Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:42][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.3 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a reaction flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and the resulting mixture was stirred for 48 hr at room temperature. The reaction was diluted with diethyl ether (50 mL) and the organic layer was washed with an aqueous solution of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 ml), after which it was dried over sodium sulfate, filtered and concentrated en vacuo. The residue was purified by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.6 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.33 (d, 1H, J=11.2 Hz), 7.15 (d, 1H, J=11.2 Hz), 7.14 (s, 1H), 7.06 (d, 2H, J=11.6 Hz), 6.79 (d, 2H, J=11.6 Hz), 5.86 (tt, 1H, J1=5.2 Hz, J2=66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3H), 3.84-3.71 (m, 2H), 3.74 (td, 2H, J1=5.6 Hz, J2=18.4 Hz), 3.66-3.54 (m, 3H), 3.30-3.36 (m, 2H), 2.78 (br s, 1H), 2.42 (br s, 1H), 1.65 (s, 2H); LC/MS: theoretical mass=488.14; observed M+1=489.2, M+Na=511.4).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH:21]([S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[S:24][CH:21]([CH3:23])[CH3:22])[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CC(C)Sc1ccccc1N
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(Cl)nc32)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc3c(Nc4ccccc4SC(C)C)nc(Cl)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 5,7-dichloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.03 g) and 2-(isopropylthio)aniline (0.1 g) in dioxane (10 mL) was heated at 100° C. for 10 h. It was then cooled down to room temperature and ethyl acetate (20 mL) was added. The mixture was washed with saturated sodium bicarbonate (10 mL), and dried over sodium sulfate. Solvent was removed under reduced pressure and the remaining residue was purified on a silica gel column (ethyl acetate:hexane=1:10) to give desired product. ESMS calculated for C21H21ClN6OS (m/z): 440.1; found (M+H+): 441.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][C:19]([N:28]([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:12])[NH:14][CH2:15][CH:16]2[CH2:17][CH2:18][C:19]([N:28]([CH3:30])[CH3:29])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The chloroformic acid 4-nitrophenyl ester (913.5 mg, 4.53 mmole) dissolved in abs. DCM (15 ml) was slowly added dropwise while cooling in ice water to a solution of (4-aminomethyl-1-phenylcyclohexyl)-dimethylamine (1 g, 4.3 mmole) in abs. DCM (15 ml) and pyridine (766 μl, 9.49 mmole). The reaction mixture was then stirred for 20 hours at RT. The red reaction mixture was worked up by washing with water (3×10 ml), with 1M HCl (3×10 ml) and with 1M NaOH (2×10 ml). The organic phase was dried with Na2SO4 and then concentrated by evaporation. The residue was a mixture of the diastereoisomers of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid 4-nitrophenyl ester (1.25 g, reddish-brown oil, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-nitrobenzoic acid (1.99 g, 9.87 mmol) was stirred for 18 hrs at 60° C. in thionyl chloride (10 ml). The excess thionyl chloride was removed by evaporation and the crude oil dissolved in chloroform (20 ml). To this solution was added ethyl (4-aminophenyl)acetate (1.18 g, 6.58 mmol) and the reaction was stirred at 60° C. for 18 hrs. The reaction was diluted with water and the phases separated. The organic layer was dried (Na2SO4), solvent evaporated and the residue purified by flash chromatography (Biotage SP4, 40+M 0→50% ethylacetate/hexane) to afford the title compound as an off white solid (2.28 g, 96%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][C:9](=[O:31])[NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:6][NH:7][CH:8]([CH3:35])[C:9]([NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)=[O:31]
Reactant: CN(CC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
The title compound of Example 19 (19 mg, 0.042 mmol) in CH2Cl2 (0.65 mL) was treated with trifluoroacetic acid (0.45 mL) and allowed to stir for 0.5 hours. The volatile components were removed under vacuum, and diethyl ether was added and evaporated three times to give the title compound (19 mg, 0.041 mmol) as a yellow, orange powder in 98% yield.
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[CH:7]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[O:30])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]([OH:30])[C:7]2[O:6][C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[N:8]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cc2ocnc2cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(O)c2nc3cnccc3o2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
i-PrMgCl (0.44 mL of a 2 mmol/mL solution in THF, 0.88 mmol) was added dropwise to a stirred solution of oxazolo[4,5-c]pyridine (105 mg, 0.87 mmol) in anhydrous THF (3 mL) at 0° C. After 1 h, a solution of 4-(2-oxo-ethyl)piperidine-1-carboxylic acid tert-butyl ester (198 mg, 0.87 mmol) in anhydrous THF (2 mL) was added, then the mixture was allowed to warm to 20° C. over 16 h, before being quenched with saturated aqueous NH4Cl (10 mL). The layers were separated, then the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash chromatography (EtOAc) of the residue furnished the title compound: m/z (ES+)=348.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[O:11])=[CH:7][C:6]=3[CH:36]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(NS(=O)(=O)c5ccccc5)ccc4o3)cc2)cc1)C(=O)O

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was sulfonylated with benzenesulfonyl chloride according to the procedure of Example 8 followed by cleavage from the resin to provide 4′-[(5-benzenesulfonylamino-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine. LCMS MH+ (m/z) 648. 1H NMR (300 MHz, CD3OD): δ 7.92-7.69 ppm (m, 9H), 7.58-7.43 ppm (m, 6H), 7.22-7.18 ppm (dd, 2H, J1=9.0 Hz, J2=2.5 Hz), 3.64 ppm (d, 1H, J=5.0 Hz), 2.09-2.01 ppm (m, 1H), 0.97 ppm (d, 3H, J=7.0 Hz), 0.90 ppm (d, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[CH:8][C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:16])[CH:17]=[CH:18][CH:19]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: O=C(c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1)N1CCOCC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with morpholine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone (58 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 23.7 mg of 337. MS (Q1) 527.2 (M)+
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([CH2:28][NH:35][C:36](=[O:37])[O:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=[C:2]3[CH3:1])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1cc(C)c2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (1.80 g) and tetrahydrofuran (43 ml) were added with stirring at room temperature milled potassium carbonate (0.93 g) and benzyl isocyanate (0.87 ml). Stirring was continued under nitrogen for 16 hours. The mixture was filtered through a pad of celite and the solids washed with ethyl acetate. Concentration followed by purification via flash column chromatography (silica gel, 2% Et3N/EtOAc) afforded 2.28 g of the desired carbamate. Recrystallization from ether gave a highly crystalline solid, m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:34])[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:35].[OH-].Cl>C1COCC1.O>[C:30]([O:29][C:27]([N:11]1[C:12]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:13](=[O:21])[N:14]([CH2:15][C:16]([O-:18])=[O:17])[C@@:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([CH3:34])[CH2:10]1)=[O:28])([CH3:31])([CH3:32])[CH3:33].[Li+:35]
Reactant: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C12CCCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step I (65 mg, 0.135 mmol) in THF (1.5 mL) and H2O (0.5 mL) was added 1 N aqueous LiOH (0.14 mL, 0.14 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 7 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=397 (M−C4H7).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:6]3[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]4[C:8]([CH:7]=3)=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=4)=[O:25])[CH2:31][CH2:30]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and cyclopropanoyl chloride. Off-white solid. MS (m/z): 503.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1)[CH2:30][CH2:31][CH3:32]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-trifluoromethyl-imidazo[1,2-a]pyrimidine (1.0 g, 3.78 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.08 ml of a 2.0M solution in tetrahydrofuran, 4.16 mmol). After stirring for 5 min tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reaction stirred for 10 min at −78° C. then allowed to warm to ambient temperature to give a solution of 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine in tetrahydrofuran (ca. 0.15M): m/z (ES+) 474, 476, 478 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[O:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[O:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1
Reactant: COc1c(-c2cc(C(=O)O)c(C)o2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cccc1-c1cc(C(=O)O)c(C)o1
Yield: 92.4 %

Procedure:
5-(2-Methoxy-3-nitro-phenyl)-2-methyl-furan-3-carboxylic acid 53c (450 mg, 1.62 mmol) was dissolved in methanol, followed by addition of 45 mg of palladium on carbon. The reaction mixture was heated to reflux for 4 hours under hydrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound 5-(2-methoxy-3-amino-phenyl)-2-methyl-furan-3-carboxylic acid 53d (370 mg, yield 92%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:33]2)=CC=1.CCOC(C)=O.Cl>COCCOC>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=[S:33])[NH2:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (340 mg, 1.0 mmol) obtained above in DME (10 mL) was added 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (485 mg, 1.2 mmol), and the mixture was stirred at 80° C. for 1 h. The reaction mixture was allowed to cool to rt, and then were added EtOAc (15 mL) and 1N hydrochloric acid (15 mL) and then the resulting suspension was filtered. The residue was washed with water (5 mL) and EtOAc (5 mL) to give the title compound (172 mg, 48%) as a yellow solid.
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]C=1)C=C.[N:23]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][C@H:24]1C(O)=O>>[C:34]([O:33][C:31]([N:23]1[CH2:30][CH2:29][CH2:28][CH:24]1[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 94 %

Procedure:
Prepared from 40 (1.16 g, 4.0 mmol) and Boc-Pro-OH according to the procedure used to prepare 100 (Scheme XVIII) to afford 1.53 g (94% yield) of the title compound as a white solid. 1H-NMR (500 MHz, CDCl3): δ 1.61 (br, 9H), 1.88 (br, 2H), 2.00-2.50 (m, 3H), 2.80-3.10 (m, H), 3.20-3.60 (m, 2H), 4.05-4.45 (m, 1.5H), 4.58-4.80 (m, 1.5H), 4.83-4.98 (m, H), 5.43-5.53 (m, H), 7.26-7.45 (m, 5H), 7.60-7.80 (d, H); Analytical HPLC: 11.32 min; LC-MS: m/e=405 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:8]=[C:7]2[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[N:8]=[C:7]2[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21

Procedure:
2,2-Dimethyl-propionic acid 5-nitro-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (370 mg, 1.13 mmol) (from Example 28) was hydrogenated using 10% Pd/C in ethanol (35 mL) at room temperature for 2 hours. The reaction was filtered and the filtrate was concentrated to give 2,2-dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[S:10][C:11]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:12][C:13]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][C:13]=1[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)OCc2ccccc2)sc1/C=C/C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(=O)O)sc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
(E)-3-(5-Benzyloxycarbonyl-3-methylthiophen-2-yl)-2-propenoic acid tert-butyl ester (1.42 g, 4.12 mmol) obtained in step 3 was dissolved in ethanol (12 mL), 10% palladium/carbon (142 mg) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, palladium/carbon was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (1.02 g, 3.77 mmol, 92%).
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:34][C@H:35]1[C:43]2[C:42]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[CH2:37][CH2:36]1.[C:50]([O:54][C:55]([N:57]1[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59][C@H:58]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@H:58]2[N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59]2)[C:65]([N:47]2[CH2:48][CH2:49][CH:44]([C:42]3[C:43]4[C@H:35]([CH3:34])[CH2:36][CH2:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:45][CH2:46]2)=[O:66])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2)CCC1(C)C
Reactant: C[C@@H]1CCc2ncnc(C3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(C3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
DIPEA (174 μL, 1.00 mmol) and O-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) were added to a solution of (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (22 mg, 0.10 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (20 mg, 0.054 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid (26 mg, 84%). 1H NMR (CD3OD, 500 MHz) δ 8.73 (s, 3H), 7.42 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.73-4.70 (m, 2H), 4.40-4.35 (m, 1H), 3.89-3.86 (m, 1H), 3.76-3.70 (m, 2H), 3.49-3.43 (m, 1H), 3.25-3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.86-2.70 (m, 3H), 2.34-2.25 (m, 1H), 2.16-2.13 (m, 1H), 1.83-1.67 (m, 2H), 1.54 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H), 1.25-1.20 (m, 3H).
Reaction SMILES: [O:1]([CH:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[N+:2]([O-:4])=[O:3].[NH2:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20]>>[C:21]([CH:18]1[CH2:19][S:20][CH:10]([C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH2:6][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH3:16])[NH:17]1)([OH:23])=[O:22]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(COc1ccccc1C=O)O[N+](=O)[O-]
Product: CC(COc1ccccc1C1NC(C(=O)O)CS1)O[N+](=O)[O-]
Yield: 30 %

Procedure:
Prepared from 2-(2-nitroxypropoxy)benzaldehyde and cysteine as described in Example XVI. Yield: 30%. Empirical formula: C13H16N2O6S. Molecular weight: 328. Melting point: 127°-130° C.