Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[O:9][CH2:8]2)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(N(CC)CC)C.[Na+].[Cl-]>CC(O)C>[CH3:15][C:6]1[C:7]2[CH2:8][O:9][C:10](=[O:14])[C:11]=2[CH:12]=[CH:13][C:5]=1[C@@H:3]1[CH2:2][O:4]1
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Temperature: 28 °C
Reaction time: 1 h

Procedure:
5-(2-Bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one (48.8 g., 181 mmol) was charged to a 5 L 3 neck round bottom equipped with overhead stirrer, thermocouple, and heating mantle. 2-Propanol (1.22 L) was added, followed by 610 mL of pH 7 0.1M potassium phosphate buffer. Buffer solution (610 mL) was charged to a 1.0 L erlenmeyer, and 2.44 g of NADP was added to the erlenmeyer and swirled to dissolve. A reducing enzyme, KRED MIF-20 (2.44 g) (available from Codexis, Inc., 200 Penobscot Drive, Redwood City, Calif. 94063, www.codexis.com, tel. 1-650-421-8100) was added to the erlenmeyer flask and the mixture was swirled to dissolve the solids. The resulting solution was added to the 5 L round bottom, which was then heated to 28° C. and aged for 6 hours, at which point the reaction was cooled to RT and triethylamine (50.2 mL, 360 mmol) was added. The resulting solution was aged at 40° C. for 1 h. The light slurry solution was cooled to RT, after which 122 g NaCl was added. The solution was aged at RT then extracted with 1.22 L isopropyl acetate (IPAc). The aqueous layer was re-extracted with 400 mL IPAc and the combined organics were washed with 400 mL 20% brine solution, dried over MgSO4, filtered and concentrated by rotary evaporation. The resulting solids were taken up in 100 mL IPAc (thick slurry). Hexanes were added (400 mL) and the suspension aged at RT then filtered and washed w/5:1 Hexanes:IPAc solution (150 mL). The crystalline solids were dried under vacuum at RT to provide 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=8.1 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 5.28 (s, 2H), 4.10 (dd, J=4.0, 2.8, 1H), 3.26 (dd, J=5.6, 4.0, 1H), 2.72 (dd, J=5.6, 2.8, 1H), 2.42 (s, 3H)
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1.[CH2:30]([O:32][C:33](=[O:40])[C:34]([CH3:39])([CH3:38])[CH2:35][C:36]#[CH:37])[CH3:31]>CCN(CC)CC.Cl[Pd]Cl.[Cu]I>[CH2:30]([O:32][C:33](=[O:40])[C:34]([CH3:39])([CH3:38])[CH2:35][C:36]#[C:37][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1)[CH3:31]
Reactant: COc1ccc(N)c(I)n1
Reactant: C#CCC(C)(C)C(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CC#Cc1nc(OC)ccc1N

Procedure:
PdCl2 (0.059 g, 0.33 mmol), CuI (0.063 g, 0.33 mmol), and PPh3 (0.173 g, 0.66 mmol) were suspended in NEt3 (40 mL) and stirred under N2. 2-Iodo-6-methoxy-pyridin-3-ylamine (1.65 g, 6.60 mmol) was added, followed by 2,2-dimethyl-pent-4-ynoic acid ethyl ester (Example 4, Step 1; 1.22 g, 7.91 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:38])[CH2:36][CH2:35]1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: O=C(Cl)C1CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][O:45][CH2:46][CH:38]1[CH2:39][NH:40][CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][O:45][CH2:46][CH:38]1[CH2:39][N:40]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:22])[CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCNCC1COC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC5COCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 58.9 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (385 mg, 0.97 mmole) was combined with 8-Oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (215 mg, 0.887 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (323 mg, 0.522 mmol) in 59% yield. MS 619.7 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2cccc(C(F)(F)F)c2)C1
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 53.7 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]methanone (29 mg, 0.074 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 15 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH3:19][N:20]([CH3:24])[C:21]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:16]=2)[CH:12]=[CH:13]1)=[O:22]
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: CN(C)C(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 6-(4-fluorophenyl)indole (2.00 g, 9.48 mmol), prepared as described in WO 93/01813, in THF (50 mL) was added KOH (2.7 g, 47.4 mmol) in a single portion and the cold bath was removed. After stirring for 15 min at ambient temperature, dimethylcarbamoyl chloride (1.3 mL, 14.2 mmol) was added via syringe and the resulting brown suspension was stirred for 4 hours at ambient temperature. The reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous NH4Cl and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford 6-(4-fluorophenyl)indole-1-carboxylic acid dimethylamide as a brown solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2OC(=O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][CH3:23]>ClC1C=CC=CC=1>[CH3:26][O:25][C:21]([C:22]1[S:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[CH:23]=1)=[O:24]
Reactant: CCC(=O)OC
Reactant: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)ns1

Procedure:
5-(4-benzyloxy-phenyl)-[1,3,4]oxathiazol-2-one (0.4 g, 1.4 mmol) and 0.23 ml of methyl propionate were dissolved in 10 ml of chlorobenzene and then refluxed overnight. The solvent was distilled off under reduced pressure and the obtained crude compound was purified by silica gel column chromatography to obtain 3-(4-benzyloxy-phenyl)-isothiazol-5-carboxylic acid methyl ester as a desired compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:29][NH2:30])(=[O:28])[CH2:26][CH3:27]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:30]/[NH:29][C:25](=[O:28])[CH2:26][CH3:27])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CCC(=O)NN
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: CCC(=O)N/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 80.7 %

Procedure:
The title compound (28.5 mg, 74%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) and propionic acid hydrazide (24.6 mg, 0.28 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.93, 10.76 (bs, 1H), 9.45 (s, 1H), 8.92 (dd, 1H), 8.41 (d, 1H), 8.18 (d, 1H), 7.83 (d, 1H), 7.53 (dd, 1H), 6.22 (s, 2H), 2.79 (q, 2H), 2.31 (s, 3H), 1.09 (t, 3H). LCMS (method E): [MH]+=393, tR=4.78 min.
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH:6]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[NH:11][CH2:12][CH2:13][Cl:14])([CH3:8])[CH3:7]>ClC(Cl)C>[CH:6]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][Cl:14])[N:1]=[O:2])([CH3:7])[CH3:8]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Dinitrogen trioxide gas (1.3 g) was introduced into a solution of the thus prepared 3-isopropyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.58 g, 9.35 mmol) in dichloroethane (50 ml) with thorough stirring at 15°-20° C., and stirring was continued for further two hours at the same temperature. The reaction mixture was vacuum-concentrated concentrated at 25° C., and purified by column chromatography (packing: silica gel; eluent: hexane/ethyl acetate 4:1) to obtain 3-isopropyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea (2.78 g, 6.75 mmol); yield 72.2%, m.p. 70°-72° C., [α]D20 +69.7° (C 1.0, methanol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:4][C@H:3]1[CH2:13][C:14]#[N:15].C(N(C(C)C)CC)(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C.CO>[C:14]([CH2:13][C@@H:3]1[CH2:4][C@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:6][CH2:7][C@@H:2]1[NH:1][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[C:29]1[CH:37]=[CH:38][CH:39]=[C:27]([C:26]([F:25])([F:41])[F:40])[CH:28]=1)#[N:15]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CC#N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CC#N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)acetonitrile (100 mg, 0.27 mmoles) in 2 ml of anhydrous acetonitrile were added diisopropylethylamine (0.24 ml, 1.35 mmoles), 2-(3-(trifluoromethyl)benzamido)acetic acid (66.6 mg, 0.27 mmoles) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (95.2 mg, 0.3 mmoles, Bachem), and the mixture was stirred for 18 hours at room temperature. Then several drops of methanol was added, and it was stirred for additional two hours. The solvent was evaporated off and the residue was purified by chromatography (silica gel, 0.7:6.3:93 cNH4H-MeOH—CH2Cl2) to give N-(2-((1S,2S,4R)-2-(cyanomethyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=439.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([Zn]CC)C.ICI.[Cl-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:14][CH:9]2[CH:10]([NH2:13])[CH2:11][CH2:12]3)=[CH:6][CH:7]=1
Reactant: CC[Zn]CC
Reactant: NC1C=C(c2ccc(F)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ICI
Solvent: ClCCl
Product: NC1CCC2(c3ccc(F)cc3)CC12

Procedure:
To a dichloromethane solution (0.28 mL) of 3-(4-fluorophenyl)cyclopent-2-enamine (55.8 mg, 0.315 mmol) synthesized in Reference Synthesis Example 223, diethylzinc (15% solution in toluene) (162 μL, 1.78 mmol) was added and then diiodomethane (127 μL, 1.58 mmol) was added at 0° C. with stirring and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].C=O.Cl.[Cl:14][CH2:15]Cl>[Cl-].[Zn+2].[Cl-]>[Cl:14][CH2:15][C:5]1[O:1][C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccco1
Reactant: ClCCl
Agent: C=O
Agent: Cl
Agent: [Cl-]
Product: CCOC(=O)c1ccc(CCl)o1
Yield: 98 %

Procedure:
To a solution of 100 g (0.71 M) of ethyl 2-furoate in 250 ml of dichloromethane are added 30.6 g (1.02 M) of paraformaldehyde and 25.4 g (0.19 M) of zinc chloride. Gaseous hydrogen chloride is passed into the reaction medium. An exothermic reaction is observed, and the temperature reaches 35° C. The evolution of gas is maintained up to the end of the reaction, which is monitored by thin-layer chromatography (TLC). The product obtained is then purified by chromatography on silica using dichloromethane as eluent, to give 134.6 g of ethyl 5-chloromethylfuran-2-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]([NH:9][CH:3]([CH2:4][CH2:5]2)[CH2:2]1)=[O:8].[ClH:10].[CH3:11][OH:12]>>[ClH:10].[NH2:9][C@@H:3]1[CH2:4][CH2:5][C@H:6]([C:7]([O:12][CH3:11])=[O:8])[CH2:1][CH2:2]1
Reactant: O=C1NC2CCC1CC2
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Reaction time: 8 h

Procedure:
Dissolve 3-isoquinuclidone (1.5 g) in methanol (50 mL) and saturated with HCl. Let stand overnight then warm to reflux for 16 hours. Evaporate the solvent in vacuo to give cis-4-amino-cyclohexanecarboxylic acid, methyl ester hydrochloride as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([OH:20])[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc2c(c1)CCCC2NC(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCC2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [6-(1-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester (2.63 g, 9.04 mmol, 1.0 eq) and MnO2 (Aldrich, 10.2 g, 117.5 mmol, 13 eq) in CH2Cl2 (100 mL) was stirred at RT overnight. The mixture was passed through a pad of Celite® and the pad was washed with CH2Cl2 (100 mL×2). The concentration of the filtrate afforded the title compound as a white sticky semi-solid. MS (ESI, pos. ion) m/z: 290 (M+1).
Reaction SMILES: Cl.[NH:2]([CH2:9][C:10]1[C:11](=[O:36])[C:12]2[C:17]([C:18](=[O:35])[C:19]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](Cl)([Cl:39])=[O:38].C1(C)C=CC=CC=1>ClCCl.C(N(C(C)C)CC)(C)C>[C:3]1([N:2]([CH2:9][C:10]2[C:11](=[O:36])[C:12]3[C:17]([C:18](=[O:35])[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:37]([Cl:39])=[O:38])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCC1=C(CNc2ccccc2)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC1=C(CN(C(=O)Cl)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Anilinomethyl-3-pentadecyl-1,4-naphthoquinone hydrochloride (9.25 g, 18.1 mmol) was dissolved in dichloromethane (100 ml). A 12 percent solution of phosgene in toluene (45 ml, 54.4 mmol) and diisopropylethylamine (50 ml) were added and the resulting solution was stirred at room temperature for about 15 minutes. The solution was then concentrated under reduced pressure and the residue was taken up in dichloromethane. The solution was washed with 2N hydrochloric acid, dried over anhydrous magnesium sulfate, filtered, and concentrated. The product was used as a crude oil in the preparation of the above PRDR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[C@H:15]([OH:34])[CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C@@H:15]([OH:34])[C@@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:48][CH:47]=2)(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Yield: 52.7 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-{isobutyl[(4-nitrophenyl)sulfonyl]amino}propylcarbamate (0.20 g, 0.29 mmol) in 3 mL of ethanol was added 64 mg of platinum (on activated-carbon, 3%. Pt). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (4:1) as eluent to provide 0.10 g (52%) of the title compound.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1.O>C(OCC)(=O)C>[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: c1ccc2c(C3CC3)cccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Yield: 64 %

Procedure:
Sodium nitrite (30 mL) was slowly added (over 2 hours) to 1-cyclopropylnaphthalene (6.4 g, 38 mmol) stirred at 0° C. The reaction mixture was stirred at 0° C. for an extra 30 min and then slowly poured into ice. Water was added, followed by ethyl acetate. After extraction, the organic layer was washed with aqueous sodium hydroxide (1%) and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-cyclopropyl-4-nitronaphthalene (5.2 g, 64%).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+].[C:12](O)(=O)[C:13]1C(=CC=C[CH:19]=1)O.[OH-].[Na+]>O>[C:1]([O:10][CH2:19][CH:13]=[CH2:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C([O-])c1ccccc1O
Reactant: O=C(O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)c1ccccc1O

Procedure:
A sodium salicylate solution, prepared from 69 g of salicylic acid (0.5 mol), 25 ml of water and 50 ml of an aqueous solution of 10N caustic soda, was introduced gradually at 60° C., over 6 hours.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1.NN.C1COCC1>C(O)C.C1COCC1>[NH2:3][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2c(cnn2CCN)c1
Reaction time: 17 h

Procedure:
Ethyl 1-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-1H-indazole-5-carboxylate (step A, 980 mg, 2.7 mmol) was dissolved in ethanol/THF (1:1, 35 mL) under nitrogen. Hydrazine (365 uL) was added and the reaction stirred 17 hours. THF (75 mL) was added and the resulting solids were filtered off. The filtrate was concentrated to an orange solid, which was purified by flash chromatography (dichoromethane/5% methanol/0.5% triethylamine). The product fractions were combined and concentrated to an orange solid (404 mg, 66%). LRMS (ES): 234.1 ([M+H]+, 100%)
Reaction SMILES: [I:1]Cl.[OH:3][CH2:4][CH:5]([CH2:16][OH:17])[CH2:6][CH2:7][N:8]1[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]>CO>[OH:3][CH2:4][CH:5]([CH2:16][OH:17])[CH2:6][CH2:7][N:8]1[CH:15]=[C:14]([I:1])[C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Reactant: ClI
Solvent: CO
Product: O=c1[nH]c(=O)n(CCC(CO)CO)cc1I
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
Iodine monochloride (500 mg, 3.08 mmol) was added to a solution of 18 (360 mg, 1.68 mmol) in dry methanol (25 ml) and the reaction mixture was stirred at 50° C. for 90 min. and then the methanol was removed in vacuo. The dry residue was treated with 5.0 ml of conc. ammonium hydroxide in 25 ml of methanol with stirring at 50° C. for 1 h. The crude reaction mixture was purified by elution from a column of silica gel by using dichloromethane-methanol (92:8, v/v) as eluent. The product 19 was obtained in 59.2% yield as a colorless gum.