Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].CC[O-].[Na+]>CC(OC)(C)C.O>[CH3:20][C:8]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7][CH2:6][CH2:5][C:4]#[CH:3]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC#C[Si](C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C#CCCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
A 3-N 250 mL flask was charged with trimethyl-(6,10,14-trimethyl-pentadeca-5,9,13-trien-1-ynyl)-silane (Ex-1B-7) (19.38 g, 64.1 mmol) and NaOEt (42 mL of a 21% w/w solution, 112 mmol). The reaction mixture was stirred at 60° C. for 4 h. After cooling to RT, the reaction mixture was diluted with MTBE (100 mL) and water (100 mL) and then filtered to remove solid present at the phase interface. The aqueous layer was extracted with MTBE (3×100 mL). The combined MTBE layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to yield 12.43 g of 6,10,14-trimethyl-pentadeca-5,9,13-trien-1-yne (Ex-1B-8) as a dark orange oil (96%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.23-5.17 (m, 1H), 5.17-5.07 (m, 2H), 2.29-1.95 (m, 13H), 1.70 (s, 3H), 1.65 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>O1CCCC1.CS(C)=O>[Br:33][C:34]1[CH:35]=[C:36](/[CH:37]=[CH:13]/[CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CC/C=C/c1cccc(Br)c1
Reaction time: 18 h

Procedure:
A 1M solution of potassium tert-butoxide in tetrahydrofuran (80 mL) was added dropwise to (3-carboxypropyl)triphenylphosphonium bromide (17 g, 40 mol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and the solution was stirred 30 min. before addition of 3-bromobenzaldehyde (4.7 mL, 40 mmol). After several minutes a precipitate was observed and an additional 20 mL of DMSO was added to aid solvation, and the reaction was stirred 18 h. The solution was poured onto water (120 mL) and washed with chloroform. The aqueous layer was acidified with conc. HCl and extracted with chloroform (3×250 mL). The organic phase was concentrated and applied to a 65i Biotage silica gel column, gradient elution from 15-65% B (A=Hexanes; B=ethyl acetate) over 2 L to give J.1, (E)-5-(3-bromophenyl)pent-4-enoic acid, 8.2 g (82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H), 2.52 (s, 4H). LC (Cond.-J1): RT=2.0 min; LRMS: Anal. Calcd. for [M−H]− C11H11BrO2: 252.97; found: 252.98.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:4][CH:3]=1>CO.[C].[Pd]>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:28][CH:29]=1
Reactant: O=C(Nc1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)Nc2ccccc2C(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
In 50 ml of methanol were suspended 1.48 g of Compound 117 obtained by Example 117 and 0.23 g of 10% palladium-carbon, and the suspension was stirred under hydrogen atmosphere at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered by using a filter aid. The solvent was evaporated under reduced pressure to afford 0.53 g of the desired compound (Compound 136).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Cl[CH2:28][C:29]1[N:30]=[CH:31][N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1>C1COCC1>[C:34]([N:32]1[CH:33]=[C:29]([CH2:28][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]2)[N:30]=[CH:31]1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (360 mg, 1.39 mmol) in anhydrous THF (10 mL) at −78° C. was added LDA (1.7 M in THF, 1.07 mL, 1.8 mmol) dropwise over 10 min. The reaction mixture was stirred at −78° C. for 1 hour, and 4-(chloromethyl)-1-trityl-1H-imidazole (500 mg, 13.9 mmol) in THF (5 mL) was added slowly. The reaction mixture was allowed to warm to room temperature over 1 hour, quenched with sat. aq. NH4Cl (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (10-50% EtOAc:Hexanes) afforded the title compound (403 mg, 51%). MS (ES+) [M+H]+=580.3.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN1CCCC1=O.C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:12][CH:13]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COC(=O)CSc1ccc(Br)cn1
Temperature: 90 °C
Yield: 39 %

Procedure:
Potassium tert-butoxide (740.0 mg, 6.60 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (0.31 mL, 3.00 mmol) and methyl 2-mercaptoacetate (0.55 mL, 6.00 mmol) in anhydrous 1-methylpyrrolidin-2-one (12.0 mL) under an argon atmosphere, in a 20 mL microwave reactor vial. The reaction mixture was sealed and heated at 90° C. for 3 mins under microwave irradiation, then successively cooled to room temperature, diluted with diethyl ether (150 mL), quenched with water (80 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×150 mL); the combined extracts were sequentially washed with water (2×150 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-(5-bromopyridin-2-ylthio)acetate A-13 (300.0 mg, Yield=39%). MS (ESI), [M+1]+ 262, 264.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:26][N:22]1[CH2:23][CH2:24][CH2:25][C@@H:21]1[CH2:20][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]=1
Reactant: Ic1ccccc1
Reactant: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(Oc3ccccc3)cc12
Yield: 6.5 %

Procedure:
A solution of (R)-5-hydroxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (Example 10, 74 mg, 0.20 mmol) and iodobenzene (61.2 mg, 0.3 mmol) with K2CO3 (41.4 mg 0.30 mmol), CuBr (17.2 0.12 mmol) and Cu powder (10 mg, 0.15 mmol) in NMP (0.7 mL) was heated at 170° C. Aqueous workup and flash chromatography (silica gel) yielded (R)-3-(1-methyl-2-pyrrolidinylmethyl)5-phenoxy-1-phenylsulfonylindole (5.8 mg, 8%, HRMS-FAB+ : C26H26N2O3S, calculated MH+ :447.17422; found MH+ : 447.17240).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[CH3:26])=[C:18](/[CH2:24][CH3:25])\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:24](/[C:18](=[C:17](/[NH:16][C:13]([NH:12][C:5]1[CH:6]=[C:7]([O:8][CH:9]([CH3:10])[CH3:11])[C:2]([Cl:1])=[CH:3][C:4]=1[F:15])=[O:14])\[CH3:26])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:25]
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(CC)=C(/C)N
Solvent: CN(C)C=O
Product: CCOC(=O)/C(CC)=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in dimethylformamide with ethyl 3-amino-2-ethylcrotonate there is obtained ethyl 2-ethyl-3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-crotonate, m.p. 112°-114° C. and from this intermediate with sodium hydride in dimethylformamide there is obtained 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 128°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH2:12]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14].O>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CCC)Cc1cccc([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
To a solution of 5.13 g of m-nitro-benzyl chloride in 100 ml benzene at 10° C. was added in small portions 6.2 g of dipropylamine over a period of 15 minutes. The reaction mixture was stirred and allowed to come to room temperature for 1.5 hours, and was then refluxed for 4 hours. Water was added to the solution and the organic layer was separated and collected. The organic layer was washed with water (3×100 ml), dried (MgSO4) and stripped to leave a dark-red oil. The product (Compound No. 1) was chromatographed over silica gel (hexane: CH2Cl2 ; 1.0:0; 4:1), to yield the title product as a yellow-amber oil. Analysis: C: calculated, 66.08; found, 65.38. H: calculated, 8.53; found 8.55. N: calculated, 11.85; found, 11.73.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:31]=[C:30]2[C:26]([C:27](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCC(=O)O)c1C
Yield: 43.7 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (234 mg), 239 mg 6-(2-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by chromatography on a silica gel column eluting with ethyl acetate:hexane 1:1 containing 0.1% acetic acid to give 182 mg (44%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].C(=O)([O-])O.[Na+]>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
3-Amino-1-propanol (4.5 g, 60.0 mmol) was added slowly to a mixture of 4-chloro-3-nitropyridine (8.0 g, 50.5 mmol) and sodium hydrogen carbonate (4.2 g, 50.0 mmol) in ethanol (200 ml). The mixture was stirred for 3 h at ambient temperature and the solvent removed under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the residue, which was extracted with ethyl acetate (3×200 ml). The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated. Crystallisation from ethyl acetate gave 4-(3-hydroxypropylamino)-3-nitropyridine (4.3 g, 43%) as an orange crystalline solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1CN
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CNS(=O)(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of 4-(chlorosulfonyl)phenyl acetate (example 5-42b) (531 mg, 2.265 mmol) in 5.0 mL of dichloromethane, was cooled to 0° C. in an ice bath. (2-methoxyphenyl)methanamine (325 μL, 2.492 mmol) and triethylamine (347 μL, 2.492 mmol) were added. The ice bath was then removed and the mixture warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated and the crude product was purified by column chromatography (hexanes/ethyl acetate=90/10 to 30/70) to afford pure 4-(N-(2-methoxybenzyl)sulfamoyl)phenyl acetate (743 mg, 89%) as a white solid. MS (M+H, 336.1) 1H NMR (400 MHz, CDCl3): δ, ppm: 2.32 (s, 3H), 3.71 (s, 3H), 4.18 (d, 2H, J=5.8 Hz), 5.15 (t, 1H, J=5.8 Hz), 6.71 (d, 1H, J=8.2 Hz), 6.82 (br t, 1H, J=7.4 Hz), 7.07(br d, 1H, J=7.4 Hz), 7.10 (d, 2H, J=8.7 Hz), 7.19 (br t, 1H, J=7.8 Hz), 7.74 (d, 2H, J=8.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[S:18]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19]1.Cl.O1CCOCC1.N>>[CH3:12][C:4]1[C:3]2[C:13](=[O:15])[NH:25][C:24]([CH2:23][C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)=[N:1][C:2]=2[S:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Reactant: N#CCc1ccsc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2nc(Cc3ccsc3)[nH]c(=O)c2c1C
Reaction time: 10 h

Procedure:
515 Milligrams of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate and 296 mg of 3-thiopheneacetonitrile were added to 8 mL of 4N hydrogen chloride-dioxane solution and stirred for 10 hours. Thereafter the liquid reaction mixture was poured on ice, and its pH was adjusted to 8-9 with 25% aqueous ammonia. Whereupon precipitated crystals were recovered by filtration and washed first with water, and then with hexane. The crude crystals were recrystallized from a liquid mixture of N,N-dimethylformamide and cyclohexane, to provide 397 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[CH:14][NH:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[K+]>CO>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]=[C:26]([C:13]2[C:10]3[CH:11]=[N:12][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:8][C:9]=3[NH:15][CH:14]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: c1cc2cnc(N3CCOCC3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(N4CCOCC4)ncc23)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridine (197 mg, 0.97 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (387 mg, 1.94 mmol) and potassium hydroxide (218 mg, 3.88 mmol) were added in MeOH (10 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (50 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×20 mL). The organic extracts was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to obtain 337 mg (91%) of the desired product. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.50. MS (electrospray): exact mass calculated for C21H28N4O3, 384.22; m/z found, 749.3 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.24 (br s, 1H), 8.77 (s, 1H), 6.95 (d, J=2.15 Hz, 1H), 6.45 (s, 1H), 6.09 (br s, 1H), 4.09-4.04 (m, 2H), 3.66 (t, J=6.06 Hz, 4H), 3.60 (t, J=5.28 Hz, 2H), 3.25 (t, J=5.09 Hz, 4H), 2.38 (d, J=6.26 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16](O)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.S(Cl)([Cl:26])=O.CN(C)C=O>ClCCl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([Cl:26])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)Cl)C(=O)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (mycophenolic acid) (32.0 g) was dissolved in dichloromethane (250 ml), followed by the addition of thionyl chloride (25.0 ml) and dimethylformamide (0.3 ml). The reaction mixture was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid chloride as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[C@@H:18]([C:19]([OH:21])=O)[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([C:19]([C@H:18]3[CH2:17][CH2:16][C:13]4([CH2:15][CH2:14]4)[CH2:12][C@@H:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[O:21])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)[C@H]1CCC2(CC2)C[C@@H]1C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid from step 7 (47 mg, 0.16 mmole) was dissolved in DMF (0.7 mL). To the solution, 1-phenylpiperazine (29 mg, 0.18 mmole) was added, followed by BOP (76 mg, 0.17 mmole). DIEA (53 mg, 0.41 mmole) was added after the mixture was stirred at r.t. for 10 min. The mixture was then stirred at r.t. overnight and quenched with sat'd NaHCO3 solution, extracted with EtOAc. The extract was washed with NaHCO3 sat'd solution, brine; dried over MgSO4. After filtration, the filtrate was concentrated. The resulting residue was purified by column chromatography to afford Benzyl (5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylate.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@H:2]([C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1)OCc1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of Z-Trp-OH (2 g, 5.9 mmol) in THF (88 mL) at 5° C. were added aniline (540 μL, 5.9 mmol) and DCC (1.6 g, 7.7 mmol). The reaction was allowed to warn up to room temperature overnight. The solvent was evaporated off and the crude was triturated with ethyl acetate (50 mL). After filtration, the organic phase was successively washed with aqueous 5% KHSO4, aqueous 10% KHCO3, brine and was dried over Na2SO4. The solvent was removed in vacuo. The crude amide was purified by precipitation in methanol/pentane to give a white amorphous solid (1.7 g, 69%). 1H NMR (300 MHz, CDCl3) δ 3.25 (dd, J=14.4 Hz, J=8 Hz, 1H, CH2), 3.46 (dd, J=14.4 Hz, J=5.3 Hz, 1H, CH2), 4.67 (m, 1H, CHα), 5.12 (m, 2H, CH2 (Z)), 5.63 (broad s, 1H, NHZ), 7.06-7.72 (m, 16H, 15 aromatic H, NH amide), 8.09 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.6 (CH2 Trp), 56.1 (CHα), 67.2 (CH2 (Z)), 111.4, 118.8, 119.9, 120.1, 122.4, 123.4, 124.5, 127.1, 128.1, 128.3, 128.6, 128.9, 136, 136.2, 137.1 (20 aromatic C), 156 (CO carbamate), 169.7 (CO amide). Anal. Calcd. for C25H23N3O3: C, 72.62; H, 5.61; N, 10.16. Found: C, 72.75; H, 5.58; N, 9.95.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8](=[O:12])[C:9](Cl)=[O:10])[CH3:6].[CH:13]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:12])[C:9]([C:20]1[CH:21]=[CH:22][C:17]([S:16][CH:13]([CH3:15])[CH3:14])=[CH:18][CH:19]=1)=[O:10])[CH3:6]
Reactant: CC(C)Sc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
In a round bottom flask was placed methylene chloride (70 mL) and aluminum trichloride (6.09 g, 45.65 mmol) and it was cooled to 0° C. in an ice bath. To this was then added dropwise chloro-oxo-acetic acid ethyl ester (3.98 mL, 35.79 mmol) keeping the temperature of the solution below 5° C. and it was then stirred for 30 min at 0° C. After this time a solution of isopropylsulfanyl-benzene (5.00 g, 32.84 mmol) in methylene chloride (5 mL) was added dropwise while keeping the temperature of the solution below 5° C. The ice bath was then removed and the reaction allowed to warm up to 25° C. and stirred for 3 h. The reaction was then cooled back down to 0° C. in an ice bath and added dropwise ice water (20 mL) keeping the temperature of the solution below 20° C. It was then stirred for 15 min and then transferred to a separatory funnel and separated. The organic phase was then washed with water (2×25 mL), saturated aqueous sodium bicarbonate solution (2×25 mL) and water (25 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford (4-isopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (5.85 g, 71%) as a yellow oil and used without further purification.