Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:63]>O1CCOCC1>[ClH:63].[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCCN3CCOCC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CCCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (95 mg, 0.112 mmol) in dioxane (40 mL) was bubbled HCl gas until saturation and then stirred at room temperature for 16 hours. Reaction mixture was concentrated and the residue was triturated with methanol (1 mL) then decanted and dried to afford N-(1-hydroxy-2-methylpropan-2-yl)-2-(6-methyl-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (42 mg, 71%) as a yellow solid. LCMS: (M+H)+=492; 1H NMR (300 MHz, DMSO+D2O): δ 9.14 (s, 1H), 8.44 (d, 1H, J=8.1 Hz), 8.36 (s, 1H), 7.59 (s, 1H), 7.17 (d, 1H, J=8.4 Hz), 4.59-4.56 (m, 2H), 4.03-3.99 (m, 2H), 3.78-3.75 (m, 4H), 3.43-3.18 (m, 6H), 2.54 (s, 3H), 2.36 (brs, 2H), 1.43 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1>>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][N:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Clc1ncc(Br)cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cnc(Cl)nc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-chloropyrimidine (251 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (30 mg, 6.8%). MS (ISN) 467.2 [(M)−]; mp 157–159° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:23][C:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1)=[O:26]
Reactant: COC(=O)c1csc(-c2cccc(OCCCCCO)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(-c2cccc(OCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(3-(5-hydroxypentyloxy)phenyl)thiazole-4-carboxylate (26), (32 mg, 0.10 mmol, 1.0 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude compound 27 was used directly for the next step.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)C(OC(C)(C)C)=O)(C)(C)C.[ClH:47].O1CCOCC1>C(Cl)Cl>[ClH:47].[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][C:34]([CH2:33][CH:22]([NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:18]2[N:17]=[C:16]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccc3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ccccc3)cc2)NS(=O)(=O)c2cccnc2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of tert-butyl({6-[(biphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (931 mg, 1.44 mmol) obtained in Example 6-(a) in methylene chloride (14.4 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (7.2 ml), and the mixture was left at room temperature for 16 hours. Further, it was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, followed by addition of methylene chloride to the residue, and a precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure at room temperature to afford the title compound (760 mg) as a white solid. (Yield: 94%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)c[nH]c2C1
Yield: 4.1 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.70 g), aminoguanidine hydrochloride (0.34 g), concentrated hydrochloric acid (0.44 ml), water (0.44 ml) and ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH/Et3N). The resulting oil was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 6) (0.04 g) as colorless crystals.
Reaction SMILES: NCCCCCCCCCCCC(O)=O.S(Cl)([Cl:18])=O.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].Cl.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(N(CC)CC)C>ClCCl.C(O)C>[ClH:18].[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[N+:31]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:29][CH:28]=[CH:27][CH:26]=2)([O-:33])=[O:32]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: CCOC(=O)CCCCCCCCCCCN
Agent: Cl
Agent: NCCCCCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Ethyl 12-aminododecanoate hydrochloride was prepared from 12-aminododecanoic acid, thionyl chloride, and ethanol by the general method of C. Temple, Jr., R. D. Elliott, and J. A. Montgomery, J. Med. Chem., 1988, 31, 697-700. The general method described in Step 1 of Example 15 was used to react 4-chloro-3-nitroquinoline (15.5 g, 74.4 mmol), ethyl 12-aminododecanoate hydrochloride (25.0 g, 89.3 mmol), and triethylamine (18.8 g, 186 mmol) in dichloromethane for 15 hours to provide ethyl 12-(3-nitroquinolin-4-ylamino)dodecanoate (30.0 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[CH:13]=1>>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]([CH2:11][N:3]3[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]3)[CH:17]=[CH:16][N:15]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: O=C1CCNCC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: Cl
Solvent: O
Product: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Piperidone hydrochloride monohydrate (3.07 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.94 g) were coupled by the same manner as described in Example 2 to give the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@H:15]2[O:19][C:18](=[O:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:14])(=O)=O)=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CO>[N:37]([CH2:12][C@@H:13]([C@H:15]1[O:19][C:18](=[O:20])[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[OH:14])=[N+:38]=[N-:39]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H]2OC(=O)C(OCc3ccccc3)=C2OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1

Procedure:
(R)-5-[2-(4-methylphenylsulfonyloxy)-(S)-1-hydroxyethyl]-3,4dibenzyloxy-5H-furan-2-one (5)† (550 mg, 1.1 mmol), sodium azide (190 mg, 1.7 mmol) and methanol (2 ml) were heated under reflux for 6 hours. The reaction mixture was cooled and most of the solvent removed by evaporation at room temperature. The resulting material was partitioned between water (25 ml) and dichloromethane (25 ml) and the aqueous phase extracted with dichloromethane (25 ml). The combined organic fractions were dried (MgSO4), filtered and volatile components evaporated under reduced pressure (8 mm/Hg) at room temperature to give the product (6) as a yellow waxy solid (375 mg, 89%). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:57]1([CH2:62][C@H:63]2[CH2:67][CH2:66][CH2:65][NH:64]2)[CH2:61][CH2:60][CH2:59][CH2:58]1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@@H:63]1[CH2:62][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 11 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine in tetrahydrofuran. Yield: 11%; C26H29Cl2N5O2 (514.454); mass spectrum: (M+H)+=514/516/518 (chlorine isotope).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[CH:50](=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.083 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (981 mg, Example 121), benzaldehyde (434.1 mg) and acetic acid (245.6 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O which caused precipitation of product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to precipitate additional product. The mixture was filtered thru a celite pad. The collected solid was rinsed with water (35 mL×2). The solid was dissolved with EtOAc (50 mL) and then eluted through the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as pink solid (570 mg; 49%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 3H), 7.26 (m, 6H), 7.07 (dd, J=8.0, 8.0 Hz, 1H), 6.60 (m, 2H), 6.54 (s, 1H), 5.04 (s, 1H), 4.50 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.98 (d, J=13.0 Hz, 1H), 3.69 (m, 1H), 3.18 (d, J=13.0 Hz, 1H), 3.02 (m, 2H), 2.70-2.52 (m, 5H), 2.00 (m, 3H), 1.73 (m, 31H), 1.26 (t, J=7.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[Li+].[OH-].[OH-].[Na+].[C:23](OCC)(=O)C>C1COCC1.CO.O>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][C@H:7]1[CH:9]1[CH2:23][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature. To the mixture was added 1.0M NaOH (15 mL), water (20 mL) and ethyl acetate (20 mL). The mixture was shaken, the phases were separated, and the organic phase was again extracted with 20 mL 0.5M NaOH. The combined aqueous phases were acidified with 1.0M HCl until pH=4 and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4), and filtered to provide the desired product as a white solid (2.62 g, 87%). 1H NMR: (DMSO-d6) δ1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS MS m/z 228 (M++H).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH:37]1([C@H:41]([NH2:43])[CH3:42])[CH2:40][CH2:39][CH2:38]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:43][C@@H:41]([CH:37]2[CH2:40][CH2:39][CH2:38]2)[CH3:42])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: C[C@@H](N)C1CCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 48.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and (R)-1-cyclobutyl-ethylamine HCl (225 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 326 mg of crude (R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-ethyl)-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:34])[CH2:22][CH2:21]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:20]2[CH2:25][CH2:24][C:23]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[CH2:22][CH2:21]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: O=C1Nc2ccccc2C12CCNCC2
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ncnc(N2CCC3(CC2)C(=O)Nc2ccccc23)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (1.0 g, 5.3 mmol) in methanol (20 mL) was added triethylamine (2.0 mL, 14.3 mmol) and spiro[indoline-3,4′-piperidin]-2-one (1072.5 mg, 5.3 mmol). The mixture was stirred at ambient temperature for 2 h and then 10 wt % Pd on C (wet) was added. The resulting mixture was stirred under hydrogen for 18 hours, diluted with methanol, and was filtered through Celite. The filtrate was concentrated, and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the mixture was filtered and dried under reduced pressure. The resulting compound was submitted to next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.86 (s, 1H), 7.45 (d, 1H), 7.20 (td, 1H), 6.98 (t, 1H), 6.87 (d, 1H), 6.30 (q, 1H), 4.15 (s, 2H), 3.45 (dd, 2H), 3.26-3.18 (m, 2H), 2.86 (d, 3H), 1.97-1.88 (m, 2H), 1.82 (dd, 2H). MS (EI) for C14H20N6O: 325.6 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>O>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1ccc(Br)cc1F
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A.H.P. U.S. Pat. No: 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1HNMR(DMSO-d6) δ 10.35 (s,1H) 7.67-7.49 (m,5H), 6.97 (d, 1H; J=8.6 Hz) 4.09 (s, 2H) 1.67(s, 6H); MS [M−H]− m/z 309. Anal. Calc. For C18H15N2FO2.0.15 H2O: C, 69.07; H, 4.93; N, 8.95. Found C, 69.27; H 5.05; N, 8.50
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:19]([F:22])([F:21])[F:20])[CH3:11])[C:6]=2[CH:23]=1.C(O[C:29]([N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1)=[O:30])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:10]([N:7]2[C:6]3[CH:23]=[C:2]([C:34]4[CH2:33][CH2:32][N:31]([C:29]([C@H:32]5[CH2:33][CH2:34][CH2:35][CH2:36][NH:31]5)=[O:30])[CH2:36][CH:35]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[N:8]2)[CH3:11])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C
Yield: 162.5 %

Procedure:
A mixture of (R)-6-bromo-1-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-1H-benzo[d][1,2,3]triazole (0.32 g, 0.8 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (0.27 g, 0.8 mmol), Pd(PPh3)4 (0.046 g, 0.039 mmol), and 2 M aqueous potassium carbonate (1.2 mL, 2.4 mmol) in 2:1toluene/ethanol (3.6 mL) was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product (0.33 g, 0.65 mmol, 83%).
Reaction SMILES: C1CN2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])C2)[C@H:3]([OH:12])C1.S(C)C>>[CH3:4][C:5]1([CH3:6])[O:11][C@@H:4]2[C@@H:5]([CH2:6][O:10][C:3]2=[O:12])[O:11]1
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Solvent: CSC
Product: CC1(C)O[C@@H]2COC(=O)[C@@H]2O1

Procedure:
Removal of the silyl protecting group from (5a) gave the diol (6), which was smoothly converted to the crystalline dimesylate (7). Selective displacement of the less hindered mesylate of (7) with sodium azide afforded (8). Palladium-catalyzed hydrogenolysis of (8) to the amine followed by filtration of the catalyst and treatment of the filtrate with sodium methoxide caused cyclization to the known crystalline bicyclic lactam (9) in 75% yield. Reduction of (9) with borane-methyl sulfide complex gave a 94% yield of crystalline (10), also a known compound (see Setoi, H.; et al J. Org. Chem. 1985, 50, 3948-3950; Bashyal, B. P.; et al Tetrahedron 1987, 43, 3083; Bennett, R. B.; et al J. Am. Chem. Soc. 1989, 111, 2580-2582; and Naruse, M.; et al J. Org. Chem. 1994, 59, 1358-1364) which was hydrolyzed to swainsonine (1) in 96% yield. While the reduction of (9) to (10) has been reported by Fleet using BH3.Me2S (see: Carpenter, N. M.; et al Tetrahedron Lett. 1989, 30, 7261-7264) their procedure involves isolation of the borane complex of (10). The present procedure is adapted from a similar one by Keck which was used to make an epimer of swainsonine, see: Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083-6089. While not the shortest synthesis, this route involves simple, reproducible steps that work well on a substantial scale. Using this method, 4.5 g of swainsonine was be prepared in 20% overall yield from the lactone (2), requiring 11 steps involving three chromatographic separations and five crystallizations.