trifluoroacetic acid (3.08 mL, 40.0 mmol). After 10 minutes, remove cooling, and after 5.5 hours at ambient temperature, add an additional 0.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g) and trifluoroacetic acid (0.62 mL) and stir at ambient temperature. After an overnight period, concentrate under reduced pressure to give a residue. Reconstitute the residue in isopropanol: chloroform (1:3, 20 mL) and set 5 minutes. Collect solid formed by suction filtration, wash with isopropanol: chloroform (3:1), and dry at ambient temperature under vacuum to give the title compound. Filter the filtrate, which contained precipitated solid and dry this solid at ambient temperature under vacuum to give a second crop of the title compound: mass spectrum (ES neg., m/e): 286.0 (M−1); NMR (1H, 300 MHz, DMSO-d6): δ 10.93 (s, 2H), 9.42 (d, 1H, J=6.9 Hz), 7.29-7.15 (m, 4H), 4.91 (d, 1H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([N:34]4[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]4)[S:3][C:4]=3[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(NC(=O)c2ccc3nc(Br)sc3c2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Reaction time: 18 h

Procedure:
2-Bromo-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (612.2 mg, 1.56 mmol), N-Boc piperazine (300.8 mg, 1.61 mmol) and diisopropylethylamine (0.3 mL, 1.72 mmol) in N-methyl-2-pyrrolidinone (5.5 mL) was stirred at 120° C. (oil bath) for 4 h, then at room temperature for 18 h. The resulting mixture was diluted with water and the solid separated from the solution. The solid was collected by filtration, dissolved in ethyl acetate, washed with water (2×), then dried, filtered and concentrated. The resulting residue was purified by flash chromatography, eluting with 5% methanol in chloroform to yield tert-butyl 4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate as a brown glassy solid.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[C:15]2[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:14]=2[C:13]2[CH:12]=[C:11]([S:22](=[O:31])(=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]=[CH:9][C:8]=2[NH:7]1>C(O)C>[O:5]=[C:6]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]2[CH:12]=[C:11]([S:22](=[O:31])(=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]=[CH:9][C:8]=2[NH:7]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Nc4ccccc4)cc3c12
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccccc3)cc2c2cc[nH]c12
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A solution of 20 μL (0.28 mmol) of thionyl chloride diluted in 0.5 mL of anhydrous ethanol is added dropwise to 27 mg (0.07 mmol) of 4-oxo-8-phenylsulfamoyl-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 0.5 mL of anhydrous ethanol. The solution is stirred under reflux for 72 hours then cooled to room temperature. The solid is filtered to give 3.5 mg (12%) of 4-oxo-8-phenylsulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COc2ccccc2)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.103 g, 0.24 mmol) and phenol (0.012 g, 0.26 mmol) in 1,4-dioxane (2 mL) was added sodium hydride (60% in mineral oil; 0.013 g, 0.29 mmol), and the reaction was stirred at 55° C. overnight. The mixture was quenched with H2O, and the solution was used directly in the hydrolysis step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[N:6][CH:7]=1.C(N([CH2:17][CH3:18])CC)C.[CH3:19]S(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][O:11][CH:17]([CH3:18])[CH3:19])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: OCC=Cc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)OCC=Cc1ccc(Br)cn1
Reaction time: 0.33 h
Yield: 33 %

Procedure:
5-Bromo-2-(3-hydroxy-1-propenyl)pyridine (8.891 g) was dissolved in tetrahydrofuran (200 ml), followed by the sequential addition of triethylamine (17.6 ml) and methanesulfonyl chloride (3.9 ml) under ice-cooling, and the mixture was stirred for 20 min. After the resulting insoluble matters were filtered off, the solution was evaporated. The resulting residue was dissolved in 2-propanol (100 ml), sodium 2-propanoxide/2-propanol solution prepared from 60% sodium hydride (2 g) and 2-propanol (70 ml) was added thereto under ice-cooling, and the resulting mixture was stirred, as it was, at room temperature for 30 min. After the resulting insoluble matters were filtered off from the reaction mixture, the resulting solution was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown oil (3.519 g, yield; 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][SiH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.C[C:14]([CH3:17])([CH3:16])[CH3:15].[Li]CCCC.[B:23](OCCCC)([O:29]CCCC)[O:24]CCCC.OP(O)(O)=O>C1COCC1>[CH3:15][C:14]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][C:4]1[CH:3]=[C:2]([B:23]([OH:29])[OH:24])[CH:7]=[CH:6][CH:5]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)C
Reactant: C[SiH](C)OCc1cccc(Br)c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A solution of {[(3-bromophenyl)methyl]oxy}(dimethyl)silane-2,2-dimethylpropane (1:1) (100.0 g, 331.9 mmol) in THF (500 mL) was cooled to −78° C., and then n-BuLi (132.7 mL, 331.9 mmol) was added dropwise. The mixture was stirred for 1 h at −78° C. Then B(OBu)3 (107.5 mL, 398.2 mmol) was added in one portion. The reaction mixture was warmed to room temperature, and stirred over night. After cooling to 0° C., 5% H3PO4 was added to pH=4-5 and the mixture stirred 0.5 h and then filtered. After removing THF, the residue was extracted with Et2O (200 mL×2), and the organic layer was dried over Na2SO4. After removing the solvent, the residue was added to water, and a white solid precipitated which was dried in vacuo to give 65.7 g of [3-({[(1,1-dimethylethyl)-(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (yield: 74.5%). 1H NMR (400 MHz, CDCl3) δ 0.14 (s, 6H), 0.98 (s 9H), 4.88 (s, 2H), 7.49-7.59 (m, 2H), 8.14 (d, J=7.6 Hz, 1H), 8.19 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@@H:9]1[CH2:10][CH2:11][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](N=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 0.04 h

Procedure:
To a mixture of (−)-(1S,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (670 mg, 3.09 mmol) (from Example 27b supra) and triphenyl phosphine (1.06 g, 4.02 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) cooled at 0° C. was added dropwise diethyl azodicarboxylate (640 μL, 0.70 g, 4.02 mmol) (Aldrich). After 2 to 3 minutes, followed a dropwise addition of diphenylphosphoryl azide (860 μL, 1.1 g, 4.02 mmol) (Aldrich). The mixture was allowed to slowly warm up to room temperature and after overnight stirring was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate filtered and concentrated to a residue that was purified by chromatography with a silica gel column using a 0–20% diethyl ether in hexanes gradient to give (−)-(1R,3R)-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 540 mg, 72%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis using HATU. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.65 (m, 6H) 1.65-1.86 (m, 6H) 1.93 (d, J=3.3 Hz, 1H) 2.07 (s, 1H) 2.04 (d, J=13.1 Hz, 1H) 2.81 (d, J=5.1 Hz, 1H) 2.78 (d, J=4.6 Hz, 3H) 2.99-3.17 (m, 2H) 3.27 (s, 4H) 3.48 (d, J=11.6 Hz, 2H) 4.83 (t, J=7.8 Hz, 1H) 7.53 (dd, J=8.3, 1.8 Hz, 1H) 7.55 (s, 1H) 8.08 (d, J=8.3 Hz, 1H) 8.17 (s, 1H) 8.43 (d, J=7.3 Hz, 1H) 8.98 (br. s., 1H) 9.54 (br. s., 1H). [M+H] calc'd for C28H38FN7O3, 540. found 540.