Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C:21]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])=[O:27])[CH3:26]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NCc1ccc(OC)cc1OC
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A clean and dry jacketed reactor was equipped with a condenser, a Claisen adapter, a temperature probe, and an addition funnel or head column. The reactor was flushed with nitrogen gas for at least 15 minutes. The reactor was then charged with 1,396 g (1 equiv., 8.3 mol) of 2,4-dimethoxybenzylamine, 1,693 g (2 equiv., 16.7 mol) of triethylamine, and 25,086 mL of THF. The mixture was cooled to from 0 to 5° C. Ethyl chlorooxoacetate (1140 g, 1 equiv., 8.3 mol) was added to an addition funnel or head column and charged to the batch at such a rate that the internal temperature did not exceed 10° C. Solids formed approximately ⅓ into the addition. After the addition was complete, the cooling was turned off and the slurry was allowed to stir for 30 minutes at from 5° C. to 15° C. When complete, the reaction was warmed to from 20° C. to 25° C. The organic phase was washed twice with 22,580 mL of 1 N HCl. The organic phase was then washed with 12,600 mL saturated sodium bicarbonate. Next, the organic phase was washed with 12,463 mL of brine and dried over magnesium sulfate. The mixture was filtered through a thin pad of celite and concentrated at from 40° C. to 45° C. to a yellow oil. A total of 2,052 g (7.7 mol, 92%) of the crude N-(2,4-dimethoxy-benzyl)-oxalamic acid ethyl ester was isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.ClCCl.Cl>[C:1]([O:5][C:6](=[O:32])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN(C)S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)O)cc1)S(C)(=O)=O
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a stirred solution of methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-((N -methylmethylsulfonamido)methyl)phenoxy)benzoate (370 mg, 0.797 mmol) in dioxane (8 ml) was added a solution of LiOH monohydrate (43.5 mg, 1.04 mmol) in water (2 ml) (0.1 M solution 4:1 dioxane/water). The reaction was stirred for 5 hours, then diluted with dichloromethane and 2 N HCl. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography to give 4-(4-(2-tert-butoxy-2-oxoethyl)-2-((N -methylmethylsulfonamido)methyl)phenoxy)benzoic acid (0.253 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:27]
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
Reaction of 2-(4-hydroxyphenylsulfonyl)-3-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[Na].Cl.[NH2:11][CH2:12][CH2:13][SH:14].Cl>C(O)C>[ClH:1].[NH2:11][CH2:12][CH2:13][S:14][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCS
Reactant: ClCc1cnccn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1cnccn1
Reaction time: 2 h

Procedure:
2-Chloromethylpyrazine (6.4 g.) was added over 20 minutes to a solution freshly prepared from sodium (0.23 g.) in ethanol (50 ml.) to which cysteamine hydrochloride (5.7 g.) had been added gradually at 0° and stirred at this temperature for 2 hours. The suspension finally obtained was stirred at room temperature overnight, acidified with hydrochloric acid (pH 5) and concentrated under reduced pressure. The dry residue was extracted with ethanol and the extracts filtered and concentrated to give the crude product. Extraction with isopropyl alcohol, with the removal of some polymeric material and the addition of ether gave a cream colored solid (3.5 g.), which was recrystallized from ethanol-ether to furnish 2-[(2-aminoethyl)thiomethyl]pyrazine hydrochloride m.p. 144°-146°.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9].[CH2:13]([O:15][Si:16](OCC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14].C(OCl)C.[Mg]>O1CCCC1>[CH2:8]([N:10]([Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[CH2:11][CH3:12])[CH3:9]
Reactant: CCNCC
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCOCl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[Si](OCC)(OCC)N(CC)CC
Reaction time: 0.5 h

Procedure:
Diethylaminotriethoxysilane was synthesized as Example 1 in the following manner. First, into a four-necked flask (volume of 1 L) equipped with a magnet seal agitator and a dropping funnel, a 100 mL of toluene, a 10 mL of tetrahydro furan, and a 14.6 g (0.2 mol) of diethylamine were introduced and then mixed and agitated. A Grignard reagent (titer=1.71 mol/L) is on the other hand supplied by 129 mL (0.22 mol) into the dropping funnel. Thereafter, while agitating, the Grignard reagent is dropped from the dropping funnel into the flask at room temperature (air-cooling), spending 30 minutes. After completion of dropping, agitating was performed at 60° C. for one hour for Grignard exchange reaction. Then, a 41.7 g (0.2 mol) of tetraethoxysilane previously introduced into the dropping funnel is dropped into the flask, spending 15 minutes. After completion of dropping, a reaction was performed at 60° C. for 2 hours. At this moment, a solid of magnesium ethoxy chloride deposited in the flask. The reacted solution was partly extracted to confirm the generation of the target product by gas chromatography. Then, in nitrogen ambient, the reacted solution in the flask was entirely transferred therefrom to a container equipped with a G4 glass filter for pressure filtration with low-pressure nitrogen (0.01 MPa). The filtered residue (magnesium ethoxy chloride) was cleansed and filtered with toluene repeatedly until the target product could not be confirmed in the filtrate. The filtrate and the mixed solution of the filtered residue and the cleanser were condensed under reduced pressure to settle and remove solvent constituents such as toluene, and subsequently distilled and purified to restore the target product. The target product is a liquid with a colorless transparent appearance, which has a boiling point of 57.5° C./5 mmHg, and a GC purity of 98.0%. The target product is identified by gas-mass chromatography, of which mass spectrum is shown in FIG. 1, and NMR is shown in FIG. 2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][N:16]([C:21](=[O:32])[CH2:22][N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[CH2:17][C:18](O)=[O:19])(=[O:12])=[O:11])([O-:3])=[O:2].CN1CCOCC1.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:14][CH2:15][N:16]([C:21](=[O:32])[CH2:22][N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17][C:18]1=[O:19])(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC(=O)O)c(=O)[nH]c1=O
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a solution of N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine (469 mg, 1.0 mmol) and N-mehtyl morpholine (330 μL, 3 mmol) in THF (10 mL) was added isobutylchloroformatre (205 mg, 1.5 mmol) at −20° C. The reaction mixture was allowed to warm to 0° C. for a period of 1 h. Then water (10 mL) was added to the reaction mixture to precipitate solid. The solid was filtered off, washed with water, dried in vacuo to give the tiltled compound (442 mg, 98%). 1H-NMR (500 MHz; DMSO-d6) δ 11.32 (s, 0.6H), 11.30 (s, 0.4H), 8.35 (m, 1H), 8.12 (dd, 1H), 8.04˜7.96 (m, 2H), 7.35 (s, 0.6H), 7.28 (s, 0.4H), 4.67 (s, 1.2H), 4.59 (s, 0.8H), 4.41 (s, 0.8H), 4.27 (s, 1.2H), 4.04 (m, 1.2H), 3.95 (m, 1.2H), 3.90˜3.85 (m, 1.6H), 1.75 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=397.2 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(O)(=O)CC[C:13]([OH:15])=[O:14]>>[C:13]([OH:15])(=[O:14])[CH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCCC(=O)O
Reactant: O=C(O)CCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
The mother liquid with the urea-succinic acid adduct removed was treated with the same strongly acidic ion exchange resin as mentioned above to remove urea. The liquor was then subjected to distillation to remove 100 g. of water and cooled to and allow to stand at 15° C. to crystallize crude adipic acid. By filtration, 12.1 g. of crude adipic acid was obtained. The thus obtained crude adipic acid contained 2.1% by weight of glutaric acid and 1.3% by weight of succinic acid. This crude adipic acid may be recycled to a purification step in the production of adipic acid to obtain pure adipic acid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[Cl:19][C:20]([Cl:41])([Cl:40])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)[N:22]=1.O>CN(C=O)C>[CH2:1]([S:3][C:4]1[N:8]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:23]3[N:22]=[C:21]([C:20]([Cl:40])([Cl:19])[Cl:41])[O:25][N:24]=3)=[CH:33][CH:34]=2)[C:7]2=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (3 g) in DMF (20 ml) was added sodium hydride (60%, oil) (0.56 g), and the mixture was stirred for 10 minutes. To the ice-cooling mixture was added [2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl bromide (6.1 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow syrupy product (4.15 g, 58%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1Br
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-4-methyl-piperazine (Intermediate 144), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].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>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of (±)-6-bromo-4-((cis-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (0.30 g, 0.62 mmol) in DMF (0.5 mL), was added 1-cyanocyclopropanecarboxylic acid (0.073 g, 0.65 mmol), BOP (0.30 g, 0.68 mmol) and DIPEA (0.23 mL, 1.31 mmol). The mixture was stirred at rt for 2 h, quenched with water, stirred, filtered and rinsed with water. The brown solid was dried under vacuum to afford (±)-6-bromo-4-((cis-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 90% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.1 min (analytical HPLC Method J).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=2)[OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:32]=[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47](O)=[O:48])[C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[C:34](=[O:40])[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=1)[CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:48])=[O:32]
Reactant: COc1cc(CC[C@@H](O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc(OC)c1OC
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cc(OC)c(OC)c(OC)c1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of alcohol 14 (650 mg, 1.5 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 382 mg, 1.5 mmol, followed by 1,3-dicyclohexylcarbodiimide (370 mg, 1.8 mmol), and 4-(dimethylamino)-pyridine (128 mg, 1.0 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-30% EtOAc/hexanes) to give (1R)-3-(3,4,5-trimethoxyphenyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (776 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.30-6.80 (m, 4 H), 6.37 (s, 2 H), 5.82 (t, J=6.1 Hz, 1 H), 5.33 (d, J=5.2 Hz, 1 H), 4.54 (s, 2 H), 3.85 (s, 6 H), 3.83 (s, 3 H), 3.38 (d, J=12.6 Hz, 1 H), 3.16 (td, J=12.8, 3.1 Hz, 1 H), 2.60 (m, 2 H), 2.45-2.05 (m, 3 H), 1.70 (m, 6 H), 1.50 (s, 9 H), 1.45 (m, 2 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 0.90 (t, J=7.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.1, 168.2, 167.6, 158.5, 153.6, 141.7, 137.0, 130.1, 120.9, 120.2, 114.6, 113.7, 105.7, 82.7, 66.2, 61.2, 56.5, 51.7, 47.1, 44.6, 38.2, 32.9, 32.4, 28.4, 26.8, 25.3, 23.9, 23.5, 21.6, 9.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](CCO)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)cc3)ccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 3a (0.13 g, 0.75 mmol), 9 (0.27 g, 0.9 mmol) and piperidine (0.1 mL) in ethanol (30 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed by rotary evaporation. The residue was purified by recrystallization from methanol affording SPOH (0.18 g) as pale red solid in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=6.8 Hz, 2H), 8.55 (s, 1H), 8.19 (m, 4H), 7.84 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.49 (m, 2H), 7.25 (t, J=7.2 Hz, 1H), 5.66 (s, 1H), 4.57 (m, 4H), 3.79 (m, 4H), 3.43 (m, 2H), 3.27 (m, 2H), 3.08 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.4, 144.4, 142.4, 141.7, 140.8, 126.4, 126.3, 126.2, 122.7, 122.6, 122.1, 121.1, 120.3, 120.0, 119.7, 110.4, 110.2, 71.2, 69.8, 68.8, 61.6, 600.1, 58.1, 42.8. HRMS (MALDI-TOF) m/z Calcd for C26H29N2O3 417.2172. Found 417.2184 [M+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12]CN(CC)CC.Cl[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[NH:11][CH2:10][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=1)[CH3:12]
Reactant: COC(=O)Cl
Reactant: NCCc1cccc(Cl)c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NCC(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-ethylamine hydrochloride (6.22 g, 30.2 mmol) and Et3N (6.1 g, 60.4 mmol) in DCM (20 mL) was added methyl chloroformate (4.28 g, 45 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then washed with water (3×10 mL), 1N HCl (10 mL) and brine (10 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue formed was dried in vacuo to give the title compound (5.5 g, 80%) as yellow oil. MS: 228.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:33])[C:7](=[O:32])[N:8](COCC[Si](C)(C)C)[N:9]=1.O=[C:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:33])[C:7](=[O:32])[NH:8][N:9]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(OCc4ccccc4)c(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 6-amino-7-benzyloxy-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.065 g, 0.19 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.061 g, 0.36 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated at 70° C. for 14 h. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.022 g, 0.36 mmol) was added. The reaction mixture was heated at 70° C. for 1 hr then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(7-benzyloxy-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.028 g, 32%). LC/MS (Table 1, Method 2) Rt=1.205 min; MS m/z: 516 [M+23]+
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](OC(C)(C)C)=O)[CH2:5][C:4]=2[CH:3]=[N:2]1.Br[CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20]>>[CH3:10][N:6]1[CH2:7][CH2:8][C:9]2=[N:1][N:2]([CH2:18][C:19]([OH:21])=[O:20])[CH:3]=[C:4]2[CH2:5]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Product: CN1CCc2nn(CC(=O)O)cc2C1

Procedure:
tert-Butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (500 mg) was submitted to alkylation with benzyl bromoacetate, followed by cleavage of the Boc protecting group and subsequent methylation of the free amine using a method analogous to that of Precursor for Example 209 step 209.2 to step 209.4. However, the mixture of regioisomers was separated at the end of the three steps (Biotage, DCM/MeOH/TEA) to afford the two isomers: