Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N+:11]2[C@@H:29]([CH:32]3[CH2:34][CH2:33]3)C[O:31][C:10]1=2)[CH:7]=[CH2:8].S.[Na]>CN(C=O)C>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH:32]2[CH2:34][CH2:33]2)[CH2:1][SH:2])[C:10]1=[O:31])[CH:7]=[CH2:8]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Reactant: CS(=O)(=O)[O-]
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CS)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (370 mg; Example 349, Step A) in DMF (1.6 mL) was added sodium hydrogensulfide (105 mg, 1.88 mmol). After being stirred at rt overnight, the reaction was quenched (sat. aq. NH4Cl solution), extracted (2×EtOAc) and the combined organics were washed with brine (3×). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, gradient elution of 10% to 40% EtOAc in hex) provided the title compound.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 57.3 %

Procedure:
A mixture of 6.82 g (20 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 3.36 g (18.5 mmol) of 2-chloro-5-trifluoromethylpyridine, 2.91 g (21 mmol) of powdered K2CO3 and 76 ml of absolute DMF was warmed to 80° C., and 460 mg of powdered K2CO3 were added with stirring at 80° C. in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (a total of 1.38 g (10 mmol) of K2CO3), and the mixture was stirred for a further 9 hours at 80° C. After removing the DMF by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after thorough mixing, and the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue (6 g) was dissolved in boiling methanol. The turbid solution formed was filtered through kieselguhr under suction, concentrated to half the volume, and cooled in an ice bath. The crystals which precipitated out were filtered off under suction and dried. The filtrate, after further concentration and cooling, precipitated further crystalline substance, which was filtered off under suction and recrystallized from a little methanol. In this fashion, 3.43 g (=57.4% yield) of 1-(4-hydroxyphenyl)-4-(5-trifluoromethylpyrid-2-yl)piperazine, melting point 178°-79° C., were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=1
Reactant: COC(=O)/C=C/c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-imidazoleacrylic acid methyl ester hydrochloride (20.0 g, 106 mmol) and triethylamine (44 ml, 318 mmol) in chloroform (500 ml) was added a solution of trityl chloride (29.5 g, 318 mmol) in chloroform (100 ml). The resulting suspension was stirred at room temperature for 24 h. The reaction mixture was then washed with water and dried over MgSO4. Filtration and removal of the solvent in vacuo to gave the title compound as a tan solid: 1H NMR (CDCl3) d 3.75 (s, 3 H), 6.54 (d, J=16 Hz, 1 H) 7.03 (s, 1 H), 7.13-7.34 (m, 15 H) 7.46 (s, 1 H), 7.51 (d, J=16 Hz 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:18])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+]>C1COCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]=[N:8][N:7]([CH3:18])[C:6]=2[C:4]([OH:5])=[O:3])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)nnn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(Br)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
5-(4-Bromo-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1.2 g, 3.87 mmol) was dissolved in THF (15 mL) and lithium hydroxide solution (0.5 N, 10 mL) was added. The mixture was stirred at room temperature for 3 hrs. TLC indicated complete consumption of the starting material. The mixture was concentrated and the residue was dissolved in water (20 mL) and filtered. The filtrate was acidified with 2N hydrochloric acid (3 mL). The white solid was filtered and dried to give 5-(4-bromo-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid as a white solid (1.03 g, 94.4% yield). m.p. 209-210° C.; LC-MS calcd for C10H8BrN3O2 (m/e) 283.0, obsd 284.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 3H), 7.66-7.72 (m, 4H), 14.20 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9]C(=O)[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N:14]([CH3:16])[CH3:15].Cl.C([O-])(=O)C.[Na+]>[OH-].[Na+]>[NH2:11][C:6]1[C:7]([C:8]([OH:13])=[O:9])=[C:2]([CH3:1])[C:3]([N:14]([CH3:15])[CH3:16])=[CH:4][CH:5]=1
Reactant: Cc1c(N(C)C)ccc2[nH]c(=O)oc(=O)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(N(C)C)ccc(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
The product of Step A (1.20 g, 5.5 mmol) was suspended in 16.5 mL of 1N NaOH and stirred at room temperature for 1 hour. The pH was adjusted to 4 with 3N HCl and concentrated to near dryness under reduced pressure. The wet residue was suspended in EtOAc and treated with sodium acetate (1.30 g, 18 mmol). The EtOAc layer was dried (Na2SO4), filtered and evaporated under reduced pressure affording 641 mg (61%) of product. 1H-NMR (300 MHz, d6-DMSO) δ 2.18 (s, 3H), 2.46 (s, 6H), 6.35 (d. J=8 Hz, 1H), 6.67 (d. J=8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(Br)cc23)C1

Procedure:
A solution of 6-bromo-4-chloroquinoline (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in NMP (0.1 M) was heated at 140° C. for 48 hours. Upon cooling the solution was poured onto ice and upon melting the solid was filtered, rinsed with H2O and pumped on to yield (S)-tert-butyl 1-(6-bromoquinolin-4-yl)piperidin-3-ylcarbamate. LC/MS=406.0/408.0 (M+H), LC=2.85 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2/[C:7](=[C:10]3\[C:11](=[O:24])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]([S:19](=[O:23])(=[O:22])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[CH2:8][CH2:9][C:4]=2[C:3]=1[C:25]([OH:27])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[OH:51][CH:44]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:43][NH:42][C:25]([C:3]1[C:4]2[CH2:9][CH2:8]/[C:7](=[C:10]3/[C:11](=[O:24])[NH:12][C:13]4[C:18]/3=[CH:17][C:16]([S:19](=[O:22])(=[O:23])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[C:5]=2[NH:6][C:2]=1[CH3:1])=[O:27]
Reactant: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)O)C(=O)N2
Reactant: NCC(O)CN1CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)NCC(O)CN1CCCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-methyl-6-[5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidene]-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example 5, 78 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) and EDC (77 mg, 0.4 mmol) in dry DMF (2 mL) was stirred at room temperature for 30 min. Then 1-amino-3-pyrrolidine-1-yl-propan-2-ol (0.4 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was crystallized and purified on a silica gel column to give 54 mg of the titled compound as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]3[C@@H:28]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=4)[CH2:27][O:26][C:25]3=[O:40])=[CH:19][C:18]=2[O:41][CH3:42])=[O:15])[CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]3[C@@H:28]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=4)[CH2:27][O:26][C:25]3=[O:40])=[CH:19][C:18]=2[O:41][CH3:42])=[O:15])[CH2:10]1
Reactant: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(OC)c2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CC[C@H](N)C3)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a solution of (S)-4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate (96 mg, 0.16 mmol, 1.0 eq) was added a solution of HCl in dioxane. The resulting mixture was stirred at rt for 3 h, and then concentrated and washed with THF to afford (S)-4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate (27 mg, 36.4%). LRMS (M+H+) m/z calculated 485.2, found 484.9. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (brs, 3H), 6.98-7.01 (m, 1H), 6.93 (s, 1H), 6.83 (d, 1H), 6.77 (d, 1H), 6.66 (s, 1H), 6.60 (d, 1H), 4.10-4.14 (m, 1H), 3.81-3.93 (m, 3H), 3.73 (s, 3H), 3.70 (s, 6H), 3.54-3.64 (m, 2H), 3.39-3.52 (m, 3H), 2.76-2.92 (m, 3H), 2.47-2.50 (m, 1H), 2.01-2.28 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:20]=2[CH:21]=1>>[CH:26]([C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([CH2:16][N:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:21][C:20]=2[CH:22]=1)=[O:27]
Reactant: O=Cc1ccc2oc(CBr)cc2c1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Product: O=Cc1ccc2oc(CN3c4ccccc4Sc4ccccc43)cc2c1
Yield: 33.2 %

Procedure:
The title compound (1.14 g, 33%) was prepared as a syrupy liquid from phenothiazine (2.87 g, 14.0 mmol) and 2-bromomethyl-5-formyl benzofuran (2.3 g, 9.6 mmol) by a similar procedure to that described in preparation 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 0.13 g (0.274 mMol) of 4-{4-Methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml of tetrahydrofuran 80.0 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 8 h, then filtered and evaporated to dryness. The residue was subjected to column chromatography on silica gel (ethyl acetate) to yield 0.048 g (37%) 4-{4-Methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester as a colorless foam. ES-MS m/e (%): 477 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](OC)=[O:6].[NH2:13][NH2:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: COC(=O)c1ccc(Cl)c(Br)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 25 %

Procedure:
Methyl 3-bromo-4-chlorobenzoate (120 mg, 0.481 mmol) was added to hydrazine (23.12 mg, 0.721 mmol) in methanol (8 mL) and refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography affording the title compound (30 mg). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=1.6 Hz), 7.60 (dd, 1H, J=2.0 & 8.0 Hz), 7.52 (d, 1H, J=8.0 Hz). ESI-MS: 250.9 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F-].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:52][OH:53]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12]([O:53][CH3:52])=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Reactant: CO
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 110 °C
Yield: 72.1 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.35 g, 0.59 mmol), Cu(I)I (113 mg, 0.59 mmol), KF on Al2O3 (40%) (241 mg, 4.15 mmol), 1,10-phenanthroline (107 mg, 0.59 mmol) and MeOH (1.2026 mL, 29.688 mmol) were placed in toluene (3 mL), degassed under argon, and then heated to 110° C. overnight. The reaction was then cooled to room temperature. EtOAc was added, and the reaction was filtered through celite and washed with EtOAc. The filtrate was then concentrated, and the resulting residue was purified by column chromatography (1:1 hexanes:EtOAc) to give the product tert-butyl 4-(5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.21 g, 71% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([N+:62]([O-:64])=[O:63])[CH:55]=1.[CH3:65][C@H:66]1[CH2:71][NH:70][CH2:69][C@@H:68]([CH3:72])[NH:67]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:65][C@H:66]1[NH:67][C@@H:68]([CH3:72])[CH2:69][N:70]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([N+:62]([O-:64])=[O:63])[CH:55]=2)[CH2:71]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1[N+](=O)[O-]

Procedure:
Palladium (II) acetate (941 mg, 4.2 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (3.93 g, 6 mmol) were heated to 50° C. in dioxane (200 ml) for 30 minutes. Cesium carbonate (20.48 g, 63 mmol), 4-bromo-2-nitroanisole (9.75 g, 42 mmol) and cis-2,6-dimethylpiperazine (14.39 g, 126 mmol) were added and the mixture heated at reflux for 18 hours. The solids were filtered through celite and washed with ethyl acetate. The residue was concentrated and dissolved in ethyl acetate and extracted with 2N hydrochloric acid (×5). The combined extracts were washed in ethyl acetate (×3), basified with 0.880 ammonia and extracted with dichloromethane (×5). The combined organic extracts were concentrated, redissolved in ethyl acetate and washed with water (×3), saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (Biotage Horizon, dichloromethane to 1:9 2M ammonia in methanol:dichloromethane) to afford the title product (D3). MS (ES+) m/e 266 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C:7]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[O:6][CH2:5][C:4]1=[O:21])[CH3:2].[ClH:22].O1CCOCC1>>[ClH:22].[CH2:1]([N:3]1[CH2:8][C:7]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:6][CH2:5][C:4]1=[O:21])[CH3:2]
Reactant: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CC2(CCNCC2)OCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round bottom flask containing tert-butyl 4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (800 mg, 2.68 mmol) was added 4M HCl in dioxane (10 mL, 40.0 mmol). The reaction mixture was placed under a nitrogen atmosphere and stirred at room temperature. After 1 h, analysis by LCMS indicated the reaction had gone to completion. The reaction mixture was concentrated in vacuo to afford the title compound as the HCl salt, which was carried forward without further purification. MS(ES)+ m/e 199.0 [M+H]+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:34])[C@H:5]([CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:9][S:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].O1CCCC1.[OH-].[Na+].Cl>O>[N:13]1([S:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:34])=[O:3])[CH2:27][C:28]2[N:29]=[C:30]([NH2:33])[S:31][CH:32]=2)=[O:26])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:11])=[O:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)N2CCOCC2)C(=O)O)cs1

Procedure:
N-(4-Morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine methyl ester monohydrochloride, 2057.6 g, and 6 L of tetrahydrofuran are charged into a 50 L reactor and stirred to a thick slurry at 0° to 5° C. A solution of 456 g of sodium hydroxide in 11.4 L of water is added over 2 hours at 0° to 5° C. After stirring the reaction mixture for 30 minutes, a solution of 630.8 mL of concentrated hydrochloric acid in 7.6 L of water is added over 2 hours at 0° to 5° C. The product precipitates as a thick slurry, which is filtered and the cake washed with water (2×500 mL). The solid is dried under vacuum at 40° C. to give 1700 g of N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine as a white solid, 99.5% pure. A second crop of 108 g is obtained of 99.7% purity by HPLC; mp 149°-151° C.
Reaction SMILES: [O:1]([C@@H:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl-].C([Al+]CC)C.C(N([CH2:34][C:35]1[C:36](=[O:48])[CH2:37][C@@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:39]=1)CC)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:34]=[C:35]1[C@@H:39]([C:11]#[C:10][C@@H:9]([O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C@H:38]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:42])[CH3:43])[CH2:37][C:36]1=[O:48]
Reactant: C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Reaction time: 0.5 h

Procedure:
(3S)-3-(tert-Butyldimethylsiloxy)-3-cyclohexylprop-1-yne (6.58 g) was dissolved in toluene (80 ml), and n-butyl lithium (3.0 M, hexane solution, 8.0 ml) was added at 0° C., followed by stirring at the same temperature for 30 minutes. To the solution was added diethylaluminum chloride (0.95 M, hexane solution 29.0 ml) at 0° C., followed by stirring until the solution reached room temperature for 30 minutes. To the solution was added (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)-cyclopent-2-en-1-one (0.25 M, toluene solution, 80.0 ml) at room temperature, followed by stirring for 15 minutes. The reaction solution, while stirring, was added to a mixture of hexane (190 ml), a saturated aqueous ammonium chloride solution (190 ml) and an aqueous hydrochloric acid solution (3 M, 56 ml), and the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (50 ml). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (developing solvent; hexane:ether=10:1) to give (3R,4R)-2-methylene-3-[(3S)-3-(tert-butyldimethylsiloxy)-3-cyclohexylprop-1-ynyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (7.92 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:25]2[CH:26]=[CH:27][NH:28][C:29]=2[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.1 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.43 g, 2.1 mmol) and potassium carbonate (0.32 g, 2.3 mmol). The product was isolated as an orange granular solid. Yield 0.49 g (56%). mp 215°-225° C. FDMS m/e=416 (M+ of free base).