Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][CH2:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCO3)c2s1

Procedure:
From (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester with tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane, bis(dibenzylideneacetone)palladium, trifurylphosphine and triethylamine in dioxane. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)nc(C)n1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(C)nc(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-amino-2,6-dimethylpyrimidine. After completion, the reaction mixture was extracted with 1M HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 0.82 min (LC-MS 2); ESI-MS: 506.0/508.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C1C=CC=CC=1>CO>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)c2ccc(F)cc2)C[C@H]1OC

Procedure:
A mixture of 11 parts of 1-(4-fluorobenzoyl)aziridine, 6.28 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 45 parts of benzene and 20 parts of methanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5.09 parts of cis-4-amino-5-chloro-N-[1-[2-[(4 -fluorobenzoyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.7° C. (compound 131).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:20][CH2:21][C@@:22]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:11](=O)[O:12]C2C=CC=CC=2)[CH3:9])=[CH:4][CH:3]=1.CN1C(=O)CCC1.[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:20][CH2:21][C@:22]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:34][C:11]2=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CC[C@](O)(CC(C)(C)O)c1ccccc1)C(=O)Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with phenyl (S)-1-(4-bromophenyl)ethyl((S)-3,5-dihydroxy-5-methyl-3-phenylhexyl)carbamate (25.0 g, 47.5 mmol) and NMP (125 mL). The resultant solution is treated with 50 wt. % aqueous KOH (12.5 mL), stirred at 25° C. for 1 hour, and treated with water (250 mL). The resultant slurry is stirred at 25° C. for 1 hour, and the solids collected by filtration. The solids are then washed with water and heptane, and dried under vacuum at 50° C. for 18 hours to provide 6 as a white solid. Yield: 19.7 g, 95.1%; 99.1%. purity by weight.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[I-].C[CH:17]=[N+:18]=[CH:19]C.[C:21](#N)C>>[CH3:17][N:18]([CH2:19][C:12]1[N:11]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]2=[N:14][CH:13]=1)[CH3:21]
Reactant: CCOC(=O)c1cccc2nccn12
Reactant: CC#N
Reactant: CC=[N+]=CC
Agent: [I-]
Product: CCOC(=O)c1cccc2ncc(CN(C)C)n12

Procedure:
To a solution of 1.90 g (10.0 mmol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine in 40 ml of acetonitrile was added 2.41 g (13.0 mmol) of N,N-dimethylmethyleneammonium iodide. The mixture was heated for two hours under reflux. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with an aqueous solution of sodium thiosulfate and an aqueous solution of sodium hydrogencarbonate, successively, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 1.496 g of the desired compound (60.6%, a pale yellow solid). This product was recrystallized from ethyl acetate to afford the desired compound (colorless crystals), m.p.117.0-118.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1.[C:16]([CH2:19][C:20](Cl)=[S:21])(=[O:18])[CH3:17]>N1C=CC=CC=1.OS(O)(=O)=O>[C:16]([CH2:19][C:20]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:21])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(=S)Cl
Reactant: COc1ccccc1SCC1NCCS1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COc1ccccc1SCC1SCCN1C(=S)CC(C)=O

Procedure:
A solution of 2-(o-methoxyphenylthio)methylthiazolidine (5 g) in pyridine (25 ml) is reacted with acetylthioacetylchloride (2.93 g) for a night at room temperature, the reaction mixture is diluted with 2N H2SO4, extracted with ethylether to give after the usual work-up 3α-acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine, m.p. 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][N:28]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(C2=CCNCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)C)CC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 164b, starting from 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and isopropyl chloroformate. The title compound was obtained as a colorless solid (yield: 32%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 491.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): (ppm)=8.51 (s, 1H), 8.04 (s, 1H), 7.16 (br s, 1H), 7.11 (s, 1H), 6.41 (s, 1H), 4.97 (sept, 1H), 4.39 (d, 1H), 4.31 (br d, 2H), 4.21 (br s, 2H), 3.96 (m, 1H), 3.72 (t, 1H), 3.18 (t, 2H), 2.63 (br s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21 (br d, 2H), 1.53 (m, 2H), 1.26 (d, 6H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2B(O)O)[CH2:14][CH2:13]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16][CH2:15][CH:12]3[CH2:13][CH2:14]3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccccc1OCC1CC1
Product: Clc1nc2c(-c3ccccc3OCC3CC3)cccn2n1

Procedure:
2-Chloro-8-(2-cyclopropylmethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-cyclopropylmethoxyphenylboronic acid in a manner analogous to Example 2c (0.47 g, 73%). MS=300 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(O)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-hydroxy-pyridin-2-yl)-benzonitrile (Preparation 22) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (149 mg, 85.2%)
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([O:12][CH2:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: OCC/C=C/Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCC/C=C/Cc1ccccc1
Reaction time: 14 h
Yield: 95.3 %

Procedure:
To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation example 236, 3.8 g, 23.42 mmol) in CH2Cl2 (40 mL) was added pyridine (2.3 mL, 28.1 mmol) and pivaloyl chloride (3.5 mL, 28.1 mmol) at 0° C. under N2. The mixture was stirred for 14 h. The resulting mixture was diluted with CH2Cl2, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (5.5 g, 80˜95%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-hydroxy-3-nitrobenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 mmol, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for hours. After cooling the reaction back down to room temperature, the reaction mixture was diluted in toluene and the organic layer was washed with 10% HCl, brine, and water. After concentrating in vacuo, the oil was purified by short silica gel plug (10% DCM in n-hexanes). Solvent was dried in vacuo to afford the 4-octyloxy-3-nitrobenzaldehyde as a slightly colored oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)\[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31](Cl)=O>CC(C)=O>[Cl:29][CH2:30][C:31]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:22]3)=[O:13])=[CH:7][CH:6]=2)[N:4]=1
Reactant: O=C(Cl)CCl
Reactant: N/C(=N\O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(-c2noc(CCl)n2)cc1)N1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottomed flask containing (Z)—N-(4-(N′-hydroxycarbamimidoyl)phenyl)isoindoline-2-carboxamide (1.5 g, 5.06 mmol) in acetone (5 ml) was added potassium carbonate (7.00 g, 50.6 mmol) in a single portion. The reaction mixture was cooled to 0° C. and 2-chloroacetyl chloride (3.22 ml, 40.5 mmol) was added slowly. The resulting mixture was warmed to room temperature and stirred for two hours. The solvent was removed and the solid was triturated with water and then filtered with water washes. The dried solid was dissolved in DMF, heated to 100° C. and stirred for two hours. Work-up with water and dichlormethane followed by chromatography provided the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1-n1cnc(Br)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
700 mg (2.35 mmol) 4-bromo-1-(2-methoxy-4-nitro-phenyl)-1H-imidazole and 2.755 g (12.2 mmol) stannous chloride dihydrate were suspended in a mixture of 40 ml ethyl acetate and 10 ml ethanol and stirred for 1 h at 70° C. The resulting mixture was poured into cold water and neutralized by addition of a saturated solution of sodium hydrogen carbonate. The product was extracted with ethyl acetate, dried and evaporated to give 627 mg (100%) of 4-(4-bromo-imidazol-1-yl)-3-methoxy-phenylamine as a yellowish solid. MS ISP (m/e): 268.0/270.1 (100/82) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.49 (s, 1H), 7.77 (s, 1 H), 7.05 (s, 1H), 6.99 (d, 2H), 6.35-6.25 (m, 2H), 3.86 (s broad, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)=[O:4].[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:13])[N:20]2[CH2:21][CH2:22][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[CH2:6]1)=[O:4]
Reactant: COCC1(C(=O)OC)CCN(CC(=O)O)C1
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC1(C(=O)OC)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a solution of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 97) (0.21 mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10, see Example 1 Step 7) (0.21 mmol), O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (78 mg, 0.21 mmol) in dry DMF (2 ml) was added N,N-diisopropylethylamine (108 μl, 0.62 mmol). The reaction mixture was stirred for 4 hours, and evaporated to a residue that was partitioned in ethyl acetate and saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried over magnesium sulfate. Evaporation of solvent provided a crude product which was chromatographed with 5% methanol in dichloromethane to furnish the title compound (97 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:36]([NH:43][C:44](=[O:52])[NH:45][CH:46]([CH3:51])[CH2:47][C:48]([NH:1][CH:2]([C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCl (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated zin vacuo. The crude compound was used next step without further purification. MS ESI 701 (M+H), 723 (M+Na).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: C1=COCCC1
Reactant: CC(=O)c1cc(CO)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(COC2CCCCO2)on1

Procedure:
A solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (252 mg, 1.79 mmol), 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol) in DCM (10 mL) was stirred at RT for 16 hr and then for a further 0.5 hr at 40° C. after the addition of more 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol). The reaction mixture was diluted with water (5 ml) and the solution extracted with DCM (2×20 ml). The combined organic layers were washed with brine (5 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Isolute, 9:1 heptane:EtOAc) to give the title intermediate: 1H NMR (500 MHz, CDCl3) delta 1.56-1.53 (2H, m), 1.68-1.60 (2H, m), 1.89-1.69 (2H, m), 2.65 (3H, s), 3.62-3.51 (1H, m), 3.93-3.78 (1H, m), 4.68 (1H, d, J=13.9 Hz), 4.75 (1H, t, J=3.3 Hz), 4.86-4.80 (1 H, m), 6.63 (1H, s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102 %

Procedure:
To an ice water cooled solution of 6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-amine (3.08 g, 13.15 mmol), prepared as above, in THF (50 mL) was added pyridine (3.19 mL, 39.44 mmol) followed by benzyl chloroformate (1.9 mL, 13.15 mmol). The resulting suspension was allowed to stir at 0° C., then after 2 hrs a further 0.5 mL of benzyl chloroformate was added and reaction mixture was allowed to stir at ambient temperature overnight. It was partitioned between EtOAc (100 mL) and water (50 mL), the organic phase was separated and the aqueous phase re extracted into EtOAc (200 mL). The organic extracts were combined, dried and concentrated to leave crude product. This was purified on a 120 g silica SiliCycle cartridge, eluting with 30-50% EtOAc/isohexane using an Isco Companion, to provide the title compound (4.94 g, 100%); 1H NMR (CDCl3) δ 1.66-1.97 (m, 8H), 2.70-2.77 (m, 1H), 3.97 (s, 4H), 5.21 (s, 2H), 6.71 (s, 1H), 7.16 (d, 1H), 7.35-7.41 (m, 5H), 7.91 (s, 1H), 8.37 (s, 1H); MS m/e MH+ 369.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([N:17]1[CH2:25][C:24]2([C:26]([O:28][CH3:29])=[O:27])[CH:19]([C:20](=[O:36])[CH2:21][CH2:22][CH:23]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[CH2:10]([N:17]1[CH2:25][C:24]2([C:26]([O:28][CH3:29])=[O:27])[CH:19]([C:20]([OH:36])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[CH2:21][CH2:22][CH:23]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)cc1)CCC2c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5.1 cm3 of 4-bromotoluene and 1 g of magnesium turnings in 100 cm3 of diethyl ether were heated at reflux for one hour. 100 cm3 of toluene were added and the mixture was heated to 60° C. under a stream of nitrogen. After cooling to a temperature in the region of 5° C., a solution of 10 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 80 cm3 of toluene was added. The reaction mixture was stirred for one hour at a temperature in the region of 20° C. and then hydrolysed with 100 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with two times 75 cm3 of ethyl acetate. The organic phases were combined, washed successively with 100 cm3 of distilled water and 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution was carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 9 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a white solid, the characteristics of which were as follows: